bluuebunny/crossref_metadata_2025 huggingface dataset:
The Blue Swimming Crab Portunus segnis in the Mediterranean Sea: Invasion Paths, Impacts and Management Measures
Authors: Castriota Luca , Falautano Manuela , Maggio Teresa , Perzia Patrizia
Published: October 2022

Invasive alien species represent one of the main environmental emergencies and are considered by the scientific community as being among the leading causes of biodiversity loss on a global scale. Therefore, detecting their pathways, hotspot areas and invasion trends becomes extremely important also for management purposes. A systematic review on presence of Portunus segnis in the Suez Canal and Mediterranean Sea was carried out in order to study the invasion paths from its entry from the Red Sea into the Suez Canal (1886) until recently (2021) through ecological indicators elaborated with GIS spatial–temporal statistics. Arrival, establishment and expansion phases and areas of P. segnis in the Mediterranean were identified. Settlement areas were detected along the Suez Canal as well as in the Levantine Sea, western Ionian Sea and Tunisian plateau ecoregions. Since 2015 a persistent area has formed in Tunisia from where the species is spreading northward and eastward. The study provides an insight on the impact of P. segnis on biodiversity and ecosystem services and proposes a series of desirable management actions to mitigate the expansion of its population. Following the 8Rs model that introduces the rules to mitigate non–indigenous species pollution, six of them (Recognize, Reduce, Replace, Reuse, Remove, and Regulate) have been identified as applicable and are discussed.
Long-Term Cardiovascular Outcome in Children with MIS-C Linked to SARS-CoV-2 Infection—An Italian Multicenter Experience
Authors: Cantarutti Nicoletta , Battista Virginia , Stagnaro Nicola , Labate Marianna Eleonora , Cicenia Marianna , Campisi Marta , Vitali Valerio , Secinaro Aurelio , Campana Andrea , Trocchio Gianluca , Drago Fabrizio
Published: October 2022

MIS-C is a multisystem inflammatory syndrome that is characterized by multi-organ failure and cardiac involvement. The aim of this study was to describe the long-term cardiovascular outcome in a cohort of MIS-C pediatric patients, who were admitted to two Italian Pediatric Referral Centers. Sixty-seven patients (mean age 8.7 ± 4.7 years, male 60%) were included; 65 (97%) of them showed cardiac involvement. All of the patients completed one month of the follow-up, and 47% completed 1 year of it. ECG abnormalities were present in 65% of them, arrhythmias were present in 9% of them during an acute phase and it disappeared at the point of discharge or later. Pericarditis were detected in 66% of them and disappeared after 6 months. Coronaritis was observed in 35% of the children during an acute phase, and there were no more instances at the 1-year point. An LV dysfunction was present in 65% of the patients at the beginning of the study, with them having a full recovery at the point of discharge and thereafter. Elevated values of the NTproBNP and hsTp were initially detected, which progressively decreased and normalized at the points of discharge and FU. The CMR at the point of FU, there was a presence of long-term myocardial scars in 50% of the patients that were tested. No deaths that were caused by MIS-C during the FU were recorded. Cardiac involvement in MIS-C patients is almost the rule, but the patients’ clinical course was satisfactory, and no additional events or sequelae were observed apart from there being long-term myocardial scars in 50% of the patients that underwent CMR.
Sulfated Polysaccharides from Chaetoceros muelleri: Macromolecular Characteristics and Bioactive Properties
Authors: Miranda-Arizmendi Valeria , Fimbres-Olivarria Diana , Miranda-Baeza Anselmo , Martínez-Robinson Karla , Rascón-Chu Agustín , De Anda-Flores Yubia , Lizardi-Mendoza Jaime , Mendez-Encinas Mayra A. , Brown-Bojorquez Francisco , Canett-Romero Rafael , Carvajal-Millan Elizabeth
Published: October 2022

In the present study, a culture of Chaetoceros muelleri, a cosmopolitan planktonic diatom microalga present in the Sea of Cortez, was established under controlled laboratory conditions. A sulfated polysaccharide (CMSP) extraction was carried out from the biomass obtained, resulting in a yield of 2.2% (w/w of dry biomass). The CMSP sample was analyzed by Fourier transform infrared spectroscopy, showing bands ranging from 3405 to 590 cm−1 and a sulfate substitution degree of 0.10. Scanning electron microscopy with elemental analysis revealed that the CMSP particles are irregularly shaped with non-acute angles and contain sulfur. High-performance liquid chromatography coupled to a dynamic light-scattering detector yielded molecular weight (Mw), polydispersity index (PDI), intrinsic viscosity [η], and hydrodynamic radius (Rh) values of 4.13 kDa, 2.0, 4.68 mL/g, and 1.3 nm, respectively, for the CMSP. This polysaccharide did not present cytotoxicity in CCD-841 colon cells. The antioxidant activity and the glycemic index of the CMSP were 23% and 49, respectively, which gives this molecule an added value by keeping low glycemic levels and exerting antioxidant activity simultaneously.
Integrated Quantitative Targeted Lipidomics and Proteomics Reveal Unique Fingerprints of Multiple Metabolic Conditions
Authors: Ivanova Anna A. , Rees Jon C. , Parks Bryan A. , Andrews Michael , Gardner Michael , Grigorutsa Eunice , Kuklenyik Zsuzsanna , Pirkle James L. , Barr John R.
Published: October 2022

