bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-Level Laser Irradiation Stimulates RANKL-Induced Osteoclastogenesis via the MAPK Pathway in RAW 264.7 Cells
Authors: Song Jae-Min , Park Bong-Soo , Shin Sang-Hun , Kim In-Ryoung
Published: June 2021

Low-level laser therapy (LLLT) is recognized as an effective medical tool for the treatment of various conditions requiring tissue repair, pain relief, inflammation treatment, and restoration of tissue dysfunction, and its development and research are growing rapidly. However, studies that analyze molecular biology by applying LLLT to osteoclasts are still insufficient to understand the mechanism. In order for LLLT to be suggested as an appropriate treatment method for the treatment of various bone diseases, it is necessary to elucidate the effect and mechanism of LLLT on osteoclast differentiation. In this study, we investigated the effect of LLLT on osteoclast differentiation using murine macrophage (RAW 264.7) cells by means of a Ga-As-Al laser (λ = 810, 80 mW). Our results indicate that LLLT did not induce cytotoxicity in RAW 264.7 cells. When LLLT was applied for 15 s to osteoclasts exposed to RANKL, the expression of NF-κB, ERK, p38, and c-Fos, which are associated with expression of NFATc1, was increased. The RT-PCR results also demonstrated significantly increased expression of osteoclast-specific genes, including NFATc1, TRAP, the calcitonin receptor, and cathepsin K, compared with the control. Taken together, we concluded that low-level laser irradiation induces osteoclastogenesis by enhancing the expression of NF-κB, MAPKs (ERK, p38), c-Fos, and NFATc1 in RAW 264.7 cells. These findings indicate that low-level laser irradiation could be considered a potential treatment option in various metabolic bone diseases that require osteoclastic activity and bone formation.
Current Status and Future Developments of Micromegas Detectors for Physics and Applications
Authors: Attié David , Aune Stephan , Berthoumieux Eric , Bossù Francesco , Colas Paul , Delbart Alain , Dupont Emmeric , Ribas Esther Ferrer , Giomataris Ioannis , Glaenzer Aude , Gómez Hector , Gunsing Frank , Jambon Fanny , Jeanneau Fabien , Lehuraux Marion , Neyret Damien , Papaevangelou Thomas , Pollacco Emanuel , Procureur Sébastien , Revolle Maxence , Schune Philippe , Segui Laura , Sohl Lukas , Vandenbroucke Maxence , Wu Zhibo
Published: June 2021

Micromegas (MICRO-MEsh GAseous Structure) detectors have found common use in different applications since their development in 1996 by the group of I. Giomataris and G. Charpak. In this review article, we present implementations of Micromegas sub-detectors in different physics experiments and highlight the current state of development for innovative detection concepts with Micromegas.
Robo-HUD: Interaction Concept for Contactless Operation of Industrial Cobotic Systems
Authors: Strazdas Dominykas , Hintz Jan , Al-Hamadi Ayoub
Published: June 2021

Intuitive and safe interfaces for robots are challenging issues in robotics. Robo-HUD is a gadget-less interaction concept for contactless operation of industrial systems. We use virtual collision detection based on time-of-flight sensor data, combined with augmented reality and audio feedback, allowing the operators to navigate a virtual menu by “hover and hold” gestures. When incorporated with virtual safety barriers, the collision detection also functions as a safety feature, slowing or stopping the robot if a barrier is breached. Additionally, a user focus recognition module monitors the awareness, enabling the interaction only when intended. Early case studies show that these features present good use-cases for inspection tasks and operation in difficult environments, where contactless operation is needed.
Thermal and Mechanical Behavior of Elastomers Incorporated with Thermoregulating Microcapsules
Authors: Borreguero Ana M. , Izarra Irene , Garrido Ignacio , Trzebiatowska Patrycja J. , Datta Janusz , Serrano Ángel , Rodríguez Juan F. , Carmona Manuel
Published: June 2021

Polyurethane (PU) is one of the principal polymers in the global plastic market thanks to its versatility and continuous improvement. In this work, PU elastomeric materials having thermoregulating properties through the incorporation of microcapsules (mSD-(LDPE·EVA-RT27)) from low-density polyethylene and vinyl acetate containing paraffin®RT27 as PCM were produced. Elastomers were synthesized while varying the molar ratio [NCO]/[OH] between 1.05 and 1.1 and the microcapsule (MC) content from 0.0 to 20.0 wt.%. The successful synthesis of the PUs was confirmed by IR analyses. All the synthesized elastomers presented a structure formed by a net of spherical microparticles and with a minimum particle size for those with 10 wt.% MC. The density and tensile strength decreased with the MC content, probably due to worse distribution into the matrix. Elastomer E-1.05 exhibited better structural and stability properties for MC contents up to 15 wt.%, whereas E-1.1, containing 20 wt.% MC, revealed mechanical and thermal synergy effects, demonstrating good structural stability and the largest latent heat. Hence, elastomers having a large latent heat (8.7 J/g) can be produced by using a molar ratio [NCO]/[OH] of 1.1 and containing 20 wt.% mSD-(LDPE·EVA-RT27).
Sound Absorbing and Insulating Low-Cost Panels from End-of-Life Household Materials for the Development of Vulnerable Contexts in Circular Economy Perspective
Authors: Neri Manuela , Levi Elisa , Cuerva Eva , Pardo-Bosch Francesc , Zabaleta Alfredo Guardo , Pujadas Pablo
Published: June 2021

