bluuebunny/crossref_metadata_2025 huggingface dataset:
Nanostructured Lipid Carriers Deliver Resveratrol, Restoring Attenuated Dilation in Small Coronary Arteries, via the AMPK Pathway
Authors: Astley Cai , Houacine Chahinez , Zaabalawi Azziza , Wilkinson Fiona , Lightfoot Adam P. , Alexander Yvonne , Whitehead Debra , Singh Kamalinder K. , Azzawi May
Published: December 2021

Nanostructured lipid carriers (NLCs) are an emerging drug delivery platform for improved drug stability and the bioavailability of antihypertensive drugs and vasoprotective nutraceutical compounds, such as resveratrol (RV). The objective of this study was to ascertain NLCs’ potential to deliver RV and restore attenuated dilator function, using an ex vivo model of acute hypertension. Trimyristin–triolein NLCs were synthesized and loaded with RV. The uptake of RV-NLCs by human coronary artery endothelial cells (HCAECs) maintained their viability and reduced both mitochondrial and cytosolic superoxide levels. Acute pressure elevation in isolated coronary arteries significantly attenuated endothelial-dependent dilator responses, which were reversed following incubation in RV-NLCs, superoxide dismutase or apocynin (p < 0.0001). RV-NLCs demonstrated a five-fold increase in potency in comparison to RV solution. At elevated pressure, in the presence of RV-NLCs, incubation with Nω-nitro-l-arginine (L-NNA) or indomethacin resulted in a significant reduction in the restored dilator component (p < 0.0001), whereas apamin and TRAM-34 had no overall effect. Incubation with the adenosine monophosphate-activated protein kinase (AMPK) inhibitor dorsomorphin significantly attenuated dilator responses (p < 0.001), whereas the SIRT-1 inhibitor EX-527 had no effect. RV-NLCs improved the impaired endothelial-dependent dilation of small coronary arteries, following acute pressure elevation, via NO and downstream COX elements, mediated by AMPK. We suggest that RV-NLCs are an effective delivery modality for improved potency and sustained drug release into the vasculature. Our findings have important implications for the future design and implementation of antihypertensive treatment strategies.
The Role of Physical Activity in Nonalcoholic and Metabolic Dysfunction Associated Fatty Liver Disease
Authors: von Loeffelholz Christian , Roth Johannes , Coldewey Sina , Birkenfeld Andreas
Published: December 2021

Sedentary behavior constitutes a pandemic health threat contributing to the pathophysiology of obesity and type 2 diabetes (T2D). Sedentarism is further associated with liver disease and particularly with nonalcoholic/metabolic dysfunction associated fatty liver disease (NAFLD/MAFLD). Insulin resistance (IR) represents an early pathophysiologic key element of NAFLD/MAFLD, prediabetes and T2D. Current treatment guidelines recommend regular physical activity. There is evidence, that physical exercise has impact on a variety of molecular pathways, such as AMP-activated protein kinase and insulin signaling as well as glucose transporter 4 translocation, modulating insulin action, cellular substrate flow and in particular ectopic lipid and glycogen storage in a positive manner. Therefore, physical exercise can lead to substantial clinical benefit in persons with diabetes and/or NAFLD/MAFLD. However, experience from long term observational studies shows that the patients’ motivation to exercise regularly appears to be a major limitation. Strategies to integrate everyday physical activity (i.e., nonexercise activity thermogenesis) in lifestyle treatment schedules might be a promising approach. This review aggregates evidence on the impact of regular physical activity on selected molecular mechanisms as well as clinical outcomes of patients suffering from IR and NAFLD/MAFLD.
Schizophrenia Patients Show Largely Similar Salience Signaling Compared to Healthy Controls in an Observational Task Environment
Authors: Culbreth Adam J. , Kasanova Zuzana , Ross Thomas J. , Salmeron Betty J. , Gold James M. , Stein Elliot A. , Waltz James A.
Published: December 2021

Recent evidence suggests that the aberrant signaling of salience is associated with psychotic illness. Salience, however, can take many forms in task environments. For example, salience may refer to any of the following: (1) the valence of an outcome, (2) outcomes that are unexpected, called reward prediction errors (PEs), or (3) cues associated with uncertain outcomes. Here, we measure brain responses to different forms of salience in the context of a passive PE-signaling task, testing whether patients with schizophrenia (SZ) showed aberrant signaling of particular types of salience. We acquired event-related MRI data from 29 SZ patients and 23 controls during the performance of a passive outcome prediction task. Across groups, we found that the anterior insula and posterior parietal cortices were activated to multiple different types of salience, including PE magnitude and heightened levels of uncertainty. However, BOLD activation to salient events was not significantly different between patients and controls in many regions, including the insula, posterior parietal cortices, and default mode network nodes. Such results suggest that deficiencies in salience processing in SZ may not result from an impaired ability to signal salience per se, but instead the ability to use such signals to guide future actions. Notably, no between-group differences were observed in BOLD signal changes associated with PE-signaling in the striatum. However, positive symptom severity was found to significantly correlate with the magnitudes of salience contrasts in default mode network nodes. Our results suggest that, in an observational environment, SZ patients may show an intact ability to activate striatal and cortical regions to rewarding and non-rewarding salient events. Furthermore, reduced deactivation of a hypothesized default mode network node for SZ participants with high levels of positive symptoms, following salient events, point to abnormalities in interactions of the salience network with other brain networks, and their potential importance to positive symptoms.
COVID-19 Neuromuscular Involvement in Post-Acute Rehabilitation
Authors: Bagnato Sergio , Ferraro Manfredi , Boccagni Cristina , Battaglia Gianluca , D’Agostino Tiziana , Prestandrea Caterina , Bellavia Marina Angela , Rubino Francesca
Published: December 2021

