bluuebunny/crossref_metadata_2025 huggingface dataset:
Biological Knowledge of Thornback Ray (Raja clavata) from the Azores: Improving Scientific Information for the Effectiveness of Species-Specific Management Measures
Authors: Santos Régis , Medeiros-Leal Wendell , Novoa-Pabon Ana , Crespo Osman , Pinho Mário
Published: July 2021

Elasmobranchs are globally recognized as vulnerable due to their life-history characteristics, fishing pressure, and habitat degradation. Among the skates and rays caught by commercial fisheries, the thornback ray Raja clavata is one of the most economically important in Northwest European seas. However, the scarcity of biological knowledge about this species in Azorean waters has limited the stock assessment types that can be conducted. To improve information on its habitat preferences, spatial distribution and movement pattern, growth, sex ratio, mortality, and reproduction, as well as to investigate long-term changes in abundance and size, this study analyzed approximately 25 years of fishery-dependent and independent data from the Azores. Raja clavata was mainly caught at depths up to 250 m. Most of the tagged fish were recaptured near the release point. A larger–deeper trend was found, and females were larger and more abundant than males. Life-history parameters showed that R. clavata has a long lifespan, large size, slow growth, and low natural mortality. The sustainability of its population is of concern to fisheries management and, while our findings suggested a relatively healthy stock in the Azores, a thorough increase in data quality is required to better understand the stock condition and prevent overexploitation.
Neurotoxic Effect of Fipronil in Male Wistar Rats: Ameliorative Effect of L-Arginine and L-Carnitine
Authors: Mahmoud Yasmina K. , Ali Ahmed A. , Abdelrazek Heba M. A. , Aldayel Tahany Saleh , Abdel-Daim Mohamed M. , El-Menyawy Menna Allah I.
Published: July 2021

The ameliorative effect of L-arginine (LA) and L-carnitine (LC) against fipronil (FPN)-induced neurotoxicity was explored. In this case, 36 adult male rats were randomly divided into six groups: group I received distilled water, group II received 500 mg/kg LA, group III received 100 mg/kg LC, group IV received 4.85 mg/kg FPN, group V received 4.85 mg/kg FPN and 500 mg/kg LA and group VI received 4.85 mg/kg FPN and 100 mg/kg LC for 6 weeks. Cognitive performance was assessed using Barnes maze (BM). Serum corticosterone, brain total antioxidant capacity (TAC), malondialdehyde (MDA) and dopamine were measured. Histopathology and immunohistochemistry of ionized calcium-binding adaptor (Iba-1), doublecortin (DCX) and serotonin (S-2A) receptors were performed. Fipronil induced noticeable deterioration in spatial learning and memory performance. In addition, FPN significantly (p < 0.05) diminished brain antioxidant defense system and dopamine coincide with elevated serum corticosterone level. Histopathological examination revealed degenerative and necrotic changes. Furthermore, Iba-1 and DCX were significantly expressed in cortex and hippocampus whereas S-2A receptors were significantly lowered in FPN group. However, administration of LA or LC alleviated FPN-induced deteriorations. In conclusion, LA and LC could be prospective candidates for mitigation of FPN-induced neurotoxicity via their antioxidant, anti-inflammatory and neuropotentiating effects.
IL-17A Damages the Blood–Retinal Barrier through Activating the Janus Kinase 1 Pathway
Authors: Byrne Eimear M. , Llorián-Salvador María , Tang Miao , Margariti Andriana , Chen Mei , Xu Heping
Published: July 2021

Blood–retinal barrier (BRB) dysfunction underlies macular oedema in many sight-threatening conditions, including diabetic macular oedema, neovascular age-related macular degeneration and uveoretinitis. Inflammation plays an important role in BRB dysfunction. This study aimed to understand the role of the inflammatory cytokine IL-17A in BRB dysfunction and the mechanism involved. Human retinal pigment epithelial (RPE) cell line ARPE19 and murine brain endothelial line bEnd.3 were cultured on transwell membranes to model the outer BRB and inner BRB, respectively. IL-17A treatment (3 days in bEnd.3 cells and 6 days in ARPE19 cells) disrupted the distribution of claudin-5 in bEnd.3 cells and ZO-1 in ARPE19 cells, reduced the transepithelial/transendothelial electrical resistance (TEER) and increased permeability to FITC-tracers in vitro. Intravitreal (20 ng/1 μL/eye) or intravenous (20 ng/g) injection of recombinant IL-17A induced retinal albumin leakage within 48 h in C57BL/6J mice. Mechanistically, IL-17A induced Janus kinase 1 (JAK1) phosphorylation in bEnd.3 but not ARPE19 cells. Blocking JAK1 with Tofacitinib prevented IL-17A-mediated claudin-5 dysmorphia in bEnd.3 cells and reduced albumin leakage in IL-17A-treated mice. Our results suggest that IL-17A can damage the BRB through the activating the JAK1 signaling pathway, and targeting this pathway may be a novel approach to treat inflammation-induced macular oedema.
Molecular Mechanisms of Resistance to Immune Checkpoint Inhibitors in Melanoma Treatment: An Update
Authors: Vukadin Sonja , Khaznadar Farah , Kizivat Tomislav , Vcev Aleksandar , Smolic Martina
Published: July 2021