Aberrations in lipid and lipoprotein metabolic pathways can lead to numerous diseases, including cardiovascular disease, diabetes, neurological disorders, and cancer. The integration of quantitative lipid and lipoprotein profiling of human plasma may provide a powerful approach to inform early disease diagnosis and prevention. In this study, we leveraged data-driven quantitative targeted lipidomics and proteomics to identify specific molecular changes associated with different metabolic risk categories, including hyperlipidemic, hypercholesterolemic, hypertriglyceridemic, hyperglycemic, and normolipidemic conditions. Based on the quantitative characterization of serum samples from 146 individuals, we have determined individual lipid species and proteins that were significantly up- or down-regulated relative to the normolipidemic group. Then, we established protein–lipid topological networks for each metabolic category and linked dysregulated proteins and lipids with defined metabolic pathways. To evaluate the differentiating power of integrated lipidomics and proteomics data, we have built an artificial neural network model that simultaneously and accurately categorized the samples from each metabolic risk category based on the determined lipidomics and proteomics profiles. Together, our findings provide new insights into molecular changes associated with metabolic risk conditions, suggest new condition-specific associations between apolipoproteins and lipids, and may inform new biomarker discovery in lipid metabolism-associated disorders.
Neutrophil Extracellular Traps (NETs) in Ocular Diseases: An Update
Authors: Zeng Jia , Wu Min , Zhou Yamei , Zhu Manhui , Liu Xiaojuan
Published: October 2022

Neutrophil extracellular traps (NETs) are net-like complexes expelled from neutrophils, composing cell-free deoxyribonucleic acid (DNA), histones, and neutrophil granule proteins. Besides capturing and eliminating pathogens, NETs also exacerbate the inflammatory response associated with various diseases, including systemic lupus erythematosus, rheumatoid arthritis, and psoriasis. Currently, there are growing reports about NETs involved in the pathogenesis of ocular diseases. This review primarily focuses on the pathogenesis of NETs in the ophthalmology field, highlighting their importance in serving as potential targets for the therapy of ocular diseases.
Introduction to Traditional Medicine and Their Role in Prevention and Treatment of Emerging and Re-Emerging Diseases
Authors: Rizvi Syed A. A. , Einstein George P. , Tulp Orien L. , Sainvil Frantz , Branly Rolando
Published: October 2022

Infectious diseases have been a threat to human health globally. The relentless efforts and research have enabled us to overcome most of the diseases through the use of antiviral and antibiotic agents discovered and employed. Unfortunately, the microorganisms have the capability to adapt and mutate over time and antibiotic and antiviral resistance ensues. There are many challenges in treating infections such as failure of the microorganisms to respond to the therapeutic agents, which has led to more chronic infections, complications, and preventable loss of life. Thus, a multidisciplinary approach and collaboration is warranted to create more potent, effective, and versatile therapies to prevent and eradicate the old and newly emerging diseases. In the recent past, natural medicine has proven its effectiveness against various illnesses. Most of the pharmaceutical agents currently used can trace their origin to the natural products in one way, shape, or form. The full potential of natural products is yet to be realized, as numerous natural resources have not been explored and analyzed. This merits continuous support in research and analysis of ancient treatment systems to explore their full potential and employ them as an alternative or principal therapy.
Pre-Treatment Hemoglobin Concentration and Absolute Monocyte Count as Independent Prognostic Factors for Survival in Localized or Locally Advanced Prostate Cancer Patients Undergoing Radiotherapy
Authors: Magrowski Łukasz , Masri Oliwia , Ciepał Jakub , Depowska Gabriela , Nowicka Zuzanna , Stando Rafał , Chimiak Krystyna , Bylica Gabriela , Czapla Barbara , Masri Małgorzata , Cichur Franciszek , Jabłońska Iwona , Gmerek Marta , Wojcieszek Piotr , Krzysztofiak Tomasz , Sadowski Jacek , Suwiński Rafał , Rajwa Paweł , Moll Matthias , Goldner Gregor , Majewski Wojciech , Miszczyk Marcin
Published: October 2022

The prognostic value of inflammatory indices, such as the absolute monocyte count (AMC), has been a subject of interest in recent prostate cancer (PCa) studies, while hemoglobin concentration (HGB) has been recognized as a survival factor in castration-resistant metastatic prostate cancer, but its value remains unclear in localized diseases. The aim of this study was to test the prognostic value of these two simple and inexpensive biomarkers for survival and was based on a cohort of 1016 patients treated with primary radiotherapy and androgen deprivation therapy for localized or locally advanced intermediate- or high-risk PCa. Complete survival data were available for all cases and were based on the National Cancer Registry, with a median observation time of 120 months (Interquartile Range (IQR) 80.9–144.7). Missing blood test data were supplemented using the Nearest Neighbor Imputation, and the Cox Proportional Hazards Regression model was used for analysis. The median age was 68.8 years (IQR 63.3–73.5). The five-year overall survival was 82.8%, and 508 patients were alive at the time of analysis. The median time between blood tests and the first day of radiotherapy was 6 days (IQR 0–19). HGB (p = 0.009) and AMC (p = 0.003) were independent prognostic factors for survival, along with age, Gleason Grade Group, clinical T stage and maximum prostate-specific antigen concentration. This study demonstrates that HGB and AMC can be useful biomarkers for overall survival in patients treated with radiotherapy for localized intermediate- or high-risk PCa.
A Candidate Therapeutic Monoclonal Antibody Inhibits Both HRSV and HMPV Replication in Mice
Authors: Fausther-Bovendo Hugues , Hamelin Marie-Eve , Carbonneau Julie , Venable Marie-Christine , Checkmahomed Liva , Lavoie Pierre-Olivier , Ouellet Marie-Ève , Boivin Guy , D’Aoust Marc-André , Kobinger Gary P.
Published: October 2022

