bluuebunny/crossref_metadata_2025 huggingface dataset:
Seed Quality of Lablab Bean (Lablab purpureus) as Influenced by Seed Maturity and Drying Methods
Authors: Hanapiah Nurul Fatin Hanani , Sinniah Uma Rani , Yusoff Martini Mohammad
Published: January 2022

The lablab bean or ‘Kacang sepat’ is a food crop originating from India and is commonly found in tropical areas such as Indonesia, Thailand and the Philippines due to its adaptability. However, in Malaysia, lablab is grown as a backyard crop, and the area cultivated with this crop is still limited. Lablab has the potential to become a commercial vegetable crop in Malaysia due to its high protein content (18–25%). Therefore, to increase lablab cultivation, good quality seeds are a prerequisite. A key factor in the production of quality seeds is the ideal harvest time of the pods during seed development and maturation and based on identifiable characteristics. The first part of this study was conducted to assess the physical characteristics of lablab pods and seeds of the cultivar Highworth (MDI 12842). Plants were grown using standard cultural practices. Pods and seeds were collected at ten different maturity stages (5, 10, 15, 20, 25, 30, 35, 40, 45, and 50 days after anthesis (DAA)). Pods and seeds showed a significant difference in size and colour at different maturity stages. Seeds harvested at 20 DAA had maximum pod and seed size. The seeds attained physiological maturity (PM) at 30 DAA when the pod colour is light reddish brown and, after being subjected to sun and oven drying, gave maximum germination percentages of 89% and 91%, respectively, while fresh seeds had only 78% germination. Results indicated that the germination percentage of lablab improved, regardless of the drying method used. Therefore, the lablab bean pod colour is a suitable indicator to be used as an easy method for the identification of the best time for pod harvesting for seed production.
Synergistic Anti-Inflammatory Effects of Lipophilic Grape Seed Proanthocyanidin and Camellia Oil Combination in LPS-Stimulated RAW264.7 Cells
Authors: Zhang Linli , Chen Juan , Liang Ruihong , Liu Chengmei , Chen Mingshun , Chen Jun
Published: January 2022

Combination drug therapy has become an effective strategy to control inflammation. Lipophilic grape seed proanthocyanidin (LGSP) and camellia oil (CO) have been independently investigated to show anti-inflammatory effects, but their synergistic anti-inflammatory effects are unknown. The aim of this study was to investigate the synergistic anti-inflammatory effects of LGSP and CO. The anti-inflammatory activity of LGSP and CO individual or in combination on RAW264.7 cells was detected by MTT assay, Griess reagent, RT-PCR, 2′,7′-dichlorfluoroescein diacetate and Western blot analysis. The combined treatment of LGSP with CO (20 μg/mL and 1 mg/mL) synergistically suppressed the production of NO, TNF-α, IL-6 and ROS. Further studies showed that the synergistic effect was attributed to their suppression of the activation of NF-κB and MAPK signaling pathways. Overall, our findings demonstrate the potential synergistic effect between LGSP and CO in LPS-induced inflammation.
Error Characteristics of GNSS Derived TEC
Authors: Ma Guanyi , Fan Jiangtao , Wan Qingtao , Li Jinghua
Published: January 2022

The Global Navigation Satellite System (GNSS) allows for the cost-effective estimation of the ionospheric total electron content (TEC). However, research on error characteristics of the derived TEC is scarce, which provides insights into the quality of the GNSS ionospheric observation. We investigate characteristics of errors in the derived TEC with data from ~260 GNSS dual-frequency receivers of the Crustal Movement Observation Network of China (CMONOC). The slant TEC is calculated from carrier phase measurements and the vertical TEC over China is fitted with a spatial resolution of 1° by 1° in latitude and longitude in four seasons of 2014. It is found that the errors of both the slant TEC and the derived TEC follow Laplace distribution rather than Gaussian distribution in all seasons. The errors of the slant TEC have sharper peaks than those of the derived TEC. The Mean Absolute Error (MAE) and Root Mean Square Error (RMSE) of the slant TEC are typically 0.04 TECU and 0.2 TECU, while the MAE and RMSE of the fitting residuals for the derived TEC are typically 1 TECU and under 2 TECU, respectively. Both MAEs and RMSEs of the derived TEC have the largest value in spring and the smallest value in summer, while the seasonal dependence is only observed in RMSE of the slant TEC.
Marine Air Pollution in Israel: Extent, Proposed Mitigation Targets, Benefits and Feasibility
Authors: Razy-Yanuv Eyal , Barak Yogev , Noam Oran , Madar Daniel
Published: January 2022

Marine air pollution is a major contributor to seaports and coastal air pollution, and Israel has yet to seriously confront this issue. This study aimed to update previous marine air pollution estimations in Israel’s two major ports: Haifa and Ashdod. The objectives were to examine technical and regulatory measures to address the problem, to propose mitigation targets and to estimate their potential benefits. Based on a model of emission-calculations that relies on an updated ship-inventory data as well as real-time ships’ location and movement tools, the combined marine NOx, SOx and PM2.5 annual emissions in these ports were found to be 18,415, 15,128 and 1453 tons, respectively. These values are considerably higher than previous estimates, are comparable to the constant pollution emitted at ground level from a 1000-MW coal powered city power plant and are 3–20 times higher than the industrial and land transportation sectors in these cities. Relatively high nickel concentration in PM was found in Israel only relatively adjacent to the Haifa and Ashdod ports. Since high nickel concentration in PM is today mainly associated with marine air pollution, this finding supports the hypothesis that marine air pollution worsens the air quality in these cities. SOx and PM2.5 emissions can be reduced by 78% and 27%, respectively, if Israel enforces the revised International Convention for the Prevention of Pollution from Ships (MARPOL) Annex VI regulations in its territorial waters. While the latter step can achieve external benefits of NIS 518.4 million/year (EUR 132 million/year), additional mitigation actions and local regulations are suggested, focusing on NOx emissions but also on other pollutant criteria. Such actions can achieve further benefits of NIS 274.3 million/year (EUR 70 million/year). Achieving the suggested targets is challenging yet attainable, and their potential benefits will probably outweigh their costs.
Central Effects of the Designer Drug Mephedrone in Mice—Basic Studies
Authors: Serefko Anna , Bielecka-Papierz Gabriela , Talarek Sylwia , Szopa Aleksandra , Skałecki Piotr , Szewczyk Bernadeta , Radziwoń-Zaleska Maria , Poleszak Ewa
Published: January 2022

