bluuebunny/crossref_metadata_2025 huggingface dataset:
RSVD for Three Quaternion Tensors with Applications in Color Video Watermark Processing
Authors: Chen Wen-Juan , Yu Shao-Wen
Published: February 2023

In this paper, we study the restricted singular-value decomposition (RSVD) for three quaternion tensors under the Einstein product, and give higher-order RSVD over the quaternion algebra, which can achieve simultaneous singular value decomposition of three quaternion tensors. Moreover, we give the algorithm for computing the RSVD of for quaternion tensors. What is more, we present a new blind color video watermarking scheme based on the forth-order RSVD over the quaternion algebra, and our numerical example demonstrates the effectiveness of the framework.
DNA Barcoding of the Genus Magnisudis (Aulopiformes: Paralepididae) with a Coastal Record and Biological Features of Magnisudis atlantica
Authors: Bañón Rafael , Almón Bruno , Rábade Sonia , Ríos María Berta , de Carlos Alejandro
Published: February 2023

One specimen of the duckbill barracudina Magnisudis atlantica of 402 mm TL was caught in a shallow coastal area in Galician waters, northwest of Spain. Morphometric and meristic parameters along with DNA barcoding, based on cytochrome c oxidase subunit I, were used to confirm the specimen identity. Neighbor-joining analysis of nominal sequences of the genus Magnisudis obtained from the Barcode of Life Data System indicates the presence of six representative groupings of potential species, in contrast to the three that are currently recognized as valid. The stomach contents showed remains of digested crustaceans, tentatively identified as Euphausiids. Histological examination of the gonads revealed the specimen to be an immature female with oocytes at the primary growth stage, indicative of a lack of hermaphroditism. The results add new biological and taxonomic data that contribute to improved understanding of these poorly characterized, mainly deep-water species, demonstrating, once again, the effectiveness of DNA barcoding for identifying deep-sea fishes and characterizing their genetic differences.
Zinc Homeostasis: An Emerging Therapeutic Target for Neuroinflammation Related Diseases
Authors: Liu Shunfeng , Wang Nan , Long Yaqian , Wu Zhuan , Zhou Shouhong
Published: February 2023

Zinc is an indispensable trace element in the human body and plays an important role in regulating normal growth and development. Zinc homeostasis in the central nervous system is closely related to the development of neuroinflammation, and synaptic zinc homeostasis disorders affect zinc homeostasis in the brain. Under the condition of synaptic zinc homeostasis, proper zinc supplementation improves the body’s immunity and inhibits neuroinflammation. Synaptic zinc homeostasis disorder in the brain promotes the occurrence and development of neuroinflammation. Cerebral ischemia and hypoxia cause a massive release of synaptic Zn2+ into the synaptic cleft, resulting in neurotoxicity and neuroinflammation. Synaptic zinc homeostasis disorder is a high-risk factor for neurodegenerative diseases. Maintaining cerebral zinc homeostasis suppresses the progression of neuroinflammation-mediated neurodegenerative diseases. This article reviews the relationship between brain zinc homeostasis and neuroinflammation and proposes that maintaining synaptic zinc homeostasis prevents neuroinflammation.
LC-MS/MS-Based Proteomics Approach for the Identification of Candidate Serum Biomarkers in Patients with Narcolepsy Type 1
Authors: Sanni Akeem , Goli Mona , Zhao Jingfu , Wang Junyao , Barsa Chloe , El Hayek Samer , Talih Farid , Lanuzza Bartolo , Kobeissy Firas , Plazzi Giuseppe , Moresco Monica , Mondello Stefania , Ferri Raffaele , Mechref Yehia
Published: February 2023

Narcolepsy type 1 (NT1) is the most common type of narcolepsy known to be caused by the loss of specific neurons responsible for producing peptide neurotransmitters (orexins/hypocretins), resulting in a sleep-wake cycle disorder. It is characterized by its association with cataplexy and abnormalities in rapid eye movement. To date, no cure has been established for this life-threatening condition. Misdiagnosis of NT1 is also quite common, although it is not exceedingly rare. Therefore, successfully identifying candidate serum biomarkers for NT1 would be a head start for accurate diagnosis and development of therapeutics for this disorder. This study aims to identify such potential serum biomarkers. A depletion protocol was employed for 27 human serum samples (16 NT1 and 11 healthy controls), followed by applying LC-MS/MS bottom-up proteomics analysis, then LC-PRM-MS for validation. The comparison of the proteome profiles of the low-abundant proteins in the samples was then investigated based on age, sex, sample groups, and the presence of the Human Leukocyte Antigen (HLA) DQB1*0602 allele. The results were tracked to gene expression studies as well as system biology to identify key proteins and understand their relationship in the pathogenesis of NT1. Our results revealed 36 proteins significantly and differentially expressed. Among the impaired pathways and bioprocesses, the complement activation pathway is impaired by six of the differentially expressed proteins (DEPs). They are coded by the genes C2, CFB, C5, C1R, C1S, and MASP1, while 11 DEPs are involved in Acute Phase Response Signaling (APRS), which are coded by the genes FN1, AMBP, APOH, CFB, CP, ITIH2, C5, C2, F2, C1, and ITIH4. The combined AUCs of the downregulated and upregulated DEPs are 0.95 and 0.76, respectively. Overall, this study reveals potential serum-protein biomarkers of NT1 and explains the possible correlation between the biomarkers and pathophysiological effects, as well as important biochemical pathways involved in NT1.
Immunogenic Cell Death Associated Molecular Patterns and the Dual Role of IL17RA in Interstitial Cystitis/Bladder Pain Syndrome
Authors: Zhang Wei , Liu Xiaodong , Wang Jiawen , Wang Xinhao , Zhang Yaoguang
Published: February 2023

