bluuebunny/crossref_metadata_2025 huggingface dataset:
Phytoplasma Taxonomy: Nomenclature, Classification, and Identification
Authors: Wei Wei , Zhao Yan
Published: July 2022

Phytoplasmas are pleomorphic, wall-less intracellular bacteria that can cause devastating diseases in a wide variety of plant species. Rapid diagnosis and precise identification of phytoplasmas responsible for emerging plant diseases are crucial to preventing further spread of the diseases and reducing economic losses. Phytoplasma taxonomy (identification, nomenclature, and classification) has lagged in comparison to culturable bacteria, largely due to lack of axenic phytoplasma culture and consequent inaccessibility of phenotypic characteristics. However, the rapid expansion of molecular techniques and the advent of high throughput genome sequencing have tremendously enhanced the nucleotide sequence-based phytoplasma taxonomy. In this article, the key events and milestones that shaped the current phytoplasma taxonomy are highlighted. In addition, the distinctions and relatedness of two parallel systems of ‘Candidatus phytoplasma’ species/nomenclature system and group/subgroup classification system are clarified. Both systems are indispensable as they serve different purposes. Furthermore, some hot button issues in phytoplasma nomenclature are also discussed, especially those pertinent to the implementation of newly revised guidelines for ‘Candidatus Phytoplasma’ species description. To conclude, the challenges and future perspectives of phytoplasma taxonomy are briefly outlined.
A Plea for a New Synthesis: From Twentieth-Century Paleobiology to Twenty-First-Century Paleontology and Back Again
Authors: Tamborini Marco
Published: July 2022

In this paper, I will briefly discuss the elements of novelty and continuity between twentieth-century paleobiology and twenty-first-century paleontology. First, I will outline the heated debate over the disciplinary status of paleontology in the mid-twentieth century. Second, I will analyze the main theoretical issue behind this debate by considering two prominent case studies within the broader paleobiology agenda. Third, I will turn to twenty-first century paleontology and address five representative research topics. In doing so, I will characterize twenty-first century paleontology as a science that strives for more data, more technology, and more integration. Finally, I will outline what twenty-first-century paleontology might inherit from twentieth-century paleobiology: the pursuit of and plea for a new synthesis that could lead to a second paleobiological revolution. Following in the footsteps of the paleobiological revolution of the 1960s and 1970s, the paleobiological revolution of the twenty-first century would enable paleontologists to gain strong political representation and argue with a decisive voice at the “high table” on issues such as the expanded evolutionary synthesis, the conservation of Earth’s environment, and global climate change.
UCS Chaperone Folding of the Myosin Head: A Function That Evolved before Animals and Fungi Diverged from a Common Ancestor More than a Billion Years Ago
Authors: Piper Peter William , Scott Julia Elizabeth , Millson Stefan Heber
Published: July 2022

The folding of the myosin head often requires a UCS (Unc45, Cro1, She4) domain-containing chaperone. Worms, flies, and fungi have just a single UCS protein. Vertebrates have two; one (Unc45A) which functions primarily in non-muscle cells and another (Unc45B) that is essential for establishing and maintaining the contractile apparatus of cardiac and skeletal muscles. The domain structure of these proteins suggests that the UCS function evolved before animals and fungi diverged from a common ancestor more than a billion years ago. UCS proteins of metazoans and apicomplexan parasites possess a tetratricopeptide repeat (TPR), a domain for direct binding of the Hsp70/Hsp90 chaperones. This, however, is absent in the UCS proteins of fungi and largely nonessential for the UCS protein function in Caenorhabditis elegans and zebrafish. The latter part of this review focusses on the TPR-deficient UCS proteins of fungi. While these are reasonably well studied in yeasts, there is little precise information as to how they might engage in interactions with the Hsp70/Hsp90 chaperones or might assist in myosin operations during the hyphal growth of filamentous fungi.
Progesterone Suppresses Uterine Contraction by Reducing Odontogenic Porphyromonas gingivalis Induced Chronic Inflammation in Mice
Authors: Teraoka Yuko , Sugimoto Jun , Konishi Haruhisa , Miyoshi Hiroshi , Furusho Hisako , Miyauchi Mutsumi , Kajioka Shunichi , Koh Iemasa , Kudo Yoshiki
Published: July 2022

Preterm birth is one of the most significant obstetric complications. Inflammation reportedly promotes uterine contraction and weakening of the fetal membrane, which induces preterm birth. Previous studies using animal models of lipopolysaccharide-induced acute inflammation have shown that progesterone (P4) promotes uterine quiescence. However, this effect is not fully understood in chronic inflammation. This study aimed to investigate the effects of P4 on uterine contractility and inflammation of the fetal membrane in mice infected with Porphyromonas gingivalis (P.g.), a major periodontal pathogen as a model of preterm birth caused by chronic inflammation. Mice were injected with 1 mg of P4 from day 15.5 to 17.5. P4 prolonged the mean gestation period of P.g mice from 18.3 to 20.4 days, and no reduction in the gestation period was observed. P4 treatment suppressed spontaneous uterine contractility and decreased oxytocin sensitivity. In addition, the expression of inflammatory cytokines in the fetal membrane was significantly reduced. Thus, P4 prevented preterm birth by suppressing enhanced uterine contractility induced by chronic inflammation in this model. This result describes the effects of P4 in a chronic inflammation model, which may lead to a better understanding of the efficacy of P4 in preventing preterm birth in humans.
Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease
Authors: Fowler Ewan Douglas , Zissimopoulos Spyros
Published: July 2022