Mephedrone belongs to the “party drugs” thanks to its psychostimulant effects, similar to the ones observed after amphetamines. Though mephedrone is used worldwide by humans and in laboratory animals, not all properties of this drug have been discovered yet. Therefore, the main aim of this study was to expand the knowledge about mephedrone’s activity in living organisms. A set of behavioral tests (i.e., measurement of the spontaneous locomotor activity, rotarod, chimney, elevated plus maze with its modification, novel object recognition, and pentylenetetrazol seizure tests) were carried out in male albino Swiss mice. Different dose ranges of mephedrone (0.05–5 mg/kg) were administered. We demonstrated that mephedrone at a dose of 5 mg/kg rapidly increased the spontaneous locomotor activity of the tested mice and its repeated administration led to the development of tolerance to these effects. Mephedrone showed the anxiolytic-like potential and improved spatial memory, but it did not affect recognition memory. Moreover, the drug seemed not to have any anticonvulsant or proconvulsant activity. In conclusion, mephedrone induces many central effects. It easily crosses the blood-brain barrier and peaks in the brain quickly after exposure. Our experiment on inducing a hyperlocomotion effect showed that mephedrone‘s effects are transient and lasted for a relatively short time.
A Peek into Pandora’s Box: COVID-19 and Neurodegeneration
Authors: Chandra Abhishek , Johri Ashu
Published: January 2022

Ever since it was first reported in Wuhan, China, the coronavirus-induced disease of 2019 (COVID-19) has become an enigma of sorts with ever expanding reports of direct and indirect effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on almost all the vital organ systems. Along with inciting acute pulmonary complications, the virus attacks the cardiac, renal, hepatic, and gastrointestinal systems as well as the central nervous system (CNS). The person-to-person variability in susceptibility of individuals to disease severity still remains a puzzle, although the comorbidities and the age/gender of a person are believed to play a key role. SARS-CoV-2 needs angiotensin-converting enzyme 2 (ACE2) receptor for its infectivity, and the association between SARS-CoV-2 and ACE2 leads to a decline in ACE2 activity and its neuroprotective effects. Acute respiratory distress may also induce hypoxia, leading to increased oxidative stress and neurodegeneration. Infection of the neurons along with peripheral leukocytes’ activation results in proinflammatory cytokine release, rendering the brain more susceptible to neurodegenerative changes. Due to the advancement in molecular biology techniques and vaccine development programs, the world now has hope to relatively quickly study and combat the deadly virus. On the other side, however, the virus seems to be still evolving with new variants being discovered periodically. In keeping up with the pace of this virus, there has been an avalanche of studies. This review provides an update on the recent progress in adjudicating the CNS-related mechanisms of SARS-CoV-2 infection and its potential to incite or accelerate neurodegeneration in surviving patients. Current as well as emerging therapeutic opportunities and biomarker development are highlighted.
Nonequivalent After-Effects of Alternating Current Stimulation on Motor Cortex Oscillation and Inhibition: Simulation and Experimental Study
Authors: Suzuki Makoto , Tanaka Satoshi , Gomez-Tames Jose , Okabe Takuhiro , Cho Kilchoon , Iso Naoki , Hirata Akimasa
Published: January 2022

The effects of transcranial alternating current stimulation (tACS) frequency on brain oscillations and cortical excitability are still controversial. Therefore, this study investigated how different tACS frequencies differentially modulate cortical oscillation and inhibition. To do so, we first determined the optimal positioning of tACS electrodes through an electric field simulation constructed from magnetic resonance images. Seven electrode configurations were tested on the electric field of the precentral gyrus (hand motor area). We determined that the Cz-CP1 configuration was optimal, as it resulted in higher electric field values and minimized the intra-individual differences in the electric field. Therefore, tACS was delivered to the hand motor area through this arrangement at a fixed frequency of 10 Hz (alpha-tACS) or 20 Hz (beta-tACS) with a peak-to-peak amplitude of 0.6 mA for 20 min. We found that alpha- and beta-tACS resulted in larger alpha and beta oscillations, respectively, compared with the oscillations observed after sham-tACS. In addition, alpha- and beta-tACS decreased the amplitudes of conditioned motor evoked potentials and increased alpha and beta activity, respectively. Correspondingly, alpha- and beta-tACSs enhanced cortical inhibition. These results show that tACS frequency differentially affects motor cortex oscillation and inhibition.
Olfactory Impairment in Parkinson’s Disease Patients with Tremor Dominant Subtype Compared to Those with Akinetic Rigid Dominant Subtype: A Pilot Study
Authors: Solla Paolo , Masala Carla , Ercoli Tommaso , Orofino Gianni , Loy Francesco , Pinna Ilenia , Fadda Laura , Defazio Giovanni
Published: January 2022