Human metapneumovirus (HMPV) and human respiratory virus (HRSV) are two leading causes of acute respiratory tract infection in young children. While there is no licensed drug against HMPV, the monoclonal antibody (mAb) Palivizumab is approved against HRSV for prophylaxis use only. Novel therapeutics against both viruses are therefore needed. Here, we describe the identification of human mAbs targeting these viruses by using flow cytometry-based cell sorting. One hundred and two antibodies were initially identified from flow cytometry-based cell sorting as binding to the fusion protein from HRSV, HMPV or both. Of those, 95 were successfully produced in plants, purified and characterized for binding activity by ELISA and neutralization assays as well as by inhibition of virus replication in mice. Twenty-two highly reactive mAbs targeting either HRSV or HMPV were isolated. Of these, three mAbs inhibited replication in vivo of a single virus while one mAb could reduce both HRSV and HMPV titers in the lung. Overall, this study identifies several human mAbs with virus-specific therapeutic potential and a unique mAb with inhibitory activities against both HRSV and HMPV.
Metabolic Assessment of Human Induced Pluripotent Stem Cells-Derived Astrocytes and Fetal Primary Astrocytes: Lactate and Glucose Turnover
Authors: Matthiesen Isabelle , Nasiri Rohollah , Tamashiro Orrego Alessandra , Winkler Thomas E. , Herland Anna
Published: October 2022

Astrocytes represent one of the main cell types in the brain and play a crucial role in brain functions, including supplying the energy demand for neurons. Moreover, they are important regulators of metabolite levels. Glucose uptake and lactate production are some of the main observable metabolic actions of astrocytes. To gain insight into these processes, it is essential to establish scalable and functional sources for in vitro studies of astrocytes. In this study, we compared the metabolic turnover of glucose and lactate in astrocytes derived from human induced pluripotent stem cell (hiPSC)-derived Astrocytes (hiAstrocytes) as a scalable astrocyte source to human fetal astrocytes (HFAs). Using a user-friendly, commercial flow-based biosensor, we could verify that hiAstrocytes are as glycogenic as their fetal counterparts, but their normalized metabolic turnover is lower. Specifically, under identical culture conditions in a defined media, HFAs have 2.3 times higher levels of lactate production compared to hiAstrocytes. In terms of glucose, HFAs have 2.1 times higher consumption levels than hiAstrocytes at 24 h. Still, as we describe their glycogenic phenotype, our study demonstrates the use of hiAstrocytes and flow-based biosensors for metabolic studies of astrocyte function.
Microbial Biosensors for Rapid Determination of Biochemical Oxygen Demand: Approaches, Tendencies and Development Prospects
Authors: Arlyapov Vyacheslav A. , Plekhanova Yulia V. , Kamanina Olga A. , Nakamura Hideaki , Reshetilov Anatoly N.
Published: October 2022

One of the main indices of the quality of water is the biochemical oxygen demand (BOD). A little over 40 years have passed since the practical application of the first microbial sensor for the determination of BOD, presented by the Japanese professor Isao Karube. This time span has brought new knowledge to and practical developments in the use of a wide range of microbial cells based on BOD biosensors. At present, this field of biotechnology is becoming an independent discipline. The traditional BOD analysis (BOD5) has not changed over many years; it takes no less than 5 days to carry out. Microbial biosensors can be used as an alternative technique for assessing the BOD attract attention because they can reduce hundredfold the time required to measure it. The review examines the experience of the creation and practical application of BOD biosensors accumulated by the international community. Special attention is paid to the use of multiple cell immobilization methods, signal registration techniques, mediators and cell consortia contained in the bioreceptor. We consider the use of nanomaterials in the modification of analytical devices developed for BOD evaluation and discuss the prospects of developing new practically important biosensor models.
Multifunctional Smart ZnSe-Nanostructure-Based Fluorescent Aptasensor for the Detection of Ochratoxin A
Authors: Nawaz Muhammad Azhar Hayat , Fazal Muhammad Waseem , Akhtar Naeem , Nawaz Mian Hasnain , Hayat Akhtar , Yu Cong
Published: October 2022

Herein, we present a comprehensive investigation of rationally designed zinc selenide (ZnSe) nanostructures to achieve highly negatively charged ZnSe nanostructures. A Microwave-assisted hydrothermal synthesis method was used to synthesize three types of ZnSe nanostructures, i.e., nanorods, µ-spheres and nanoclusters, as characterized by a zeta potential analyzer, X-ray diffraction (XRD), scanning electron microscopy (SEM), Raman spectroscopy and BET, which were labeled as type A, B and C. Three different solvents were used for the synthesis of type A, B and C ZnSe nanostructures, keeping other synthesis conditions such as temperature, pressure and precursors ratio constant. Based on two heating time intervals, 6 and 9 h, types A, B and C were further divided into types A6, A9, B6, B9, C6 and C9. ZnSe nanostructures were further evaluated based on their fluorescent quenching efficiency. The maximum fluorescence quenching effect was exhibited by the ZnSe-B6 type, which can be attributed to its highly negative surface charge that favored its strong interaction with cationic dye Rhodamine B (Rh-B). Further, the optimized ZnSe-B6 was used to fabricate an aptasensor for the detection of a food-based toxin, ochratoxin-A (OTA). The developed aptasensor exhibited a limit of detection of 0.07 ng/L with a wide linear range of 0.1 to 200 ng/L.
Fabrication of CeO2/GCE for Electrochemical Sensing of Hydroquinone
Authors: Chaudhary Archana , Khan Mohd Quasim , Khan Rais Ahmad , Alsalme Ali , Ahmad Khursheed , Kim Haekyoung
Published: October 2022

