bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of Process Conditions on Improvement of the Compressive Strengths of Reticulated Porous Zirconia
Authors: Lee Sujin , Lee Chae-Young , Ha Jang-Hoon , Lee Jongman , Song In-Hyuck , Kwon Se-Hun
Published: February 2022

In recent years, there has been growing interest in porous ceramics in many research areas given their superior thermal and chemical resistance capabilities, unlike porous metals and porous polymers. Among the various types of porous ceramics, reticulated porous ceramics can offer significant industrial potential due to the low density and high permeability of these materials. However, industrial applications are somewhat rare owing to the rather low compressive strength of reticulated porous ceramics compared to other types of porous ceramics. Although there have been many studies related to reticulated porous ceramics, few have focused on reticulated porous zirconia. Therefore, the aim of this study is to determine how to obtain a high compressive strength in reticulated porous zirconia by optimizing the process conditions of the solid loading level and the particle size and by using additives in a zirconia slurry sample. Furthermore, the authors assess the effects on the microstructure and compressive strength of multiple slurry coating, specifically from one to three. In conclusion, the effect of varying these various process conditions on the resulting improvement in compression strength was investigated, and the compression strength of reticulated porous zirconia was significantly increased from 0.14 to 9.43 MPa. The characteristics investigated include the pore characteristics (pore density, pore size and pore structure), the sintering behavior (linear shrinkage), the mechanical properties (compressive strength), and the dielectric properties (dielectric breakdown strength).
The Effects of Resistance Training on Architecture and Volume of the Upper Extremity Muscles: A Systematic Review of Randomised Controlled Trials and Meta-Analyses
Authors: Yagiz Gokhan , Akaras Esedullah , Kubis Hans-Peter , Owen Julian Andrew
Published: February 2022

To systematically review the effects of exercise on fascicle geometry and muscle size parameters of the upper extremity muscles, the CENTRAL, CINAHL, PubMed and OpenGrey databases were searched on 31 July 2021. Finally, 17 randomised controlled trials (RCTs) were included in this systematic review. High-intensity bench press training (g = 1.03) and 12 RM bench press exercises (g = 1.21) showed a large effect size on increasing pectoralis major muscle size. In the elbow extensors, large effects were reported for an increase in muscle size with isometric maximal voluntary co-contraction training (g = 1.97), lying triceps extension exercise (g = 1.25), and nonlinear periodised resistance training (g = 2.07). In addition, further large effects were achieved in the elbow flexors via traditional elbow flexion exercises (g = 0.93), concentric low-load forearm flexion-extension training (g = 0.94, g = 1), isometric maximal voluntary co-contraction training (g = 1.01), concentric low-load forearm flexion-extension training with blood flow restriction (g = 1.02, g = 1.07), and nonlinear periodised resistance training (g = 1.13, g = 1.34). Regarding the forearm muscles, isometric ulnar deviation training showed a large effect (g = 2.22) on increasing the flexor carpi ulnaris and radialis muscle size. Results show that these training modalities are suitable for gaining hypertrophy in the relevant muscles with at least four weeks of training duration. Future RCTs should investigate the effects of exercise modalities on the triceps brachii fascicle geometry, the infraspinatus muscle thickness (MT) and the subscapular MT due to their associations with sports performance.
Heat Transfer Analysis and Effects of (Silver and Gold) Nanoparticles on Blood Flow Inside Arterial Stenosis
Authors: Hussain Azad , Sarwar Lubna , Rehman Aysha , Akbar Sobia , Gamaoun Fehmi , Coban Hasan Huseyin , Almaliki Abdulrazak H. , Alqurashi Maram S.
Published: February 2022