From a construction point of view, neighborhoods with residents living at or below the poverty threshold are characterized by low energy efficiency buildings, in which people live in acoustic discomfort with no viable options for home improvements, as they usually can not afford the materials and labor costs associated. An alternative to this is to use low-cost insulating elements made of non-conventional materials with acceptable acoustic properties. Given that household materials at their end-of-life (EoLHM) are free of costs and available also to the more disadvantaged population, they can be used to build acoustic panels for such contexts. This approach embraces several benefits since it reduces the amount of waste produced, the footprint deriving from the extraction of new raw materials and, by highlighting the potential of the EoLHM, discourages the abandonment of waste. In this paper, the acoustic properties of EoLHM, such as cardboard, egg-cartons, clothes, metal elements and combinations of them, are investigated by means of the impedance tube technique. The measured sound absorption coefficient and transmission loss have shown that EoLHM can be used for the realization of acoustic panels. However, since none of the analyzed materials shows absorbing and insulating properties at the same time, EoLHM must be wisely selected. This innovative approach supports the circular economy and the improvement for the living condition of low-income households.
IoT Open-Source Architecture for the Maintenance of Building Facilities
Authors: Villa Valentina , Naticchia Berardo , Bruno Giulia , Aliev Khurshid , Piantanida Paolo , Antonelli Dario
Published: June 2021

The introduction of the Internet of Things (IoT) in the construction industry is evolving facility maintenance (FM) towards predictive maintenance development. Predictive maintenance of building facilities requires continuously updated data on construction components to be acquired through integrated sensors. The main challenges in developing predictive maintenance tools for building facilities is IoT integration, IoT data visualization on the building 3D model and implementation of maintenance management system on the IoT and building information modeling (BIM). The current 3D building models do not fully interact with IoT building facilities data. Data integration in BIM is challenging. The research aims to integrate IoT alert systems with BIM models to monitor building facilities during the operational phase and to visualize building facilities’ conditions virtually. To provide efficient maintenance services for building facilities this research proposes an integration of a digital framework based on IoT and BIM platforms. Sensors applied in the building systems and IoT technology on a cloud platform with opensource tools and standards enable monitoring of real-time operation and detecting of different kinds of faults in case of malfunction or failure, therefore sending alerts to facility managers and operators. Proposed preventive maintenance methodology applied on a proof-of-concept heating, ventilation and air conditioning (HVAC) plant adopts open source IoT sensor networks. The results show that the integrated IoT and BIM dashboard framework and implemented building structures preventive maintenance methodology are applicable and promising. The automated system architecture of building facilities is intended to provide a reliable and practical tool for real-time data acquisition. Analysis and 3D visualization to support intelligent monitoring of the indoor condition in buildings will enable the facility managers to make faster and better decisions and to improve building facilities’ real time monitoring with fallouts on the maintenance timeliness.
AIM-E: E-Region Auroral Ionosphere Model
Authors: Nikolaeva Vera , Gordeev Evgeny , Sergienko Tima , Makarova Ludmila , Kotikov Andrey
Published: June 2021

The auroral oval is the high-latitude region of the ionosphere characterized by strong variability of its chemical composition due to precipitation of energetic particles from the magnetosphere. The complex nature of magnetospheric processes cause a wide range of dynamic variations in the auroral zone, which are difficult to forecast. Knowledge of electron concentrations in this highly turbulent region is of particular importance because it determines the propagation conditions for the radio waves. In this work we introduce the numerical model of the auroral E-region, which evaluates density variations of the 10 ionospheric species and 39 reactions initiated by both the solar extreme UV radiation and the magnetospheric electron precipitation. The chemical reaction rates differ in more than ten orders of magnitude, resulting in the high stiffness of the ordinary differential equations system considered, which was solved using the high-performance Gear method. The AIM-E model allowed us to calculate the concentration of the neutrals NO, N(4S), and N(2D), ions N+, N2+, NO+, O2+, O+(4S), O+(2D), and O+(2P), and electrons Ne, in the whole auroral zone in the 90‒150 km altitude range in real time. The model results show good agreement with observational data during both the quiet and disturbed geomagnetic conditions.
Management of Residual Hearing with Cartilage Conduction Hearing Aid after Lateral Temporal Bone Resection: Our Institutional Experience
Authors: Komune Noritaka , Higashino Yoshie , Ishikawa Kazuha , Tabuki Tomoko , Masuda Shogo , Koike Kensuke , Hongo Takahiro , Sato Kuniaki , Uchi Ryutaro , Miyazaki Masaru , Shimamoto Ryo , Tsuchihashi Nana Akagi , Kogo Ryunosuke , Noda Teppei , Matsumoto Nozomu , Nakagawa Takashi
Published: June 2021