The ryanodine receptor (RyR2) has a critical role in controlling Ca2+ release from the sarcoplasmic reticulum (SR) throughout the cardiac cycle. RyR2 protein has multiple functional domains with specific roles, and four of these RyR2 protomers are required to form the quaternary structure that comprises the functional channel. Numerous mutations in the gene encoding RyR2 protein have been identified and many are linked to a wide spectrum of arrhythmic heart disease. Gain of function mutations (GoF) result in a hyperactive channel that causes excessive spontaneous SR Ca2+ release. This is the predominant cause of the inherited syndrome catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, rare hypoactive loss of function (LoF) mutations have been identified that produce atypical effects on cardiac Ca2+ handling that has been termed calcium release deficiency syndrome (CRDS). Aberrant Ca2+ release resulting from both GoF and LoF mutations can result in arrhythmias through the Na+/Ca2+ exchange mechanism. This mini-review discusses recent findings regarding the role of RyR2 domains and endogenous regulators that influence RyR2 gating normally and with GoF/LoF mutations. The arrhythmogenic consequences of GoF/LoF mutations will then be discussed at the macromolecular and cellular level.
Dostarlimab: A Review
Authors: Costa Bárbara , Vale Nuno
Published: July 2022

Dostarlimab (JEMPERLI) is a PD-1 monoclonal antibody for the treatment of adult patients, with mismatch repair deficient (dMMR), recurrent or advanced endometrial cancer that has progressed on or following prior therapy with a platinum-containing regimen. As determined by an FDA-approved test this indication was granted rapid approval based on the rate of tumor response and the duration of the response. Continued approval for this indication is conditioned on further confirmatory trials demonstrating and documenting clinical benefit. In June 2022, the clinical trial NCT04165772 reported a 100% remission rate for rectal cancer. This clinical trial brought proof that we can match a tumor and the genetics of what is driving it, with therapy. This clinical trial continues to enroll patient and is currently enrolling patients with gastric, prostate, and pancreatic cancers. Dostarlamib is being recommended for rectal cancer. The focus of this review is to summarize the existing knowledge regarding Dostarlimab and explore the possibilities of mono- and combination therapies.
Cargo Recognition Mechanisms of Yeast Myo2 Revealed by AlphaFold2-Powered Protein Complex Prediction
Authors: Liu Yong , Li Lingxuan , Yu Cong , Zeng Fuxing , Niu Fengfeng , Wei Zhiyi
Published: July 2022

Myo2, a yeast class V myosin, transports a broad range of organelles and plays important roles in various cellular processes, including cell division in budding yeast. Despite the fact that several structures of Myo2/cargo adaptor complexes have been determined, the understanding of the versatile cargo-binding modes of Myo2 is still very limited, given the large number of cargo adaptors identified for Myo2. Here, we used ColabFold, an AlphaFold2-powered and easy-to-use tool, to predict the complex structures of Myo2-GTD and its several cargo adaptors. After benchmarking the prediction strategy with three Myo2/cargo adaptor complexes that have been determined previously, we successfully predicted the atomic structures of Myo2-GTD in complex with another three cargo adaptors, Vac17, Kar9 and Pea2, which were confirmed by our biochemical characterizations. By systematically comparing the interaction details of the six complexes of Myo2 and its cargo adaptors, we summarized the cargo-binding modes on the three conserved sites of Myo2-GTD, providing an overall picture of the versatile cargo-recognition mechanisms of Myo2. In addition, our study demonstrates an efficient and effective solution to study protein–protein interactions in the future via the AlphaFold2-powered prediction.
Nanoscopic Spatial Association between Ras and Phosphatidylserine on the Cell Membrane Studied with Multicolor Super Resolution Microscopy
Authors: Koester Anna M. , Tao Kai , Szczepaniak Malwina , Rames Matthew J. , Nan Xiaolin
Published: July 2022

Recent work suggests that Ras small GTPases interact with the anionic lipid phosphatidylserine (PS) in an isoform-specific manner, with direct implications for their biological functions. Studies on PS-Ras associations in cells, however, have relied on immuno-EM imaging of membrane sheets. To study their spatial relationships in intact cells, we have combined the use of Lact-C2-GFP, a biosensor for PS, with multicolor super resolution imaging based on DNA-PAINT. At ~20 nm spatial resolution, the resulting super resolution images clearly show the nonuniform molecular distribution of PS on the cell membrane and its co-enrichment with caveolae, as well as with unidentified membrane structures. Two-color imaging followed by spatial analysis shows that KRas-G12D and HRas-G12V both co-enrich with PS in model U2OS cells, confirming previous observations, yet exhibit clear differences in their association patterns. Whereas HRas-G12V is almost always co-enriched with PS, KRas-G12D is strongly co-enriched with PS in about half of the cells, with the other half exhibiting a more moderate association. In addition, perturbations to the actin cytoskeleton differentially impact PS association with the two Ras isoforms. These results suggest that PS-Ras association is context-dependent and demonstrate the utility of multiplexed super resolution imaging in defining the complex interplay between Ras and the membrane.
Recent Advances in Single-Molecule Sensors Based on STM Break Junction Measurements
Authors: Lv Shan-Ling , Zeng Cong , Yu Zhou , Zheng Ju-Fang , Wang Ya-Hao , Shao Yong , Zhou Xiao-Shun
Published: July 2022