Over the past decade, immune checkpoint inhibitors (ICI) have revolutionized the treatment of advanced melanoma and ensured significant improvement in overall survival versus chemotherapy. ICI or targeted therapy are now the first line treatment in advanced melanoma, depending on the tumor v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational status. While these new approaches have changed the outcomes for many patients, a significant proportion of them still experience lack of response, known as primary resistance. Mechanisms of primary drug resistance are not fully elucidated. However, many alterations have been found in ICI-resistant melanomas and possibly contribute to that outcome. Furthermore, some tumors which initially responded to ICI treatment ultimately developed mechanisms of acquired resistance and subsequent tumor progression. In this review, we give an overview of tumor primary and acquired resistance mechanisms to ICI and discuss future perspectives with regards to new molecular targets and combinatorial therapies.
Lipoprotein(a) Where Do We Stand? From the Physiopathology to Innovative Terapy
Authors: Iannuzzo Gabriella , Tripaldella Maria , Mallardo Vania , Morgillo Mena , Vitelli Nicoletta , Iannuzzi Arcangelo , Aliberti Emilio , Giallauria Francesco , Tramontano Anna , Carluccio Raffaele , Calcaterra Ilenia , Di Minno Matteo Nicola Dario , Gentile Marco
Published: July 2021

A number of epidemiologic studies have demonstrated a strong association between increasing lipoprotein a [Lp(a)] and cardiovascular disease. This correlation was demonstrated independent of other known cardiovascular (CV) risk factors. Screening for Lp(a) in the general population is not recommended, although Lp(a) levels are predominantly genetically determined so a single assessment is needed to identify patients at risk. In 2019 ESC/EAS guidelines recommend Lp(a) measurement at least once a lifetime, fo subjects at very high and high CV risk and those with a family history of premature cardiovascular disease, to reclassify patients with borderline risk. As concerning medications, statins play a key role in lipid lowering therapy, but present poor efficacy on Lp(a) levels. Actually, treatment options for elevated serum levels of Lp(a) are very limited. Apheresis is the most effective and well tolerated treatment in patients with high levels of Lp(a). However, promising new therapies, in particular antisense oligonucleotides have showed to be able to significantly reduce Lp(a) in phase II RCT. This review provides an overview of the biology and epidemiology of Lp(a), with a view to future therapies.
Influence of Different Types of Infill Walls on the Hysteretic Performance of Reinforced Concrete Frames
Authors: Wang Fei , Zhao Kaozhong , Zhang Jianwei , Yan Kai
Published: July 2021

To study the influence of masonry infill walls on the hysteretic performance of reinforced concrete frames, a cyclic experiment was conducted for three two-story and two-span reinforced concrete frame structures, including one reinforced concrete frame without infill walls and two frames with infill walls. Whether the infill walls were constructed in the frames and the type of infilled material were the main parameters of the test. The major results reveal that: the infill walls clearly changed the mechanical mechanism of the frame structure at the early stage of loading, magnified the stiffness and horizontal bearing capacity of the frame structure, and enhanced the energy dissipation capacity of the frame structure, but reduced the deformation performance of the frame structure. In the later stage of loading, the infill walls would no longer work as one with the frame gradually with the failure of the infill walls, and the above performance of the structure would approach the empty frame structure. Moreover, the initial stiffness, energy dissipation capacity, and horizontal bearing capacity of the frame with infill walls of clay hollow bricks were the highest among the three specimens. But due to the strong diagonal bracing effect, the damage to the top of the columns and beam-column joints was serious, the yield displacement was reduced significantly, and the shear failure of the top of the columns and the joints occurred prematurely, which showed poor performance of deformation and ductility. However, the frame with infill walls of relatively soft aerated lightweight concrete blocks showed better performance of deformation and ductility.
Identification of Critical Success Factors (CSFs) of BIM Software Selection: A Combined Approach of FCM and Fuzzy DEMATEL
Authors: Patel Tirth , Bapat Hirakraj , Patel Daksh , van der Walt Jacobus Daniel
Published: July 2021

The architecture, engineering, and construction (AEC) industry has seen a significant rise in the adoption of Building Information Modeling (BIM) in the last few years. BIM software have launched with numerous robust capabilities and features to satisfy the ever-demanding needs of the AEC industry. Various factors are associated with the selection of BIM software depending on a company’s requirements and constraints. BIM software selection is a daunting process as most AEC industries are unaware of the factors to consider when making this important decision. This study focuses on identifying the critical success factors (CSFs) and their interrelationship for efficient BIM software selection. For this research, a questionnaire was developed and disseminated in two stages in India, the United States of America (U.S.A.), Germany, and the United Kingdom (U.K.). In the first stage, a total of twenty-six identified CSFs were analyzed with the factor comparison method (FCM) to identify the top fifteen CSFs. Subsequently, the identified top fifteen CSFs were further assessed by implementing Fuzzy DEMATEL to categorize them into cause-and-effect groups based on respective influence strength, depicted with a causal diagram. Out of fifteen CSFs, five and ten factors were grouped into the cause group and effect group for BIM software selection, respectively. The most important factors were identified as software functionality, BIM adoption strategies and processes, interoperability, staff competencies, BIM standards and regional regulations. The outcome of this research can help BIM user companies improve their BIM software selection framework and decision-making process during purchasing software.
Cellulitis Is Associated with Severe Breast Cancer-Related Lymphedema: An Observational Study of Tissue Composition
Authors: Jørgensen Mads Gustaf , Hermann Anne Pernille , Madsen Anette Riis , Christensen Steffanie , Ingwersen Kim Gordon , Thomsen Jørn Bo , Sørensen Jens Ahm
Published: July 2021