Hydroquinone is a widely used derivative of phenol which has a negative influence on human beings and the environment. The determination of the accurate amount of hydroquinone is of great importance. Recently, the fabrication of an electrochemical sensing device has received enormous attention. In this study, we reported on the facile synthesis of cerium dioxide (CeO2) nanoparticles (NPs). The CeO2 NPs were synthesized using cerium nitrate hexahydrate as a precursor. For determining the physicochemical properties of synthesized CeO2 NPs, various advanced techniques, viz., powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and X-ray photoelectron spectroscopy (XPS), were studied. Further, these synthesized CeO2 NPs were used for the modification of a glassy carbon electrode (CeO2/GCE), which was utilized for the sensing of hydroquinone (HQ). A decent detection limit of 0.9 µM with a sensitivity of 0.41 µA/µM cm2 was exhibited by the modified electrode (CeO2/GCE). The CeO2/GCE also exhibited good stability, selectivity, and repeatability towards the determination of HQ.
Sleep Quality Mediates the Effect of Sensitization-Associated Symptoms, Anxiety, and Depression on Quality of Life in Individuals with Post-COVID-19 Pain
Authors: Pacho-Hernández Juan C. , Fernández-de-las-Peñas César , Fuensalida-Novo Stella , Jiménez-Antona Carmen , Ortega-Santiago Ricardo , Cigarán-Mendez Margarita
Published: October 2022

A better understanding of biological and emotional variables associated with health-related quality of life in people with long-COVID is needed. Our aim was to identify potential direct and indirect effects on the relationships between sensitization-associated symptoms, mood disorders such as anxiety/depressive levels, and sleep quality on health-related quality of life in people suffering from post-COVID-19 pain. One hundred and forty-six individuals who were hospitalized due to COVID-19 during the first wave of the pandemic and suffering from long-term post-COVID-19 pain completed different patient-reported outcome measures (PROMs), including clinical features, symptoms associated with sensitization of the central nervous system (Central Sensitization Inventory), mood disorders (Hospital Anxiety and Depressive Scale), sleep quality (Pittsburgh Sleep Quality Index), and health-related quality of life (paper-based five-level version of EuroQol-5D) in a face-to-face interview conducted at 18.8 (SD 1.8) months after hospitalization. Different mediation models were conducted to assess the direct and indirect effects of the associations among the different variables. The mediation models revealed that sensitization-associated symptoms and depressive levels directly affected health-related quality of life; however, these effects were not statistically significant when sleep quality was included. In fact, the effect of sensitization-associated symptomatology on quality of life (β = −0.10, 95% CI −0.1736, −0.0373), the effect of depressive levels on quality of life (β= −0.09, 95% CI −0.1789, −0.0314), and the effect of anxiety levels on quality of life (β = −0.09, 95% CI −0.1648, −0.0337) were all indirectly mediated by sleep quality. This study revealed that sleep quality mediates the relationship between sensitization-associated symptoms and mood disorders (depressive/anxiety levels) with health-related quality of life in individuals who were hospitalized with COVID-19 at the first wave of the pandemic and reporting post-COVID-19 pain. Longitudinal studies will help to determine the clinical implications of these findings.
Air Pressure Differences over External Walls in New and Retrofitted Schools and Daycare Centers
Authors: Kauppinen Antti , Kiviste Mihkel , Pirhonen Joni , Tuominen Eero , Laukkarinen Anssi , Huttunen Petteri , Vinha Juha
Published: October 2022

Air pressure differences are a key factor in the behavior of building ventilation and air leakages through the building envelope. Field measurements of the air pressure differences over the building envelope were conducted in 24 Finnish municipal service buildings. The measured buildings were mainly schools and daycare centers, of which half were new buildings and half recently retrofitted. All buildings had mechanical ventilation. The measurements were conducted during 2016–2018. The total number of measurement points was 100, and the duration of individual time series varied. According to the results, the mean air pressure difference was within the range of national recommendations (small underpressure indoors) in 81–89% of measurement points, but some cases experienced either strong underpressure or overpressure conditions. In some cases, the air pressure difference showed a clear stepwise constant behavior, while other cases showed larger temporal variation. The conditions varied between different operating situations and the time of year. The study also supports the current recommendation that air pressure difference measurements should be done as continuous measurements of at least one week duration.
A Study on Mega-Shelter Layout Planning Based on User Behavior
Authors: Kim Young Ook , Kim Joo Young , Yum Ha Yoon , Lee Jin Kyoung
Published: October 2022