The current investigation was based on a simulation employing CFD in COMSOL Multiphysics. The base fluid that was used in this simulation was blood. The flow was considered as a laminar, unsteady and incompressible Newtonian fluid, and the Newtonian nature of blood is acceptable at high shear rate. The behavior of blood flow was analyzed with the objective of obtaining pressure, temperature and velocity effects through an arterial stenosis. Two types of nanoparticles were used in this work: silver (Ag) and gold (Au). The equations of mass, momentum and energy were solved by utilizing the CFD technique. A fine element size mesh was generated through COMSOL. The results of this analysis show that velocity changes through confined parts of the artery, the velocity in a diseased region is higher and the velocity decreases before and after the stenotic region. In the heat transfer feature, the upper and lower boundary temperature was set to 24.85 °C and 27.35 °C, respectively. The nanoparticles affected the physical properties of blood, such as thermal conductivity, density, dynamic viscosity and specific heat. The addition of gold and silver nanoparticles prevented overheating because both nanoparticles have a high thermal conductivity, which has a principal role in dissipating temperature quickly. Nusselt number variations were also calculated and the results show that the curve decreases inside the stenosis. It could be concluded that the streamlines show abnormal behavior and recirculation occurs just after the stenosed area at t = 0.7 s and 1 s. These results will help greatly in the treatment of stenosed arteries.
Rotating Binaries
Authors: Gupta Anant , Aberkane Idriss J. , Ghosh Sourangshu , Abold Adrian , Rahn Alexander , Sultanow Eldar
Published: February 2022

This paper investigates the behavior of rotating binaries. A rotation by r digits to the left of a binary number B exhibits in particular cases the divisibility l∣N1(B)·r+1, where l is the bit-length of B and N1(B) is the Hamming weight of B, that is the number of ones in B. The integer r is called the left-rotational distance. We investigate the connection between this rotational distance, the length, and the Hamming weight of binary numbers. Moreover, we follow the question under which circumstances the above-mentioned divisibility is true. We have found out and will demonstrate that this divisibility occurs for kn+c cycles.
Multi-Year Variations in Atmospheric Water Vapor in the Baikal Natural Territory According to GPS Observations
Authors: Dembelov Mikhail , Bashkuev Yuri
Published: February 2022

The data of GPS measurements at the permanent observation points IRKM (Irkutsk, 52°13′ N, 104°19′ E, h = 509 m), ULAZ (Ulan-Ude, 51°48′ N, 107°37′ E, h = 517 m) and BADG (Badary, 51°46′ N, 102°14′ E, h = 848 m) located within the Baikal natural area (Eastern Siberia) are considered. A comparison was made of the time series of the tropospheric moisture content levels obtained at the IRKM site from GPS observations and radiosonde data, and at the BADG site from GPS observations and measurements with a water vapor radiometer (WVR) during 2020. The average deviation of the difference in total moisture content data during 2020 in the form of precipitable water according to GPS and WVR observations was about 0.12 mm, or about 1.1% relative to the average value, and the cross-correlation coefficient between the data is very high (K = 0.92). The use of GPS observations to obtain continuous data on the moisture content of the troposphere is substantiated. A series of processed data on the total moisture content based on GPS measurements using surface meteorological data for the period 1999–2020 for the IRKM and ULAZ sites and for the period 2006–2020 for the BADG site were obtained. Linear trends of total moisture content were determined for observation points: IRKM (−0.35 mm per decade, –2.7%), ULAZ (+0.47 mm per decade, +3.9%) and BADG (+1.41 mm per decade, 13.4%). Moreover, at the IRKM and ULAZ points, the surface temperature trends in the same period were positive and amounted to +0.4 K and +0.7 K per decade, respectively. The article confirms the trends identified in the work of Ross and Elliott for the territory of Eastern Siberia.
Distinguishing Convective-Transition Moisture-Temperature Relationships with a Constellation of Polarimetric Radio Occultation Observations in and near Convection
Authors: Turk F. Joseph , Padullés Ramon , Morabito David D. , Emmenegger Todd , Neelin J. David
Published: February 2022

Convective transition statistics serve as diagnostics for the parameterization of convection in climate and weather forecast models by characterizing the dependence of convection on the humidity-temperature environment. The observed strong pickup of precipitation as a function of layer-averaged water vapor and temperature is captured in models with varying accuracy. For independent observational verification, a low-Earth orbiting satellite constellation of Global Navigation Satellite System (GNSS) polarimetric radio occultation (PRO) measurements would be spaced such that adjacent RO would capture different profiles within and immediately adjacent to convection. Here, the number of profile observations needed to distinguish between convective transition relations by different tropospheric temperature ranges is determined, over different tropical oceanic basins. To obtain these, orbit simulations were performed by flying different satellite constellations over global precipitation from the Global Precipitation Measurement (GPM) mission, varying the numbers of satellites, orbit altitude, and inclination. A 45-degree orbit inclination was found to be a good tradeoff between maximizing the number of observations collected per day, and the desired 50–150-km spacing between individual RO ray paths. Assuming a set of reasonable assumptions for net data yield, three tropospheric temperatures can be distinguished by 1 K with a six-month on-orbit duration from a constellation of at least three satellites.
Differences According to Age in the Diagnostic Performance of Cardiac Biomarkers to Predict Frailty in Patients with Acute Heart Failure
Authors: Aguilar-Iglesias Lara , Merino-Merino Ana , Sanchez-Corral Ester , Garcia-Sanchez Maria-Jesus , Santos-Sanchez Isabel , Saez-Maleta Ruth , Perez-Rivera Jose-Angel
Published: February 2022