Cellulitis is a common complication in Breast Cancer-Related Lymphedema (BCRL). The excess amount of fat and lean mass in BCRL is a vital factor in patient stratification, prognosis, and treatments. However, it is not known whether cellulitis is associated with the excess fat and lean mass in BCRL. Therefore, this prospective observational study was designed to fundamentally understand the heterogonous biocomposition of BCRL. For this study, we consecutively enrolled 206 patients with unilateral BCRL between January 2019 and February 2020. All patients underwent Dual-Energy X-Ray Absorptiometry scans, bioimpedance spectroscopy, indocyanine green lymphangiography comprehensive history of potential risk factors, and a clinical exam. Multivariate linear and beta regression models were used to determine the strength of association and margins effect. Sixty-nine patients (33%) had at least one previous episode of cellulitis. Notably, a previous episode of cellulitis was associated with 20 percentage points more excess fat and 10 percentage points more excess lean mass compared to patients without cellulitis (p < 0.05). Moreover, each 1 increase in the patients BMI was associated with a 0.03 unit increase in the fat mass proportion of the lymphedema arm. Cellulitis was associated with more excess fat and lean arm mass in BCRL. In addition, patients BMI affect the proportion of fat mass in the arm.
Targeting c-IAP1, c-IAP2, and Bcl-2 Eliminates Senescent Glioblastoma Cells Following Temozolomide Treatment
Authors: Schwarzenbach Christian , Tatsch Larissa , Brandstetter Vilar Juliana , Rasenberger Birgit , Beltzig Lea , Kaina Bernd , Tomicic Maja T. , Christmann Markus
Published: July 2021

Therapy of malignant glioma depends on the induction of O6-methylguanine by the methylating agent temozolomide (TMZ). However, following TMZ exposure, most glioma cells evade apoptosis and become senescent and are thereby protected against further anticancer therapy. This protection is thought to be dependent on the senescent cell anti-apoptotic pathway (SCAP). Here we analyzed the factors involved in the SCAP upon exposure to TMZ in glioblastoma cell lines (LN-229, A172, U87MG) and examined whether inhibition of these factors could enhance TMZ-based toxicity by targeting senescent cells. We observed that following TMZ treatment, c-IAP2 and Bcl-2 were upregulated. Inhibition of these SCAP factors using non-toxic concentrations of the small molecule inhibitors, BV6 and venetoclax, significantly increased cell death, as measured 144 h after TMZ exposure. Most importantly, BV6 and venetoclax treatment of senescent cells strongly increased cell death after an additional 120 h. Moreover, Combenefit analyses revealed a significant synergy combining BV6 and venetoclax. In contrast to BV6 and venetoclax, AT406, embelin, and TMZ itself, teniposide and the PARP inhibitor pamiparib did not increase cell death in senescent cells. Based on these data, we suggest that BV6 and venetoclax act as senolytic agents in glioblastoma cells upon TMZ exposure.
Influence of the Position and Composition of Radiometals and Radioiodine Labels on Imaging of Epcam Expression in Prostate Cancer Model Using the DARPin Ec1
Authors: Deyev Sergey M. , Xu Tianqi , Liu Yongsheng , Schulga Alexey , Konovalova Elena , Garousi Javad , Rinne Sara S. , Larkina Maria , Ding Haozhong , Gräslund Torbjörn , Orlova Anna , Tolmachev Vladimir , Vorobyeva Anzhelika
Published: July 2021

The epithelial cell adhesion molecule (EpCAM) is intensively overexpressed in 40–60% of prostate cancer (PCa) cases and can be used as a target for the delivery of drugs and toxins. The designed ankyrin repeat protein (DARPin) Ec1 has a high affinity to EpCAM (68 pM) and a small size (18 kDa). Radiolabeled Ec1 might be used as a companion diagnostic for the selection of PCa patients for therapy. The study aimed to investigate the influence of radiolabel position (N- or C-terminal) and composition on the targeting and imaging properties of Ec1. Two variants, having an N- or C-terminal cysteine, were produced, site-specifically conjugated to a DOTA chelator and labeled with cobalt-57, gallium-68 or indium-111. Site-specific radioiodination was performed using ((4-hydroxyphenyl)-ethyl)maleimide (HPEM). Biodistribution of eight radiolabeled Ec1-probes was measured in nude mice bearing PCa DU145 xenografts. In all cases, positioning of a label at the C-terminus provided the best tumor-to-organ ratios. The non-residualizing [125I]I-HPEM label provided the highest tumor-to-muscle and tumor-to-bone ratios and is more suitable for EpCAM imaging in early-stage PCa. Among the radiometals, indium-111 provided the highest tumor-to-blood, tumor-to-lung and tumor-to-liver ratios and could be used at late-stage PCa. In conclusion, label position and composition are important for the DARPin Ec1.
Accelerated T2-Weighted TSE Imaging of the Prostate Using Deep Learning Image Reconstruction: A Prospective Comparison with Standard T2-Weighted TSE Imaging
Authors: Gassenmaier Sebastian , Afat Saif , Nickel Marcel Dominik , Mostapha Mahmoud , Herrmann Judith , Almansour Haidara , Nikolaou Konstantin , Othman Ahmed E.
Published: July 2021