Background: Parkinson’s disease (PD) may present different motor subtypes depending on the predominant symptoms (tremor or rigidity/bradykinesia). Slower disease progression and cognitive decline were observed in tremor-dominant (TD) patients compared to those with the akinetic-rigid dominant (ARD) subtype. Although olfactory dysfunctions are well-known disturbances in PD patients, correlations among PD different subtypes and olfactory impairment were not clearly studied. Thus, we investigated the possible olfactory impairment in PD patients with TD and ARD subtypes as compared to healthy controls. Methods: A sample of 132 participants were enrolled: 62 PD patients divided into ARD (n = 42) and TD (n = 20) subgroups using tremor/rigidity ratio, and 70 healthy controls. Olfactory function was assessed with the Sniffin’ Sticks Test. Results: Odor threshold was significantly lower in the ARD than in the TD subtype, while odor identification, discrimination scores, and their sum (TDI score) were not significantly different. On multivariate linear regression analysis, the tremor/rigidity ratio was a significant predictor of odor threshold. Conclusions: Our pilot study showed a significant olfactory dysfunction in PD patients with the ARD subtype. This evidence confirms the biological relevance of clinical subgroups in PD patients, suggesting the existence of a different pathophysiological mechanism between the ARD and TD clinical subtypes.
Narrative Review of the Post-Operative Management of Prostate Cancer Patients: Is It Really the End of Adjuvant Radiotherapy?
Authors: Bourbonne Vincent , Pradier Olivier , Schick Ulrike
Published: January 2022

Despite three randomized trials indicating a significant reduction in biochemical recurrence (BCR) in high-risk patients, adjuvant radiotherapy (aRT) was rarely performed, even in patients harboring high-risk features. aRT is associated with a higher risk of urinary incontinence and is often criticized for the lack of patient selection criteria. With a BCR rate reaching 30–70% in high-risk patients, a consensus between urologists and radiation oncologists was needed, leading to three different randomized trials challenging aRT with early salvage radiotherapy (eSRT). In these three different randomized trials with event-free survival as the primary outcome and a planned meta-analysis, eSRT appeared as non-inferior to aRT, answering, for some, this never-ending question. For many, however, the debate persists; these results raised several questions among urologists and radiation oncologists. BCR is thought to be a surrogate for clinically meaningful endpoints such as overall survival and cancer-specific survival but may be poorly efficient in comparison with metastasis-free survival. Imaging of rising prostate-specific antigen (PSA), post-operative persistent PSA and BCR was revolutionized by the broader use of MRI and nuclear imaging such as PET-PSMA; these imaging modalities were not analyzed in the previous randomized trials. A sub-group of very high-risk patients could possibly benefit from an adjuvant radiotherapy; but their usual risk factors such as high Gleason score or invaded surgical margins mean they are unable to be selected. More precise biomarkers of early BCR or even metastatic-relapse were developed in this setting and could be useful for the patients’ stratification. In this review, we insist on the need for multidisciplinary discussions to fully comprehend the individual characteristics of each patient and propose the best treatment strategy for every patient.
Incident Colorectal Cancer in Inflammatory Bowel Disease
Authors: Neri Benedetto , Scribano Maria Lia , Armuzzi Alessandro , Castiglione Fabiana , D’Incà Renata , Orlando Ambrogio , Festa Stefano , Riegler Gabriele , Fries Walter , Meucci Gianmichele , Alvisi Patrizia , Mocciaro Filippo , Papi Claudio , Mossa Michelangela , Sena Giorgia , Guidi Luisa , Testa Anna , Renna Sara , Frankovic Iris , Viola Anna , Patturelli Marta , Chiaramonte Carlo , Biancone Livia ,   on behalf of IG-IBD (Italian Group for the Study of Inflammatory Bowel Disease)
Published: January 2022

Colorectal cancer (CRC) risk is increased in Inflammatory Bowel Disease (IBD) and surveillance needs to be tailored according to individual risk. The open issues include the role of the characteristics of IBD and CRC in determining the long-term outcome. These issues were assessed in our multicenter study, including a cohort of 56 IBD patients with incident CRC. The clinical and histopathological features of IBD patients and of CRC were recorded. Incident CRC in IBD occurred at a young age (≤40 years) in 25% of patients (median age 55.5 (22–76)). Mucinous signet-ring carcinoma was detected in 6 out of the 56 (10.7%) patients, including 4 with Ulcerative Colitis (UC) and 2 with Crohn’s disease (CD). CRC was more frequently diagnosed by colonoscopy in UC (85.4% vs. 50%; p = 0.01) and by imaging in Crohn’s Disease CD (5.8% vs. 31.8%; p = 0.02). At onset, CRC-related symptoms occurred in 29 (51.9%) IBD patients. The time interval from the diagnosis of IBD to CRC was shorter in UC and CD patients with >40 years (p = 0.002; p = 0.01). CRC-related death occurred in 10 (29.4%) UC and in 6 (27.2%) CD patients (p = 0.89), with a short time interval from CRC to death (UC vs. CD: 6.5 (1–68) vs. 14.5 (8–40); p = 0.85; IBD: 12 months (1–68)). CRC occurring at a young age, a short time interval from the diagnosis of IBD to CRC-related death in the elderly, CRC-symptoms often mimicking IBD relapse and the observed high mortality rate may support the need of closer surveillance intervals in subgroups of patients.
The Application of Metabolomics in Recent Colorectal Cancer Studies: A State-of-the-Art Review
Authors: Gold Andrew , Choueiry Fouad , Jin Ning , Mo Xiaokui , Zhu Jiangjiang
Published: January 2022