Background: Coronavirus disease 2019 (COVID-19) is associated with muscle and nerve injuries as a consequence of prolonged critical illness or the infection itself. In this study, we evaluated neuromuscular involvement in patients who underwent post-acute intensive rehabilitation after COVID-19. Methods: Clinical and neurophysiological evaluations, including nerve conduction studies and electromyography, were performed on 21 consecutive patients admitted for rehabilitation after COVID-19. Results: Clinical signs suggesting muscle or nerve involvement (weakness, reduced deep tendon reflexes, impaired sensitivity, abnormal gait) were found in 19 patients. Neurophysiological examinations confirmed neuromuscular involvement in 17 patients: a likely association of critical illness myopathy (CIM) and critical illness polyneuropathy (CIP) was found in 5 patients; CIM alone was found in 4 patients; axonal sensory-motor polyneuropathy was found in 4 patients (CIP in 2 patients, metabolic polyneuropathy in 2 patients); Guillain-Barré syndrome was found in 2 patients (classical demyelinating sensory-motor polyneuropathy and acute motor axonal neuropathy, respectively); peroneal nerve injury was found in 1 patient; and pre-existing L4 radiculopathy was found in 1 patient. Conclusions: Neuromuscular involvement is a very common finding among patients admitted for rehabilitation after COVID-19, and proper investigation should be conducted when muscle or nerve injury is suspected for adequate rehabilitative strategy planning.
Associations between Sex Hormones and Circulating Growth Differentiation Factor-15 in Male Patients with Major Depressive Disorder
Authors: Sun Ting , Peng Rui , Sun Xiaojun , Li Yan
Published: December 2021

The interaction between the endocrine system and inflammation is crucial pathogenesis of depression. Our study aimed at exploring the possible relationship between sex hormones and growth differentiation factor-15 (GDF-15), a common indicator of inflammation in male patients with major depressive disorder (MDD). Methods: GDF-15 levels of 121 male MDD patients were compared with 105 healthy subjects with the help of a Cobas 8000 automatic chemiluminescence immunoanalyzer. Results: (1) MDD patients showed higher GDF-15 levels, a lower testosterone (T) level and testosterone/estradiol ratio (T/E2 ratio) than healthy subjects (all p < 0.05). (2) Serum T levels and the T/E2 ratio were inversely associated with GDF-15 serum levels (all p < 0.05). (3) HAMD-24 scores were positively correlated with the levels of GDF-15 (p < 0.01), but not with T levels, estradiol (E2) levels, and the T/E2 ratio (all p > 0.05). Conclusion: The high level of GDF-15 was correlated with a low T/E2 ratio and T deficiency in male MDD patients. The above results demonstrate that up-regulation of serum GDF-15 and down-regulation of T and T/E2 ratio may be correlated with the occurrence and severity of depression. So, changing the level of GDF-15 by regulating the proportion of sex hormones may play a key role in the prognosis and treatment of depression.
Resting-State Functional Magnetic Resonance Imaging for Surgical Neuro-Oncology Planning: Towards a Standardization in Clinical Settings
Authors: Sparacia Gianvincenzo , Parla Giuseppe , Mamone Giuseppe , Caruso Mariangela , Torregrossa Fabio , Grasso Giovanni
Published: December 2021

Resting-state functional magnetic resonance imaging (rest-f-MRI) is a neuroimaging technique that has demonstrated its potential in providing new insights into brain physiology. rest-f-MRI can provide useful information in pre-surgical mapping aimed to balancing long-term survival by maximizing the extent of resection of brain neoplasms, while preserving the patient’s functional connectivity. Rest-fMRI may replace or can be complementary to task-driven fMRI (t-fMRI), particularly in patients unable to cooperate with the task paradigm, such as children or sedated, paretic, aphasic patients. Although rest-fMRI is still under standardization, this technique has been demonstrated to be feasible and valuable in the routine clinical setting for neurosurgical planning, along with intraoperative electrocortical mapping. In the literature, there is growing evidence that rest-fMRI can provide valuable information for the depiction of glioma-related functional brain network impairment. Accordingly, rest-fMRI could allow a tailored glioma surgery improving the surgeon’s ability to increase the extent of resection (EOR), and simultaneously minimize the risk of damage of eloquent brain structures and neuronal networks responsible for the integrity of executive functions. In this article, we present a review of the literature and illustrate the feasibility of rest-fMRI in the clinical setting for presurgical mapping of eloquent networks in patients affected by brain tumors, before and after tumor resection.
Analysis of Formwork System Selection Criteria for Building Construction Projects: A Comparative Study
Authors: Terzioglu Taylan , Polat Gul , Turkoglu Harun
Published: December 2021