We explore the spatial layouts of mega-shelters and suggest better spatial planning strategies. A mega-shelter for refugees contains multiple functions, such as dormitory, dining, medical, kitchen, storage, and community areas. Post-disaster refugees often suffer from PTSD that affects their mental health and spatial cognitive ability. The spatial configuration of a mega-shelter can accelerate their recovery by providing an environment that not only satisfies the basic needs, but one that can improve their spatial cognitive ability and promote a sense of community in this new, albeit temporary, small society. Four mega-shelters in the U.S., Australia, and Japan were analyzed using space syntax methods, specifically axial line analysis and visibility graph analysis (VGA), as well as justified graph analysis. The comparative analysis shows that while specific spatial layouts are different, all shelters were designed from a manager’s perspective. The movements of the refugees were sometimes unnecessarily exposed to supervision and control, and community areas were often found in locations with low accessibility. By incorporating strategies such as siting community space in areas with high global integration values and adopting transition areas, mega-shelters can create an environment that can enhance the refugees’ will to recover and rebuild by promoting communications with neighbors and various community activities.
Semi-Transparent Water-Based Trombe Walls for Passive Air and Water Heating
Authors: Singh Harmeet , O’Brien Paul G.
Published: October 2022

Trombe walls provide a passive source of heating and ventilation for buildings. However, Trombe walls can also cause overheating during hot and sunny weather conditions. In this work, we investigate the potential of a multifunctional Trombe wall design, comprising a tinted acrylic sheet submerged in a water wall that functions as a thermal storage medium. The tinted acrylic sheet absorbs incident light, which is then converted to heat and absorbed by the water. The proposed Trombe wall can function as a tinted semi-transparent window to add aesthetic value. Furthermore, heated water rises to the top of the Trombe wall where it can be removed, which provides the dual benefit of preventing overheating and providing a source of preheated water for applications within the building. Experimental results performed on a laboratory-scale Trombe wall prototype showed that the percentage of solar-simulated light energy incident onto the Trombe wall prototype, over a period of five hours, that was stored as thermal energy in the water increased from 60.3% to 83.2% when tinted glass was inserted in the water storage wall. Furthermore, the temperature of the water at the top of the Trombe wall reached ~56 °C, which is suitable to be used as pre-heated water in building applications.
Relation Extraction of Domain Knowledge Entities for Safety Risk Management in Metro Construction Projects
Authors: Xu Na , Chang Hong , Xiao Bai , Zhang Bo , Li Jie , Gu Tiantian
Published: October 2022

Gathering experience and organizing knowledge from a large number of engineering construction projects is conducive to more effective and efficient safety risk management in construction projects. Metro construction practitioners often find it difficult to determine what professional knowledge is needed to establish better management. By constructing the knowledge structure of safety risk management, which is composed of domain knowledge entities (DKEs) and their hierarchical relations, practitioners can systematically master the knowledge of safety management, enhance safety management levels, and reduce the occurrence of accidents. Traditionally, domain knowledge structure was determined by experts, the mistakes occur due to the limitations of individual knowledge, and high time costs are unavoidable due to the massive amount of data. Therefore, in this study, we used a rule-based Chinese-language natural language processing (C-NLP) method to automatically extract the hierarchical relations between DKEs from a large dataset of unstructured text documents; we aimed to clarify the affiliation relationship and parallel relationship between DKEs. First, 68,817 sources of literature written in Chinese were collected. Next, the specific syntactic structures of relations of the DKEs were analyzed. Hierarchical extraction rules, including 16 hyponymic indicators and 8 appositive indicators, were revealed based on the linguistic characteristics. Then, the relations were extracted from test dataset. The precision and recall values were used to verify the model. Finally, the hierarchical relations of all the DKEs were extracted, and the knowledge structure was formed. The proposed method of hierarchical relation extraction contributes to the quick automatic construction of knowledge structures and minimizes expert bias. The knowledge structures can be used to guide safety training and can assist practitioners in safety risk management.
Single-Cell Identification of Melanoma Biomarkers in Circulating Tumor Cells
Authors: Fankhauser Reilly , Chang Matthew , Garrison Zachary , Berryman Rachel , Lucero Olivia M. , Fuiten Allison , DePatie Nicholas , Seifert Hilary , Kulkarni Rajan P.
Published: October 2022

The current standard for investigating tumors is surgical biopsy, which is costly, invasive, and difficult to perform serially. As an adjunct, circulating tumor cells (CTCs)—cells that have broken away from the primary tumor or metastatic sites—can be obtained from a blood draw and offer the potential for obtaining serial genetic information and serving as biomarkers. Here, we detail the potential for melanoma CTCs to serve as biomarkers and discuss a clinically viable methodology for single-cell CTC isolation and analysis that overcomes previous limitations. We explore the use of melanoma CTC biomarkers by isolating and performing single-cell RNA sequencing on CTCs from melanoma patients. We then compared transcriptional profiles of single melanoma CTCs against A375 cells and peripheral blood mononuclear cells to identify unique genes differentially regulated in circulating melanoma tumor cells. The information that can be obtained via analysis of these CTCs has significant potential in disease tracking.
Development of a Neurotensin-Derived 68Ga-Labeled PET Ligand with High In Vivo Stability for Imaging of NTS1 Receptor-Expressing Tumors
Authors: Schindler Lisa , Moosbauer Jutta , Schmidt Daniel , Spruss Thilo , Grätz Lukas , Lüdeke Steffen , Hofheinz Frank , Meister Sebastian , Echtenacher Bernd , Bernhardt Günther , Pietzsch Jens , Hellwig Dirk , Keller Max
Published: October 2022