Single-molecule recognition and detection with the highest resolution measurement has been one of the ultimate goals in science and engineering. Break junction techniques, originally developed to measure single-molecule conductance, recently have also been proven to have the capacity for the label-free exploration of single-molecule physics and chemistry, which paves a new way for single-molecule detection with high temporal resolution. In this review, we outline the primary advances and potential of the STM break junction technique for qualitative identification and quantitative detection at a single-molecule level. The principles of operation of these single-molecule electrical sensing mainly in three regimes, ion, environmental pH and genetic material detection, are summarized. It clearly proves that the single-molecule electrical measurements with break junction techniques show a promising perspective for designing a simple, label-free and nondestructive electrical sensor with ultrahigh sensitivity and excellent selectivity.
Electrochemical Signal Amplification Strategies and Their Use in Olfactory and Taste Evaluation
Authors: Wang Xinqian , Lu Dingqiang , Liu Yuan , Wang Wenli , Ren Ruijuan , Li Ming , Liu Danyang , Liu Yujiao , Liu Yixuan , Pang Guangchang
Published: July 2022

Biosensors are powerful analytical tools used to identify and detect target molecules. Electrochemical biosensors, which combine biosensing with electrochemical analysis techniques, are efficient analytical instruments that translate concentration signals into electrical signals, enabling the quantitative and qualitative analysis of target molecules. Electrochemical biosensors have been widely used in various fields of detection and analysis due to their high sensitivity, superior selectivity, quick reaction time, and inexpensive cost. However, the signal changes caused by interactions between a biological probe and a target molecule are very weak and difficult to capture directly by using detection instruments. Therefore, various signal amplification strategies have been proposed and developed to increase the accuracy and sensitivity of detection systems. This review serves as a reference for biosensor and detector research, as it introduces the research progress of electrochemical signal amplification strategies in olfactory and taste evaluation. It also discusses the latest signal amplification strategies currently being employed in electrochemical biosensors for nanomaterial development, enzyme labeling, and nucleic acid amplification techniques, and highlights the most recent work in using cell tissues as biosensitive elements.
Simultaneous Observation of Mouse Cortical and Hippocampal Neural Dynamics under Anesthesia through a Cranial Microprism Window
Authors: Zhang Rujin , Zhuang Chaowei , Wang Zilin , Xiao Guihua , Chen Kunsha , Li Hao , Tong Li , Mi Weidong , Xie Hao , Cao Jiangbei
Published: July 2022

The fluorescence microscope has been widely used to explore dynamic processes in vivo in mouse brains, with advantages of a large field-of-view and high spatiotemporal resolution. However, owing to background light and tissue scattering, the single-photon wide-field microscope fails to record dynamic neural activities in the deep brain. To achieve simultaneous imaging of deep-brain regions and the superficial cortex, we combined the extended-field-of-view microscopy previously proposed with a novel prism-based cranial window to provide a longitudinal view. As well as a right-angle microprism for imaging above 1 mm, we also designed a new rectangular-trapezoidal microprism cranial window to extend the depth of observation to 1.5 mm and to reduce brain injury. We validated our method with structural imaging of microglia cells in the superficial cortex and deep-brain regions. We also recorded neuronal activity from the mouse brains in awake and anesthesitized states. The results highlight the great potential of our methods for simultaneous dynamic imaging in the superficial and deep layers of mouse brains.
Quantitation of MicroRNA-155 in Human Cells by Heterogeneous Enzyme-Linked Oligonucleotide Assay Coupled with Mismatched Catalytic Hairpin Assembly Reaction
Authors: Bodulev Oleg L. , Galkin Ivan I. , Zhao Shulin , Pletyushkina Olga Y. , Sakharov Ivan Y.
Published: July 2022

In the present work, we describe the development of a chemiluminescent enzyme-linked oligonucleotide assay coupled with mismatched catalytic hairpin assembly (mCHA) amplification for the quantitative determination of microRNA-155. To improve its sensitivity, a polymerase-free mCHA reaction was applied as an isothermal amplification method. The detection limit of the proposed assay was 400 fM. In addition, the high specificity of the assay was demonstrated. The proposed assay allowed assessment of the content of microRNA-155 in human cancer lines such as HepG2, Caco2, MCF7, and HeLa. The quantitation of microRNA-155 was performed after purification of short RNAs (less than 200 nt) from cell lysates since a high matrix effect was observed without this pre-treatment. The results of the quantitative determination of the microRNA content in cells were normalized using nematode microRNA-39, the concentration of which was determined using a heterogeneous assay developed by us using a strategy identical to that of the microRNA-155 assay.
Expression and Prognostic Value of Melanoma-Associated Antigen D2 in Gliomas
Authors: Yan Jun , Li Shenyu , Lenahan Cameron , Chen Hainan , Wen Jing , Huang Qianrong , Jiang Qian , Guo Fangzhou , Deng Teng , Mo Ligen
Published: July 2022

Introduction: The melanoma-associated antigen D2 (MAGED2) is one of the melanoma-associated antigen family members. It is commonly overexpressed in a variety of malignancies. However, the mechanism and function of MAGED2 in glioma remain unknown. Methods: The MAGED2 expression level and the correlations between clinical characteristics were analyzed with the data from the CGGA and TCGA datasets. MAGED2 expression in 98 glioma tissues was measured using RT-qPCR, Western blot, and immunohistochemistry. CCK-8, colony formation, and EdU assays were used to assess the effect of MAGED2 on U251-MG cell proliferation. Flow cytometry was used to track changes in the cell cycle and cell apoptosis following plasmid transfection with CRISPRi. Results: MAGED2 was shown to be highly expressed in glioma tissues, and high MAGED2 expression predicted poor prognosis. Furthermore, MAGED2 knockdown significantly inhibited the proliferation of U251-MG cells by preventing cell cycle arrest at the G0/G1 phase and triggering apoptosis. In line with in vitro findings, the results of the xenograft experiment and immunohistochemistry also showed that MAGED2 suppression inhibited tumor development and decreased Ki-67 expression levels. Conclusions: MAGED2 may be a possible biomarker for glioma and an important prognostic factor for glioma patients.
Evaluation of Axial Compression Slenderness Limits of High and Ultra-High-Strength Steel Circular Hollow Sections
Authors: Shaker Fattouh M. F. , Zarzor Kyrolos , Gaawan Sameh , Deifalla Ahmed , Salem Mohamed
Published: July 2022