The formwork system (FWS) in reinforced concrete (RC) construction is a critical component. The appropriate FWS is selected based on a number of conflicting and compromising criteria, and the selection of the FWS is carried out by construction professionals with different technical and/or administrative backgrounds. The perspectives and perceptions of construction professionals and companies involved in the FWS selection process may vary depending on their motives. In addition, some building structural parameters may have a significant impact on the FWS selection criteria. Most of the former studies investigated the FWS selection criteria from only the perspective of contractors and neglected the potential differences in the perspectives and perceptions of different construction professionals (i.e., owners (CO), project managers (PM), construction managers (CM), site engineers (SE), planning engineers (PL), procurement engineers (PR), technical office engineers (TO), and formwork design and/or formwork sales engineers (FD/FSL)) and companies specialized in different fields (i.e., project management service (PMS), engineering and design (ENG/DSG), formwork and scaffolding (FW/SCF), and general and/or sub-contractor (GC/SC)) regarding this issue. Moreover, the impact of building structural parameters on the FWS selection criteria has not been investigated. This study aims to fill this knowledge gap through analysing the FWS selection criteria for building construction projects while comparing the perspectives and perceptions of different groups of construction professionals and companies and investigating how FWS selection criteria are affected by the building structural parameters. Based on a comprehensive literature review, 35 FWS selection criteria were identified and a questionnaire was developed. The questionnaire data obtained from 222 Turkish construction professionals were statistically analysed using mean score analysis, the Kruskal–Wallis test, and the Mann–Whitney U test. According to the study’s findings, the FD/FSL group presented significant statistical differences regarding the FWS selection criteria as compared to the CO, PM/CM/SE, and PL/PR/TO groups. Moreover, the total area of building construction and total building height significantly affected the FWS selection criteria. This study serves to underscore the perspectives of various groups of construction professionals and the critical connection between the structural parameters and FWS selection criteria. The findings of this study may guide construction professionals to select the appropriate FWS for their building construction projects.
Design of Cold-Mixed High-Toughness Ultra-Thin Asphalt Layer towards Sustainable Pavement Construction
Authors: Yu Jiangmiao , Yang Nikun , Chen Fuda , Chen Yanlin , Lin Zhuohan , Yu Huayang
Published: December 2021

Ultra-thin asphalt overlay has become the mainstream measure of road preventive maintenance due to its good economic benefits and road performance. However, hot mix asphalt concrete technology is widely used at present, which is not the most ideal way to promote energy saving and emission reduction in the field of road maintenance. At the same time, the ultra-thin friction course based on cold mix technology, such as slurry seal layer, micro-surface, and other technologies, are still far behind the hot mix friction course in terms of crack resistance. In this research, by establishing an integrated design of materials and structures, a cold paving technology called “high-toughness cold-mixed ultra-thin pavement (HCUP)” is proposed. The high-viscosity emulsified bitumen prepared by using high-viscosity and high-elasticity modified bitumen is used as the binder and sticky layer of HCUP. The thickness of HCUP is 0.8–2.0 cm, the typical thickness is 1.2 cm, and the nominal maximum size of the coarse aggregate is 8 mm. Indoor tests show that HCUP-8 has water stability, anti-skid performance, high temperature performance, peeling resistance, and crack resistance that are not weaker than traditional hot-mixed ultra-thin wear layers such as AC-10, Novachip, and GT-8. At the same time, the test road paving further proved that HCUP-8 has excellent road performance with a view to providing new ideas for low-carbon and environmentally friendly road materials.
Behaviour of Lightweight Concrete Wall Panel under Axial Loading: Experimental and Numerical Investigation toward Sustainability in Construction Industry
Authors: Rahman Muhammad , Ting Timothy , Lau Hieng , Nagaratnam Brabha , Poologanathan Keerthan
Published: December 2021

Awareness of sustainability in construction has led to the utilization of waste material such as oil palm shell (OPS) in concrete production. The feasibility of OPS as alternative aggregates in concrete has been widely studied at the material level. Meanwhile, nonlinear concrete material properties are not taken into account in the conventional concrete wall design equations, resulting in underestimation of lightweight concrete’s wall axial capacity. Against these sustainability and technical contexts, this research investigated the buckling behavior of OPS-based lightweight self-compacting concrete (LWSCC) wall. Failure mode, load-deflection responses, and ultimate strength were assessed experimentally. Numerical models have been developed and validated against experimental results. Parametric studies were conducted to study the influence of parameters like slenderness ratio, eccentricity, compressive strength, and elastic modulus. The results showed that the axial strength of concrete wall was very much dependent on these parameters. A generalized semi-empirical design equation, based on equivalent concrete stress block and modified by mathematical regression, has been proposed. The ratio of average calculated results to test results of the proposed equation, when compared to ACI 318, AS 3600, and Eurocode 2 equations, are respectively improved from 0.36, 0.31, and 0.42 to 0.97. This research demonstrates that OPS-based LWSCC concrete can be used for structural axial components and that the equation developed can serve a good guideline for its design, which could encourage automation and promote sustainability in the construction industry.
Thermal Performance of LSF Wall Systems with Vacuum Insulation Panels
Authors: Rajanayagam Heshachanaa , Upasiri Irindu , Poologanathan Keerthan , Gatheeshgar Perampalam , Sherlock Paul , Konthesingha Chaminda , Nagaratnam Brabha , Perera Dilini
Published: December 2021