The unclear etiology and pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS) are responsible for the lack of effective treatment and the poor patient prognosis. Various studies show that chronic inflammation and immune responses are important factors contributing to the pathogenesis of IC/BPS. The process of immunogenic cell death (ICD) involves both the immune response and inflammatory process, and the involvement of ICD in IC/BPS pathogenesis has not been explored. Two IC/BPS transcriptome datasets collected from the Gene Expression Omnibus (GEO) database were used to identify distinct ICD-associated molecular patterns (IAMPs). IAMPs and IC/BPS subtypes were found to be related. The inflammatory immune microenvironments (IIME) in different IAMPs were studied. The potential mechanism by which the interleukin 17 receptor A (IL17RA) influences IC/BPS was examined using in vitro assays. The expression of ICD-related genes (IRGs) was upregulated in IC/BPS bladders, compared with normal bladders. Disease prediction models, based on differentially expressed IRGs, could accurately predict IC/BPS. The IC/BPS patients had two distinct IAMPs, each with its own subtype and clinical features and association with remodeling IIME. IL17RA, a well-established IC/BPS bladder biomarker, mediates both the inflammatory insult and the protective responses. In summary, the current study identified different IAMPs in IC/BPS, which may be involved in the pathogenesis of IC/BPS by remodeling the IIME. The chronic inflammatory process in IC/BPS may be prolonged by IL17RA, which could mediate both pro- and anti-inflammatory responses. The IL17RA-associated pathway may play a significant role in the development of IC/BPS and can be used as a therapeutic target.
Plasmon Modulated Upconversion Biosensors
Authors: Molkenova Anara , Choi Hye Eun , Park Jeong Min , Lee Jin-Ho , Kim Ki Su
Published: February 2023

Over the past two decades, lanthanide-based upconversion nanoparticles (UCNPs) have been fascinating scientists due to their ability to offer unprecedented prospects to upconvert tissue-penetrating near-infrared light into color-tailorable optical illumination inside biological matter. In particular, luminescent behavior UCNPs have been widely utilized for background-free biorecognition and biosensing. Currently, a paramount challenge exists on how to maximize NIR light harvesting and upconversion efficiencies for achieving faster response and better sensitivity without damaging the biological tissue upon laser assisted photoactivation. In this review, we offer the reader an overview of the recent updates about exciting achievements and challenges in the development of plasmon-modulated upconversion nanoformulations for biosensing application.
Framing of Poly(arylene-ethynylene) around Carbon Nanotubes and Iodine Doping for the Electrochemical Detection of Dopamine
Authors: Paul Jose , Moniruzzaman Md , Kim Jongsung
Published: February 2023

Dopamine (DA), an organic biomolecule that acts as both a hormone and a neurotransmitter, is essential in regulating emotions and metabolism in living organisms. The accurate determination of DA is important because it indicates early signs of serious neurological disorders. Covalent organic frameworks (COFs) and metal–organic frameworks (MOFs) have received considerable attention in recent years as promising porous materials with an unrivaled degree of tunability for electrochemical biosensing applications. This study adopted a solvothermal strategy for the synthesis of a conjugated microporous poly(arylene ethynylene)-4 (CMP-4) network using the Sonagashira–Hagihara cross-coupling reaction. To increase the crystallinity and electrical conductivity of the material, CMP-4 was enveloped around carbon nanotubes (CNTs), followed by iodine doping. When used as an electrochemical probe, the as-synthesized material (I2-CMP-CNT-4) exhibited excellent selectivity and sensitivity to dopamine in the phosphate-buffered solution. The detection limits of the electrochemical sensor were 1 and 1.7 μM based on cyclic voltammetry (CV) and differential pulse voltammetry (DPV).
Development of a New Lab-on-Paper Microfluidics Platform Using Bi-Material Cantilever Actuators for ELISA on Paper
Authors: Heidari-Bafroui Hojat , Kumar Ashutosh , Hahn Cameron , Scholz Nicholas , Charbaji Amer , Rahmani Nassim , Anagnostopoulos Constantine , Faghri Mohammad
Published: February 2023

In this paper, we present a novel and cost-effective lab-on-paper microfluidics platform for performing ELISA autonomously, with no user intervention beyond adding the sample. The platform utilizes two Bi-Material Cantilever Valves placed in a specially designed housing. The integration of these valves in a specific channel network forms a complete fluidic logic circuit for performing ELISA on paper. The housing also incorporates an innovative reagent storage and release mechanism that minimizes variability in the volume of reagents released into the reagent pads. The platform design was optimized to minimize variance in the time of fluid wicking from the reagent pad, using a randomized design of experiment. The platform adheres to the World Health Organization’s ASSURED principles. The optimized design was used to conduct an ELISA for detecting rabbit immunoglobulin G (IgG) in a buffer, with a limit of detection of 2.27 ng/mL and a limit of quantification of 8.33 ng/mL. This represents a 58% improvement over previous ELISA methods for detecting rabbit IgG in buffer using portable microfluidic technology.
Machine Learning Techniques Reveal Aberrated Multidimensional EEG Characteristics in Patients with Depression
Authors: Li Gang , Zhong Hongyang , Wang Jie , Yang Yixin , Li Huayun , Wang Sujie , Sun Yu , Qi Xuchen
Published: February 2023