Multiparametric MRI (mpMRI) of the prostate has become the standard of care in prostate cancer evaluation. Recently, deep learning image reconstruction (DLR) methods have been introduced with promising results regarding scan acceleration. Therefore, the aim of this study was to investigate the impact of deep learning image reconstruction (DLR) in a shortened acquisition process of T2-weighted TSE imaging, regarding the image quality and diagnostic confidence, as well as PI-RADS and T2 scoring, as compared to standard T2 TSE imaging. Sixty patients undergoing 3T mpMRI for the evaluation of prostate cancer were prospectively enrolled in this institutional review board-approved study between October 2020 and March 2021. After the acquisition of standard T2 TSE imaging (T2S), the novel T2 TSE sequence with DLR (T2DLR) was applied in three planes. Overall, the acquisition time for T2S resulted in 10:21 min versus 3:50 min for T2DLR. The image evaluation was performed by two radiologists independently using a Likert scale ranging from 1–4 (4 best) applying the following criteria: noise levels, artifacts, overall image quality, diagnostic confidence, and lesion conspicuity. Additionally, T2 and PI-RADS scoring were performed. The mean patient age was 69 ± 9 years (range, 49–85 years). The noise levels and the extent of the artifacts were evaluated to be significantly improved in T2DLR versus T2S by both readers (p < 0.05). Overall image quality was also evaluated to be superior in T2DLR versus T2S in all three acquisition planes (p = 0.005–<0.001). Both readers evaluated the item lesion conspicuity to be superior in T2DLR with a median of 4 versus a median of 3 in T2S (p = 0.001 and <0.001, respectively). T2-weighted TSE imaging of the prostate in three planes with an acquisition time reduction of more than 60% including DLR is feasible with a significant improvement of image quality.
Role of Inflammatory and Immune-Nutritional Prognostic Markers in Patients Undergoing Surgical Resection for Biliary Tract Cancers
Authors: Conci Simone , Campagnaro Tommaso , Danese Elisa , Lombardo Ezio , Isa Giulia , Vitali Alessandro , Marchitelli Ivan , Bagante Fabio , Pedrazzani Corrado , De Bellis Mario , Ciangherotti Andrea , Guglielmi Alfredo , Lippi Giuseppe , Ruzzenente Andrea
Published: July 2021

The relationship between immune-nutritional status and tumor growth; biological aggressiveness and survival, is still debated. Therefore, this study aimed to evaluate the prognostic performance of different inflammatory and immune-nutritional markers in patients who underwent surgery for biliary tract cancer (BTC). The prognostic role of the following inflammatory and immune-nutritional markers were investigated: Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), Prognostic Index (PI), Neutrophil to Lymphocyte ratio (NLR), Platelet to Lymphocyte ratio (PLR), Lymphocyte to Monocyte ratio (LMR), Prognostic Nutritional Index (PNI). A total of 282 patients undergoing surgery for BTC were included. According to Cox regression and ROC curves analysis for survival, LMR had the best prognostic performances, with hazard ratio (HR) of 1.656 (p = 0.005) and AUC of 0.652. Multivariable survival analysis identified the following independent prognostic factors: type of BTC (p = 0.002), T stage (p = 0.014), N stage (p < 0.001), histological grading (p = 0.045), and LMR (p = 0.025). Conversely, PNI was related to higher risk of severe morbidity (p < 0.001) and postoperative mortality (p = 0.005). In conclusion, LMR appears an independent prognostic factor of long-term survival, whilst PNI seems associated with worse short-term outcomes.
The Role of Tumor-Associated Macrophages in Hematologic Malignancies
Authors: Cencini Emanuele , Fabbri Alberto , Sicuranza Anna , Gozzetti Alessandro , Bocchia Monica
Published: July 2021

The tumor microenvironment includes dendritic cells, T-cytotoxic, T-helper, reactive B-lymphoid cells and macrophages; these reactive cells could interplay with malignant cells and promote tumor growth and survival. Among its cellular components, tumor-associated macrophages (TAM) represent a component of the innate immune system and play an important role, especially in hematologic malignancies. Depending on the stimuli that trigger their activation, TAM are polarized towards form M1, contributing to antitumor responses, or M2, associated with tumor progression. Many studies demonstrated a correlation between TAM, disease progression and the patient’s outcome in lymphoproliferative neoplasms, such as Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), even if with conflicting results. A critical hurdle to overcome is surely represented by the heterogeneity in the choice of the optimal markers and methods used for TAM analysis (gene-expression profile vs. immunohistochemistry, CD163vs. CD68vs. CD163/CD68 double-positive cells). TAM have been recently linked to the development and progression of multiple myeloma and leukemia, with a critical role in the homing of malignant cells, drug resistance, immune suppression and angiogenesis. As such, this review will summarize the role of TAM in different hematologic malignancies, focusing on the complex interplay between TAM and tumor cells, the prognostic value of TAM and the possible TAM-targeted therapeutic strategies.
Lineage Plasticity in Cancer: The Tale of a Skin-Walker
Authors: Thankamony Archana P. , Subbalakshmi Ayalur Raghu , Jolly Mohit Kumar , Nair Radhika
Published: July 2021

Lineage plasticity, the switching of cells from one lineage to another, has been recognized as a cardinal property essential for embryonic development, tissue repair and homeostasis. However, such a highly regulated process goes awry when cancer cells exploit this inherent ability to their advantage, resulting in tumorigenesis, relapse, metastasis and therapy resistance. In this review, we summarize our current understanding on the role of lineage plasticity in tumor progression and therapeutic resistance in multiple cancers. Lineage plasticity can be triggered by treatment itself and is reported across various solid as well as liquid tumors. Here, we focus on the importance of lineage switching in tumor progression and therapeutic resistance of solid tumors such as the prostate, lung, hepatocellular and colorectal carcinoma and the myeloid and lymphoid lineage switch observed in leukemias. Besides this, we also discuss the role of epithelial-mesenchymal transition (EMT) in facilitating the lineage switch in biphasic cancers such as aggressive carcinosarcomas. We also discuss the mechanisms involved, current therapeutic approaches and challenges that lie ahead in taming the scourge of lineage plasticity in cancer.
Primary Endoscopic Endonasal Management of Giant Pituitary Adenomas: Outcome and Pitfalls from a Large Prospective Multicenter Experience
Authors: Chibbaro Salvatore , Signorelli Francesco , Milani Davide , Cebula Helene , Scibilia Antonino , Bozzi Maria , Messina Raffaella , Zaed Ismail , Todeschi Julien , Ollivier Irene , Mallereau Charles , Dannhoff Guillaume , Romano Antonio , Cammarota Francesco , Servadei Franco , Pop Raoul , Baloglu Seyyid , Lasio Giovanni , Luca Florina , Goichot Bernard , Proust Francois , Ganau Mario
Published: July 2021