Overexpression of the neurotensin receptor type 1 (NTS1R), a peptide receptor located at the plasma membrane, has been reported for a variety of malignant tumors. Thus, targeting the NTS1R with 18F- or 68Ga-labeled ligands is considered a straightforward approach towards in vivo imaging of NTS1R-expressing tumors via positron emission tomography (PET). The development of suitable peptidic NTS1R PET ligands derived from neurotensin is challenging due to proteolytic degradation. In this study, we prepared a series of NTS1R PET ligands based on the C-terminal fragment of neurotensin (NT(8–13), Arg8-Arg9-Pro10-Tyr11-Ile12-Leu13) by attachment of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) via an Nω-carbamoylated arginine side chain. Insertion of Ga3+ in the DOTA chelator gave potential PET ligands that were evaluated concerning NTS1R affinity (range of Ki values: 1.2–21 nM) and plasma stability. Four candidates were labeled with 68Ga3+ and used for biodistribution studies in HT-29 tumor-bearing mice. [68Ga]UR-LS130 ([68Ga]56), containing an N-terminal methyl group and a β,β-dimethylated tyrosine instead of Tyr11, showed the highest in vivo stability and afforded a tumor-to-muscle ratio of 16 at 45 min p.i. Likewise, dynamic PET scans enabled a clear tumor visualization. The accumulation of [68Ga]56 in the tumor was NTS1R-mediated, as proven by blocking studies.
PRELP Regulates Cell–Cell Adhesion and EMT and Inhibits Retinoblastoma Progression
Authors: Hopkins Jack , Asada Ken , Leung Alex , Papadaki Vasiliki , Davaapil Hongorzul , Morrison Matthew , Orita Tomoko , Sekido Ryohei , Kosuge Hirofumi , Reddy M. Ashwin , Kimura Kazuhiro , Mitani Akihisa , Tsumoto Kouhei , Hamamoto Ryuji , Sagoo Mandeep S. , Ohnuma Shin-ichi
Published: October 2022

Retinoblastoma (RB) is the most common intraocular pediatric cancer. Nearly all cases of RB are associated with mutations compromising the function of the RB1 tumor suppressor gene. We previously demonstrated that PRELP is widely downregulated in various cancers and our in vivo and in vitro analysis revealed PRELP as a novel tumor suppressor and regulator of EMT. In addition, PRELP is located at chromosome 1q31.1, around a region hypothesized to be associated with the initiation of malignancy in RB. Therefore, in this study, we investigated the role of PRELP in RB through in vitro analysis and next-generation sequencing. Immunostaining revealed that PRELP is expressed in Müller glial cells in the retina. mRNA expression profiling of PRELP−/− mouse retina and PRELP-treated RB cells found that PRELP contributes to RB progression via regulation of the cancer microenvironment, in which loss of PRELP reduces cell–cell adhesion and facilitates EMT. Our observations suggest that PRELP may have potential as a new strategy for RB treatment.
SF3B1 Mutations in Hematological Malignancies
Authors: Cilloni Daniela , Itri Federico , Bonuomo Valentina , Petiti Jessica
Published: October 2022

Recently, mutations in the genes involved in the spliceosome have attracted considerable interest in different neoplasms. Among these, SF3B1 mutations have acquired great interest, especially in myelodysplastic syndromes, as they identify a subgroup of patients who can benefit from personalized therapy. The SF3B1 gene encodes the largest subunit of the splicing factor 3b protein complex and is critical for spliceosome assembly and mRNA splicing. The mutated SF3B1 gene encodes for a protein with a different mRNA processing mechanism that results in the aberrant splicing of many mRNAs, which can be downregulated. Although there are many mRNAs affected by a splicing alteration, only a few of these have been directly related to the pathogenesis of several diseases. In this review, we took a snapshot of the current knowledge on the implications of SF3B1 mutations in different hematological malignancies.
TERT Promoter and BRAF V600E Mutations in Papillary Thyroid Cancer: A Single-Institution Experience in Korea
Authors: Kim Min Jhi , Kim Jin Kyong , Kim Gi Jeong , Kang Sang-Wook , Lee Jandee , Jeong Jong Ju , Chung Woong Youn , Kim Daham , Nam Kee-Hyun
Published: October 2022

Telomerase reverse transcriptase (TERT) promoter mutation has been investigated for its clinical and prognostic significance in aggressive papillary thyroid cancer (PTC). In this study, we aimed to assess the prevalence, clinicopathologic features, and treatment outcomes of TERT mutation-positive PTCs along with the common BRAF V600E mutation. We performed mutational analyses for BRAF and the TERT promoter in thyroid cancer patients who had undergone surgery at our institution since 2019. We reviewed and analyzed 7797 patients with PTC in this study. The prevalence of BRAF V600E and TERT promoter mutations was 84.0% and 1.1%, respectively. Multifocal gene mutations in bilateral PTCs were identified. TERT promoter mutations were associated with older age, larger tumor size, tumor multifocality, tumor variants, advanced stages, more adjuvant radioactive iodine treatment (RAI), higher stimulated serum thyroglobulin level before RAI, and more uptakes in the regions outside the surgical field on a post-RAI whole-body scan. The coexistence of BRAF V600E and TERT promoter mutations exacerbated all clinicopathologic characteristics. The frequency of TERT promoter mutations was the lowest in this study, compared to previous studies. TERT promoter mutations consistently correlated with aggressive PTCs, and the synergistic effect of both mutations was evident. Specific clinical settings in our institution and in Korea may have led to these distinctive results. Prospective multicenter studies with longer follow-up periods are required to establish valuable oncologic outcomes.
Mutant C. elegans p53 Together with Gain-of-Function GLP-1/Notch Decreases UVC-Damage-Induced Germline Cell Death but Increases PARP Inhibitor-Induced Germline Cell Death
Authors: Canar Jorge , Manandhar-Sasaki Prima , Bargonetti Jill
Published: October 2022