Background: There is no guideline for hearing compensation after temporal bone resection. This study aimed to retrospectively analyze surgical cases with reconstruction for hearing preservation after temporal bone malignancy resection and propose a new alternative to compensate for hearing loss. Methods: We retrospectively reviewed the medical records of 30 patients who underwent lateral temporal bone surgery for temporal bone malignancy at our institution and examined their hearing abilities after surgery. Result: The hearing outcomes of patients with an external auditory meatus reconstruction varied widely. The mean postoperative air–bone gap at 0.5, 1, 2, and 4 kHz ranged from 22.5 dB to 71.25 dB. On the other hand, the average difference between the aided sound field thresholds with cartilage conduction hearing aid and bone conduction thresholds at 0.5, 1, 2, and 4 kHz ranged from −3.75 to 41.25. More closely located auricular cartilage and temporal bone resulted in smaller differences between the aided sound field and bone conduction thresholds. Conclusions: There is still room for improvement of surgical techniques for reconstruction of the auditory meatus to preserve hearing after temporal bone resection. The cartilage conduction hearing aid may provide non-invasive postoperative hearing compensation after lateral temporal bone resection.
An Antagonistic Peptide of Gpr1 Ameliorates LPS-Induced Depression through the Hypothalamic-Pituitary-Ovarian Axis
Authors: Li Rongrong , Ma Chiyuan , Xiong Yue , Zhao Huashan , Yang Yali , Xue Li , Wang Baobei , Xiao Tianxia , Chen Jie , Lei Xiaohua , Ma Baohua , Zhang Jian
Published: June 2021

Depression affects the reproductive axis at the hypothalamus and pituitary levels, which has a significant impact on female fertility. It has been reported that G protein-coupled receptor 1 (Gpr1) mRNA is expressed in both the hypothalamus and ovaries. However, it is unclear whether there is a relationship between Gpr1 and depression, and its role in ovarian function is unknown. Here, the expression of Gpr1 was recorded in the hypothalamus of normal female mice, and co-localized with gonadotrophin-releasing hormone (GnRH) and corticotropin-releasing factor (CRF). We established a depression mouse model to evaluate the antidepressant effect of G5, an antagonistic peptide of Gpr1. The results show that an intraperitoneal injection of G5 improves depressant–like behaviors remarkably, including increased sucrose intake in the sucrose preference test and decreased immobility time in the forced swimming tests. Moreover, G5 treatment increased the release of reproductive hormone and the expression of ovarian gene caused by depression. Together, our findings reveal a link between depression and reproductive diseases through Gpr1 signaling, and suggest antagonistic peptide of Gpr1 as a potential therapeutic application for hormone-modulated depression in women.
RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 Activation
Authors: Yue Chia-Herng , Oner Muhammet , Chiu Chih-Yuan , Chen Mei-Chih , Teng Chieh-Lin , Wang Hsin-Yi , Hsieh Jer-Tsong , Lai Chih-Ho , Lin Ho
Published: June 2021

Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the parafollicular C-cells, which produces the hormone calcitonin. RET is a transmembrane receptor protein-tyrosine kinase, which is highly expressed in MTC. Our previous studies reported that cyclin-dependent kinase 5 (CDK5) plays a crucial role in cancer progression, including MTC. However, the role of CDK5 in GDNF-induced RET signaling in medullary thyroid cancer proliferation remains unknown. Here, we investigated RET activation and its biochemically interaction with CDK5 in GDNF-induced medullary thyroid cancer proliferation. Our results demonstrated that GDNF stimulated RET phosphorylation and thus subsequently resulted in CDK5 activation by its phosphorylation. Activated CDK5 further caused STAT3 activation by its specific phosphorylation at Ser727. Moreover, we also found that GDNF treatment enhanced ERK1/2 and EGR1 activity, which is involved in p35 activation. Interestingly, we identified for the first time that CDK5 physically interacted with RET protein in MTC. Overall, our results provide a new mechanism for medullary thyroid cancer cell proliferation, suggesting that targeting CDK5 may be a promising therapeutic candidate for human medullary thyroid cancer in the near future.
Novel Treatment Strategy Using Second-Generation Androgen Receptor Inhibitors for Non-Metastatic Castration-Resistant Prostate Cancer
Authors: Chung Doo Yong , Ha Jee Soo , Cho Kang Su
Published: June 2021

Non-metastatic castration-resistant prostate cancer (nmCRPC) is defined by a progressively rising prostate-specific antigen level, despite a castrate level of testosterone, in the absence of obvious radiologic evidence of metastatic disease on conventional imaging modalities. As a significant proportion of patients with nmCRPC develop metastatic diseases, the therapeutic goals of physicians for these patients are to delay metastasis development, preserve quality of life, and increase overall survival (OS). Since 2018, the treatment of nmCRPC has changed dramatically with the introduction of second-generation androgen receptor inhibitors, such as enzalutamide (ENZA), apalutamide (APA), and darolutamide (DARO). These drugs demonstrated substantial improvements in metastasis-free survival (MFS) and OS in phase III randomized clinical trials. In addition, these drugs have an excellent safety profile, preserve quality of life, and can delay disease-related symptoms. A recently published indirect meta-analysis reported that APA and ENZA showed better findings in MFS and that DARO had relatively fewer adverse effects. However, in the absence of a direct comparison, careful interpretation is required. Thus, APA, ENZA, and DARO should be considered the new standard drugs for treating nmCRPC.
Telomerase Reverse Transcriptase Increases Proliferation and Lifespan of Human NK Cells without Immortalization
Authors: Streltsova Maria A. , Ustiuzhanina Maria O. , Barsov Eugene V. , Kust Sofya A. , Velichinskii Rodion A. , Kovalenko Elena I.
Published: June 2021