Frailty has traditionally been studied in the elderly population but scarcely in younger individuals. The objective of the present study is to analyze differences according to age in the diagnostic performance of cardiac biomarkers to predict frailty in patients admitted to the hospital for acute heart failure (AHF). A frailty assessment was performed with the SPPB and FRAIL scales (score > 3). We included 201 patients who were divided according to age: those older and younger than 75 years. In the younger group, no biomarker was related to the presence of frailty. This was mainly determined by age and comorbidities. In the elderly group, NT-proBNP was significantly related to the presence of frailty, but none of the baseline characteristics were. The best cut-off point in the elderly group for NT-proBNP was 4000 pg/mL. The area under the curve (AUC) for proBNP for frailty detection was 0.62 in the elderly. Another similar frailty scale, the SPPB, also showed a similar AUC in this group; however, adding the NT-proBNP (one point if NT-proBNP < 4000 pg/mL), it showed a slightly higher yield (AUC 0.65). The addition of biomarkers could improve frailty detection in members of the elderly population who are admitted to the hospital for AHF.
Inflammation Promotes Oxidative and Nitrosative Stress in Chronic Myelogenous Leukemia
Authors: Đikić Dragoslava , Bogdanović Andrija , Marković Dragana , Mitrović-Ajtić Olivera , Subotički Tijana , Diklić Miloš , Vukotić Milica , Dragojević Teodora , Živković Emilija , Santibanez Juan F. , Čokić Vladan P.
Published: February 2022

Chronic inflammation is characterized by the production of reactive oxygen species (ROS), reactive nitrogen species, and inflammatory cytokines in myeloproliferative neoplasms (MPNs). In addition to these parameters, the aim of this study was to analyze the influence of ROS on the proliferation-related AKT/mTOR signaling pathway and the relationship with inflammatory factors in chronic myelogenous leukemia (CML). The activity of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase is reduced in erythrocytes while levels of the oxidative stress markers malondialdehyde and protein carbonyl are elevated in the plasma of patients with CML. In addition, nitrogen species (nitrotyrosine, iNOS, eNOS) and inflammation markers (IL-6, NFkB, and S100 protein) were increased in granulocytes of CML while anti-inflammatory levels of IL-10 were decreased in plasma. CML granulocytes exhibited greater resistance to cytotoxic H2O2 activity compared to healthy subjects. Moreover, phosphorylation of the apoptotic p53 protein was reduced while the activity of the AKT/mTOR signaling pathway was increased, which was further enhanced by oxidative stress (H2O2) in granulocytes and erythroleukemic K562 cells. IL-6 caused oxidative stress and DNA damage that was mitigated using antioxidant or inhibition of inflammatory NFkB transcription factor in K562 cells. We demonstrated the presence of oxidative and nitrosative stress in CML, with the former mediated by AKT/mTOR signaling and stimulated by inflammation.
AAV-Vectored Expression of the Vascular Normalizing Agents 3TSR and Fc3TSR, and the Anti-Angiogenic Bevacizumab Extends Survival in a Murine Model of End-Stage Epithelial Ovarian Carcinoma
Authors: Stegelmeier Ashley A. , Santry Lisa A. , Guilleman Matthew M. , Matuszewska Kathy , Minott Jessica A. , Yates Jacob G. E. , Stevens Brenna A. Y. , Thomas Sylvia P. , Vanderkamp Sierra , Hanada Kiersten , Pei Yanlong , Rghei Amira D. , van Vloten Jacob P. , Pereira Madison , Thompson Brad , Major Pierre P. , Petrik James J. , Bridle Byram W. , Wootton Sarah K.
Published: February 2022