Purpose: To evaluate factors influencing clinical and radiological outcome of extended endoscopic endonasal transtuberculum/transplanum approach (EEA-TTP) for giant pituitary adenomas (GPAs). Methods: We recruited prospectively all consecutive GPAs patients undergoing EEA-TTP between 2015 and 2019 in 5 neurosurgical centers. Preoperative clinical and radiologic features, visual and hormonal outcomes, extent of resection (EoR), complications and recurrence rates were recorded and analyzed. Results: Of 1169 patients treated for pituitary adenoma, 96 (8.2%) had GPAs. Seventy-eight (81.2%) patients had visual impairment, 12 (12.5%) had headaches, 3 (3.1%) had drowsiness due to hydrocephalus, and 53 (55.2%) had anterior pituitary insufficiency. EoR was gross or near-total in 46 (47.9%) and subtotal in 50 (52.1%) patients. Incomplete resection was associated with lateral suprasellar, intraventricular and/or cavernous sinus extension and with firm/fibrous consistence. At the last follow-up, all but one patient (77, 98.7%) with visual deficits improved. Headache improved in 8 (88.9%) and anterior pituitary function recovered in 27 (50.9%) patients. Recurrence rate was 16.7%, with 32 months mean recurrence-free survival. Conclusions: EEA-TTP is a valid option for GPAs and seems to provide better outcomes, lower rate of complications and higher EoR compared to one- or multi-stage microscopic, non-extended endoscopic transsphenoidal, and transcranial resections.
PFKFB3 Inhibition Sensitizes DNA Crosslinking Chemotherapies by Suppressing Fanconi Anemia Repair
Authors: Ninou Anna Huguet , Lehto Jemina , Chioureas Dimitrios , Stigsdotter Hannah , Schelzig Korbinian , Åkerlund Emma , Gudoityte Greta , Joneborg Ulrika , Carlson Joseph , Jonkers Jos , Seashore-Ludlow Brinton , Gustafsson Nina Marie Susanne
Published: July 2021

Replicative repair of interstrand crosslinks (ICL) generated by platinum chemotherapeutics is orchestrated by the Fanconi anemia (FA) repair pathway to ensure resolution of stalled replication forks and the maintenance of genomic integrity. Here, we identify novel regulation of FA repair by the cancer-associated glycolytic enzyme PFKFB3 that has functional consequences for replication-associated ICL repair and cancer cell survival. Inhibition of PFKFB3 displays a cancer-specific synergy with platinum compounds in blocking cell viability and restores sensitivity in treatment-resistant models. Notably, the synergies are associated with DNA-damage-induced chromatin association of PFKFB3 upon cancer transformation, which further increases upon platinum resistance. FA pathway activation triggers the PFKFB3 assembly into nuclear foci in an ATR- and FANCM-dependent manner. Blocking PFKFB3 activity disrupts the assembly of key FA repair factors and consequently prevents fork restart. This results in an incapacity to replicate cells to progress through S-phase, an accumulation of DNA damage in replicating cells, and fork collapse. We further validate PFKFB3-dependent regulation of FA repair in ex vivo cultures from cancer patients. Collectively, targeting PFKFB3 opens up therapeutic possibilities to improve the efficacy of ICL-inducing cancer treatments.
Glyoxalase 1 Expression as a Novel Diagnostic Marker of High-Grade Prostatic Intraepithelial Neoplasia in Prostate Cancer
Authors: Rounds Liliana , Nagle Ray B. , Muranyi Andrea , Jandova Jana , Gill Scott , Vela Elizabeth , Wondrak Georg T.
Published: July 2021

Glyoxalase 1 (GLO1) is an enzyme involved in the detoxification of methylglyoxal (MG), a reactive oncometabolite formed in the context of energy metabolism as a result of high glycolytic flux. Prior clinical evidence has documented GLO1 upregulation in various tumor types including prostate cancer (PCa). However, GLO1 expression has not been explored in the context of PCa progression with a focus on high-grade prostatic intraepithelial neoplasia (HGPIN), a frequent precursor to invasive cancer. Here, we have evaluated GLO1 expression by immunohistochemistry in archival tumor samples from 187 PCa patients (stage 2 and 3). Immunohistochemical analysis revealed GLO1 upregulation during tumor progression, observable in HGPIN and PCa versus normal prostatic tissue. GLO1 upregulation was identified as a novel hallmark of HGPIN lesions, displaying the highest staining intensity in all clinical patient specimens. GLO1 expression correlated with intermediate–high risk Gleason grade but not with patient age, biochemical recurrence, or pathological stage. Our data identify upregulated GLO1 expression as a molecular hallmark of HGPIN lesions detectable by immunohistochemical analysis. Since current pathological assessment of HGPIN status solely depends on morphological features, GLO1 may serve as a novel diagnostic marker that identifies this precancerous lesion.
Canopy Homolog 2 as a Novel Molecular Target in Hepatocarcinogenesis
Authors: Kakehashi Anna , Suzuki Shugo , Shiota Masayuki , Raymo Nina , Gi Min , Tachibana Taro , Stefanov Vasily , Wanibuchi Hideki
Published: July 2021