Despite significant advances in metallurgy and the potential to create high and ultra-high-strength steel, all international specifications for steel design provide little information about the limits of slenderness for high-strength steel sections (HSSs) and don’t provide anything about the design of ultra-high-strength steel sections (UHSSs). The current international steel codes such as AISC 360-16 and EC3 can be applied only to steel grades up to S690 and S460, respectively, according to their limitations. These approaches for normal-strength steel are used for HSSs and UHSSs without extensive studies to determine their accuracy in these cases. Therefore, it is one of the main objectives of this study. The behavior of high and ultra-high-strength steel circular hollow sections under axial compression load is studied in this research. Sixteen nonlinear finite element (FE) models were generated to replicate stub column tests that were experimentally tested by others in previous research. Hence, a parametric study was conducted using forty FE models developed to investigate the local buckling behavior under various slenderness ratios comprehensively. The developed models covered slenderness ratios ranging from 20 to 1226 and steel grades S460 and S1100 with yield stress equal to 460 MPa and 1152 MPa, respectively. The FE results were combined with 105 previously collected experimental results to assess the applicability of existing codified design methodologies in the Euro code and the North American codes of cold-formed circular hollow sections (CHSs). Based on the results of this study, new cross-section slenderness limits and new design equations for more efficient simple designs were presented for circular hollow sections of HSSs and UHSSs and compared with the results of experimental tests and FE models.
The Third Solar Decathlon China Buildings for Achieving Carbon Neutrality
Authors: Li Bin , Guo Weihong , Liu Xiao , Zhang Yuqing , Caneparo Luca
Published: July 2022

This research explored buildings for carbon neutrality to solve the global warming problem in the Third Solar Decathlon China (SDC). The methods were derived from subjective and objective evaluation aspects based on the competition rules. Then, the results of the concepts, technologies, and prospects of 15 buildings were output. The conclusion was summarized after a discussion as follows: (1) Solving global warming through carbon neutrality is widely required and research into this issue is required now. (2) Research methods were determined via five subjective and five objective contests with multiple sub-contests. (3) Fifteen buildings’ concepts, technologies, and prospects were determined regarding the carbon neutrality aspect. (4) A good architectural design concept was needed before building for carbon neutrality. (5) This research summarized the current development of architecture concepts and technologies in academia and industry. (6) Thirty-five kinds of active and passive technologies were determined, where PV as an active method and modular assembly as a passive method were the most used in this competition. (7) The technologies used with a low frequency, such as wind turbine, Stirling engine, hydrogen fuel cell, UHPC, PCM, and SST walls technologies, also need further attention. (8) The prospect of carbon neutrality, especially for energy production in residential buildings, may shift people’s passive acceptance of carbon neutrality to active energy production. (9) Using ANP to produce the SDC ranking may be considered for more scientific investigations to demonstrate the carbon neutrality effect. (10) The limitations will continue to be researched in the future. Finally, this research aimed to make a contribution to solving the global warming for sustainable development.
Qualitative and Quantitative Performance of Magnetic Resonance Image Compilation (MAGiC) Method: An Exploratory Analysis for Head and Neck Imaging
Authors: Konar Amaresha Shridhar , Paudyal Ramesh , Shah Akash Deelip , Fung Maggie , Banerjee Suchandrima , Dave Abhay , Lee Nancy , Hatzoglou Vaios , Shukla-Dave Amita
Published: July 2022

The present exploratory study investigates the performance of a new, rapid, synthetic MRI method for diagnostic image quality assessment and measurement of relaxometry metric values in head and neck (HN) tumors and normal-appearing masseter muscle. The multi-dynamic multi-echo (MDME) sequence was used for data acquisition, followed by synthetic image reconstruction on a 3T MRI scanner for 14 patients (3 untreated and 11 treated). The MDME enables absolute quantification of physical tissue properties, including T1 and T2, with a shorter scan time than the current state-of-the-art methods used for relaxation measurements. The vendor termed the combined package MAGnetic resonance imaging Compilation (MAGiC). In total, 48 regions of interest (ROIs) were analyzed, drawn on normal-appearing masseter muscle and tumors in the HN region. Mean T1 and T2 values obtained from normal-appearing muscle were 880 ± 52 ms and 46 ± 3 ms, respectively. Mean T1 and T2 values obtained from tumors were 1930 ± 422 ms and 77 ± 13 ms, respectively, for the untreated group, 1745 ± 410 ms and 107 ± 61 ms, for the treated group. A total of 1552 images from both synthetic MRI and conventional clinical imaging were assessed by the radiologists to provide the rating for T1w and T2w image contrasts. The synthetically generated qualitative T2w images were acceptable and comparable to conventional diagnostic images (93% acceptability rating for both). The acceptability ratings for MAGiC-generated T1w, and conventional images were 64% and 100%, respectively. The benefit of MAGiC in HN imaging is twofold, providing relaxometry maps in a clinically feasible time and the ability to generate a different combination of contrast images in a single acquisition.
Proton Beam Therapy versus Photon Radiotherapy for Stage I Non-Small Cell Lung Cancer
Authors: Suh Yang-Gun , Noh Jae Myoung , Lee Doo Yeul , Kim Tae Hyun , Bayasgalan Unurjargal , Pyo Hongryull , Moon Sung Ho
Published: July 2022