Depression has become one of the most common mental illnesses, causing serious physical and mental harm. However, there remain unclear and uniform physiological indicators to support the diagnosis of clinical depression. This study aimed to use machine learning techniques to investigate the abnormal multidimensional EEG features in patients with depression. Resting-state EEG signals were recorded from 41 patients with depression and 34 healthy controls. Multiple dimensional characteristics were extracted, including power spectral density (PSD), fuzzy entropy (FE), and phase lag index (PLI). These three different dimensional characteristics with statistical differences between two groups were ranked by three machine learning algorithms. Then, the ranked characteristics were placed into the classifiers according to the importance of features to obtain the optimal feature subset with the highest classification accuracy. The results showed that the optimal feature subset contained 86 features with the highest classification accuracy of 98.54% ± 0.21%. According to the statistics of the optimal feature subset, PLI had the largest number of features among the three categories, and the number of beta features was bigger than other rhythms. Moreover, compared to the healthy controls, the PLI values in the depression group increased in theta and beta rhythms, but decreased in alpha1 and alpha2 rhythms. The PSD of theta and beta rhythms were significantly greater in depression group than that in healthy controls, and the FE of beta rhythm showed the same trend. These findings indicate that the distribution of abnormal multidimensional features is potentially useful for the diagnosis of depression and understanding of neural mechanisms.
Distinct Neuropsychological Correlates of Apathy Sub-Domains in Multiple Sclerosis
Authors: Raimo Simona , Gaita Mariachiara , Costanzo Antonio , Spitaleri Daniele , Santangelo Gabriella
Published: February 2023

Background: Apathy is relatively frequent and significantly associated with clinical and cognitive outcomes in Multiple Sclerosis (MS), even if previous research has produced mixed results. This varied picture could be due to most studies treating apathy as a unitary construct, despite the evidence showing that apathy is a multifaceted syndrome including three different sub-domains (i.e., cognitive, affective, and behavioral). This study aims to investigate the neuropsychological correlates of apathy fractionated into its three sub-domains in participants with MS. Methods: Eighty-five participants with MS underwent a comprehensive neuropsychological battery. The severity of apathy symptoms was assessed by the self-report version of the Apathy Evaluation Scale. Results: Correlational analysis showed that cognitive apathy sub-domain scores had a high correlation with the performances obtained at cognitive tests tapping into inhibitory control (i.e., IML and Strop test-interference task), whereas the affective apathy sub-domain scores had a high correlation with the performances obtained at cognitive test tapping into the use of executive functions in visuospatial abilities (i.e., Clock Drawing Test). Moreover, linear regression analysis results showed that the cognitive apathy sub-domain scores predicted executive functioning domain scores and that the cognitive and affective apathy sub-domains scores predicted visuospatial abilities domain scores. Conclusion: These results confirm that apathy is a multidimensional concept with important neuropsychological correlates, visible only when it is fractionated into its sub-domains.
The Role of Mass Media in Promoting the Dual Career of the Performance Athlete
Authors: Onose Ionut , Onose Raluca-Mihaela , Abalasei Beatrice-Aurelia
Published: February 2023

Background: One of the most pressing problems for athletes is related to the end of their career, a situation that presents serious challenges in the attempt to enter the labor market in the absence of an adequate education. Despite the fact that successful sports students encounter some problems in terms of time allocated to school, consistent work will ultimately provide them with a rewarding career and, most importantly, a relevant social role to inspire other athletes who are at the beginning of their careers. A successful approach to dual career cannot take place if athletes and their entourage (coaches, parents, teachers) are not aware of its importance. By analyzing the concept from different angles by professionals (EU, governments, ministries), dual career can be implemented in an efficient way and much faster if the appropriate institutions are involved. The use of mass media to create interest and content in the sports field has managed to produce major interest among specialists in the field. Methods: In this study, the answers of 30 mass media specialists were analyzed to understand how “dual career” is promoted for the performance athlete in the mass media in Romania. In order to analyze if there is any connection between mass media, dual career and the profile of the performance athlete, we applied a chi-square test and Pearson and Spearman correlations. Results: The obtained results indicate a weak connection between the analyzed terms. Conclusions: The conclusions reached allow us to form an overview of the analyzed terms, managing to create directions for action in order to constantly improve the phenomenon in Romania.
Synthetic Datasets for Rebar Instance Segmentation Using Mask R-CNN
Authors: Wang Haoyu , Ye Zhiming , Wang Dejiang , Jiang Haili , Liu Panpan
Published: February 2023

The construction and inspection of reinforcement rebar currently rely entirely on manual work, which leads to problems such as high labor requirements and labor costs. Rebar image detection using deep learning algorithms can be employed in construction quality inspection and intelligent construction; it can check the number, spacing, and diameter of rebar on a construction site, and guide robots to complete rebar tying. However, the application of deep learning algorithms relies on a large number of datasets to train models, while manual data collection and annotation are time-consuming and laborious. In contrast, using synthetic datasets can achieve a high degree of automation of annotation. In this study, using rebar as an example, we proposed a mask annotation methodology based on BIM software and rendering software, which can establish a large and diverse training set for instance segmentation, without manual labeling. The Mask R-CNN trained using both real and synthetic datasets demonstrated a better performance than the models trained using only real datasets or synthetic datasets. This synthetic dataset generation method could be widely used for various image segmentation tasks and provides a reference for other computer vision engineering tasks and deep learning tasks in related fields.
Comfort and Economic Viability of Personal Ceiling Fans Assisted by Night Ventilation in a Renovated Office Building
Authors: Knudsen Mattis , Rissetto Romina , Carbonare Nicolas , Wagner Andreas , Schweiker Marcel
Published: February 2023