NK cells are the first line of defense against viruses and malignant cells, and their natural functionality makes these cells a promising candidate for cancer cell therapy. The genetic modifications of NK cells, allowing them to overcome some of their inherent limitations, such as low proliferative potential, can enable their use as a therapeutic product. We demonstrate that hTERT-engineered NK cell cultures maintain a high percentage of cells in the S/G2 phase for an extended time after transduction, while the life span of NK cells is measurably extended. Bulk and clonal NK cell cultures pre-activated in vitro with IL-2 and K562-mbIL21 feeder cells can be transduced with hTERT more efficiently compared with the cells activated with IL-2 alone. Overexpressed hTERT was functionally active in transduced NK cells, which displayed upregulated expression of the activation marker HLA-DR, and decreased expression of the maturation marker CD57 and activating receptor NKp46. Larger numbers of KIR2DL2/3+ cells in hTERT-engineered populations may indicate that NK cells with this phenotype are more susceptible to transduction. The hTERT-modified NK cells demonstrated a high natural cytotoxic response towards K562 cells and stably expressed Ki67, a proliferation marker. Overall, our data show that ectopic hTERT expression in NK cells enhances their activation and proliferation, extends in vitro life span, and can be a useful tool in developing NK-based cancer cell therapies.
The Effect of Different Concentrations of Halothane Anaesthesia on the Electroencephalograph of Rock Doves (Columba livia)
Authors: Lehmann Heidi S. , Beausoleil Ngaio J. , Kongara Kavitha , Singh Preet M. , Musk Gabrielle C. , Johnson Craig B.
Published: June 2021

Anaesthetic agents and doses used can significantly impact cerebrocortical responsiveness as assessed by electroencephalography (EEG). The objective of this study was to evaluate the effect of three different halothane concentrations on the EEG of Rock Doves using measures of frequency distribution and burst suppression. Eight healthy Rock Doves (Columba livia) were anaesthetized with halothane in oxygen, their tracheas intubated and their lungs mechanically ventilated. Five minutes of EEG were recorded at three multiples of minimum anaesthetic concentration (MAC), 1× MAC (1.6%), 1.5× MAC (2.4%) and 2× MAC (3.2%), presented in ascending then descending order. Fast Fourier transformation of the raw EEG record gave the median frequency (F50), spectral edge frequency (F95) and the total power (Ptot). Burst suppression, expressed as inactive compared to active EEG (%), was calculated on a representative two-minute section of the raw EEG. Data were analysed using repeated-measures one-way ANOVA with Tukey post hoc correction for comparison of 1×, 1.5× and 2× MAC. Three of eight birds demonstrated negligible (<1%) burst suppression. No effect of halothane concentration on burst suppression incidence was seen. A significant decrease in all measured frequency variables (F50, p = 0.04; F95p = 0.02; Ptotp < 0.0001) occurred between 1× and 2× MAC. Halothane anaesthesia at MAC multiples of 1×, 1.5× and 2× in the Rock Dove can be considered suitable where cortical responsiveness is desired.
BIM-Based Energy Analysis and Sustainability Assessment—Application to Portuguese Buildings
Authors: Carvalho José , Almeida Manuela , Bragança Luís , Mateus Ricardo
Published: June 2021

Buildings are responsible for several negative impacts on the environment, most of them related to nonrenewable energy consumption, increasing the concern regarding buildings energy efficiency. In this context, computer software has been used to estimate the energy needs of the built environment, and the Building Information Modelling (BIM) methodology can be used to simplify this process. This study aims to validate a BIM-based framework to streamline the energy analysis of Portuguese buildings, based on the method of the national regulation for the thermal performance of residential buildings. Currently, designers need to spend considerable time assessing all the building characteristics and performing the mandatory calculations for energy performance analysis. It is also intended to link the results of the energy simulation with a Building Sustainability Assessment method—SBToolPT-H. The purpose is to demonstrate how it is possible to benefit from this approach to simultaneously improve building sustainability during the design stage. To do so, different case studies were modelled in Autodesk Revit and exported to a BIM energy tool to perform energy simulation analysis. The results were validated against the official assessment method of the Portuguese thermal regulation and were successfully used to assess the SBToolPT-H energy efficiency category. The research outcomes provide design teams with a reliable BIM-based framework to improve building energy performance and to develop thermal projects while enhancing building sustainability. It also increases the knowledge about the integration of sustainability assessment in the BIM environment, providing new insights for complete integration.
Analysis of Incorporating a Phase Change Material in a Roof for the Thermal Management of School Buildings in Hot-Humid Climates
Authors: Hwang Ruey-Lung , Chen Bi-Lian , Chen Wei-An
Published: June 2021

Strategies to reduce energy consumption are presently experiencing vigorous development. Phase change materials (PCMs) are novel materials that can reduce indoor temperatures via the change in material phase. Regarding the situation in Taiwan, there is no practical utilization of PCMs in school buildings at present, especially in combination with rooftops. In this paper, we discuss the feasibility and utilization potential of installing PCMs in the rooftops of school buildings. School buildings located in northern and southern Taiwan (Taipei and Kaohsiung) were selected to analyze the energy-saving potential and optimization of indoor thermal comfort by installing PCMs with different properties in rooftops over two time periods, including the air conditioning (AC) and natural ventilation (NV) seasons. Based on the simulation results, the feasible patterns of PCM simultaneity are found to be appropriate for improved indoor comfort and energy saving during the different seasons. Specifically, the efficient phase change temperature (PCT) for different PCM thicknesses is clarified to be 29 °C. The economic thickness of PCM was clarified to be 20 mm for Taipei and Kaohsiung. Through the recommendations proposed in this study, it is expected that the PCMs may be efficiently implemented in school buildings to realize the goal of energy conservation and improve thermal comfort.
Immune Inflammation Pathways as Therapeutic Targets to Reduce Lethal Prostate Cancer in African American Men
Authors: Kiely Maeve , Ambs Stefan
Published: June 2021