Lightweight Steel Frames (LSF) in building construction are becoming more popular due to their fast, clean, and flexible constructability. Typical LSF wall panels are made of cold-formed and thin-walled steel lipped channel studs with plasterboard linings. Due to the high thermal conductivity of steel, these LSF components must be well engineered and covered against unintended thermal bridges. Therefore, it is essential to investigate the heat transfer of the LSF wall of different configurations and reduce heat loss through walls by lowering the thermal transmittance, which would ultimately minimise the energy consumption in buildings. The effect of novel thermal insulation material, Vacuum Insulation Panels (VIP), their position on the LSF wall configuration, and Oriented Strand Board (OSB) and plasterboard’s effect on the thermal transmittance of LSF walls were investigated through numerical analysis. A total of 56 wall configurations and 112 finite element models were analysed and compared with the minimum U-value requirements of UK building regulations. Numerical model results exhibited that using plasterboards instead of OSB has no considerable effect on the U-value of the LSF walls. However, 77% (4 times) of U-value reduction was exhibited by introducing the 20 mm VIP. Moreover, the position of the VIP to the U-value of LSF was negligible. Based on the results, optimum LSF wall configurations were proposed by highlighting the construction methods. Additionally, this study, through literature, seeks to identify other areas in which additional research can be conducted to achieve the desired thermal efficiency of buildings using LSF wall systems.
Removal of Hydrophobic Contaminants from the Soil by Adsorption onto Carbon Materials and Microbial Degradation
Authors: Dewangan Shippi , Bhatia Amarpreet K. , Singh Ajaya Kumar , Carabineiro Sónia A. C.
Published: December 2021

The pollution of soil is a worldwide concern as it has harmful consequences on the environment and human health. With the continuous expansion of industry and agriculture, the content of hydrophobic organic pollutants in the soil has been increasing, which has caused serious pollution to the soil. The removal of hydrophobic organic contaminants from soil, aiming to recover environmental safety, is an urgent matter to guarantee sufficient food and water for populations. Adsorption has proven to be an effective and economically practicable method for removing organic contaminants. This paper summarizes the use of low-cost adsorbents, such as biochar and activated carbon, for removing hydrophobic organic contaminants from soil. Biochar is usually appropriate for the adsorption of organic contaminants via the adsorption mechanisms of electrostatic interaction, precipitation, and ion exchange. Biochar also has numerous benefits, such as being obtained from several kinds of raw materials, having low costs, recyclability, and potential for environmental treatment. This paper illustrates biochar’s adsorption mechanism for organic contaminants and discusses the microbial degradation of hydrophobic organic contaminants.
Vaccine Responses in Adult Hematopoietic Stem Cell Transplant Recipients: A Comprehensive Review
Authors: Janssen Michelle , Bruns Anke , Kuball Jürgen , Raijmakers Reinier , van Baarle Debbie
Published: December 2021

Consensus on timing of post-hematopoietic stem cell transplantation (HSCT) vaccination is currently lacking and is therefore assessed in this review. PubMed was searched systematically for articles concerning vaccination post-HSCT and included a basis in predefined criteria. To enable comparison, data were extracted and tables were constructed per vaccine, displaying vaccine response as either seroprotection or seroconversion for allogeneic HSCT (alloHSCT) and autologous HSCT (autoHSCT) separately. A total of 33 studies were included with 1914 patients in total: 1654 alloHSCT recipients and 260 autoHSCT recipients. In alloHSCT recipients, influenza vaccine at 7–48 months post-transplant resulted in responses of 10–97%. After 12 months post-transplant, responses were >45%. Pneumococcal vaccination 3–25 months post-transplant resulted in responses of 43–99%, with the response increasing with time. Diphtheria, tetanus, pertussis, poliomyelitis and Haemophilus influenzae type b at 6–17 months post-transplant: 26–100%. Meningococcal vaccination at 12 months post-transplant: 65%. Hepatitis B vaccine at 6–23 months post-transplant: 40–94%. Measles, mumps and rubella at 41–69 months post-transplant: 19–72%. In general, autoHSCT recipients obtained slightly higher responses compared with alloHSCT recipients. Conclusively, responses to childhood immunization vaccines post-HSCT are poor in comparison with healthy individuals. Therefore, evaluation of response might be indicated. Timing of revaccination is essential for optimal response. An individualized approach might be necessary for optimizing vaccine responses.
NS-11021 Modulates Cancer-Associated Processes Independently of BK Channels in Melanoma and Pancreatic Duct Adenocarcinoma Cell Lines
Authors: Remigante Alessia , Zuccolini Paolo , Barbieri Raffaella , Ferrera Loretta , Morabito Rossana , Gavazzo Paola , Pusch Michael , Picco Cristiana
Published: December 2021

Potassium channels have emerged as regulators of carcinogenesis, thus introducing possible new therapeutic strategies in the fight against cancer. In particular, the large-conductance Ca2+-activated K+ channel, often referred to as BK channel, is involved in several cancer-associated processes. Here, we investigated the effects of different BK activators, NS-11021, NS-19504, and BMS-191011, in IGR39 (primary melanoma cell line) and Panc-1 (primary pancreatic duct carcinoma cell line), highly expressing the channel, and in IGR37 (metastatic melanoma cell line) that barely express BK. Our data showed that NS-11021 and NS-19504 potently activated BK channels in IGR39 and Panc-1 cells, while no effect on channel activation was detected in IGR37 cells. On the contrary, BK channel activator BMS-191011 was less effective. However, only NS-11021 showed significant effects in cancer-associated processes, such as cell survival, migration, and proliferation in these cancer cell lines. Moreover, NS-11021 led to an increase of intracellular Ca2+ concentration, independent of BK channel activation, thus complicating any interpretation of its role in the regulation of cancer-associated mechanisms. Overall, we conclude that the activation of the BK channel by itself is not sufficient to produce beneficial anti-cancer effects in the melanoma and PDAC cell lines examined. Importantly, our results raise an alarm flag regarding the use of presumably specific BK channel openers as anti-cancer agents.
Basosquamous Carcinoma: A Commentary
Authors: Fotiadou Christina , Apalla Zoe , Lazaridou Elizabeth
Published: December 2021