Colorectal cancer (CRC) is a highly prevalent disease with poor prognostic outcomes if not diagnosed in early stages. Current diagnosis techniques are either highly invasive or lack sufficient sensitivity. Thus, identifying diagnostic biomarkers of CRC with high sensitivity and specificity is desirable. Metabolomics represents an analytical profiling technique with great promise in identifying such biomarkers and typically represents a close tie with the phenotype of a specific disease. We thus conducted a systematic review of studies reported from January 2012 to July 2021 relating to the detection of CRC biomarkers through metabolomics to provide a collection of knowledge for future diagnostic development. We identified thirty-seven metabolomics studies characterizing CRC, many of which provided metabolites/metabolic profile-based diagnostic models with high sensitivity and specificity. These studies demonstrated that a great number of metabolites can be differentially regulated in CRC patients compared to healthy controls, adenomatous polyps, or across stages of CRC. Among these metabolite biomarkers, especially dysregulated were certain amino acids, fatty acids, and lysophosphatidylcholines. Additionally, we discussed the contribution of the gut bacterial population to pathogenesis of CRC through their modulation to fecal metabolite pools and summarized the established links in the literature between certain microbial genera and altered metabolite levels in CRC patients. Taken together, we conclude that metabolomics presents itself as a promising and effective method of CRC biomarker detection.
MicroRNAs: Emerging Regulators of Metastatic Bone Disease in Breast Cancer
Authors: Haider Marie-Therese , Smit Daniel J. , Taipaleenmäki Hanna
Published: January 2022

Bone metastasis is a frequent complication in patients with advanced breast cancer. Once in the bone, cancer cells disrupt the tightly regulated cellular balance within the bone microenvironment, leading to excessive bone destruction and further tumor growth. Physiological and pathological interactions in the bone marrow are mediated by cell–cell contacts and secreted molecules that include soluble proteins as well as RNA molecules. MicroRNAs (miRNAs) are short non-coding RNAs that post-transcriptionally interfere with their target messenger RNA (mRNA) and subsequently reduce protein abundance. Since their discovery, miRNAs have been identified as critical regulators of physiological and pathological processes, including breast cancer and associated metastatic bone disease. Depending on their targets, miRNAs can exhibit pro-tumorigenic or anti-tumorigenic functions and serve as diagnostic and prognostic biomarkers. These properties have encouraged pre-clinical and clinical development programs to investigate miRNAs as biomarkers and therapeutic targets in various diseases, including metastatic cancers. In this review, we discuss the role of miRNAs in metastatic bone disease with a focus on breast cancer and the bone microenvironment and elaborate on their potential use for diagnostic and therapeutic purposes in metastatic bone disease and beyond.
Platelet and Cancer-Cell Interactions Modulate Cancer-Associated Thrombosis Risk in Different Cancer Types
Authors: Palacios-Acedo Ana-Luisa , Langiu Mélanie , Crescence Lydie , Mège Diane , Dubois Christophe , Panicot-Dubois Laurence
Published: January 2022

The first cause of death in cancer patients, after tumoral progression itself, is thrombo-embolic disease. This cancer-associated hypercoagulability state is known as Trousseau’s syndrome, and the risk for developing thrombotic events differs according to cancer type and stage, as well as within patients. Massive platelet activation by tumor cells is the key mediator of thrombus formation in Trousseau’s syndrome. In this literature review, we aimed to compare the interactions between cancer cells and platelets in three different cancer types, with low, medium and high thrombotic risk. We chose oral squamous cell carcinoma for the low-thrombotic-risk, colorectal adenocarcinoma for the medium-thrombotic-risk, and pancreatic carcinoma for the high-thrombotic-risk cancer type. We showcase that understanding these interactions is of the highest importance to find new biomarkers and therapeutic targets for cancer-associated thrombosis.
Exosomal Proteins and Lipids as Potential Biomarkers for Lung Cancer Diagnosis, Prognosis, and Treatment
Authors: Hsu Ming-Tsung , Wang Yu-Ke , Tseng Yufeng Jane
Published: January 2022

Exosomes participate in cell–cell communication by transferring molecular components between cells. Previous studies have shown that exosomal molecules derived from cancer cells and liquid biopsies can serve as biomarkers for cancer diagnosis and prognosis. The exploration of the molecules transferred by lung cancer-derived exosomes can advance the understanding of exosome-mediated signaling pathways and mechanisms. However, the molecular characterization and functional indications of exosomal proteins and lipids have not been comprehensively organized. This review thoroughly collected data concerning exosomal proteins and lipids from various lung cancer samples, including cancer cell lines and cancer patients. As potential diagnostic and prognostic biomarkers, exosomal proteins and lipids are available for clinical use in lung cancer. Potential therapeutic targets are mentioned for the future development of lung cancer therapy. Molecular functions implying their possible roles in exosome-mediated signaling are also discussed. Finally, we emphasized the importance and value of lung cancer stem cell-derived exosomes in lung cancer therapy. In summary, this review presents a comprehensive description of the protein and lipid composition and function of lung cancer-derived exosomes for lung cancer diagnosis, prognosis, and treatment.
Comparative Analysis of the APOL1 Variants in the Genetic Landscape of Renal Carcinoma Cells
Authors: Tzukerman Maty , Shamai Yeela , Abramovich Ifat , Gottlieb Eyal , Selig Sara , Skorecki Karl
Published: January 2022