Epithelial ovarian cancer is the deadliest gynecological malignancy. The lack of effective treatments highlights the need for novel therapeutic interventions. The aim of this study was to investigate whether sustained adeno-associated virus (AAV) vector-mediated expression of vascular normalizing agents 3TSR and Fc3TSR and the antiangiogenic monoclonal antibody, Bevacizumab, with or without oncolytic virus treatment would improve survival in an orthotopic syngeneic mouse model of epithelial ovarian carcinoma. AAV vectors were administered 40 days post-tumor implantation and combined with oncolytic avian orthoavulavirus-1 (AOaV-1) 20 days later, at the peak of AAV-transgene expression, to ascertain whether survival could be extended. Flow cytometry conducted on blood samples, taken at an acute time point post-AOaV-1 administration (36 h), revealed a significant increase in activated NK cells in the blood of all mice that received AOaV-1. T cell analysis revealed a significant increase in CD8+ tumor specific T cells in the blood of AAV-Bevacizumab+AOaV-1 treated mice compared to control mice 10 days post AOaV-1 administration. Immunohistochemical staining of primary tumors harvested from a subset of mice euthanized 90 days post tumor implantation, when mice typically have large primary tumors, secondary peritoneal lesions, and extensive ascites fluid production, revealed that AAV-3TSR, AAV-Fc3TSR+AOaV-1, or AAV-Bevacizumab+AOaV-1 treated mice had significantly more tumor-infiltrating CD8+ T cells than PBS controls. Despite AAV-mediated transgene expression waning faster in tumor-bearing mice than in non-tumor bearing mice, all three of the AAV therapies significantly extended survival compared to control mice; with AAV-Bevacizumab performing the best in this model. However, combining AAV therapies with a single dose of AOaV-1 did not lead to significant extensions in survival compared to AAV therapies on their own, suggesting that additional doses of AOaV-1 may be required to improve efficacy in this model. These results suggest that vectorizing anti-angiogenic and vascular normalizing agents is a viable therapeutic option that warrants further investigation, including optimizing combination therapies.
Translational Implications of Dysregulated Pathways and microRNA Regulation in Quadruple-Negative Breast Cancer
Authors: Qattan Amal , Al-Tweigeri Taher , Suleman Kausar
Published: February 2022

Triple-negative breast cancers (HER2−, ER−, PR−) continue to present a unique treatment challenge and carry unfavorable prognoses. The elucidation of novel therapeutic targets has necessitated the re-evaluation of stratification approaches to best predict prognosis, treatment response and theranostic and prognostic markers. Androgen receptor expression and function have important implications on proliferation, tumor progression, immunity and molecular signaling in breast cancer. Accordingly, there has been increasing support for classification of androgen receptor-negative triple-negative breast cancer or quadruple-negative breast cancer (QNBC). QNBC has unique molecular, signaling and expression regulation profiles, particularly those affected by microRNA regulatory networks. microRNAs are now known to regulate AR-related targets and pathways that are dysregulated in QNBC, including immune checkpoint inhibitors (ICIs), SKP2, EN1, ACSL4 and EGFR. In this review, we explore and define the QNBC tumor subtype, its molecular and clinical distinctions from other subtypes, miRNA dysregulation and function in QNBC, and knowledge gaps in the field. Potential insights into clinical and translational implications of these dysregulated networks in QNBC are discussed.
Perceived Anger in Clear and Conversational Speech: Contributions of Age and Hearing Loss
Authors: Morgan Shae D. , Ferguson Sarah Hargus , Crain Ashton D. , Jennings Skyler G.
Published: February 2022