In the present study, the role of a novel protein involved in neurite development and endoplasmic reticulum (ER) stress, canopy homolog 2 (CNPY2), was investigated in mouse and human hepatocarcinogenesis. Firstly, a sensitive quantitative and qualitative detection of protein expression using QSTAR Elite LC-Ms/Ms was performed for the analysis of lysates of microdissected hepatocellular altered foci (AF), adenomas (HCAs), carcinomas (HCCs) and peri-tumoral livers from C57Bl/6J mice treated with diethylnitrosamine (DEN) and then maintained for 27 or 38 weeks on basal diet. Significant overexpression of 18.5 kDa CNPY2 processed form was demonstrated in AF, HCAs and HCCs, while low expression was observed in the livers of DEN-treated and control mice. Furthermore, CNPY2 elevation in AF and tumors was coordinated with accumulation of numerous cytoskeletal proteins, including cytokeratins 8 and 18, actin, non-muscle myosin and septin 9 and those involved in ER and mitochondrial stresses such as calreticulin, prohibitins 1 and 2 and YME1-like-1. Knockdown of CNPY2 in Huh7 and HepG2 human liver cancer cells resulted in significant suppression of cell survival and invasive potential, inhibition of cyclin D1, induction of p21Waf1/Cip1 and suppression of the apoptosis inhibitor Bcl2. In contrast, transfection of a mouse CNPY2 (mCNPY2-Ds-Red) vector plasmid in Huh7 and HepG2 cancer cells, with subsequent accumulation of CNPY2 in the ER, resulted in significant increase in cancer cells survival. Clinicopathological analysis in 90 HCV-positive HCC patients, revealed significant association of CNPY2 overexpression with poor overall (p = 0.041) survival. Furthermore, CNPY2 increase was associated with vessel invasion (p = 0.038), poor histological differentiation (p = 0.035) and advanced clinical stage (p = 0.016). In conclusion, CNPY2 is a promising molecular target elevated early in hepatocarcinogenesis and prognostic marker for human HCV-associated HCC. CNPY2 is involved in the processes of ER stress, cell cycle progression, proliferation, survival and invasion of liver tumor cells.
Risk Score Generated from CT-Based Radiomics Signatures for Overall Survival Prediction in Non-Small Cell Lung Cancer
Authors: Le Viet-Huan , Kha Quang-Hien , Hung Truong Nguyen Khanh , Le Nguyen Quoc Khanh
Published: July 2021

This study aimed to create a risk score generated from CT-based radiomics signatures that could be used to predict overall survival in patients with non-small cell lung cancer (NSCLC). We retrospectively enrolled three sets of NSCLC patients (including 336, 84, and 157 patients for training, testing, and validation set, respectively). A total of 851 radiomics features for each patient from CT images were extracted for further analyses. The most important features (strongly linked with overall survival) were chosen by pairwise correlation analysis, Least Absolute Shrinkage and Selection Operator (LASSO) regression model, and univariate Cox proportional hazard regression. Multivariate Cox proportional hazard model survival analysis was used to create risk scores for each patient, and Kaplan–Meier was used to separate patients into two groups: high-risk and low-risk, respectively. ROC curve assessed the prediction ability of the risk score model for overall survival compared to clinical parameters. The risk score, which developed from ten radiomics signatures model, was found to be independent of age, gender, and stage for predicting overall survival in NSCLC patients (HR, 2.99; 95% CI, 2.27–3.93; p < 0.001) and overall survival prediction ability was 0.696 (95% CI, 0.635–0.758), 0.705 (95% CI, 0.649–0.762), 0.657 (95% CI, 0.589–0.726) (AUC) for 1, 3, and 5 years, respectively, in the training set. The risk score is more likely to have a better accuracy in predicting survival at 1, 3, and 5 years than clinical parameters, such as age 0.57 (95% CI, 0.499–0.64), 0.552 (95% CI, 0.489–0.616), 0.621 (95% CI, 0.544–0.689) (AUC); gender 0.554, 0.546, 0.566 (AUC); stage 0.527, 0.501, 0.459 (AUC), respectively, in 1, 3 and 5 years in the training set. In the training set, the Kaplan–Meier curve revealed that NSCLC patients in the high-risk group had a lower overall survival time than the low-risk group (p < 0.001). We also had similar results that were statistically significant in the testing and validation set. In conclusion, risk scores developed from ten radiomics signatures models have great potential to predict overall survival in NSCLC patients compared to the clinical parameters. This model was able to stratify NSCLC patients into high-risk and low-risk groups regarding the overall survival prediction.
ArtiSential® Articulated Wrist-Like Instruments and Their First Application in Pediatric Minimally Invasive Surgery: Case Reports and Literature Review of the Most Commonly Available Robot-Inspired Devices
Authors: Parente Giovanni , Thomas Eduje , Cravano Sara , Di Mitri Marco , Vastano Marzia , Gargano Tommaso , Cerasoli Tosca , Ruspi Francesca , Libri Michele , Lima Mario
Published: July 2021

Background: Robotic surgery is currently a reality in surgical practice, and many endeavors have been made to extend its application also in pediatric surgery. In the absence of easy access to a robotic surgical system, new devices have been developed to offer a valid alternative such as wristed instruments. These differ from conventional laparoscopic instruments owing to a wrist-like mechanism at the tip, which faithfully reproduces the movements of the surgeon’s hands, regaining more movement’s degrees; Methods: We present two case reports in which the patients were subjected to minimally invasive procedures with aid of wristed instruments, followed by a review of the literature regarding the devices commonly marketed; Results: Articulated or wristed instruments render the same features seen in robotic surgery, such as major dexterity in smaller spaces, restitution of more natural movements and the ability to get over obstacles in a direct visual line. Our center recently equipped with ArtiSential® articulated instruments and so far, they have proven to be of great value; Conclusions: wristed instruments could represent a standpoint for surgeons wanting to benefit from the advantages of robotic surgery with a cost-sensitive perspective.
The Epidemic of Obesity in a Pandemic Era: Urgency to Invest in Adolescent Health
Authors: Bacopoulou Flora
Published: July 2021