An expected increase in the use of air conditioning by 2050 will significantly increase electricity demand and come at a cost to the environment. Implementing passive cooling strategies and focusing on personal environmental control systems (PECSs) could help to address this issue. While numerous studies have investigated the positive impact of PECSs on thermal comfort and energy savings, their overall economic benefit has been poorly addressed. We present an economic evaluation of personal fans for an office building in Germany. Building performance simulation was used to compare passive and active cooling concepts, and sensitivity analysis was performed for different climate scenarios. A cost-benefit analysis was carried out, including an assessment of investment and operating costs and the monetary value of relative performance. The transferability of comfort and productivity into costs is the novelty of this paper. The results showed that by supplementing night ventilation with personal fans, discomfort hours could be reduced by up to 50%. However, the initial investment of the fan is not compensated by savings in productivity losses compared to night ventilation alone. A reduction in the cost of the technology could help to economically offset the investment. The results contribute to the literature on the economic evaluation of a PECS by proposing a framework to motivate its implementation in buildings.
Health-Related Quality of Life as Assessed by the EQ-5D-5L Predicts Outcomes of Patients Treated with Azacitidine—A Prospective Cohort Study by the AGMT
Authors: Pleyer Lisa , Heibl Sonja , Tinchon Christoph , Vallet Sonia , Schreder Martin , Melchardt Thomas , Stute Norbert , Föhrenbach Quiroz Kim Tamara , Leisch Michael , Egle Alexander , Scagnetti Lukas , Wolf Dominik , Beswick Richard , Drost Manuel , Larcher-Senn Julian , Grochtdreis Thomas , Vaisband Marc , Hasenauer Jan , Zaborsky Nadja , Greil Richard , Stauder Reinhard
Published: February 2023

In this prospective study (NCT01595295), 272 patients treated with azacitidine completed 1456 EuroQol 5-Dimension (EQ-5D) questionnaires. Linear mixed-effect modelling was used to incorporate longitudinal data. When compared with a matched reference population, myeloid patients reported more pronounced restrictions in usual activities (+28%, p < 0.0001), anxiety/depression (+21%, p < 0.0001), selfcare (+18%, p < 0.0001) and mobility (+15%, p < 0.0001), as well as lower mean EQ-5D-5L indices (0.81 vs. 0.88, p < 0.0001), and lower self-rated health on the EuroQol Visual Analogue Scale (EQ-VAS) (64 vs. 72%, p < 0.0001). After multivariate-adjustment, (i) the EQ-5D-5L index assessed at azacitidine start the predicted time with clinical benefit (TCB) (9.6 vs. 6.6 months; p = 0.0258; HR = 1.43), time to next treatment (TTNT) (12.8 vs. 9.8 months; p = 0.0332; HR = 1.42) and overall survival (OS) (17.9 vs. 12.9 months; p = 0.0143; HR = 1.52); (ii) Level Sum Score (LSS) predicted azacitidine response (p = 0.0160; OR = 0.451) and the EQ-5D-5L index showed a trend (p = 0.0627; OR = 0.522); (iii) up to 1432 longitudinally assessed EQ-5D-5L response/clinical parameter pairs revealed significant associations of EQ-5D-5L response parameters with haemoglobin level, transfusion dependence and hematologic improvement. Significant increases of the likelihood ratios were observed after addition of LSS, EQ-VAS or EQ-5D-5L-index to the International Prognostic Scoring System (IPSS) or the revised IPSS (R-IPSS), indicating that they provide added value to these scores.
Cancer Disparities among Pacific Islanders: A Review of Sociocultural Determinants of Health in the Micronesian Region
Authors: Pineda Eric , Benavente Ryan , Gimmen Megan Y. , DeVille Nicole V. , Taparra Kekoa
Published: February 2023

It is well appreciated that the social determinants of health are intimately related with health outcomes. However, there is a paucity of literature that explores these themes comprehensively for the indigenous people within Micronesia. Certain Micronesia-specific factors, such as transitions from traditional diets, the consumption of betel nut, and exposure to radiation from the nuclear bomb testing in the Marshall Islands, have predisposed certain Micronesian populations to an increased risk of developing a variety of malignancies. Furthermore, severe weather events and rising sea levels attributed to climate change threaten to compromise cancer care resources and displace entire Micronesian populations. The consequences of these risks are expected to increase the strain on the already challenged, disjointed, and burdened healthcare infrastructure in Micronesia, likely leading to more expenses in off-island referrals. A general shortage of Pacific Islander physicians within the workforce reduces the number of patients that can be seen, as well as the quality of culturally competent care that is delivered. In this narrative review, we comprehensively underscore the health disparities and cancer inequities faced by the underserved communities within Micronesia.
Multimodal Treatments for Brain Metastases from Renal Cell Carcinoma: Results of a Multicentric Retrospective Study
Authors: Navarria Pierina , Pessina Federico , Minniti Giuseppe , Franzese Ciro , Marini Beatrice , D’agostino Giuseppe , Badalamenti Marco , Raspagliesi Luca , Reggiori Giacomo , Lobefalo Francesca , Fariselli Laura , Franceschini Davide , Bellu Luisa , Clerici Elena , Pinzi Valentina , Scorsetti Marta
Published: February 2023