A previous investigation demonstrated differences between younger adult normal-hearing listeners and older adult hearing-impaired listeners in the perceived emotion of clear and conversational speech. Specifically, clear speech sounded angry more often than conversational speech for both groups, but the effect was smaller for the older listeners. These listener groups differed by two confounding factors, age (younger vs. older adults) and hearing status (normal vs. impaired). The objective of the present study was to evaluate the contributions of aging and hearing loss to the reduced perception of anger in older adults with hearing loss. We investigated perceived anger in clear and conversational speech in younger adults with and without a simulated age-related hearing loss, and in older adults with normal hearing. Younger adults with simulated hearing loss performed similarly to normal-hearing peers, while normal-hearing older adults performed similarly to hearing-impaired peers, suggesting that aging was the primary contributor to the decreased anger perception seen in previous work. These findings confirm reduced anger perception for older adults compared to younger adults, though the significant speaking style effect—regardless of age and hearing status—highlights the need to identify methods of producing clear speech that is emotionally neutral or positive.
Ethical Considerations in Clinical Trials for Disorders of Consciousness
Authors: Young Michael J. , Bodien Yelena G. , Edlow Brian L.
Published: February 2022

As the clinical trial landscape for patients with disorders of consciousness (DoC) expands, consideration of associated ethical challenges and opportunities is of ever-increasing importance. Responsible conduct of research in the vulnerable population of persons with DoC, including those with coma, vegetative state/unresponsive wakefulness syndrome (VS/UWS), minimally conscious state (MCS), covert cortical processing (CCP), and cognitive motor dissociation (CMD), demands proactive deliberation of unique ethical issues that may arise and the adoption of robust protections to safeguard patients, surrogates, and other key stakeholders. Here we identify and critically evaluate four central categories of ethical considerations in clinical trials involving participants with DoC: (1) autonomy, respect for persons and informed consent of individuals with liminal consciousness; (2) balancing unknown benefits and risks, especially considering the epistemological gap between behavior and consciousness that complicates ordinary ascription of subjective states; (3) disclosure to surrogates and clinical teams of investigational results pertaining to consciousness; and (4) justice considerations, including equitable access to clinical trial enrollment across communities and geographies. We outline guiding principles and research opportunities for clinicians, neuroethicists, and researchers engaged in DoC clinical trials to advance ethical study design and deployment in this complex yet crucial area of investigation.
Clinical and Biological Factors Are Associated with Treatment-Resistant Depression
Authors: Buoli Massimiliano , Capuzzi Enrico , Caldiroli Alice , Ceresa Alessandro , Esposito Cecilia Maria , Posio Cristina , Auxilia Anna Maria , Capellazzi Martina , Tagliabue Ilaria , Surace Teresa , Legnani Francesca , Cirella Luisa , Di Paolo Martina , Nosari Guido , Zanelli Quarantini Francesco , Clerici Massimo , Colmegna Fabrizia , Dakanalis Antonios
Published: February 2022

Background: Treatment-resistant depression (TRD) is a debilitating condition associated with unmet clinical needs. Few studies have explored clinical characteristics and serum biomarkers associated with TRD. Aims: We investigated whether there were differences in clinical and biochemical variables between patients affected by TRD than those without. Methods: We recruited 343 patients (165 males and 178 females) consecutively hospitalized for MDD to the inpatient clinics affiliated to the Fondazione IRCCS Policlinico, Milan, Italy (n = 234), and ASST Monza, Italy (n = 109). Data were obtained through a screening of the clinical charts and blood analyses conducted during the hospitalization. Results: TRD versus non-TRD patients resulted to be older (p = 0.001), to have a longer duration of illness (p < 0.001), to be more currently treated with a psychiatric poly-therapy (p < 0.001), to have currently more severe depressive symptoms as showed by the Hamilton Depression Rating Scale (HAM-D) scores (p = 0.016), to have lower bilirubin plasma levels (p < 0.001). In addition, more lifetime suicide attempts (p = 0.035), more antidepressant treatments before the current episode (p < 0.001), and a lower neutrophil to lymphocyte ratio at borderline statistically significant level (p = 0.060) were all associated with the TRD group. Conclusion: We identified candidate biomarkers associated with TRD such as bilirubin plasma levels and NLR, to be confirmed by further studies. Moreover, TRD seems to be associated with unfavorable clinical factors such as a predisposition to suicidal behaviors. Future research should replicate these results to provide robust data in support of the identification of new targets of treatment and implementation of prevention strategies for TRD.
Life-Cycle Assessment of Sculptured Tiles for Building Envelopes in Mediterranean Climate
Authors: Pushkar Svetlana , Yezioro Abraham , Hershcovich Cheli , Grobman Yasha J.
Published: February 2022