Basosquamous carcinoma is a rare, aggressive non-melanoma skin cancer with features that lie between those of basal cell carcinoma and squamous cell carcinoma. A lot of controversy has been raised around the classification, pathogenesis, histologic morphology, biologic behavior, prognosis and management of this tumor. This is a narrative review based on an electronic search of articles published in PubMed in English language which had in their title the terms “basosquamous carcinoma” and/or “metatypical carcinoma of the skin”. The aim of this review was to summarize and evaluate current data regarding epidemiology, clinical presentation, dermoscopic and histopathologic characteristics, as well as the genetics and management of BSC, in order to shed some more light onto this intriguing entity. As a conclusion, dermoscopy, deep incisional biopsies and immunohistologic techniques (Ber-EP4) should be applied in clinically suspicious lesions in order to achieve an early diagnosis and better prognosis of this tumor. Surgical treatments, including wide excision and Mohs’ micrographic surgery, remain the treatment of choice. Finally, vismodegib, a Hedgehog pathway inhibitor, must be thoroughly investigated, with large controlled trials, since it may offer an alternative solution to irresectable or difficult-to-treat, locally advanced cases of basosquamous carcinoma.
Essential Thrombocythemia in Children and Adolescents
Authors: Putti Maria Caterina , Bertozzi Irene , Randi Maria Luigia
Published: December 2021

This paper reviews the features of pediatric essential thrombocythemia (ET). ET is a rare disease in children, challenging pediatric and adult hematologists alike. The current WHO classification acknowledges classical Philadelphia-negative MPNs and defines diagnostic criteria, mainly encompassing adult cases. The presence of one of three driver mutations (JAK2V617F, CALR, and MPL mutations) represent the proof of clonality typical of ET. Pediatric ET cases are thus usually confronted by adult approaches. These can fit only some patients, because only 25–40% of cases present one of the driver mutations. The diagnosis of hereditary, familial thrombocytosis and the exclusion of reactive/secondary thrombocytosis must be part of the diagnostic process in children and can clarify most of the negative cases. Still, many children present a clinical, histological picture of ET, with a molecular triple wild-type status. Moreover, prognosis seems more benign, at least within the first few decades of follow-up. Thrombotic events are rare, and only minor hemorrhages are ordinarily observed. As per the management, the need to control symptoms must be balanced with the collateral effects of lifelong drug therapy. We conclude that these differences concert a compelling case for a very careful therapeutic approach and advocate for the importance of further cooperative studies.
64Cu-ATSM Predicts Efficacy of Carbon Ion Radiotherapy Associated with Cellular Antioxidant Capacity
Authors: Nachankar Ankita , Oike Takahiro , Hanaoka Hirofumi , Kanai Ayaka , Sato Hiro , Yoshida Yukari , Obinata Hideru , Sakai Makoto , Osu Naoto , Hirota Yuka , Takahashi Akihisa , Shibata Atsushi , Ohno Tatsuya
Published: December 2021

Carbon ion radiotherapy is an emerging cancer treatment modality that has a greater therapeutic window than conventional photon radiotherapy. To maximize the efficacy of this extremely scarce medical resource, it is important to identify predictive biomarkers of higher carbon ion relative biological effectiveness (RBE) over photons. We addressed this issue by focusing on cellular antioxidant capacity and investigated 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. We found that the carbon ion RBE correlated with 64Cu-ATSM uptake both in vitro and in vivo. High RBE/64Cu-ATSM cells showed greater steady-state levels of antioxidant proteins and increased capacity to scavenge reactive oxygen species in response to X-rays than low RBE/64Cu-ATSM counterparts; this upregulation of antioxidant systems was associated with downregulation of TCA cycle intermediates. Furthermore, inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) sensitized high RBE/64Cu-ATSM cells to X-rays, thereby reducing RBE values to levels comparable to those in low RBE/64Cu-ATSM cells. These data suggest that the cellular activity of Nrf2-driven antioxidant systems is a possible determinant of carbon ion RBE predictable by 64Cu-ATSM uptake. These new findings highlight the potential clinical utility of 64Cu-ATSM imaging to identify high RBE tumors that will benefit from carbon ion radiotherapy.
Microglial Cytokines Induce Invasiveness and Proliferation of Human Glioblastoma through Pyk2 and FAK Activation
Authors: Nuñez Rebeca E. , del Valle Miguel Mayol , Ortiz Kyle , Almodovar Luis , Kucheryavykh Lilia
Published: December 2021