Although the relative risk of renal cell carcinoma associated with chronic kidney injury is particularly high among sub-Saharan African ancestry populations, it is unclear yet whether the APOL1 gene risk variants (RV) for kidney disease additionally elevate this risk. APOL1 G1 and G2 RV contribute to increased risk for kidney disease in black populations, although the disease mechanism has still not been fully deciphered. While high expression levels of all three APOL1 allelic variants, G0 (the wild type allele), G1, and G2 are injurious to normal human cells, renal carcinoma cells (RCC) naturally tolerate inherent high expression levels of APOL1. We utilized CRISPR/Cas9 gene editing to generate isogenic RCC clones expressing APOL1 G1 or G2 risk variants on a similar genetic background, thus enabling a reliable comparison between the phenotypes elicited in RCC by each of the APOL1 variants. Here, we demonstrate that knocking in the G1 or G2 APOL1 alleles, or complete elimination of APOL1 expression, has major effects on proliferation capacity, mitochondrial morphology, cell metabolism, autophagy levels, and the tumorigenic potential of RCC cells. The most striking effect of the APOL1 RV effect was demonstrated in vivo by the complete abolishment of tumor growth in immunodeficient mice. Our findings suggest that, in contrast to the WT APOL1 variant, APOL1 RV are toxic for RCC cells and may act to suppress cancer cell growth. We conclude that the inherent expression of non-risk APOL1 G0 is required for RCC tumorigenicity. RCC cancer cells can hardly tolerate increased APOL1 risk variants expression levels as opposed to APOL1 G0.
Gene-Directed Enzyme/Prodrug Therapy of Rat Brain Tumor Mediated by Human Mesenchymal Stem Cell Suicide Gene Extracellular Vesicles In Vitro and In Vivo
Authors: Tibensky Miroslav , Jakubechova Jana , Altanerova Ursula , Pastorakova Andrea , Rychly Boris , Baciak Ladislav , Mravec Boris , Altaner Cestmir
Published: January 2022

MSC-driven, gene-directed enzyme prodrug therapy (GDEPT) mediated by extracellular vesicles (EV) represents a new paradigm—cell-free GDEPT tumor therapy. In this study, we tested the efficacy of yeast cytosine deaminase::uracilphosphoribosyl transferase (yCD::UPRT-MSC)-exosomes, in the form of conditioned medium (CM) to inhibit the growth of C6 glioblastoma cells both in vitro and in vivo. MSCs isolated from human adipose tissue, umbilical cord, or dental pulp engineered to express the yCD::UPRT gene secreted yCD::UPRT-MSC-exosomes that in the presence of the prodrug 5-fluorocytosine (5-FC), inhibited the growth of rat C6 glioblastoma cells and human primary glioblastoma cells in vitro in a dose-dependent manner. CM from these cells injected repeatedly either intraperitoneally (i.p.) or subcutaneously (s.c.), applied intranasally (i.n.), or infused continuously by an ALZET osmotic pump, inhibited the growth of cerebral C6 glioblastomas in rats. A significant number of rats were cured when CM containing yCD::UPRT-MSC-exosomes conjugated with 5-FC was repeatedly injected i.p. or applied i.n. Cured rats were subsequently resistant to challenges with higher doses of C6 cells. Our data have shown that cell-free GDEPT tumor therapy mediated by the yCD::UPRT-MSC suicide gene EVs for high-grade glioblastomas represents a safer and more practical approach that is worthy of further investigation.
Primary Tumor Resection Decelerates Disease Progression in an Orthotopic Mouse Model of Metastatic Prostate Cancer
Authors: Linxweiler Johannes , Hajili Turkan , Zeuschner Philip , Menger Michael D. , Stöckle Michael , Junker Kerstin , Saar Matthias
Published: January 2022

Radical prostatectomy in oligometastatic prostate cancer is a matter of intense debate. Besides avoiding local complications, it is hypothesized that primary tumor resection may result in better oncological outcomes. The aim of our study was to analyze the effect of primary tumor resection on disease progression in an orthotopic prostate cancer mouse model. First, the optimal time point for primary tumor resection, when metastases have already occurred, but the primary tumor is still resectable, was determined as 8 weeks after inoculation of 5 × 105 LuCaP136 cells. In a second in vivo experiment, 64 mice with metastatic prostate cancer were randomized into two groups, primary tumor resection or sham operation, and disease progression was followed up for 10 weeks. The technique of orthotopic primary tumor resection was successfully established. Compared with the sham operation group, mice with primary tumor resection showed a significantly longer survival (p < 0.001), a significantly slower PSA increase (p < 0.01), and a lower number of lung metastases (p = 0.073). In conclusion, primary tumor resection resulted in slower disease progression and longer survival in an orthotopic mouse model of metastatic prostate cancer. In future studies, this model will be used to unravel the molecular mechanisms of primary tumor/metastasis interaction in prostate cancer.
Combined Inhibition of Polo-Like Kinase-1 and Wee1 as a New Therapeutic Strategy to Induce Apoptotic Cell Death in Neoplastic Mast Cells
Authors: Mancini Manuela , Monaldi Cecilia , De Santis Sara , Rondoni Michela , Papayannidis Cristina , Sartor Chiara , Curti Antonio , Bruno Samantha , Cavo Michele , Soverini Simona
Published: January 2022