Despite substantial improvements in cancer survival, not all population groups have benefitted equally from this progress. For prostate cancer, men of African descent in the United States and England continue to have about double the rate of fatal disease compared to other men. Studies suggest that when there is equal access to care, survival disparities are greatly diminished. However, notable differences exist in prostate tumor biology across population groups. Ancestral factors and disparate exposures can lead to altered tumor biology, resulting in a distinct disease etiology by population group. While equal care remains the key target to improve survival, additional efforts should be made to gain comprehensive knowledge of the tumor biology in prostate cancer patients of African descent. Such an approach may identify novel intervention strategies in the era of precision medicine. A growing body of evidence shows that inflammation and the immune response may play a distinct role in prostate cancer disparities. Low-grade chronic inflammation and an inflammatory tumor microenvironment are more prevalent in African American patients and have been associated with adverse outcomes. Thus, differences in activation of immune–inflammatory pathways between African American and European American men with prostate cancer may exist. These differences may influence the response to immune therapy which is consistent with recent observations. This review will discuss mechanisms by which inflammation may contribute to the disparate outcomes experienced by African American men with prostate cancer and how these immunogenic and inflammatory vulnerabilities could be exploited to improve their survival.
High Basal Maximal Standardized Uptake Value (SUVmax) in Follicular Lymphoma Identifies Patients with a Low Risk of Long-Term Relapse
Authors: Assanto Giovanni Manfredi , Ciotti Giulia , Brescini Mattia , De Luca Maria Lucia , Annechini Giorgia , D’Elia Gianna Maria , Agrippino Roberta , Del Giudice Ilaria , Martelli Maurizio , Chiaravalloti Agostino , Pulsoni Alessandro
Published: June 2021

Background: Despite that the unfavorable prognostic role of a high Total Metabolic Tumor Volume (TMTV) in Follicular Lymphoma has been demonstrated, the role of SUVmax alone at baseline PET/CT could have a different prognostic role. Patients and Methods: We performed a retrospective observational monocentric cohort study. All patients affected by FL who underwent a basal PET/CT were included. Two subgroups were identified and compared in terms of PFS and OS: (A) Basal SUVmax ≤ 6; and (B) Basal SUVmax > 6. Results: Ninety-four patients were included, 34 in group A (36.2%) and 60 in group B (63.8%). The PFS at two years was comparable in the two groups (97%). The five-year PFS was 73.5% for group A and 95% for group B (p 0.005). The five-year PFS in the whole cohort was 87.5%. A clear advantage was confirmed in group A in the absence of other risk factors. Patients with SUVmax ≤ 6 and no risk factors showed a 5-year PFS of 73% against 83% for patients with SUVmax > 6 and at least two risk factors. Conclusion: A high FDG uptake favorably correlated with PFS. A low basal SUVmax reflected a higher rate of late relapse requiring a prolonged follow-up. The basal SUVmax is an approachable parameter with prognostic implications.
Are Adaptive Chemotherapy Schedules Robust? A Three-Strategy Stochastic Evolutionary Game Theory Model
Authors: Dua Rajvir , Ma Yongqian , Newton Paul K.
Published: June 2021

We investigate the robustness of adaptive chemotherapy schedules over repeated cycles and a wide range of tumor sizes. Using a non-stationary stochastic three-component fitness-dependent Moran process model (to track frequencies), we quantify the variance of the response to treatment associated with multidrug adaptive schedules that are designed to mitigate chemotherapeutic resistance in an idealized (well-mixed) setting. The finite cell (N tumor cells) stochastic process consists of populations of chemosensitive cells, chemoresistant cells to drug 1, and chemoresistant cells to drug 2, and the drug interactions can be synergistic, additive, or antagonistic. Tumor growth rates in this model are proportional to the average fitness of the tumor as measured by the three populations of cancer cells compared to a background microenvironment average value. An adaptive chemoschedule is determined by using the N→∞ limit of the finite-cell process (i.e., the adjusted replicator equations) which is constructed by finding closed treatment response loops (which we call evolutionary cycles) in the three component phase-space. The schedules that give rise to these cycles are designed to manage chemoresistance by avoiding competitive release of the resistant cell populations. To address the question of how these cycles perform in practice over large patient populations with tumors across a range of sizes, we consider the variances associated with the approximate stochastic cycles for finite N, repeating the idealized adaptive schedule over multiple periods. For finite cell populations, the distributions remain approximately multi-Gaussian in the principal component coordinates through the first three cycles, with variances increasing exponentially with each cycle. As the number of cycles increases, the multi-Gaussian nature of the distribution breaks down due to the fact that one of the three sub-populations typically saturates the tumor (competitive release) resulting in treatment failure. This suggests that to design an effective and repeatable adaptive chemoschedule in practice will require a highly accurate tumor model and accurate measurements of the sub-population frequencies or the errors will quickly (exponentially) degrade its effectiveness, particularly when the drug interactions are synergistic. Possible ways to extend the efficacy of the stochastic cycles in light of the computational simulations are discussed.
Male and Female Fertility: Prevention and Monitoring Hodgkin’ Lymphoma and Diffuse Large B-Cell Lymphoma Adult Survivors. A Systematic Review by the Fondazione Italiana Linfomi
Authors: Viviani Simonetta , Caccavari Valentina , Gerardi Chiara , Ramadan Safaa , Allocati Eleonora , Minoia Carla , Guarini Attilio , Di Russo Anna
Published: June 2021