In September 2015, United Nations’ 193 member states signed up to the Sustainable Development Goals (SDGs) of the global development agenda 2030 [...]
Neglecting Maternal Depression Compromises Child Health and Development Outcomes, and Violates Children’s Rights in South Africa
Authors: Mokwena Kebogile Elizabeth
Published: July 2021

The intention of the South African Children’s Act 38 of 2005 is to provide guarantees for the protection and promotion of optimum health and social outcomes for all children. These guarantees are the provision of basic nutrition, basic health care and social services, optimal family or parental care, as well as protection from maltreatment, neglect and abuse services. However, despite these guarantees, child and maternal mortality remain high in South Africa. The literature identifies maternal depression as a common factor that contributes to negative health and social outcomes for both mothers and their children. Despite the availability of easy-to-use tools, routine screening for maternal depression is not carried out in public health services, which is the source of services for the majority of women in South Africa. The results are that the mothers miss out on being diagnosed and treated for maternal depression, which results in negative child outcomes, such as malnutrition, as well as impacts on mental, social and physical health, and even death. The long-term impacts of untreated maternal depression include compromised child cognitive development, language acquisition and deviant behaviors and economic disadvantage in later life. The author concludes that the neglect of screening for, and treatment of maternal depression therefore violates the constitutional rights of the affected children, and goes against the spirit of the Constitution. The author recommends that maternal and child health services integrate routine screening for maternal depression, which will not only satisfy the Constitutional mandate, but also improve the health and developmental outcomes of the children and reduce child mortality.
Clean Technol. 2021 Young Investigator Award: Announcement and Interview with the Winner
Authors:   Clean Technologies Editorial Office
Published: July 2021

After an extensive voting period, we are pleased to present the winner of the Clean Technol [...]
Trends of Hydroclimatic Intensity in Colombia
Authors: Mesa Oscar , Urrea Viviana , Ochoa Andrés
Published: July 2021

Prediction of precipitation changes caused by global climate change is a practical and scientific problem of high complexity. To advance, we look at the record of all available rain gauges in Colombia and at the CHIRPS database to estimate trends in essential variables describing precipitation, including HY-INT, an index of the hydrologic cycle’s intensity. Most of the gauges and cells do not show significant trends. Moreover, the signs of the statistically significant trends are opposite between the two datasets. Satisfactory explanation for the discrepancy remains open. Among the CHIRPS database’s statistically significant trends, the western regions (Pacific and Andes) tend to a more intense hydrologic cycle, increasing both intensity and mean dry spell length, whereas for the northern and eastern regions (Caribbean, Orinoco, and Amazon), the tendencies are opposite. This dipole in trends suggests different mechanisms: ENSO affects western Colombia more directly, whereas rainfall in the eastern regions depends more on the Atlantic Ocean, Caribbean Sea, and Amazon basin dynamics. Nevertheless, there is countrywide accord among gauges and cells with significant increasing trends for annual precipitation. Overall, these observations constitute essential evidence of the need for developing a more satisfactory theory of climate change effects on tropical precipitation.
Effective-Field Theory for Model High-Tc Cuprates
Authors: Moskvin Alexander , Panov Yuri
Published: July 2021

Starting with a minimal model for the CuO2 planes with the on-site Hilbert space reduced to only three effective valence centers [CuO4]7−,6−,5− (nominally Cu1+,2+,3+) with different conventional spin and different orbital symmetry, we propose a unified non-BCS model that allows one to describe the main features of the phase diagrams of doped cuprates within the framework of a simple effective field theory. Unconventional bosonic superconducting phase related with a two-particle quantum transport is shown to compete with antiferromagnetic insulating phase, charge order, and metallic Fermi liquid via phase separation regime.
Neurocosmetics in Skincare—The Fascinating World of Skin–Brain Connection: A Review to Explore Ingredients, Commercial Products for Skin Aging, and Cosmetic Regulation
Authors: Rizzi Vito , Gubitosa Jennifer , Fini Paola , Cosma Pinalysa
Published: July 2021

The “modern” cosmetology industry is focusing on research devoted to discovering novel neurocosmetic functional ingredients that could improve the interactions between the skin and the nervous system. Many cosmetic companies have started to formulate neurocosmetic products that exhibit their activity on the cutaneous nervous system by affecting the skin’s neuromediators through different mechanisms of action. This review aims to clarify the definition of neurocosmetics, and to describe the features of some functional ingredients and products available on the market, with a look at the regulatory aspect. The attention is devoted to neurocosmetic ingredients for combating skin stress, explaining the stress pathways, which are also correlated with skin aging. “Neuro-relaxing” anti-aging ingredients derived from plant extracts and neurocosmetic strategies to combat inflammatory responses related to skin stress are presented. Afterwards, the molecular basis of sensitive skin and the suitable neurocosmetic ingredients to improve this problem are discussed. With the aim of presenting the major application of Botox-like ingredients as the first neurocosmetics on the market, skin aging is also introduced, and its theory is presented. To confirm the efficacy of the cosmetic products on the market, the concept of cosmetic claims is discussed.
Photoluminescent Properties of Hydroxyapatite and Hydroxyapatite/Multi-Walled Carbon Nanotube Composites
Authors: Figueroa-Rosales Edna X. , Martínez-Juárez Javier , García-Díaz Esmeralda , Hernández-Cruz Daniel , Sabinas-Hernández Sergio A. , Robles-Águila Maria J.
Published: July 2021