Proton beam therapy (PBT) and photon radiotherapy for stage I non-small cell lung cancer (NSCLC) were compared in terms of clinical outcomes and dosimetry. Data were obtained from patients who underwent PBT or photon radiotherapy at two institutions—the only two facilities where PBT is available in the Republic of Korea. Multivariate Cox proportional hazards models and propensity score-matched analyses were used to compare local progression-free survival (PFS) and overall survival (OS). Survival and radiation exposure to the lungs were compared in the matched population. Of 289 patients included in the analyses, 112 and 177 underwent PBT and photon radiotherapy, respectively. With a median follow-up duration of 27 months, the 2-year local PFS and OS rates were 94.0% and 83.0%, respectively. In the multivariate analysis, a biologically effective dose (BED10, using α/β = 10 Gy) of ≥125 cobalt gray equivalents was significantly associated with improved local PFS and OS. In the matched analyses, the local PFS and OS did not differ between groups. However, PBT showed significantly lower lung and heart radiation exposure in the mean dose, V5, and V10 than photon radiotherapy. PBT significantly reduced radiation exposure to the heart and lungs without worsening disease control in stage I NSCLC patients.
Systematic Identification of the RNA-Binding Protein STAU2 as a Key Regulator of Pancreatic Adenocarcinoma
Authors: Wang Xiao , Kuang Wenbin , Ding Jiayu , Li Jiaxing , Ji Minghui , Chen Weijiao , Shen Hao , Shi Zhongrui , Wang Dawei , Wang Liping , Yang Peng
Published: July 2022

Pancreatic adenocarcinoma (PAAD) is a highly aggressive cancer. RNA-binding proteins (RBPs) regulate highly dynamic post-transcriptional processes and perform very important biological functions. Although over 1900 RBPs have been identified, most are considered markers of tumor progression, and further information on their general role in PAAD is not known. Here, we report a bioinformatics analysis that identified five hub RBPs and produced a high-value prognostic model based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Among these, the prognostic signature of the double-stranded RNA binding protein Staufen double-stranded RNA (STAU2) was identified. Firstly, we found that it is a highly expressed critical regulator of PAAD associated with poor clinical outcomes. Accordingly, the knockdown of STAU2 led to a profound decrease in PAAD cell growth, migration, and invasion and induced apoptosis of PAAD cells. Furthermore, through multiple omics analyses, we identified the key target genes of STAU2: Palladin cytoskeletal associated protein (PALLD), Heterogeneous nuclear ribonucleoprotein U (HNRNPU), SERPINE1 mRNA Binding Protein 1 (SERBP1), and DEAD-box polypeptide 3, X-Linked (DDX3X). Finally, we found that a high expression level of STAU2 not only helps PAAD evade the immune response but is also related to chemotherapy drug sensitivity, which implies that STAU2 could serve as a potential target for combinatorial therapy. These findings uncovered a novel role for STAU2 in PAAD aggression and resistance, suggesting that it probably represents a novel therapeutic and drug development target.
Early Outcome, Cosmetic Result and Tolerability of an IOERT-Boost Prior to Adjuvant Whole-Breast Irradiation
Authors: Jazmati Danny , Bölke Edwin , Halfmann Kati , Tamaskovics Bálint , Ruckhäberle Eugen , Fehm Tanja , Hoffmann Jürgen , Krug David , Nestle Krämling Carolin , Corradini Stefanie , Budach Wilfried , Mohrmann Svjetlana , Haussmann Jan , Matuschek Christiane
Published: July 2022

Background/Aims: Due to its favorable dose distribution and targeting of the region at highest risk of recurrence due to direct visualization of tumor bed, intraoperative electron radiation therapy (IOERT) is used as part of a breast-conserving treatment approach. The aim of this study was to analyze tumor control and survival, as well as the toxicity profile, and cosmetic outcomes in patients irradiated with an IOERT boost for breast cancer. Materials and Methods: 139 Patients treated at our institution between January 2010 and January 2015 with a single boost dose of 10 Gy to the tumor bed during breast-conserving surgery followed by whole-breast irradiation were retrospectively analyzed. Results: 139 patients were included in this analysis. The median age was 54 years (range 28–83 years). The preferred surgical strategy was segmental resection with sentinel lymphonodectomy (66.5%) or axillary dissection (23.1%). Regarding adjuvant radiotherapy, the vast majority received 5 × 1.8 Gy to 50.4 Gy. At a median follow-up of 33.6 months, recurrence-free and overall survival were 95.5% and 94.9%, respectively. No patient developed an in-field recurrence. Seven patients (5.0%) died during the follow-up period, including two patients due to disease recurrence (non-in-field). High-grade (CTCAE > 2) perioperative adverse events attributable to IOERT included wound healing disorder (N = 1) and hematoma (N = 1). High-grade late adverse events (LENT-SOMA grade III) were reported only in one patient with fat necrosis. Low-grade late adverse events (LENT-SOMA grade I-II) included pain (18.0%), edema (10.5%), fibrosis (21%), telangiectasia (4.5%) and pigmentation change (23.0%). The mean breast retraction assessment score was 1.66 (0–6). Both patients and specialists rated the cosmetic result “excellent/good” in 84.8% and 87.9%, respectively. Conclusion: Our study reports favorable data on the cosmetic outcome as well as the acute and early long-term tolerability for patients treated with an IOERT boost. Our oncologic control rates are comparable to the previous literature. However, prospective investigations on the role of IOERT in comparison to other boost procedures would be desirable.
The Role of PSMA PET/CT in the Primary Diagnosis and Follow-Up of Prostate Cancer—A Practical Clinical Review
Authors: Lisney Anna Rebecca , Leitsmann Conrad , Strauß Arne , Meller Birgit , Bucerius Jan Alexander , Sahlmann Carsten-Oliver
Published: July 2022