Background: Adult patients with Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL) have prolonged survival but face the risk of treatment-induced impaired fertility. This systematic review, conducted by Fondazione Italiana Linfomi (FIL) researchers, aims to evaluate the incidence of treatment-related infertility, fertility preservation options, fertility assessment measures, and the optimal interval between the end of treatment and conception. Methods: MEDLINE, the Cochrane Library, and EMBASE were systematically searched up to September 2020 for published cohort, case–control, and cross-sectional studies on fertility issues. Results: Forty-five eligible studies were identified. Gonadotoxicity was related to sex, type and dosage of treatment, and, in females, to age. After receiving alkylating-agent-containing regimens, less than 30% of males recovered spermatogenesis, and 45% of females ≥30 years in age retained regular menstrual cycles. Sperm cryopreservation was offered to the majority of patients; sperm utilization resulted in a 33–61% pregnancy rate. After ovarian tissue transplantation, the spontaneous pregnancy and live birth rates were 38% and 23%; after IVF, the live birth rate was 38.4%. No data could be extracted on the utilization rate of cryopreserved mature oocytes. The results of studies on GnRH analogs are controversial; therefore, their use should not be considered an alternative to established cryopreservation techniques. Sperm count, FSH, and inhibin-B levels were appropriate measures to investigate male fertility; serum AMH levels and antral follicle count were the most appropriate markers for ovarian reserve. No data could be found regarding the optimal interval between the end of treatment and conception. Conclusions: The risk of infertility should be discussed with adult lymphoma patients at the time of diagnosis, and fertility preservation options should be proposed before first-line treatment with alkylating-agent-containing regimens.
The Impact of Thromboprophylaxis on the Survival of Patients with Advanced Pancreatic Cancer. The Pancreatic Cancer and Tinzaparin (PaCT) Study
Authors: Karamouzis Michalis V. , Athanasiadis Ilias , Samelis Georgios , Vallilas Christos , Bokas Alexandros , Nikolaidi Adamantia , Dimitriadou Areti , Sarantis Panagiotis , Pistamaltzian Nikolaos , Schizas Dimitrios , Papalampros Alexandros , Felekouras Evangelos , Dimitroulis Dimitrios , Antoniou Eustathios , Sotiropoulos Georgios , Papakotoulas Pavlos
Published: June 2021

Pancreatic cancer (PaC) induces a prothrombotic and hypercoagulable state. The aim of this study was to investigate the effect of tinzaparin in combination with chemotherapy. The PaCT (pancreatic cancer and tinzaparin) study was a retrospective observational study that collected data regarding progression free survival (PFS) in advanced or metastatic PaC patients who received thromboprophylaxis with tinzaparin during chemotherapy with nab-paclitaxel (N) and gemcitabine (G). The primary end point was to compare, from already published data, the PFS of patients receiving thromboprophylaxis with tinzaparin with the PFS of patients receiving chemotherapy with N–G but no thromboprophylaxis. Secondary end points were efficacy and safety of anticoagulation. In total, 110 PaC patients, 93% with advanced or metastatic disease, treated with N–G and tinzaparin (10,291 ± 1176 Anti-Xa IU, OD, median duration 8.7, IQR: 5.6–11.9 months) were enrolled. Of these, 52% were males and; the median age was 68 (40–86 years). The tumor was located to in the pancreatic head at in 45% of the patients. The median PFS was 7.9 months (IQR: 5.0–11.8 months). Out of 14 similar studies (involving 2994 patients) identified via systematic search, it was determined that the weighted PFS of patients receiving N–G but no anticoagulation was 5.6 months. Therefore, patients receiving tinzaparin had 39.54% higher PFS than patients without thromboprophylaxis (p < 0.05). During the follow-up period of 18.3 ± 11.7 months, three (2.7%) thrombotic events were recorded while two clinically relevant non-major bleeding events occurred (1.9%). In conclusion, PFS in advanced PaC patients undergoing chemotherapy is positively impacted by anticoagulation. Thromboprophylaxis with tinzaparin in treatment dose is efficient and safe.
Leptomeningeal Metastases from Solid Tumors: Recent Advances in Diagnosis and Molecular Approaches
Authors: Pellerino Alessia , Brastianos Priscilla K. , Rudà Roberta , Soffietti Riccardo
Published: June 2021