The TP53 gene is mutated in over 50% of human cancers, and the C. elegansp53-1(cep-1) gene encodes the ortholog CEP-1. CEP-1 is activated by ultraviolet type C (UVC)-induced DNA damage and activates genes that induce germline apoptosis. UVC treatment of gain-of-function glp-1(ar202gf)/Notch tumorous animals reduces germline stem cell numbers (and overall tumor size), while UVC treatment of double-mutant cep-1/p53(gk138);glp-1/Notch(ar202gf) increases DNA damage adducts and stem cell tumor volume. We compared UVC-induced mitotic stem cell death and animal lifespans for the two different C. elegans tumorous strains. C. elegans stem cell compartment death has never been observed, and we used engulfed small stem cells, notable by green fluorescent puncta, to count cell death events. We found UVC treatment of glp-1(ar202gf) animals increased stem cell death and increased lifespan. However, UVC treatment of double-mutant cep-1/p53(gk138);glp-1/Notch(ar202gf) animals decreased stem cell death, increased tumor volume, and decreased animal lifespan. There are pharmacological agents that induce p53-independent cell death of human cells in culture; and two notable protocols are the PARP-trapping agents of temozolomide plus talazoparib and the nucleoside analogue 8-amino-adenosine. It is important to determine ways to rapidly test for pharmacological agents able to induce p53-independent cell death. We tested feeding cep-1/p53(gk138);glp-1/Notch(ar202gf) nematodes with either 8-amino-adenosine or temozolomide plus talazoparib and found both were able to decrease tumor volume. This is the first comparison for p53-independent responses in cep-1/p53(gk138);glp-1/Notch(ar202gf) animals and showed UVC DNA damage increased tumor volume and decreased lifespan while PARP inhibition decreased tumor volume.
Head-to-Head Comparison of BRAF/MEK Inhibitor Combinations Proposes Superiority of Encorafenib Plus Trametinib in Melanoma
Authors: Schulz Alexander , Raetz Jennifer , Karitzky Paula C. , Dinter Lisa , Tietze Julia K. , Kolbe Isabell , Käubler Theresa , Renner Bertold , Beissert Stefan , Meier Friedegund , Westphal Dana
Published: October 2022

BRAFV600 mutations in melanoma are targeted with mutation-specific BRAF inhibitors in combination with MEK inhibitors, which have significantly increased overall survival, but eventually lead to resistance in most cases. Additionally, targeted therapy for patients with NRASmutant melanoma is difficult. Our own studies showed that BRAF inhibitors amplify the effects of MEK inhibitors in NRASmutant melanoma. This study aimed at identifying a BRAF and MEK inhibitor combination with superior anti-tumor activity to the three currently approved combinations. We, thus, assessed anti-proliferative and pro-apoptotic activities of all nine as well as resistance-delaying capabilities of the three approved inhibitor combinations in a head-to-head comparison in vitro. The unconventional combination encorafenib/trametinib displayed the highest activity to suppress proliferation and induce apoptosis, acting in an additive manner in BRAFmutant and in a synergistic manner in NRASmutant melanoma cells. Correlating with current clinical studies of approved inhibitor combinations, encorafenib/binimetinib prolonged the time to resistance most efficiently in BRAFmutant cells. Conversely, NRASmutant cells needed the longest time to establish resistance when treated with dabrafenib/trametinib. Together, our data indicate that the most effective combination might not be currently used in clinical settings and could lead to improved overall responses.
Clinical and Molecular Features of KRAS-Mutated Lung Cancer Patients Treated with Immune Checkpoint Inhibitors
Authors: Zhao Dan , Li Haiqing , Mambetsariev Isa , Mirzapoiazova Tamara , Chen Chen , Fricke Jeremy , Kulkarni Prakash , Villaflor Victoria , Arvanitis Leonidas , Hamilton Stanley , Afkhami Michelle , Pillai Raju , Armstrong Brian , Erhunmwunsee Loretta , Massarelli Erminia , Sattler Martin , Amini Arya , Salgia Ravi
Published: October 2022