Hydroxyapatite (HAp) and hydroxyapatite/multi-walled carbon nanotube (MWCNT) composites were obtained by the co-precipitation method, followed by ultrasound-assisted and microwave radiation and thermal treatment at 250 °C. X-ray diffraction (XRD) confirmed the presence of a hexagonal phase in all the samples, while Fourier-transform infrared (FTIR) spectroscopy elucidated the interaction between HAp and MWCNTs. The photoluminescent technique revealed that HAp and the composite with non-functionalized MWCNTs present a blue luminescence, while the composite with functionalized MWCNTs, under UV-vis radiation shows an intense white emission. These findings allowed presentation of a proposal for the use of HAp and HAp with functionalized MWCNTs as potential materials for optoelectronic and medical applications.
Patterns and Predictors of First-Line Taxane Use in Patients with Metastatic Triple-Negative Breast Cancer in US Clinical Practice
Authors: O’Shaughnessy Joyce , Emens Leisha A. , Chui Stephen Y. , Wang Wei , Russell Kenneth , Lin Shih-Wen , Flores Avile Carlos , Luhn Patricia , Schneeweiss Andreas
Published: July 2021

We investigated first-line (1L) treatment patterns and predictors of taxane use to better understand the evolving metastatic triple-negative breast cancer (mTNBC) treatment landscape. This retrospective analysis of the Truven Health MarketScan® (Somers, NY, USA) Database included women with mTNBC who received 1L therapy within six months of diagnosis (January 2005–June 2015). Multivariate logistic regression models identified predictors of taxane use, adjusting for prognostic factors. A total of 2271 women with newly diagnosed mTNBC received 1L treatment during the study period. Half received a 1L taxane (53%), more often in combination than as monotherapy (58% versus 42%), though this varied by specific taxane. Nab-Paclitaxel monotherapy increased substantially after 2010. More recent treatment year (odds ratio, 2.16 (95% CI 1.69–2.76]) and number of metastases (≥3 versus 1: 1.73 (1.25–2.40)) predicted taxane monotherapy versus combination. Having a health maintenance organization versus a preferred provider organization plan predicted less nab-paclitaxel versus paclitaxel (0.32 (0.13–0.80)) or docetaxel (0.30 (0.10–0.89)) use. More recent index year (2011–2015 vs. 2005–2010) was the only predictor favoring nab-paclitaxel versus paclitaxel (2.01 (1.26–3.21)) or docetaxel (3.63 (2.11–6.26)). Taxane-containing regimens remained the most common 1L mTNBC treatments. Paclitaxel and nab-paclitaxel use changed substantially over time, with nab-paclitaxel use associated with insurance coverage.
Discrimination of Cancer Stem Cell Markers ALDH1A1, BCL11B, BMI-1, and CD44 in Different Tissues of HNSCC Patients
Authors: Sharaf Kariem , Lechner Axel , Haider Stefan P. , Wiebringhaus Robert , Walz Christoph , Kranz Gisela , Canis Martin , Haubner Frank , Gires Olivier , Baumeister Philipp
Published: July 2021

Cancer stem cells (CSCs) are accountable for the progress of head and neck squamous cell carcinoma (HNSCC). This exploratory study evaluated the expression of molecular CSC markers in different tissues of HNSCC patients. Tissue specimens of primary tumor, lymph node metastases and macroscopically healthy mucosa of 12 consecutive HNSCC patients, that were treated with surgery and adjuvant radio(chemo)therapy upon indication, were collected. Samples were assessed for the expression of p16 as a surrogate for HPV-related disease and different molecular stem cell markers (ALDH1A1, BCL11B, BMI-1, and CD44). In the cohort, seven patients had HPV-related HNSCC; six thereof were oropharyngeal squamous cell carcinoma. While expression of BMI-1 and BCL11B was significantly lower in healthy mucosa than both tumor and lymph node metastasis, there were no differences between tumor and lymph node metastasis. In the HPV-positive sub-cohort, these differences remained significant for BMI-1. However, no significant differences in these three tissues were found for ALDH1A1 and CD44. In conclusion, this exploratory study shows that CSC markers BMI-1 and BCL11B discriminate between healthy and cancerous tissue, whereas ALDH1A1 and CD44 were expressed to a comparable extent in healthy mucosa and cancerous tissues.
Diversity Loss in Coralligenous Structuring Species Impacted by Fishing Gear and Marine Litter
Authors: Ferrigno Federica , Appolloni Luca , Donnarumma Luigia , Di Stefano Floriana , Rendina Francesco , Sandulli Roberto , Russo Giovanni Fulvio
Published: July 2021

Coralligenous structuring species (CSS) form a group of marine megabenthic species with an engineering capacity. Since they are highly vulnerable to anthropogenic activities, they have been selected for the Marine Strategy Framework Directive (MSFD) monitoring programs. The pressure and impact of fishing gear and marine litter on these species were evaluated through the image analysis of 54 remotely operated vehicle (ROV) routes along the Campania coasts (Tyrrhenian Sea, Italy). CSS density was calculated as the number of colonies/100 m2. Anthropogenic pressure was estimated as the frequency of frames showing longline, nets, other gear, plastic objects, metal objects, and other litter; while the impact was expressed as the frequency showing necrosis/epibiosis, broken/upturned and covered/entangled colonies. Cnidaria dominate in the Napoli, Campanella and Capri areas, while Bryozoa dominate in Cilento N and Cilento S areas. Campanella and Capri appeared to be the least heterogeneous despite their higher CSS densities, which was possibly related to the dominance of a few species. These areas were the most affected by showing the highest numbers of fishing gear (longlines) and marine litter (metal objects) recorded, amongst which longlines are the most abundant. In addition, these fishing areas are either close to a large urban center or located along popular touristic routes. In all the areas, colonies with necrosis/epibiosis (CNE) impact are present with low-moderate values, while the category gears covering/entangling (GCE) impact prevails in the Campanella and Capri areas, and this is strictly connected to the high presence of fishing gear.