The aim of this study was to evaluate the clinical outcomes of a large series of brain metastatic renal cell carcinoma (BMRCC) patients treated in three Italian centers. Methods: A total of 120 BMRCC patients with a total of 176 lesions treated were evaluated. Patients received surgery plus postoperative HSRS, single-fraction SRS, or hypofractionated SRS (HSRS). Local control (LC), brain distant failure (BDF), overall survival (OS), toxicities, and prognostic factors were assessed. Results: The median follow-up time was 77 months (range 16–235 months). Surgery plus HSRS was performed in 23 (19.2%) cases, along with SRS in 82 (68.3%) and HSRS in 15 (12.5%). Seventy-seven (64.2%) patients received systemic therapy. The main total dose and fractionation used were 20–24 Gy in single fraction or 32–30 Gy in 4–5 daily fractions. Median LC time and 6 month and 1, 2 and 3 year LC rates were nr, 100%, 95.7% ± 1.8%, 93.4% ± 2.4%, and 93.4% ± 2.4%. Median BDF time and 6 month and 1, 2 and 3 year BDF rates were n.r., 11.9% ± 3.1%, 25.1% ± 4.5%, 38.7% ± 5.5%, and 44.4% ± 6.3%, respectively. Median OS time and 6 month and 1, 2 and 3 year OS rates were 16 months (95% CI: 12–22), 80% ± 3.6%, 58.3% ± 4.5%, 30.9% ± 4.3%, and 16.9% ± 3.6, respectively. No severe neurological toxicities occurred. Patients with a favorable/intermediate IMDC score, a higher RCC-GPA score, an early occurrence of BMs from primary diagnosis, absence of EC metastases, and a combined local treatment (surgery plus adjuvant HSRS) had a better outcome. Conclusions: SRS/HSRS is proven to be an effective local treatment for BMRCC. A careful evaluation of prognostic factors is a valid step to manage the optimal therapeutic strategy for BMRCC patients.
From Localized Mild Hyperthermia to Improved Tumor Oxygenation: Physiological Mechanisms Critically Involved in Oncologic Thermo-Radio-Immunotherapy
Authors: Vaupel Peter , Piazena Helmut , Notter Markus , Thomsen Andreas R. , Grosu Anca-L. , Scholkmann Felix , Pockley Alan Graham , Multhoff Gabriele
Published: February 2023

(1) Background: Mild hyperthermia (mHT, 39–42 °C) is a potent cancer treatment modality when delivered in conjunction with radiotherapy. mHT triggers a series of therapeutically relevant biological mechanisms, e.g., it can act as a radiosensitizer by improving tumor oxygenation, the latter generally believed to be the commensurate result of increased blood flow, and it can positively modulate protective anticancer immune responses. However, the extent and kinetics of tumor blood flow (TBF) changes and tumor oxygenation are variable during and after the application of mHT. The interpretation of these spatiotemporal heterogeneities is currently not yet fully clarified. (2) Aim and methods: We have undertaken a systematic literature review and herein provide a comprehensive insight into the potential impact of mHT on the clinical benefits of therapeutic modalities such as radio- and immuno-therapy. (3) Results: mHT-induced increases in TBF are multifactorial and differ both spatially and with time. In the short term, changes are preferentially caused by vasodilation of co-opted vessels and of upstream normal tissue vessels as well as by improved hemorheology. Sustained TBF increases are thought to result from a drastic reduction of interstitial pressure, thus restoring adequate perfusion pressures and/or HIF-1α- and VEGF-mediated activation of angiogenesis. The enhanced oxygenation is not only the result of mHT-increased TBF and, thus, oxygen availability but also of heat-induced higher O2 diffusivities, acidosis- and heat-related enhanced O2 unloading from red blood cells. (4) Conclusions: Enhancement of tumor oxygenation achieved by mHT cannot be fully explained by TBF changes alone. Instead, a series of additional, complexly linked physiological mechanisms are crucial for enhancing tumor oxygenation, almost doubling the initial O2 tensions in tumors.
A Review of Translational Research for Targeted Therapy for Metastatic Colorectal Cancer
Authors: Ruff Samantha M. , Pawlik Timothy M.
Published: February 2023

Colorectal cancer is the third most common cause of cancer-related death in the United States, with 20% of patients presenting with metastatic disease at the time of diagnosis. Metastatic colon cancer is often treated with a combination of surgery, systemic therapy (chemotherapy, biologic therapy, immunotherapy), and/or regional therapy (hepatic artery infusion pumps). Utilizing the molecular and pathologic features of the primary tumor to tailor treatment for patients may improve overall survival. Rather than a “one size fits all” approach, a more nuanced treatment plan guided by the unique features of a patient’s tumor and the tumor’s microenvironment can more effectively treat the disease. Basic science work to elucidate new drug targets, understand mechanisms of evasion, and develop drugs and drug combinations is critical to inform clinical trials and identify novel, effective therapies for metastatic colorectal cancer. Through the lens of key targets for metastatic colorectal cancer, this review discusses how work in the basic science lab translates into clinical trials.
Dose Distribution of High Dose-Rate and Low Dose-Rate Prostate Brachytherapy at Different Intervals—Impact of a Hydrogel Spacer and Prostate Volume
Authors: Haddad Hathal , Hermani Horst , Hanitzsch Herbert , Heidrich Albert , Pinkawa Michael
Published: February 2023