Glioblastoma is the most aggressive brain tumor in adults. Multiple lines of evidence suggest that microglia create a microenvironment favoring glioma invasion and proliferation. Our previous studies and literature reports indicated the involvement of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) in glioma cell proliferation and invasion, stimulated by tumor-infiltrating microglia. However, the specific microglia-released factors that modulate Pyk2 and FAK signaling in glioma cells are unknown. In this study, 20 human glioblastoma specimens were evaluated with the use of RT-PCR and western blotting. A Pierson correlation test demonstrated a correlation (0.6–1.0) between the gene expression levels for platelet-derived growth factor β(PDGFβ), stromal-derived factor 1α (SDF-1α), IL-6, IL-8, and epidermal growth factor (EGF) in tumor-purified microglia and levels of p-Pyk2 (Y579/Y580) and p-FAK(Y925) in glioma cells. siRNA knockdown against Pyk2 or FAK in three primary glioblastoma cell lines, developed from the investigated specimens, in combination with the cytokine receptor inhibitors gefitinib (1 μM), DMPQ (200 nM), and burixafor (1 μM) identified EGF, PDGFβ, and SDF-1α as key extracellular factors in the Pyk2- and FAK-dependent activation of invadopodia formation and the migration of glioma cells. EGF and IL-6 were identified as regulators of the Pyk2- and FAK-dependent activation of cell viability and mitosis.
Opportunities and Limitations of Pelvic Exenteration Surgery
Authors: Lampe Björn , Luengas-Würzinger Verónica , Weitz Jürgen , Roth Stephan , Rawert Friederike , Schuler Esther , Classen-von Spee Sabrina , Fix Nando , Baransi Saher , Dizdar Anca , Mallmann Peter , Schaser Klaus-Dieter , Bogner Andreas
Published: December 2021

Purpose: The practice of exenterative surgery is sometimes controversial and has garnered a certain scepticism. Surgical studies are difficult to conduct due to insufficient data. The aim of this review is to present the current standing of pelvic exenteration from a surgical, gynaecological and urological point of view. Methods: This review is based upon a literature review (MEDLINE (PubMed), CENTRAL (Cochrane) and EMBASE (Elsevier)) of retrospective studies on exenterative surgery from 1993–2020. Using MeSH (Medical Subject Headings) search terms, 1572 publications were found. These were evaluated and screened with respect to their eligibility using algorithms and well-defined inclusion and exclusion criteria. Therefore, the guidelines for systematic reviews (PRISMA) were used. Results: A complete tumour resection (R0) often represents the only curative option for advanced pelvic carcinomas and their recurrences. A recent systematic review showed significant symptom relief in 80% of palliative patients after pelvic exenteration. Surgical limitations (distant metastases, involvement of the pelvic wall, etc.) are diminished by adequate surgical expertise and close interdisciplinary cooperation. While the mortality rate is low (2–5%), the still relatively high morbidity rate (32–84%) can be minimized by optimizing the perioperative setting. Following exenterations, roughly 79–82% of patients report satisfying results according to PROs (patient-reported outcomes). Conclusion: Due to multimodality treatment strategies combined with extended surgical expertise and patients’ preferences, pelvic exenteration can be offered nowadays with low mortality and acceptable postoperative quality of life. The possibilities of surgical treatment are often underestimated. A multi-centre database (PelvEx Collaborative) was established to collect data and experiences to optimize the research in this field.
The Role of Plasma Membrane Viscosity in the Response and Resistance of Cancer Cells to Oxaliplatin
Authors: Shimolina Liubov , Gulin Alexander , Ignatova Nadezhda , Druzhkova Irina , Gubina Margarita , Lukina Maria , Snopova Ludmila , Zagaynova Elena , Kuimova Marina K. , Shirmanova Marina
Published: December 2021

Maintenance of the biophysical properties of membranes is essential for cell survival upon external perturbations. However, the links between a fluid membrane state and the drug resistance of cancer cells remain elusive. Here, we investigated the role of membrane viscosity and lipid composition in the responses of cancer cells to oxaliplatin and the development of chemoresistance. Plasma membrane viscosity was monitored in live colorectal cancer cells and tumor xenografts using two-photon excited fluorescence lifetime imaging microscopy (FLIM) using the fluorescent molecular rotor BODIPY 2. The lipid profile was analyzed using time-of-flight secondary ion mass spectrometry (ToF-SIMS). It was found that the plasma membrane viscosity increased upon oxaliplatin treatment, both in vitro and in vivo, and that this correlated with lower phosphatidylcholine and higher cholesterol content. The emergence of resistance to oxaliplatin was accompanied by homeostatic adaptation of the membrane lipidome, and the recovery of lower viscosity. These results suggest that maintaining a constant plasma membrane viscosity via remodeling of the lipid profile is crucial for drug resistance in cancer.
Integrative Analysis Identifies Multi-Omics Signatures That Drive Molecular Classification of Uveal Melanoma
Authors: Mo Qianxing , Wan Lixin , Schell Michael J. , Jim Heather , Tworoger Shelley S. , Peng Guang
Published: December 2021

By iCluster analysis, we found that the integrative molecular classification of the UM was primarily driven by DNA copy number variation on chromosomes 3, 6 and 8, differential methylation and expression of genes involved in the immune system, cell morphogenesis, movement and migration, and differential mutation of genes including GNA11, BAP1, EIF1AX, SF3B1 and GNAQ. Integrative analysis revealed that pathways including IL6/JAK/STAT3 signaling, angiogenesis, allograft rejection, inflammatory response and interferon gamma response were hypomethylated and up-regulated in the M3 iSubtype, which was associated with a worse overall survival, compared to the D3 iSubtype. Using two independent gene expression datasets, we demonstrated that the subtype-driving genes had an excellent prognostic power in classifying UM into high- or low-risk groups for metastasis. Integrative analysis of UM multi-omics data provided a comprehensive view of UM biology for understanding the underlying mechanism leading to UM metastasis. The concordant molecular alterations at multi-omics levels revealed by our integrative analysis could be used for patient stratification towards personalized management and surveillance.
The Vulvar Cancer Risk in Differentiated Vulvar Intraepithelial Neoplasia: A Systematic Review
Authors: Voss Féline O. , Thuijs Nikki B. , Vermeulen Ravi F. M. , Wilthagen Erica A. , van Beurden Marc , Bleeker Maaike C. G.
Published: December 2021