Systemic mastocytosis (SM) is due to the pathologic accumulation of neoplastic mast cells in one or more extracutaneous organ(s). Although midostaurin, a multikinase inhibitor active against both wild-type and D816V-mutated KIT, improves organ damage and symptoms, a proportion of patients relapse or have resistant disease. It is well known that Aurora kinase A (AKA) over-expression promotes tumorigenesis, but its role in the pathogenesis of systemic mastocytosis (SM) has not yet been investigated. Evidence from the literature suggests that AKA may confer cancer cell chemo-resistance, inhibit p53, and enhance Polo-like kinase 1 (Plk1), CDK1, and cyclin B1 to promote cell cycle progression. In this study, we aimed to investigate the pathogenetic role of AKA and Plk1 in the advanced forms of SM. We demonstrate here, for the first time, that SM cell lines display hyper-phosphorylated AKA and Plk1. Danusertib (Aurora kinase inhibitor) and volasertib (Plk1 inhibitor) inhibited growth and induced apoptotic cell death in HMC-1.1 and -1.2 cells. Their growth-inhibitory effects were associated with cell cycle arrest and the activation of apoptosis. Cell cycle arrest was associated with increased levels of phospho-Wee1. Wee1 inhibition by MK1775 after 24 h treatment with danusertib or volasertib, when cells were arrested in G2 phase and Wee1, was overexpressed and hyper-activated, resulting in a significantly higher rate of apoptosis than that obtained from concomitant treatment with danusertib or volasertib + MK1775 for 48 h. In conclusion, Plk1 and AKA, alone or together with Wee1, are attractive therapeutic targets in neoplastic MCs. Repurposing Plk1 or AKA ± Wee1 inhibitors in advanced clinical development for other indications is a therapeutic strategy worthy of being explored, in order to improve the outcome of patients with advanced SM.
Exploring the Evolving Scope of Neoadjuvant Immunotherapy in NSCLC
Authors: Roller John F. , Veeramachaneni Nirmal K. , Zhang Jun
Published: January 2022

While lung cancer remains the leading cause of cancer death worldwide, lung cancer mortality has notably decreased in the past decade. Immunotherapy with immune checkpoint inhibitors have played a noteworthy role in contributing to this improved survival, particularly for patients with non-small cell lung cancer (NSCLC). However, until now the benefits have primarily been seen in patients with advanced or metastatic disease. Several recent early phase and ongoing phase III trials have been assessing whether the treatment benefit of immunotherapy in NSCLC can extend to the neoadjuvant setting for resectable diseases. In this comprehensive narrative review, we evaluate the most recent efficacy and safety data from these studies. We also outline questions that will need to be further examined to legitimate neoadjuvant immunotherapy’s role in NSCLC treatment, including the best surrogate marker of response, the incorporation of liquid biopsy for disease monitoring, the ability to be combined with other treatment modalities, the need for further adjuvant therapy, and potential future treatment combinations.
The Grey Zones of Classic Hodgkin Lymphoma
Authors: Bosch-Schips Jan , Granai Massimo , Quintanilla-Martinez Leticia , Fend Falko
Published: January 2022

Classic Hodgkin lymphoma (CHL) is a well-defined neoplasm characterized by the presence of a minority of pathognomonic Hodgkin and Reed–Sternberg (HRS) cells in a reactive inflammatory background. Although genotypically of B cell origin, HRS cells exhibit a downregulated B cell program and therefore are set apart from other B cell lymphomas in the current WHO classification. However, cases with morphological and phenotypic features overlapping with CHL have been recognized, and the category of B cell lymphoma—unclassifiable—with features intermediate between diffuse large B cell lymphoma (DLBCL) and CHL, also termed grey zone lymphoma, was first introduced into the WHO classification in 2008 as provisional entity. These cases, as well as others raising a differential diagnosis of CHL can present diagnostic problems, as well as therapeutic challenges. Whereas some of these lymphomas only represent biologically unrelated morphological mimics, others, especially mediastinal grey zone lymphoma, exhibit genetic and gene expression profiles which overlap with CHL, indicating a true biological relationship. In this review, we address areas of diagnostic difficulties between CHL and other lymphoma subtypes, discuss the biological basis of true grey zone lymphoma based on recent molecular studies and delineate current concepts for the classification of these rare tumors.
Xylan Deconstruction by Thermophilic Thermoanaerobacterium bryantii Hemicellulases Is Stimulated by Two Oxidoreductases
Authors: Yi Zhuolin , Su Xiaoyun , Asangba Abigail E. , Abdel-Hamid Ahmed M. , Chakraborty Siddhartha , Dodd Dylan , Stroot Peter G. , Mackie Roderick I. , Cann Isaac
Published: January 2022

Thermoanaerobacterium bryantii strain mel9T is a thermophilic bacterium isolated from a waste pile of a corn-canning factory. The genome of T. bryantii mel9T was sequenced and a hemicellulase gene cluster was identified. The cluster encodes seven putative enzymes, which are likely an endoxylanase, an α-glucuronidase, two oxidoreductases, two β-xylosidases, and one acetyl xylan esterase. These genes were designated tbxyn10A, tbagu67A, tbheoA, tbheoB, tbxyl52A, tbxyl39A, and tbaxe1A, respectively. Only TbXyn10A released reducing sugars from birchwood xylan, as shown by thin-layer chromatography analysis. The five components of the hemicellulase cluster (TbXyn10A, TbXyl39A, TbXyl52A, TbAgu67A, and TbAxe1A) functioned in synergy to hydrolyze birchwood xylan. Surprisingly, the two putative oxidoreductases increased the enzymatic activities of the gene products from the xylanolytic gene cluster in the presence of NADH and manganese ions. The two oxidoreductases were therefore named Hemicellulase-Enhancing Oxidoreductases (HEOs). All seven enzymes were thermophilic and acted in synergy to degrade xylans at 60 °C. Except for TbXyn10A, the other enzymes encoded by the gene cluster were conserved with high amino acid identities (85–100%) in three other Thermoanaerobacterium species. The conservation of the gene cluster is, therefore, suggestive of an important role of these enzymes in xylan degradation by these bacteria. The mechanism for enhancement of hemicellulose degradation by the HEOs is under investigation. It is anticipated, however, that the discovery of these new actors in hemicellulose deconstruction will have a significant impact on plant cell wall deconstruction in the biofuel industry.
Plasma Small Extracellular Vesicles with Complement Alterations in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration
Authors: Bellini Sonia , Saraceno Claudia , Benussi Luisa , Squitti Rosanna , Cimini Sara , Ricci Martina , Canafoglia Laura , Coppola Cinzia , Puoti Gianfranco , Ferrari Clarissa , Longobardi Antonio , Nicsanu Roland , Lombardi Marta , D’Arrigo Giulia , Verderio Claudia , Binetti Giuliano , Rossi Giacomina , Ghidoni Roberta
Published: January 2022