Life-cycle assessments (LCAs) were conducted to evaluate sculptured cement mortar tiles, proposed by Hershcovich et al. (2021), and conventional cement mortar flat tiles for thermal insulation of a typical residential building in Mediterranean climate. The production (P) and operational energy (OE) stages were compared between the sculptured tiles and the conventional flat tiles. The P stage used Portland cement with 95% clinker (CEM I) and Portland limestone cement with 65% clinker (CEM II). The OE stage used 31% coal, 56% natural gas, and 13% photovoltaic (PV) (adopted in 2020) and 8% coal, 57% natural gas, and 35% PV (planned for 2025). The ReCiPe2016 single-score method was used to assess environmental damage over short (20 years), long (100 years), and infinite (1000 years) time horizons of living pollutants. The results show that the use of sculptured tiles caused environmental damage in the short time horizon and environmental benefits in the long and infinite time horizons in the 2020 scenario, while it led to environmental benefits only in the infinite time horizon in the 2025 scenario.
COVID-19 Pandemic and Its Effects on the Usage of Information Technologies in the Construction Industry: The Case of Romania
Authors: Leontie Vlad , Maha Liviu-George , Stoian Iuliana Claudia
Published: February 2022

The COVID-19 pandemic has made the world face a whole new reality, and the measures taken for slowing the spread of the disease included social distancing, as well as national, regional, or local lockdowns and restrictions regarding the movement of people. For such an important sector of the Romanian economy as the construction industry, the restrictive measures imposed by the authorities led to postponing, delaying, or stopping the current projects. This paper aims at investigating the main effects of the COVID-19 pandemic on the Romanian construction sector, as well as the role of the digitalization process in mitigating the negative impact on the companies activating in this domain, in the context of the current levels of use of information technologies. The research involved the use of qualitative (exploratory in-depth interviews) and quantitative (online surveys applied to members of the local building sector, such as engineers, architects, contractors, and managers) data collection methods, respectively descriptive statistics for data categorization and interpretation. In general, the Romanian construction sector was only slightly affected, with the most significant negative effects being the delays and cost overrun due to safety and health issues. This paper is one of the first studies to explore and assess the effects of COVID-19 on the Romanian construction industry and the role of digitalization in reducing the pandemic impact. The main findings reveal that the companies in this industry that have a high digitalization degree overpassed in a smoother manner the current pandemic situation.
The Never-Ending History of Octreotide in Thymic Tumors: A Vintage or A Contemporary Drug?
Authors: Montella Liliana , Ottaviano Margaret , Morra Rocco , Pietroluongo Erica , De Placido Pietro , Tortora Marianna , Sorrentino Chiara , Facchini Gaetano , De Placido Sabino , Giuliano Mario , Palmieri Giovannella
Published: February 2022

Thymic epithelial tumors are rare tumors usually presenting as a mass located in the anterior mediastinum and/or with symptoms deriving from associated paraneoplastic syndromes. Unresectable platinum-refractory tumors are often treated with alternative regimens, including chemotherapeutic agents as well as chemo-free regimens. The most popular unconventional therapy is represented by the somatostatin analog octreotide, which can be used alone or with prednisone. The in vivo expression of somatostatin receptors documented by imaging with indium-labeled octreotide or gallium-68 Dotapeptides, the successful use of octreotide and prednisone in a chemo-refractory patient, and, thereafter, the experiences from a case series have enforced the idea that this treatment merits consideration—as proved by its inclusion in the National Comprehensive Cancer Network guidelines. In the present review, we analyze the preclinical basis for the therapeutic use of somatostatin and prednisone in refractory thymic tumors and discuss the available studies looking at future perspectives.
The Use of ctDNA for BRAF Mutation Testing in Routine Clinical Practice in Patients with Advanced Melanoma
Authors: Sobczuk Paweł , Kozak Katarzyna , Kopeć Sylwia , Rogala Paweł , Świtaj Tomasz , Koseła-Paterczyk Hanna , Gos Aleksandra , Tysarowski Andrzej , Rutkowski Piotr
Published: February 2022