Differentiated vulvar intraepithelial neoplasia (dVIN) is the precursor of human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (VSCC). Given the rare incidence of dVIN, limited information on the exact cancer risk is available. We systematically reviewed the primary and recurrent VSCC risk in patients with dVIN, as well as the time to cancer development. A systematic search was performed up to July 2021 according to the PRISMA guidelines. Five reviewers independently screened articles on title, abstract and full text, followed by critical appraisal of selected articles using the Quality in Prognostic Studies (QUIPS) tool. Of the 455 screened articles, 7 were included for analysis. The absolute risk for primary VSCC in dVIN varied between 33 and 86%, with a median time to progression to VSCC of 9–23 months. The risk of developing recurrent VSCC in dVIN associated VSCC was 32–94%, with a median time to recurrence of 13–32 months. In conclusion, patients with dVIN have a high risk of developing primary and recurrent VSCC with a short time to cancer progression. Increased awareness, timely recognition, aggressive treatment and close follow-up of HPV-independent vulvar conditions including dVIN is therefore strongly recommended.
Cognitive Impairment in Older Cancer Patients Treated with First-Line Chemotherapy
Authors: Dos Santos Mélanie , Licaj Idlir , Bellera Carine , Cany Laurent , Binarelli Giulia , Soubeyran Pierre , Joly Florence
Published: December 2021

Older cancer patients are vulnerable to chemotherapy-related cognitive impairment. We prospectively evaluated cognitive impairment and its predictive factors during first-line chemotherapy in elderly cancer patients (≥70 years). Cognitive function was evaluated by the Mini-Mental State Examination (MMSE) with adjusted scores for age and sociocultural level. Multidimensional geriatric assessment was performed at baseline and during chemotherapy including the MMSE, Instrumental Activities in Daily Living (IADL), Mini-Nutritional Assessment (MNA), and the Geriatric Depression Scale (GDS15). Quality of life (QoL) was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) QoL Questionnaire (QLQ-C30). Of 364 patients included, 310 had two MMSE evaluations including one at baseline and were assessed. Among these patients, 86 (27.7%) had abnormal MMSE, 195 (62.9%) abnormal MNA, 223 (71.9%) abnormal IADL, and 137 (43.1%) had depressive symptoms at baseline. MMSE impairment during chemotherapy was observed in 58 (18.7%) patients. Abnormal baseline MNA (odds ratio (OR) = 1.87, p = 0.021) and MMSE (OR = 2.58, p = 0.022) were independent predictive factors of MMSE impairment. These results suggest that pre-existing cognitive impairment and malnutrition are predictive factors for cognitive decline during chemotherapy in elderly cancer patients. Detection and management of these risk factors should be systematically considered in this population before starting chemotherapy.
Effectively Synthesizing SO4/TiO2 Catalyst and Its Performance for Converting Ethanol into Diethyl Ether (DEE)
Authors: Wijaya Karna , Putri Alya Rahmadhani , Sudiono Sri , Mulijani Sri , Patah Aep , Wibowo Arief Cahyo , Saputri Wahyu Dita
Published: December 2021

This SO4/TiO2 catalyst as a heterogeneous acidic catalyst was synthesized in various concentrations of H2SO4. The activity and selectivity of the SO4/TiO2 catalyst on the dehydration reaction of ethanol to diethyl ether were studied as well. The SO4/TiO2 was prepared from TiO2 powder by wet impregnation method with a various aqueous solution of H2SO4 (1; 2; 3 M H2SO4) and calcination temperature (400, 500, and 600 °C) to obtain a catalyst with optimum acidity. The catalysts were characterized using FTIR, XRD, SEM-EDX, SAA, TGA/DSC, and acidity test gravimetrically with ammonia. The liquid product of DEE was analyzed by gas chromatography (GC) to analyze the selectivity of the catalyst. The catalyst TS-3-400 had the highest activity and selectivity in the dehydration reaction of ethanol to diethyl ether at a temperature of 225 °C, with a conversion of 51.83% and a DEE selectivity of 1.72%.
Geniposide Ameliorated Dexamethasone-Induced Cholesterol Accumulation in Osteoblasts by Mediating the GLP-1R/ABCA1 Axis
Authors: Zheng Yizhou , Xiao Yaosheng , Zhang Di , Zhang Shanshan , Ouyang Jing , Li Linfu , Shi Weimei , Zhang Rui , Liu Hai , Jin Qi , Chen Zhixi , Xu Daohua , Wu Longhuo
Published: December 2021