Cutting-edge research suggests endosomal/immune dysregulation in GRN/C9orf72-associated frontotemporal lobar degeneration (FTLD). In this retrospective study, we investigated plasma small extracellular vesicles (sEVs) and complement proteins in 172 subjects (40 Sporadic FTLD, 40 Intermediate/Pathological C9orf72 expansion carriers, and 49 Heterozygous/Homozygous GRN mutation carriers, 43 controls). Plasma sEVs (concentration, size) were analyzed by nanoparticle tracking analysis; plasma and sEVs C1q, C4, C3 proteins were quantified by multiplex assay. We demonstrated that genetic/sporadic FTLD share lower sEV concentrations and higher sEV sizes. The diagnostic performance of the two most predictive variables (sEV concentration/size ratio) was high (AUC = 0.91, sensitivity 85.3%, specificity 81.4%). C1q, C4, and C3 cargo per sEV is increased in genetic and sporadic FTLD. C4 (cargo per sEV, total sEV concentration) is increased in Sporadic FTLD and reduced in GRN+ Homozygous, suggesting its specific unbalance compared with Heterozygous cases. C3 plasma level was increased in genetic vs. sporadic FTLD. Looking at complement protein compartmentalization, in control subjects, the C3 and C4 sEV concentrations were roughly half that in respect to those measured in plasma; interestingly, this compartmentalization was altered in different ways in patients. These results suggest sEVs and complement proteins as potential therapeutic targets to mitigate neurodegeneration in FTLD.
Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype—Different Onset
Authors: Capiau Sara , Smet Joél , De Paepe Boel , Yildiz Yilmaz , Arslan Mutluay , Stevens Olivier , Verschoore Maxime , Stepman Hedwig , Seneca Sara , Vanlander Arnaud
Published: January 2022

Human mitochondrial disease exhibits large variation of clinical phenotypes, even in patients with the same causative gene defect. We illustrate this heterogeneity by confronting clinical and biochemical data of two patients with the uncommon pathogenic homoplasmic NC_012920.1(MT-ATP6):m.9035T>C variant in MT-ATP6. Patient 1 presented as a toddler with severe motor and speech delay and spastic ataxia without extra-neurologic involvement. Patient 2 presented in adolescence with ataxia and ophthalmoplegia without cognitive or motor impairment. Respiratory chain complex activities were normal in cultured skin fibroblasts from both patients when calculated as ratios over citrate synthase activity. Native gels found presence of subcomplexes of complex V in fibroblast and/or skeletal muscle. Bioenergetic measurements in fibroblasts from both patients detected reduced spare respiratory capacities and altered extracellular acidification rates, revealing a switch from mitochondrial respiration to glycolysis to uphold ATP production. Thus, in contrast to the differing disease presentation, biochemical evidence of mitochondrial deficiency turned out quite similar. We conclude that biochemical analysis remains a valuable tool to confirm the genetic diagnosis of mitochondrial disease, especially in patients with new gene variants or atypical clinical presentation.
Pathogenic Mechanism of Autoimmune Diabetes Mellitus in Humans: Potential Role of Streptozotocin-Induced Selective Autoimmunity against Human Islet β-Cells
Authors: Zhu Bao Ting
Published: January 2022

Human type 1 diabetes mellitus is a chronic autoimmune disease characterized by the selective loss of insulin-producing β-cells in pancreatic islets of genetically susceptible individuals. In this communication, a new hypothesis is postulated which is based on the observations that streptozotocin (STZ), a chemically reactive and cytotoxic compound produced by certain gram-positive bacteria, can be preferentially taken up into islet β-cells and induce cytotoxicity and autoimmunity. It is hypothesized that humans might be occasionally exposed to STZ through opportunistic infections with the STZ-producing bacteria and/or through ingestion of certain food products that contain STZ. In addition, the potential presence of the STZ-producing bacteria in the gut microbiota of some individuals might be another source of long-term STZ exposure. Because of the high chemical reactivity of STZ and its breakdown products, these chemicals can covalently modify certain cellular macromolecules (e.g., DNA and proteins), and the covalently modified cellular components would serve as new antigens, potentially capable of inducing both humoral and cellular autoimmune responses in the islets of certain individuals. In addition to STZ exposure, the eventual development of autoimmunity against STZ-exposed islet β-cells also depends critically on the genetic predisposition of the susceptible individuals plus the opportunistic presence of a conducive, strong environmental trigger, which often is presented as severe febrile viral infections subsequently inducing strong aberrant reactions of the body’s immune system. The proposed pathogenic hypothesis is supported by a considerable body of direct and indirect evidence from laboratory animal studies and clinical observations. Certainly, more experimental and clinical studies are needed to carefully further examine each of the key components of the proposed pathogenic hypothesis.
Time, Space and Agency in the Finnish Cultural Sector at the Time of COVID-19
Authors: Haapakorpi Arja , Leinonen Minna , Otonkorpi-Lehtoranta Katri
Published: January 2022