Leptomeningeal metastases (LM) from solid tumors represent an unmet need of increasing importance due to an early use of MRI for diagnosis and improvement of outcome of some molecular subgroups following targeted agents and immunotherapy. In this review, we first discussed factors limiting the efficacy of targeted agents in LM, such as the molecular divergence between primary tumors and CNS lesions and CNS barriers at the level of the normal brain, brain tumors and CSF. Further, we reviewed pathogenesis and experimental models and modalities, such as MRI (with RANO and ESO/ESMO criteria), CSF cytology and liquid biopsy, to improve diagnosis and monitoring following therapy. Efficacy and limitations of targeted therapies for LM from EGFR-mutant and ALK-rearranged NSCLC, HER2-positive breast cancer and BRAF-mutated melanomas are reported, including the use of intrathecal administration or modification of traditional cytotoxic compounds. The efficacy of checkpoint inhibitors in LM from non-druggable tumors, in particular triple-negative breast cancer, is discussed. Last, we focused on some recent techniques to improve drug delivery.
An Overview on Diffuse Large B-Cell Lymphoma Models: Towards a Functional Genomics Approach
Authors: Yanguas-Casás Natalia , Pedrosa Lucía , Fernández-Miranda Ismael , Sánchez-Beato Margarita
Published: June 2021

Lymphoma research is a paradigm of the integration of basic and clinical research within the fields of diagnosis and therapy. Clinical, phenotypic, and genetic data are currently used to predict which patients could benefit from standard treatment. However, alternative therapies for patients at higher risk from refractoriness or relapse are usually empirically proposed, based on trial and error, without considering the genetic complexity of aggressive B-cell lymphomas. This is primarily due to the intricate mosaic of genetic and epigenetic alterations in lymphomas, which are an obstacle to the prediction of which drug will work for any given patient. Matching a patient’s genes to drug sensitivity by directly testing live tissues comprises the “precision medicine” concept. However, in the case of lymphomas, this concept should be expanded beyond genomics, eventually providing better treatment options for patients in need of alternative therapeutic approaches. We provide an overview of the most recent findings in diffuse large B-cell lymphomas genomics, from the classic functional models used to study tumor biology and the response to experimental treatments using cell lines and mouse models, to the most recent approaches with spheroid/organoid models. We also discuss their potential relevance and applicability to daily clinical practice.
The Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS): Design and Methodology
Authors: Legget Malcolm. , Cameron Vicky. , Poppe Katrina. , Aish Sara , Earle Nikki , Choi Yeunhyang , Bradbury Kathryn. , Wall Clare , Stewart Ralph , Kerr Andrew , Harrison Wil , Devlin Gerry , Troughton Richard , Richards A. , Porter Graeme , Gladding Patrick , Rolleston Anna , Doughty Robert
Published: June 2021

Background. Each year, approximately 5000 New Zealanders are admitted to hospital with first-time acute coronary syndrome (ACS). The Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS) is a prospective longitudinal cohort study embedded within the All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) registry in six hospitals. The objective of MENZACS is to examine the relationship between clinical, genomic, and cardiometabolic markers in relation to presentation and outcomes post-ACS. Methods. Patients with first-time ACS are enrolled and study-specific research data is collected alongside the ANZACS-QI registry. The research blood samples are stored for future genetic/biomarker assays. Dietary information is collected with a food frequency questionnaire and information about physical activity, smoking, and stress is also collected via questionnaire. Detailed family history, ancestry, and ethnicity data are recorded on all participants. Results. During the period between 2015 and 2019, there were 2015 patients enrolled. The mean age was 61 years, with 60% of patients aged <65 years and 21% were female. Ethnicity and cardiovascular (CV) risk factor distribution was similar to ANZACS-QI: 13% Māori, 5% Pacific, 5% Indian, and 74% NZ European. In terms of CV risk factors, 56% were ex-/current smokers, 42% had hypertension, and 19% had diabetes. ACS subtype was ST elevation myocardial infarction (STEMI) in 41%, non-ST elevation myocardial infarction (NSTEM) in 54%, and unstable angina in 5%. Ninety-nine percent of MENZACS participants underwent coronary angiography and 90% had revascularization; there were high rates of prescription of secondary prevention medications upon discharge from hospital. Conclusion. MENZACS represents a cohort with optimal contemporary management and will be a significant epidemiological bioresource for the study of environmental and genetic factors contributing to ACS in New Zealand’s multi-ethnic environment. The study will utilise clinical, nutritional, lifestyle, genomic, and biomarker analyses to explore factors influencing the progression of coronary disease and develop risk prediction models for health outcomes.
Surface Modification of Electrocatalyst for Optimal Adsorption of Reactants in Oxygen Evolution Reaction
Authors: Kim Hong Soo , Kim Hwapyong , Flores Monica Claire , Jung Gyu-Seok , In Su-Il
Published: June 2021