Background: Overexposure to glucocorticoid (GC) produces various clinical complications, including osteoporosis (OP), dyslipidemia, and hypercholesterolemia. Geniposide (GEN) is a natural iridoid compound isolated from Eucommia ulmoides. Our previous study found that GEN could alleviate dexamethasone (DEX)-induced differentiation inhibition of MC3T3-E1 cells. However, whether GEN protected against Dex-induced cholesterol accumulation in osteoblasts was still unclear. Methods: DEX was used to induce rat OP. Micro-CT data was obtained. The ALP activity and mineralization were determined by the staining assays, and the total intracellular cholesterol was determined by the ELISA kits. The protein expression was detected by western blot. Results: GEN ameliorated Dex-induced micro-structure damages and cell differentiation inhibition in the bone trabecula in rats. In MC3T3-E1 cells, Dex enhanced the total intracellular cholesterol, which reduced the activity of cell proliferation and differentiation. Effectively, GEN decreased DEX-induced cholesterol accumulation, enhanced cell differentiation, and upregulated the expression of the GLP-1R/ABCA1 axis. In addition, inhibition of ABAC1 expression reversed the actions of GEN. Treatment with Exendin9-39, a GLP-1R inhibitor, could abrogate the protective activity of GEN. Conclusions: GEN ameliorated Dex-induced accumulation of cholesterol and inhibition of cell differentiation by mediating the GLP-1R/ABCA1 axis in MC3T3-E1 cells.
Perturbation of Cellular Redox Homeostasis Dictates Divergent Effects of Polybutyl Cyanoacrylate (PBCA) Nanoparticles on Autophagy
Authors: Sønstevold Tonje , Engedal Nikolai , Torgersen Maria Lyngaas
Published: December 2021

Nanoparticles (NPs) are used in our everyday life, including as drug delivery vehicles. However, the effects of NPs at the cellular level and their impacts on autophagy are poorly understood. Here, we demonstrate that the NP drug delivery vehicle poly(butyl cyanoacrylate) (PBCA) perturbs redox homeostasis in human epithelial cells, and that the degree of redox perturbation dictates divergent effects of PBCA on autophagy. Specifically, PBCA promoted functional autophagy at low concentrations, whereas it inhibited autophagy at high concentrations. Both effects were completely abolished by the antioxidant N-acetyl cysteine (NAC). High concentrations of PBCA inhibited MAP1LC3B/GABARAP lipidation and LC3 flux, and blocked bulk autophagic cargo flux induced by mTOR inhibition. These effects were mimicked by the redox regulator H2O2. In contrast, low concentrations of PBCA enhanced bulk autophagic cargo flux in a Vps34-, ULK1/2- and ATG13-dependent manner, yet interestingly, without an accompanying increase in LC3 lipidation or flux. PBCA activated MAP kinase signaling cascades in a redox-dependent manner, and interference with individual signaling components revealed that the autophagy-stimulating effect of PBCA required the action of the JNK and p38–MK2 pathways, whose activities converged on the pro-autophagic protein Beclin-1. Collectively, our results reveal that PBCA exerts a dual effect on autophagy depending on the severity of the NP insult and the resulting perturbation of redox homeostasis. Such a dual autophagy-modifying effect may be of general relevance for redox-perturbing NPs and have important implications in nanomedicine.
Aspects of the Epigenetic Regulation of EMT Related to Cancer Metastasis
Authors: Nowak Ewa , Bednarek Ilona
Published: December 2021

Epithelial to mesenchymal transition (EMT) occurs during the pathological process associated with tumor progression and is considered to influence and promote the metastatic cascade. Characterized by loss of cell adhesion and apex base polarity, EMT enhances cell motility and metastasis. The key markers of the epithelial to mesenchymal transition are proteins characteristic of the epithelial phenotype, e.g., E-cadherin, cytokeratins, occludin, or desmoplakin, the concentration and activity of which are reduced during this process. On the other hand, as a result of acquiring the characteristics of mesenchymal cells, an increased amount of N-cadherin, vimentin, fibronectin, or vitronectin is observed. Importantly, epithelial cells undergo partial EMT where some of the cells show both epithelial and mesenchymal characteristics. The significant influence of epigenetic regulatory mechanisms is observed in the gene expression involved in EMT. Among the epigenetic modifications accompanying incorrect genetic reprogramming in cancer are changes in the level of DNA methylation within the CpG islands and posttranslational covalent changes of histone proteins. All observed modifications, which are stable but reversible changes, affect the level of gene expression leading to the development and progression of the disease, and consequently affect the uncontrolled growth of the population of cancer cells.
Mitochondrial Phenotypes in Parkinson’s Diseases—A Focus on Human iPSC-Derived Dopaminergic Neurons
Authors: Heger Leonie M. , Wise Rachel M. , Hees J. Tabitha , Harbauer Angelika B. , Burbulla Lena F.
Published: December 2021

Established disease models have helped unravel the mechanistic underpinnings of pathological phenotypes in Parkinson’s disease (PD), the second most common neurodegenerative disorder. However, these discoveries have been limited to relatively simple cellular systems and animal models, which typically manifest with incomplete or imperfect recapitulation of disease phenotypes. The advent of induced pluripotent stem cells (iPSCs) has provided a powerful scientific tool for investigating the underlying molecular mechanisms of both familial and sporadic PD within disease-relevant cell types and patient-specific genetic backgrounds. Overwhelming evidence supports mitochondrial dysfunction as a central feature in PD pathophysiology, and iPSC-based neuronal models have expanded our understanding of mitochondrial dynamics in the development and progression of this devastating disorder. The present review provides a comprehensive assessment of mitochondrial phenotypes reported in iPSC-derived neurons generated from PD patients’ somatic cells, with an emphasis on the role of mitochondrial respiration, morphology, and trafficking, as well as mitophagy and calcium handling in health and disease. Furthermore, we summarize the distinguishing characteristics of vulnerable midbrain dopaminergic neurons in PD and report the unique advantages and challenges of iPSC disease modeling at present, and for future mechanistic and therapeutic applications.