The importance of PSMA PET/CT in both primary diagnostics and prostate cancer recurrence has grown steadily since its introduction more than a decade ago. Over the past years, a vast amount of data have been published on the diagnostic accuracy and the impact of PSMA PET/CT on patient management. Nevertheless, a large heterogeneity between studies has made reaching a consensus difficult; this review aims to provide a comprehensive clinical review of the available scientific literature, covering the currently known data on physiological and pathological PSMA expression, influencing factors, the differences and pitfalls of various tracers, as well as the clinical implications in initial TNM-staging and in the situation of biochemical recurrence. This review has the objective of providing a practical clinical overview of the advantages and disadvantages of the examination in various clinical situations and the body of knowledge available, as well as open questions still requiring further research.
Bone-Targeted Agents and Metastasis Prevention
Authors: Coleman Robert
Published: July 2022

The use of bone-targeted treatments has transformed the clinical care of many patients with metastatic breast cancer. In addition, due to the profound effects of bisphosphonates and denosumab on bone physiology and the bone microenvironment, the potential of bone-targeted agents to modify the process of metastasis has been studied extensively. Many adjuvant trials with bisphosphonates in early breast cancer have been performed. Variable outcomes in terms of disease recurrence have been reported, with any treatment benefits apparently influenced by the age and menopausal status of the patients. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted a meta-analysis of individual patient data from all available randomised trials to investigate this observation further. This meta-analysis failed to show any benefits of adjuvant bisphosphonates in premenopausal women, but highly significant improvements in bone recurrence (RR = 0.72; 95% CI 0.60–0.86, 2p = 0.0002) and breast cancer mortality (RR = 0.82; 95% CI 0.73–0.93, 2p = 0.002) were seen in the 11,767 postmenopausal women included in the meta-analysis. As a result, clinical guidelines recommend the incorporation of adjuvant bisphosphonates that inhibit osteoclast activity into routine clinical care. Denosumab, which has similar effects on bone cell physiology, appears not to consistently influence disease outcomes, perhaps suggesting that it is the “off target” effects of bisphosphonates on immune function and the biological processes involved in metastasis that are important. Predictive biomarkers beyond menopause are being sought and assessment of the transcription factor MAF (mesenchymal aponeurotic fibrosarcoma gene) appears to identify patients able to benefit from the addition of a bisphosphonate to standard adjuvant anticancer therapies.
Novel Dicarboximide BK124.1 Breaks Multidrug Resistance and Shows Anticancer Efficacy in Chronic Myeloid Leukemia Preclinical Models and Patients’ CD34+/CD38− Leukemia Stem Cells
Authors: Stukan Iga , Gryzik Marek , Hoser Grażyna , Want Andrew , Grabowska-Pyrzewicz Wioleta , Zdioruk Mikolaj , Napiórkowska Mariola , Cieślak Marcin , Królewska-Golińska Karolina , Nawrot Barbara , Basak Grzegorz , Wojda Urszula
Published: July 2022

The search is ongoing for new anticancer therapeutics that would overcome resistance to chemotherapy. This includes chronic myeloid leukemia, particularly suitable for the studies of novel anticancer compounds due to its homogenous and well-known genetic background. Here we show anticancer efficacy of novel dicarboximide denoted BK124.1 (C31H37ClN2O4) in a mouse CML xenograft model and in vitro in two types of chemoresistant CML cells: MDR1 blasts and in CD34+ patients’ stem cells (N = 8) using immunoblotting and flow cytometry. Intraperitoneal administration of BK124.1 showed anti-CML efficacy in the xenograft mouse model (N = 6) comparable to the commonly used imatinib and hydroxyurea. In K562 blasts, BK124.1 decreased the protein levels of BCR-ABL1 kinase and its downstream effectors, resulting in G2/M cell cycle arrest and apoptosis associated with FOXO3a/p21waf1/cip1 upregulation in the nucleus. Additionally, BK124.1 evoked massive apoptosis in multidrug resistant K562-MDR1 cells (IC50 = 2.16 μM), in CD34+ cells from CML patients (IC50 = 1.5 µM), and in the CD34+/CD38− subpopulation consisting of rare, drug-resistant cancer initiating stem cells. Given the advantages of BK124.1 as a potential chemotherapeutic and its unique ability to overcome BCR-ABL1 dependent and independent multidrug resistance mechanisms, future development of BK124.1 could offer a cure for CML and other cancers resistant to present drugs.
The Organic Bromide Sources Adjusting the Shape and Band Structures of BiOBr Nanosheets for Enhanced Photodegradation Performances of BPA
Authors: Xia Donghao , Sun Kaiyang , Zeng Youwei , Wang Lulu , Zhang Yi , Shen Jie , Wu Zhaohui , Feng Wenhui
Published: July 2022

Bismuth oxybromide (BiOBr) nanosheets were prepared by employing organic bromide sources. In the presence of organic bromide sources, the effects of different conditions on the band structure, shape, size, and light responses of BiOBr nanosheets were examined. The reaction conditions, including different types of organic bromide sources, solvent, concentration, temperature, and time, were examined regarding the formation of BiOBr nanosheets. Then, the photocatalytic performances of different BiOBr nanosheets were also examined. Especially, the BiOBr nanosheets obtained from the addition of over 2 mmol of tetramethyl ammonium bromide (TMAB) in mannitol or EG at a higher temperature and longer reaction time showed superior photocatalytic activity. The enhanced photocatalytic performance of bisphenol A over these BiOBr nanosheets was achieved within 50 min due to efficient charge transfer and separation.
Recent Advances of Green Catalytic System I2/DMSO in C–C and C–Heteroatom Bonds Formation
Authors: Wang Jia-Qi , Zuo Zhen-Yu , He Wei
Published: July 2022