The study aimed to compare the dose distribution in permanent low-dose-rate brachytherapy (LDR-BT) and high-dose-rate brachytherapy (HDR-BT), specifically focusing on the impact of a spacer and prostate volume. The relative dose distribution of 102 LDR-BT patients (prescription dose 145 Gy) at different intervals was compared with the dose distribution of 105 HDR-BT patients (232 HDR-BT fractions with prescription doses of 9 Gy, n = 151, or 11.5 Gy, n = 81). A hydrogel spacer (10 mL) was only injected before HDR-BT. For the analysis of dose coverage outside the prostate, a 5 mm margin was added to the prostate volume (PV+). Prostate V100 and D90 of HDR-BT and LDR-BT at different intervals were comparable. HDR-BT was characterized by a considerably more homogenous dose distribution and lower doses to the urethra. The minimum dose in 90% of PV+ was higher for larger prostates. As a consequence of the hydrogel spacer in HDR-BT patients, the intraoperative dose at the rectum was considerably lower, especially in smaller prostates. However, prostate volume dose coverage was not improved. The dosimetric results well explain clinical differences between these techniques reported in the literature review, specifically comparable tumor control, higher acute urinary toxicity rates in LDR-BT in comparison to HDR-BT, decreased rectal toxicity after spacer placement, and improved tumor control after HDR-BT in larger prostate volumes.
Prediction of Gastrointestinal Tract Cancers Using Longitudinal Electronic Health Record Data
Authors: Read Andrew J. , Zhou Wenjing , Saini Sameer D. , Zhu Ji , Waljee Akbar K.
Published: February 2023

Background: Luminal gastrointestinal (GI) tract cancers, including esophageal, gastric, small bowel, colorectal, and anal cancers, are often diagnosed at late stages. These tumors can cause gradual GI bleeding, which may be unrecognized but detectable by subtle laboratory changes. Our aim was to develop models to predict luminal GI tract cancers using laboratory studies and patient characteristics using logistic regression and random forest machine learning methods. Methods: The study was a single-center, retrospective cohort at an academic medical center, with enrollment between 2004–2013 and with follow-up until 2018, who had at least two complete blood counts (CBCs). The primary outcome was the diagnosis of GI tract cancer. Prediction models were developed using multivariable single timepoint logistic regression, longitudinal logistic regression, and random forest machine learning. Results: The cohort included 148,158 individuals, with 1025 GI tract cancers. For 3-year prediction of GI tract cancers, the longitudinal random forest model performed the best, with an area under the receiver operator curve (AuROC) of 0.750 (95% CI 0.729–0.771) and Brier score of 0.116, compared to the longitudinal logistic regression model, with an AuROC of 0.735 (95% CI 0.713–0.757) and Brier score of 0.205. Conclusions: Prediction models incorporating longitudinal features of the CBC outperformed the single timepoint logistic regression models at 3-years, with a trend toward improved accuracy of prediction using a random forest machine learning model compared to a longitudinal logistic regression model.
Lynch Syndrome and Gynecologic Tumors: Incidence, Prophylaxis, and Management of Patients with Cancer
Authors: Capasso Ilaria , Santoro Angela , Lucci Cordisco Emanuela , Perrone Emanuele , Tronconi Francesca , Catena Ursula , Zannoni Gian Franco , Scambia Giovanni , Fanfani Francesco , Lorusso Domenica , Duranti Simona
Published: February 2023

This review provides a comprehensive update on recent evidence regarding gynecologic tumors associated with Lynch Syndrome (LS). Endometrial cancer (EC) and ovarian cancer (OC) are the first and second most common gynecologic malignancies in developed countries, respectively, and LS is estimated to be the hereditary cause in 3% of both EC and OC. Despite the increasing evidence on LS-related tumors, few studies have analyzed the outcomes of LS-related EC and OC stratified by mutational variant. This review aims to provide a comprehensive overview of the literature and comparison between updated international guidelines, to help outline a shared pathway for the diagnosis, prevention, and management of LS. Through the widespread adoption of the immunohistochemistry-based Universal Screening, LS diagnosis and identification of mutational variants could be standardized and recognized by international guidelines as a feasible, reproducible, and cost-effective method. Furthermore, the development of a better understanding of LS and its mutational variants will support our ability to better tailor EC and OC management in terms of prophylactic surgery and systemic treatment in the light of the promising results shown by immunotherapy.
MRI Characteristics of Pediatric and Young-Adult Renal Cell Carcinoma: A Single-Center Retrospective Study and Literature Review
Authors: Beek Justine N. van der , Krijger Ronald R. de , Nievelstein Rutger A. J. , Bex Axel , Klijn Aart J. , Heuvel-Eibrink Marry M. van den , Littooij Annemieke S.
Published: February 2023

Pediatric renal cell carcinoma (RCC) is a rare malignancy. Magnetic resonance imaging (MRI) is the preferred imaging modality for assessment of these tumors. The previous literature has suggested that cross-sectional-imaging findings differ between RCC and other pediatric renal tumors and between RCC subtypes. However, studies focusing on MRI characteristics are limited. Therefore, this study aims to identify MRI characteristics of pediatric and young-adult RCC, through a single-center case series and literature review. Six identified diagnostic MRI scans were retrospectively assessed, and an extensive literature review was conducted. The included patients had a median age of 12 years (63–193 months). Among other subtypes, 2/6 (33%) were translocation-type RCC (MiT-RCC) and 2/6 (33%) were clear-cell RCC. Median tumor volume was 393 cm3 (29–2191 cm3). Five tumors had a hypo-intense appearance on T2-weighted imaging, whereas 4/6 were iso-intense on T1-weighted imaging. Four/six tumors showed well-defined margins. The median apparent diffusion coefficient (ADC) values ranged from 0.70 to 1.20 × 10−3 mm2/s. In thirteen identified articles focusing on MRI characteristics of MiT-RCC, the majority of the patients also showed T2-weighted hypo-intensity. T1-weighted hyper-intensity, irregular growth pattern and limited diffusion–restriction were also often described. Discrimination of RCC subtypes and differentiation from other pediatric renal tumors based on MRI remains difficult. Nevertheless, T2-weighted hypo-intensity of the tumor seems a potential distinctive characteristic.
Novel PRUNE2 Germline Mutations in Aggressive and Benign Parathyroid Neoplasms
Authors: Storvall Sara , Ryhänen Eeva , Karhu Auli , Schalin-Jäntti Camilla
Published: February 2023