The organization of working times and workplaces has typically been diverse and hybrid for people working in culture. Work is characterized by precarious conditions such as short-term contracts and seasonal employment. The impact of COVID-19 has shown the vulnerability and uniqueness of the employment conditions in this sector. We collected personal written texts from people working in the cultural sector in spring 2020, when in Finland the first wave of COVID-19 was subsiding and nobody knew when the next wave would come. We analyzed the ways cultural workers constructed agency on temporal and relational dimensions as regards work and non-work. The content analytic approach highlighted two main types of situational agencies, the normative employment agency and the precarious work agency, both of which were shaped by the uncertain conditions of the cultural sector. Due to the differing employment conditions, both intensification of work and small agency were present in work of the cultural sector and posed challenges to the management of time and the future. However, the terms and conditions for agency construction varied, even under similar circumstances.
Aromatic Polyesters Containing Ether and a Kinked Aromatic Amide Structure in the Main Chain: Synthesis and Characterisation
Authors: Deokar Satish S. , Joshi Makarand D. , Tamboli Asiya M. , Alshehri Sultan , Ghoneim Mohammed M. , Truong Nguyen Tam Nguyen , Tamboli Mohaseen S. , Maldar Noormahamad N.
Published: January 2022

A novel bisphenol containing preformed multiple ether and amide linkages, N, N′-Bis (4-hydroxyphenoxyphenylene) isophthalamide (IPCD), was prepared and analysed by spectroscopic methods. New aromatic polyesters were prepared by polycondensation of IPCD with 1, 3-benzene diacidchloride and/or 1, 4-benzene diacidchloride. These obtained polyesters were structurally analysed by infra-red spectroscopy, measurements of inherent viscosity, wide-angle X-ray diffraction patterns, and thermal techniques such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solubility tests in organic solvents. The synthesised polyesters had high molecular weights, as indicated by their inherent viscosities from 0.67 to 0.78 dL/g in N-methyl-2-pyrrolidone. The incorporation of ether and kinked aromatic amide moieties in the main polyester chains greatly affected the properties of these aromatic polyesters. The prepared polyesters readily dissolved in amide-type polar aprotic solvents and pyridine, indicating their solution processability. The DSC curves above the polyesters showed glass transition temperatures of 194 to 269 °C. TGA indicated that these newly obtained polyesters were stable up to 301 °C and retained a 39 to 48% weight at 900 °C. W-XRD analyses showed that the newly synthesised polyesters were amorphous, which is reflected in their solubility behaviour.
The Influence of Polymeric Sealing Treatment on the Wear Performance of PEO Coating Deposited on AZ31 Mg Alloy
Authors: Wang Qun , Tu Sisi , Rao Yuqin , Chidambaram Seshadri Ramachandran
Published: January 2022

A plasma electrolytic oxidation (PEO) coating fabricated on AZ31 Mg alloy was sealed with polymeric sealant. The sealant penetrated into the PEO coating and filled the micropores and microcracks of the coating. The effect of the sealant treatment on the sliding wear behavior of the PEO coating was investigated by systematically varying the axial wear loads applied onto the unsealed and sealed PEO coatings. The results of the sliding wear tests revealed that the polymeric sealing treatment enhanced the wear resistance of the Mg-based PEO coating by reducing the wear rate and by improving the load-bearing capacity.
The Effects of Several Metal Nanoparticles on Seed Germination and Seedling Growth: A Meta-Analysis
Authors: Guo Huanhuan , Liu Yong , Chen Jidai , Zhu Yan , Zhang Zihan
Published: January 2022

Using the proper means to improve seed germination is of great significance in agriculture and forestry. Here, a meta-analysis was used to examine whether metal nanoparticle treatments have a specific effect on the seed germination and seedling growth of agricultural species. Using the Web of Science (1950–2021), PubMed (1950–2021), and Scopus (1950–2021) databases, a paper search was conducted using the following items (“nanoparticles” and “seed germination”, “nanomaterials” and “seed germination”) to filter the references in the title, abstract, and keywords of the published articles. The results indicated that nanoparticle (NP) treatments had a significantly positive effect on the final germination percentage (FGP), with a mean difference (MD) (that is, the overall effect) of 1.97 (0.96, 2.98) for the silver (Ag)-NP subgroup, 1.21 (0.34, 2.09) for the other-NP subgroup, 1.40 (0.88, 1.92) for the total based on the NP types, 1.47 (0.85, 2.09) for the “Concentrations: <50 mg/L” subgroup, and 1.40 (0.88, 1.92) for the total based on the NP concentrations. Similarly, root length (RL) was positively and significantly affected by NP treatment, with an MD (95% CI) of 0.92 (0.76, 1.09) for the zinc (Zn)-NP subgroup, 0.79 (0.65, 0.92) for the other-NP subgroup, 0.82 (0.72, 0.93) for the total based on the NP types, 0.90 (0.77, 1.04) for the “Concentrations: ≤50 mg/L” subgroup, 0.80 (0.60, 0.99) for the “Concentrations: >50 mg/L” subgroup, and 0.82 (0.72, 0.93) for the total based on the NP concentrations. However, there was no statistical correlation between the nanoparticle concentrations and shoot length (SL), due to the inclusion of zero in the 95% CI of the overall effect. Therefore, Ag-NPs could increase the FGP more than other-NPs, while Zn-NPs enhanced RL more. Moreover, NPs at lower concentrations could improve the FGP and RL of crop species to a larger extent than NPs at higher concentrations. This meta-analysis can provide a reference for the nanoparticle treatment technology utilization in agricultural and forest seeds.