Developing a green, practical and efficient method for the formation of C–C and C–Heteroatom bonds is an important topic in modern organic synthetic chemistry. In recent years, the I2/DMSO catalytic system has attracted wide attention because of its green, high efficiency, atomic economy, low cost, mild reaction conditions and it is environment-friendly, which is more in line with the requirements of sustainable chemistry. Heteroatom-containing compounds have shown lots of important applications in pharmaceutical synthesis, agrochemicals, material chemistry and organic dyes. At present, the I2/DMSO catalytic system has been successfully applied to the synthesis of various heteroatom-containing compounds. The C–C and C–Heteroatom bonds have been formed efficiently, which has been proved to be a green and mild catalytic system. In this review, the research achievements of the I2/DMSO catalytic system in the formation of C–C and C–Heteroatom bonds from 2015 to date are described, and the research area is prospected. This review attempts to reveal the general law of iodine catalysis and lay a foundation for the design of new reactions.
Transcriptional and Epigenetic Consequences of DMSO Treatment on HepaRG Cells
Authors: Dubois-Pot-Schneider Hélène , Aninat Caroline , Kattler Kathrin , Fekir Karim , Jarnouen Kathleen , Cerec Virginie , Glaise Denise , Salhab Abdulrahman , Gasparoni Gilles , Takashi Kubo , Ishida Seiichi , Walter Jörn , Corlu Anne
Published: July 2022

Dimethyl sulfoxide (DMSO) is used to sustain or favor hepatocyte differentiation in vitro. Thus, DMSO is used in the differentiation protocol of the HepaRG cells that present the closest drug-metabolizing enzyme activities to primary human hepatocytes in culture. The aim of our study is to clarify its influence on liver-specific gene expression. For that purpose, we performed a large-scale analysis (gene expression and histone modification) to determine the global role of DMSO exposure during the differentiation process of the HepaRG cells. The addition of DMSO drives the upregulation of genes mainly regulated by PXR and PPARα whereas genes not affected by this addition are regulated by HNF1α, HNF4α, and PPARα. DMSO-differentiated-HepaRG cells show a differential expression for genes regulated by histone acetylation, while differentiated-HepaRG cells without DMSO show gene signatures associated with histone deacetylases. In addition, we observed an interplay between cytoskeleton organization and EMC remodeling with hepatocyte maturation.
Vertebrate Cell Differentiation, Evolution, and Diseases: The Vertebrate-Specific Developmental Potential Guardians VENTX/NANOG and POU5/OCT4 Enter the Stage
Authors: Ducos Bertrand , Bensimon David , Scerbo Pierluigi
Published: July 2022

During vertebrate development, embryonic cells pass through a continuum of transitory pluripotent states that precede multi-lineage commitment and morphogenesis. Such states are referred to as “refractory/naïve” and “competent/formative” pluripotency. The molecular mechanisms maintaining refractory pluripotency or driving the transition to competent pluripotency, as well as the cues regulating multi-lineage commitment, are evolutionarily conserved. Vertebrate-specific “Developmental Potential Guardians” (vsDPGs; i.e., VENTX/NANOG, POU5/OCT4), together with MEK1 (MAP2K1), coordinate the pluripotency continuum, competence for multi-lineage commitment and morphogenesis in vivo. During neurulation, vsDPGs empower ectodermal cells of the neuro-epithelial border (NEB) with multipotency and ectomesenchyme potential through an “endogenous reprogramming” process, giving rise to the neural crest cells (NCCs). Furthermore, vsDPGs are expressed in undifferentiated-bipotent neuro-mesodermal progenitor cells (NMPs), which participate in posterior axis elongation and growth. Finally, vsDPGs are involved in carcinogenesis, whereby they confer selective advantage to cancer stem cells (CSCs) and therapeutic resistance. Intriguingly, the heterogenous distribution of vsDPGs in these cell types impact on cellular potential and features. Here, we summarize the findings about the role of vsDPGs during vertebrate development and their selective advantage in evolution. Our aim to present a holistic view regarding vsDPGs as facilitators of both cell plasticity/adaptability and morphological innovation/variation. Moreover, vsDPGs may also be at the heart of carcinogenesis by allowing malignant cells to escape from physiological constraints and surveillance mechanisms.
Mitigation of Memory Impairment with Fermented Fucoidan and λ-Carrageenan Supplementation through Modulating the Gut Microbiota and Their Metagenome Function in Hippocampal Amyloid-β Infused Rats
Authors: Zhang Ting , Wu Xuangao , Yuan Heng , Huang Shaokai , Park Sunmin
Published: July 2022