Parathyroid tumors are mostly sporadic but can also occur in familial forms, including different kinds of genetic syndromes with varying phenotypes and penetrance. Recently, somatic mutations of the tumor suppressor gene PRUNE2 were found to be frequent in parathyroid cancer (PC). The germline mutation status of PRUNE2 was investigated in a large cohort of patients with parathyroid tumors from the genetically homogenous Finnish population, 15 of which had PC, 16 atypical parathyroid tumors (APT), and 6 benign parathyroid adenomas (PA). Mutations in previously established hyperparathyroidism-related genes were screened with a targeted gene panel analysis. Nine PRUNE2 germline mutations with a minor allele frequency (MAF) of <0.05 were found in our cohort. Five of these were predicted to be potentially damaging and were identified in two patients with PC, two with APT, and three with PA. The mutational status was not associated with the tumor group nor related to the clinical picture or severity of the disease. Still, the frequent finding of rare germline mutations of PRUNE2 may point to the gene playing a role in the pathogenesis of parathyroid neoplasms.
Dietary Intake of Anthocyanidins and Renal Cancer Risk: A Prospective Study
Authors: Xu Xin , Zhu Yi , Li Shiqi , Xia Dan
Published: February 2023

Evidence on the association between anthocyanidin intake and renal cancer risk is limited. The aim of this study was to assess the association of anthocyanidin intake with renal cancer risk in the large prospective Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. The cohort for this analysis consisted of 101,156 participants. A Cox proportional hazards regression model was used to estimate the hazard ratios (HRs) and the 95% confidence intervals (CIs). A restricted cubic spline model with three knots (i.e., 10th, 50th, and 90th percentiles) was used to model a smooth curve. A total of 409 renal cancer cases were identified over a median follow-up of 12.2 years. In the categorical analysis with a fully adjusted model, a higher dietary anthocyanidin consumption was associated with a lower risk of renal cancer (HRQ4vsQ1: 0.68; 95% CI: 0.51–0.92; p for trend < 0.010). A similar pattern was obtained when anthocyanidin intake was analyzed as a continuous variable. The HR of one-SD increment in the anthocyanidin intake for renal cancer risk was 0.88 (95% CI: 0.77–1.00, p = 0.043). The restricted cubic spline model revealed a reduced risk of renal cancer with a higher intake of anthocyanidins and there was no statistical evidence for nonlinearity (p for nonlinearity = 0.207). In conclusion, in this large American population, a higher dietary anthocyanidin consumption was associated with a lower risk of renal cancer. Future cohort studies are warranted to verify our preliminary findings and to explore the underlying mechanisms in this regard.
Unveiling the Role of the Proton Gateway, Uncoupling Proteins (UCPs), in Cancer Cachexia
Authors: Joshi Mit , Patel Bhoomika M.
Published: February 2023

Uncoupling proteins (UCPs) are identified as carriers of proton ions between the mitochondrial inner membrane and the mitochondrial matrix. ATP is mainly generated through oxidative phosphorylation in mitochondria. The proton gradient is generated across the inner mitochondrial membrane and the mitochondrial matrix, which facilitates a smooth transfer of electrons across ETC complexes. Until now, it was thought that the role of UCPs was to break the electron transport chain and thereby inhibit the synthesis of ATP. UCPs allow protons to pass from the inner mitochondrial membrane to the mitochondrial matrix and decrease the proton gradient across the membrane, which results in decreased ATP synthesis and increased production of heat by mitochondria. In recent years, the role of UCPs in other physiological processes has been deciphered. In this review, we first highlighted the different types of UCPs and their precise location across the body. Second, we summarized the role of UCPs in different diseases, mainly metabolic disorders such as obesity and diabetes, cardiovascular complications, cancer, wasting syndrome, neurodegenerative diseases, and kidney complications. Based on our findings, we conclude that UCPs play a major role in maintaining energy homeostasis, mitochondrial functions, ROS production, and apoptosis. Finally, our findings reveal that mitochondrial uncoupling by UCPs may treat many diseases, and extensive clinical studies are required to meet the unmet need of certain diseases.
Correlations between Molecular Alterations, Histopathological Characteristics, and Poor Prognosis in Esophageal Adenocarcinoma
Authors: Orsini Arianna , Mastracci Luca , Bozzarelli Isotta , Ferrari Anna , Isidori Federica , Fiocca Roberto , Lugaresi Marialuisa , D’Errico Antonietta , Malvi Deborah , Cataldi-Stagetti Erica , Spaggiari Paola , Tomezzoli Anna , Albarello Luca , Ristimäki Ari , Bottiglieri Luca , Krishnadath Kausilia K. , Rosati Riccardo , Fumagalli Romario Uberto , De Manzoni Giovanni , Räsänen Jari , Martinelli Giovanni , Mattioli Sandro , Bonora Elena ,   on behalf of the EACSGE Consortium
Published: February 2023