Assessment of BRAF mutation status is mandatory in advanced, treatment-naïve melanoma patients. Liquid biopsy can be an alternative in cases with inadequate or unavailable tumor tissue. The aim of our study was to evaluate the clinical utility of plasma circulating tumor DNA analysis for BRAF mutation testing and to assess outcomes of therapy with BRAF/MEK inhibitors initiated based on the liquid biopsy results. This was a retrospective single-center analysis of 46 patients (21 female, 25 male) with advanced melanoma who underwent circulating tumor DNA (ctDNA) BRAF mutation testing. A BRAF mutation was found in 45.7% (21/46) of liquid biopsies and 44.8% (13/29) of tissue samples. In patients with both ctDNA and tissue samples (n = 29), the concordance between the results of both tests was 82.8%. A BRAF mutation was detected in 7/17 (41.2%) patients with only ctDNA analysis. In 18 patients, therapy with BRAF/MEK inhibitors was initiated on the basis of the result of liquid biopsy. The objective response rate was 77.8 %, and the median PFS was 6.0 months. Our study confirms the clinical utility of BRAF mutation detection in plasma ctDNA. This study provides initial real-world data showing that treatment with BRAF/MEK inhibitors could be commenced based on liquid biopsy results.
Antibody–Drug Conjugates as an Emerging Therapy in Oncodermatology
Authors: Esnault Clara , Schrama David , Houben Roland , Guyétant Serge , Desgranges Audrey , Martin Camille , Berthon Patricia , Viaud-Massuard Marie-Claude , Touzé Antoine , Kervarrec Thibault , Samimi Mahtab
Published: February 2022

Antibody–drug conjugates (ADCs) are an emerging class of therapeutics, with twelve FDA- and EMA-approved drugs for hematological and solid cancers. Such drugs consist in a monoclonal antibody linked to a cytotoxic agent, allowing a specific cytotoxicity to tumor cells. In recent years, tremendous progress has been observed in therapeutic approaches for advanced skin cancer patients. In this regard, targeted therapies (e.g., kinase inhibitors) or immune checkpoint-blocking antibodies outperformed conventional chemotherapy, with proven benefit to survival. Nevertheless, primary and acquired resistances as well as adverse events remain limitations of these therapies. Therefore, ADCs appear as an emerging therapeutic option in oncodermatology. After providing an overview of ADC design and development, the goal of this article is to review the potential ADC indications in the field of oncodermatology.
A Polytherapy Strategy Using Vincristine and ALK Inhibitors to Sensitise EML4-ALK-Positive NSCLC
Authors: Sampson Josephina , Ju Hyun-min , Song Ji-young , Fry Andrew M. , Bayliss Richard , Choi Jene
Published: February 2022

The oncogenic fusion of EML4-ALK is present in about 4–6% of non-small cell lung cancer (NSCLC). A targeted approach with ALK tyrosine kinase inhibitors (TKIs) has been proven highly effective in ALK-positive NSCLC patients. However, despite the initial responses, the outcome of the treatment is variable. Previous studies have shown that the differential response depends in part on the type of EML4-ALK variant. Here, we examined the combination of ALK inhibitors and microtubule poison, vincristine, in cells expressing EML4-ALK V1 and V3, the two most common variants in NSCLC. We showed that combination therapy of ALK-TKIs with vincristine had anti-proliferative effects and blocked RAS/MAPK, PI3K/AKT and JAK/STAT3 signalling pathways in EML4-ALK V1 but not V3 cells. Our results demonstrate that high levels of tubulin acetylation are associated with poor response to vincristine in EML4-ALK V3 cells. Additionally, we demonstrated differences in microtubule stability between the two EML4-ALK fusions. EML4-ALK V3 cells exhibited dynamic microtubules that confer poor response to vincristine compared to V1 cells. Hence, we suggested that the portion of EML4 in the fusion has an important role for the outcome of the combination treatment.
Value of Targeted Biopsies and Combined PSMA PET/CT and mp-MRI Imaging in Locally Recurrent Prostate Cancer after Primary Radiotherapy
Authors: Rasing Marnix , van Son Marieke , Moerland Marinus , de Keizer Bart , Wessels Frank , Jonges Trudy , van de Pol Sandrine , Eppinga Wietse , Noteboom Juus , Lagendijk Jan , van der Voort van Zijp Jochem , Peters Max
Published: February 2022