Background: The molecular and clinical features of KRAS-mutated lung cancer patients treated with immunotherapy have yet to be characterized, which could guide the development of therapeutics targeting KRAS with potential immuno-oncology treatment combinations. Research Question: Do KRAS-mutated patients with different subtypes and comutations have different clinical responses and overall survival (OS) to checkpoint inhibitors? Study Design and Methods: 87 patients with NSCLC at the City of Hope who received immune checkpoint inhibitors were identified and analyzed retrospectively. Tumor genomic alterations were extracted from the clinical data with next-generation sequencing using various platforms. Demographic, clinical, molecular, and pathological information was collected with the approval of the institutional review board of the City of Hope. OS was calculated if it was available at the study time point, and responses were determined according to the RECIST v1.1. Results: Among 87 patients, 32 had a KRAS G12C mutation (36.8%), 19 had G12V (21.9%), 18 had G12D (20.7%), 6 had G12A (6.9%), 3 had G12R (3.45%), and 10 had amplification (11.49%) and other uncommon mutations. G12D had a statistically significant Odds Ratio (OR) between patients who had responses and progression of the disease (OR (95% CI) = 0.31 (0.09–0.95), p < 0.05), with 5 G12D-mutated patients having responses and 11 G12D-mutated patients having progression of the disease. In the univariate analysis with OS, there was a trend of better OS in the G12D-mutated patients, with no statistically significant difference in terms of OS between the patients who had G12D mutation and the patients who had other KRAS mutations (HR (95% CI) = 0.53 (0.21–1.36), p = 0.185). The median OS was significantly worse with KRAS comutation CDKN2A/B loss (4.2 vs. 16.9 months, HR = 3.07 (1.09–8.69), p < 0.05) and MET (3.4 vs. 17 months, HR = 3.80 (1.44–10.05), p < 0.01), which were included for the multivariate analysis. The OS with other KRAS comutations was not statistically significant, including STK11 and KEAP1. Conclusion: KRAS mutation subtypes such as G12D and comutations such as CDKN2/A and MET may modulate the immunotherapy responses and outcomes in lung cancer.
The Prognostic Value of Postoperative Radiotherapy for Thymoma and Thymic Carcinoma: A Propensity-Matched Study Based on SEER Database
Authors: Zhang Chi , Wang Qin , Hu Liwen , Cong Zhuangzhuang , Qiang Yong , Xu Fei , Zhang Zheng , Luo Chao , Qiu Bingmei , Li Xiaokun , Shen Yi
Published: October 2022

(1) Objectives: The effect of postoperative radiotherapy (PORT) for thymoma and thymic carcinoma remains controversial. This study aimed to investigate the prognostic value of PORT for thymoma and thymic carcinoma in a population-based registry. (2) Methods: This retrospective study used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients diagnosed with thymoma and thymic carcinoma between 2010 and 2019. Propensity score matching was performed to adjust statistical influences between the PORT and non-PORT groups. (3) Results: A total of 2558 patients with thymoma (n = 2138) or thymic carcinoma (n = 420) were included. In the multivariate analysis, PORT was an independent prognostic factor for OS (overall survival; p < 0.001) and CSS (cancer-specific survival; p = 0.001) in thymoma and an independent prognostic factor for OS in thymic carcinoma (p = 0.018). Subgroup analyses revealed that PORT was beneficial to OS and CSS in patients with Masaoka-Koga stage IIB-IV thymoma (OS: IIB, p < 0.001; III-IV, p = 0.005; CSS: IIB, p = 0.015; III-IV, p = 0.002) and stage IIB thymic carcinoma (OS: p = 0.012; CSS: p = 0.029). (4) Conclusion: This propensity-matched analysis identified the prognostic value of PORT in thymoma and thymic carcinoma based on the SEER database. For patients with stage IIB-IV thymoma and stage IIB thymic carcinoma, PORT was associated with improved OS and CSS. A more positive attitude towards the use of PORT for nonlocalized thymoma and thymic carcinoma may be appropriate.
The Contribution of Commercial Metal Amides to the Chemical Recycling of Waste Polyesters
Authors: Santulli Federica , Lamberti Marina , Annunziata Andrea , Lastra Rita Chiara , Mazzeo Mina
Published: October 2022

Simple and commercially available metal amides are investigated as catalysts for the chemical depolymerization of polyesters of commercial interest such as polylactide (PLA) and polyethylene terephthalate (PET) via alcoholysis. In the alcoholysis reactions performed with methanol or ethanol at room temperature, Zn, Mg, and Y amides showed the highest activities, while the amides of group 4 metals were revealed as poor catalysts. During the ethanolysis of PLA at higher temperatures and the glycolysis of PET, the good activity of the Zn amide was preserved, while for Mg and Y amides, a significant decrease was observed. The reaction temperature had an opposite effect on the performance of group 4 amides, with the Zr amide revealed to be the best catalyst in the PET glycolysis, reaching activities comparable to the best ones reported in the literature for metal catalysts (78% BHET yield within one hour at 180 °C). These studies represent new opportunities for the sustainable recycling of plastics, which are currently being used on a large scale, and provide significant contributions to the design of a circular economy model in the plastic industry.
Boron and Phosphorus Co-Doped Graphitic Carbon Nitride Cooperate with Bu4NBr as Binary Heterogeneous Catalysts for the Cycloaddition of CO2 to Epoxides
Authors: Yang Chaokun , Zhao Xin , Yang Tuantuan
Published: October 2022

The development of a cost-effective heterogeneous catalytic system for the cycloaddition reaction of CO2 and epoxides is of great importance. In this manuscript, three kinds of boron and phosphorus co-doping graphitic carbon nitride (BP-CN) were prepared and characterized. Among them, BP-CN-1 displayed the optimal catalytic performance in the presence of Bu4NBr (tetrabutylammonium bromide) for the CO2 cycloaddition with propylene oxide, and 95% propylene carbonate yield was obtained under a 120 °C, 2 MPa, 6 h condition. Moreover, the BP-CN-1/Bu4NBr catalytic system is compatible with various epoxides and also exhibits excellent recycling performance under metal- and solvent-free conditions. Hence, BP-CN-1 exhibited an attractive application for the efficient fixation of CO2 due to the simple, eco-friendly synthesis route and effective catalytic activity.