Esophageal adenocarcinoma (EAC) is a severe malignancy with increasing incidence, poorly understood pathogenesis, and low survival rates. We sequenced 164 EAC samples of naïve patients (without chemo-radiotherapy) with high coverage using next-generation sequencing technologies. A total of 337 variants were identified across the whole cohort, with TP53 as the most frequently altered gene (67.27%). Missense mutations in TP53 correlated with worse cancer-specific survival (log-rank p = 0.001). In seven cases, we found disruptive mutations in HNF1alpha associated with other gene alterations. Moreover, we detected gene fusions through massive parallel sequencing of RNA, indicating that it is not a rare event in EAC. In conclusion, we report that a specific type of TP53 mutation (missense changes) negatively affected cancer-specific survival in EAC. HNF1alpha was identified as a new EAC-mutated gene.
Potential Role of Circulating miRNAs for Breast Cancer Management in the Neoadjuvant Setting: A Road to Pave
Authors: Benvenuti Chiara , Tiberio Paola , Gaudio Mariangela , Jacobs Flavia , Saltalamacchia Giuseppe , Pindilli Sebastiano , Zambelli Alberto , Santoro Armando , De Sanctis Rita
Published: February 2023

Recently, circulating microRNAs (miRNAs) have emerged as potential non-invasive biomarkers for breast cancer (BC) management. In the context of BC patients undergoing neoadjuvant chemotherapy (NAC), the possibility of obtaining repeated, non-invasive biological samples from patients before, during, and after treatment is incredibly convenient and provides the opportunity to investigate circulating miRNAs as diagnostic, predictive, and prognostic tools. The present review aims to summarize major findings in this setting, thus highlighting their potential applicability in daily clinical practice and their possible limitations. In all the contexts (diagnostic, predictive, and prognostic), circulating miR-21-5p and miR-34a-5p have emerged as the most promising non-invasive biomarkers for BC patients undergoing NAC. Specifically, their high baseline level could discriminate between BC patients and healthy controls. On the other hand, in predictive and prognostic investigations, low circulating miR-21-5p and miR-34a-5p levels may identify patients with better outcomes, in terms of both treatment response and invasive disease-free survival. However, the findings in this field have been very heterogeneous. Indeed, pre-analytical and analytical variables, as well as factors related to patients, may explain the inconsistency among different study results. Thus, further clinical trials, with more precise patient inclusion criteria and more standardized methodological approaches, are definitely needed to better define the potential role of these promising non-invasive biomarkers.
Bispecific T-Cell Engagers Therapies in Solid Tumors: Focusing on Prostate Cancer
Authors: Simão Diana C. , Zarrabi Kevin K. , Mendes José L. , Luz Ricardo , Garcia Jorge A. , Kelly William K. , Barata Pedro C.
Published: February 2023

Over the past decade, immunotherapy has demonstrated an impressive improvement in treatment outcomes for multiple cancers. Following the landmark approvals for use of immune checkpoint inhibitors, new challenges emerged in various clinical settings. Not all tumor types harbor immunogenic characteristics capable of triggering responses. Similarly, many tumors’ immune microenvironment allows them to become evasive, leading to resistance and, thus, limiting the durability of responses. To overcome this limitation, new T-cell redirecting strategies such as bispecific T-cell engager (BiTE) have become attractive and promising immunotherapies. Our review provides a comprehensive perspective of the current evidence of BiTE therapies in solid tumors. Considering that immunotherapy has shown modest results in advanced prostate cancer to date, we review the biologic rationale and promising results of BiTE therapy in this clinical setting and discuss potential tumor-associated antigens that may be integrated into BiTE construct designs. Our review also aims to evaluate the advances of BiTE therapies in prostate cancer, illustrate the major obstacles and underlying limitations, and discuss directions for future research.
Discordance of HER2-Low between Primary Tumors and Matched Distant Metastases in Breast Cancer
Authors: Almstedt Katrin , Krauthauser Lisa , Kappenberg Franziska , Wagner Daniel-Christoph , Heimes Anne-Sophie , Battista Marco J. , Anic Katharina , Krajnak Slavomir , Lebrecht Antje , Schwab Roxana , Brenner Walburgis , Weikel Wolfgang , Rahnenführer Jörg , Hengstler Jan G. , Roth Wilfried , Hasenburg Annette , Stewen Kathrin , Schmidt Marcus
Published: February 2023

We examined differences in HER2 expression between primary tumors and distant metastases, particularly within the HER2-negative primary breast cancer cohort (HER2-low and HER2-zero). The retrospective study included 191 consecutive paired samples of primary breast cancer and distant metastases diagnosed between 1995 and 2019. HER2-negative samples were divided into HER2-zero (immunohistochemistry [IHC] score 0) and HER2-low (IHC score 1+ or 2+/in situ hybridization [ISH]-negative). The main objective was to analyze the discordance rate between matched primary and metastatic samples, focusing on the site of distant metastasis, molecular subtype, and de novo metastatic breast cancer. The relationship was determined by cross-tabulation and calculation of Cohen′s Kappa coefficient. The final study cohort included 148 paired samples. The largest proportion in the HER2-negative cohort was HER2-low [primary tumor 61.4% (n = 78), metastatic samples 73.5% (n = 86)]. The discordance rate between the HER2 status of primary tumors and corresponding distant metastases was 49.6% (n = 63) (Kappa −0.003, 95%CI −0.15–0.15). Development of a HER2-low phenotype occurred most frequently (n = 52, 40.9%), mostly with a switch from HER2-zero to HER2-low (n = 34, 26.8%). Relevant HER2 discordance rates were observed between different metastatic sites and molecular subtypes. Primary metastatic breast cancer had a significantly lower HER2 discordance rate than secondary metastatic breast cancer [30.2% (Kappa 0.48, 95%CI 0.27–0.69) versus 50.5% (Kappa 0.14, 95% CI −0.03–0.32)]. This highlights the importance of evaluating potentially therapy-relevant discordance rates between a primary tumor and corresponding distant metastases.