Technological development after the industrial revolution has improved the quality of human life, but global energy consumption continues to increase due to population growth and the development of fossil fuels. Therefore, numerous studies have been conducted to develop sustainable long-term and renewable alternative energy sources. The anodic electrode, which is one of the two-electrode system components, is an essential element for effective energy production. In general, precious metal-based electrocatalysts show high OER reactions from the anodic electrode, but it is difficult to scale up due to their low abundance and high cost. To overcome these problems, transition metal-based anodic electrodes, which exhibit advantages with respect to their low cost and high catalytic activities, are in the spotlight nowadays. Among them, stainless steel is a material with a high ratio of transition metal components, i.e., Fe, Ni, and Cr, and has excellent corrosion resistance and low cost. However, stainless steel shows low electrochemical performance due to its slow sluggish kinetics and lack of active sites. In this study, we fabricated surface modified electrodes by two methods: (i) anodization and (ii) hydrogen peroxide (H2O2) immersion treatments. As a result of comparing the two methods, the change of the electrode surface and the electrochemical properties were not confirmed in the H2O2 immersion method. On the other hand, the porous electrode (PE) fabricated through electrochemical anodization shows a low charge transfer resistance (Rct) and high OER activity due to its large surface area compared to the conventional electrode (CE). These results confirm that the synthesis process of H2O2 immersion is an unsuitable method for surface modification. In contrast, the PE fabricated by anodization can increase the OER activity by providing high adsorption of reactants through surface modification.
Tandem Olefin Metathesis/α-Ketohydroxylation Revisited
Authors: Patrzałek Michał , Zasada Aleksandra , Kajetanowicz Anna , Grela Karol
Published: June 2021

EWG-activated and polar quaternary ammonium salt-tagged ruthenium metathesis catalysts have been applied in a two-step one-pot metathesis-oxidation process leading to functionalized α-hydroxyketones (acyloins). In this assisted tandem process, the metathesis catalyst is used first to promote ring-closing metathesis (RCM) and cross-metathesis (CM) steps, then upon the action of Oxone™ converts into an oxidation catalyst able to transform the newly formed olefinic product into acyloin under mild conditions.
Human Microcephaly Protein RTTN Is Required for Proper Mitotic Progression and Correct Spindle Position
Authors: Chou En-Ju , Tang Tang K.
Published: June 2021

Autosomal recessive primary microcephaly (MCPH) is a complex neurodevelopmental disorder characterized by a small brain size with mild to moderate intellectual disability. We previously demonstrated that human microcephaly RTTN played an important role in regulating centriole duplication during interphase, but the role of RTTN in mitosis is not fully understood. Here, we show that RTTN is required for normal mitotic progression and correct spindle position. The depletion of RTTN induces the dispersion of the pericentriolar protein γ-tubulin and multiple mitotic abnormalities, including monopolar, abnormal bipolar, and multipolar spindles. Importantly, the loss of RTTN altered NuMA/p150Glued congression to the spindle poles, perturbed NuMA cortical localization, and reduced the number and the length of astral microtubules. Together, our results provide a new insight into how RTTN functions in mitosis.
iPLA2β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury
Authors: Jin Tingting , Lin Jun , Gong Yingchao , Bi Xukun , Hu Shasha , Lv Qingbo , Chen Jiaweng , Li Xiaoting , Chen Jiaqi , Zhang Wenbin , Wang Meihui , Fu Guosheng
Published: June 2021

Both calcium-independent phospholipase A2 beta (iPLA2β) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA2β is increased during myocardial ischemia/reperfusion (I/R) injury, concomitant with the induction of ER stress and the upregulation of cell death. We further show that the levels of iPLA2β in serum collected from acute myocardial infarction (AMI) patients and in samples collected from both in vivo and in vitro I/R injury models are significantly elevated. Further, iPLA2β knockout mice and siRNA mediated iPLA2β knockdown are employed to evaluate the ER stress and cell apoptosis during I/R injury. Additionally, cell surface protein biotinylation and immunofluorescence assays are used to trace and locate iPLA2β. Our data demonstrate the increase of iPLA2β augments ER stress and enhances cardiomyocyte apoptosis during I/R injury in vitro and in vivo. Inhibition of iPLA2β ameliorates ER stress and decreases cell death. Mechanistically, iPLA2β promotes ER stress and apoptosis by translocating to ER upon myocardial I/R injury. Together, our study suggests iPLA2β contributes to ER stress-induced apoptosis during myocardial I/R injury, which may serve as a potential therapeutic target against ischemic heart disease.
The Multifaceted Functions of Autophagy in Breast Cancer Development and Treatment
Authors: Niklaus Nicolas J. , Tokarchuk Igor , Zbinden Mara , Schläfli Anna M. , Maycotte Paola , Tschan Mario P.
Published: June 2021

Macroautophagy (herein referred to as autophagy) is a complex catabolic process characterized by the formation of double-membrane vesicles called autophagosomes. During this process, autophagosomes engulf and deliver their intracellular content to lysosomes, where they are degraded by hydrolytic enzymes. Thereby, autophagy provides energy and building blocks to maintain cellular homeostasis and represents a dynamic recycling mechanism. Importantly, the clearance of damaged organelles and aggregated molecules by autophagy in normal cells contributes to cancer prevention. Therefore, the dysfunction of autophagy has a major impact on the cell fate and can contribute to tumorigenesis. Breast cancer is the most common cancer in women and has the highest mortality rate among all cancers in women worldwide. Breast cancer patients often have a good short-term prognosis, but long-term survivors often experience aggressive recurrence. This phenomenon might be explained by the high heterogeneity of breast cancer tumors rendering mammary tumors difficult to target. This review focuses on the mechanisms of autophagy during breast carcinogenesis and sheds light on the role of autophagy in the traits of aggressive breast cancer cells such as migration, invasion, and therapeutic resistance.
Special Issue in Honor of Shlomo Magdassi—Bringing Basic Colloid Science into Industrial Products
Authors: Kamyshny Alexander , Starov Victor M.
Published: June 2021

The majority of basic research that is conducted by Prof. Shlomo Magdassi in materials science [...]