Attenuating acetylcholinesterase and insulin/insulin-like growth factor-1 signaling in the hippocampus is associated with Alzheimer’s disease (AD) development. Fucoidan and carrageenan are brown and red algae, respectively, with potent antibacterial, anti-inflammatory, antioxidant and antiviral activities. This study examined how low-molecular-weight (MW) and high-MW fucoidan and λ-carrageenan would improve memory impairment in Alzheimer’s disease-induced rats caused by an infusion of toxic amyloid-β(Aβ). Fucoidan and λ-carrageenan were dissected into low-MW by Luteolibacter algae and Pseudoalteromonas carrageenovora. Rats receiving an Aβ(25–35) infusion in the CA1 region of the hippocampus were fed dextrin (AD-Con), 1% high-MW fucoidan (AD-F-H), 1% low-MW fucoidan (AD-F-L), 1% high-MW λ-carrageenan (AD-C-H), and 1% low-MW λ-carrageenan (AD-C-L) for six weeks. Rats to receive saline infusion (Normal-Con) had an AD-Con diet. The AD-F-L group showed an improved memory function, which manifested as an enhanced Y-maze spontaneous alternation test, water maze, and passive avoidance tests, similar to the Normal-Con group. AD-F-L also potentiated hippocampal insulin signaling and increased the expression of ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) in the hippocampus. AD-C-L improved the memory function mainly by increasing the BDNF content. AD-F-H and AD-C-H did not improve the memory function. Compared to AD-Con, the ascending order of AD-C-H, AD-F-H, AD-C-L, and AD-F-L increased insulin signaling by enhancing the pSTAT3→pAkt→pGSK-3β pathway. AD-F-L improved glucose tolerance the most. Compared to AD-CON, the AD-F-L treatment increased the serum acetate concentrations and compensated for the defect of cerebral glucose metabolism. AD-Con increased Clostridium, Terrisporobacter and Sporofaciens compared to Normal-Con, and AD-F-L and AD-C-L increased Akkermentia. In conclusion, AD-F-L and AD-C-L alleviated the memory function in the rats with induced AD symptoms by modulating.
Impact of In Vitro Long-Term Low-Level DEHP Exposure on Gene Expression Profile in Human Granulosa Cells
Authors: Nenadov Dragana Samardzija , Pogrmic-Majkic Kristina , Tesic Biljana , Kokai Dunja , Fa Nedeljkovic Svetlana , Stanic Bojana , Andric Nebojsa
Published: July 2022

Here, we applied a model of long-term exposure of human granulosa cells to low environmentally relevant levels of di(2-ethylhexyl) phthalate (DEHP). This approach provides more relevant data regarding the impact of DEHP on the function of human granulosa cells. The immortalized human granulosa cells HGrC1 were exposed to 50 nM and 250 nM DEHP for four weeks. The cells were collected every week to analyze the basal granulosa cells’ functions. A portion of the DEHP-exposed cells was stimulated with forskolin (FOR) for 48 h. Steroidogenesis was investigated using ELISA, whereas DNBQ sequencing and RT-qPCR were used to analyze gene expression. The results show that steroidogenesis was not affected by DEHP exposure. RNAsequencing shows that DEHP caused week- and concentration-specific changes in various genes and functions in HGrC1. Sulfotransferase family 1A member 3 (SULT1A3) and 4 (SULT1A4), which are involved in catecholamine metabolism, were the most prominent genes affected by DEHP under both the basal and FOR-stimulated conditions in all four weeks of exposure. This study showed, for the first time, that SULT1A3 and SULT1A4 are expressed in human granulosa cells, are regulated by FOR, and are affected by low-level DEHP exposure. These data provide new insight into the relationship between DEHP, SULT1A3, and SULT1A4 in human granulosa cells.
The Assessment of Fatigue in Rheumatoid Arthritis Patients and Its Impact on Their Quality of Life
Authors: Dar Waseem R. , Mir Irfan A. , Siddiq Summra , Nadeem Mir , Singh Gurmeet
Published: July 2022

Introduction: Rheumatoid arthritis (RA) is a common autoimmune illness that manifests mostly as chronic, symmetric, and progressive polyarthritis with a global frequency of 0.3–1.0%. RA is a disease that affects people all over the world. In India, the prevalence is estimated to be 0.7%, with around 10 million persons suffering from RA. Most people with rheumatoid arthritis experience fatigue on most days, with over 70% experiencing symptoms similar to chronic fatigue syndrome. Patients rate fatigue as a top priority and believe this unmanageable symptom is ignored by clinicians; a systematic review shows the biological agents for RA inflammation have only a small effect on fatigue. Fatigue predicts and reduces the quality of life, and it is as difficult to cope with as pain. Physicians have traditionally concentrated on the inflammatory aspects of the illness (e.g., synovitis), whereas RA patients have prioritized pain, exhaustion, sleep difficulties, and other quality-of-life issues. Aims and Objectives: The basic aim of the study was to access the incidence of fatigue in rheumatoid arthritis and evaluate its impact on the quality of life in these patients using the MAF scale (multidimensional assessment of fatigue) after prior permission for the first time in an Asian population. Results: A total of 140 subjects and 100 controls were included in the study. Age was closely matched between the study subjects and controls. Among study subjects with the disease, 94 (67%) had a disease duration ≤ 5 years, 26 (19%) had a disease duration between 6–10 years, 10 (7%) had a duration of 11–15 years and 10 (7%) had >10 years disease duration. Among the sample, 31 (25%) study subjects had a DAS score ≤ 4.0, 63 (50%) study subjects had a DAS score (disease activity score) between 4.01 and 6.0, and in the remaining 31 (25%) study subjects, the DAS score was >6.0. The mean DAS score among study subjects was 4.96, and the study subjects had a mean activity of daily living (ADL) score of 11.64; controls had a mean score of 2.42 with a statistically significant p-value. The global fatigue index was higher in study subjects, with a mean of 33.16 in contrast with a mean of 14.41 in the controls with a significant p-value. Conclusion: Our study fatigue was a persistent problem, despite treatment. The median level of fatigue experienced by study subjects with RA was high. Therefore, as persistent fatigue is associated with functional loss, fatigue in RA remains an ‘unmet need’ and continues to be ignored by clinicians.