Radiorecurrent prostate cancer is conventionally confirmed using systematic and/or targeted biopsies. The availability of multiparametric (mp) MRI and prostate specific membrane antigen (PSMA) PET/CT has increased diagnostic accuracy. The objective was to determine the positive predictive value (PPV) of combined mp-MRI and PSMA PET/CT and whether pathology verification with MR-targeted biopsies remains necessary for patients with radiorecurrent prostate cancer. Patients with locally recurrent prostate cancer who were referred for 19 Gy single-dose MRI-guided focal salvage high dose rate (HDR) brachytherapy between 2015 and 2018 were included in the current analysis. Patients were selected if they underwent pre-biopsy mp-MRI and PSMA PET/CT. Based on these images, lesions suspect for isolated tumor recurrence were transperineally biopsied using transrectal ultrasound fused with MRI. A total of 41 patients were identified from the database who underwent cognitive targeted (n = 7) or MRI/PSMA-transrectal ultrasound (TRUS) fused targeted (n = 34) biopsies. A total of 40 (97.6%) patients had positive biopsies for recurrent cancer. Five patients initially had negative biopsies (all MRI/PSMA-TRUS fusion targeted), four of whom recurrence was confirmed after a re-biopsy. One (2.4%) patient refused re-biopsy, leading to a positive predictive value (PPV) for combined imaging of 97.6%. Biopsies can therefore safely be withheld when the results of the combined mp-MRI and PSMA PET/CT are conclusive, avoiding an unnecessary invasive and burdensome procedure.
Oxidative Coupling of Methane over Pt/Al2O3 at High Temperature: Multiscale Modeling of the Catalytic Monolith
Authors: Chawla Jaspreet , Schardt Sven , Angeli Sofia , Lott Patrick , Tischer Steffen , Maier Lubow , Deutschmann Olaf
Published: February 2022

At high temperatures, the oxidative coupling of methane (OCM) is an attractive approach for catalytic conversion of methane into value-added chemicals. Experiments with a Pt/Al2O3-coated catalytic honeycomb monolith were conducted with varying CH4/O2 ratios, N2 dilution at atmospheric pressure, and very short contact times. The reactor was modeled by a multiscale approach using a parabolic two-dimensional flow field description in the monolithic channels coupled with a heat balance of the monolithic structure, and multistep surface reaction mechanisms as well as elementary-step, gas phase reaction mechanisms. The contribution of heterogeneous and homogeneous reactions, both of which are important for the optimization of C2 products, is investigated using a combination of experimental and computational methods. The oxidation of methane, which takes place over the platinum catalyst, causes the adiabatic temperature increase required for the generation of CH3 radicals in the gas phase, which are essential for the formation of C2 species. Lower CH4/O2 ratios result in higher C2 selectivity. However, the presence of OH radicals at high temperatures facilitates subsequent conversion of C2H2 at a CH4/O2 ratio of 1.4. Thereby, C2 species selectivity of 7% was achieved at CH4/O2 ratio of 1.6, with 35% N2 dilution.
Electrochemical Degradation of Nitrobenzene Wastewater: From Laboratory Experiments to Pilot-Scale Industrial Application
Authors: Liu Dunyi , Liao Zhangjiu , Hu Ziyi , Shang Enxiang
Published: February 2022

In this study, the electrochemical degradation of nitrobenzene (NB) was conducted on the Ti/SnO2-Sb/Ce-PbO2 anode with excellent functional performance. The effect of applied current density, electrode distance, pH value and initial concentration on the reaction kinetics of NB was systematically studied. The total organic carbon (TOC) removal rate reached 91.5% after 60 min of electrolysis under optimal conditions. Eight aromatic intermediate products of NB were identified by using a gas chromatography coupled with a mass spectrometer, and two aliphatic carboxylic acids were qualitatively analyzed using a high-performance liquid chromatograph. The electrochemical mineralization mechanism of NB was proposed based on the detected intermediates and the identified key active oxygen specie. It was supposed that the hydroxyl radical produced on an anode attacked NB to form hydroxylated NB derivatives, followed by the benzene ring opening reactions with the formation of aliphatic carboxylic acids, which mineralized to CO2 and H2O. In addition, NB was reduced to less stable aniline on the cathode surface, which resulted in actualized mineralization. The successful pilot-scale industrial application in combination with wastewater containing NB with the influent concentration of 80–120 mg L−1 indicated that electrochemical oxidation has great potential to abate NB in practical wastewater treatment.
Advances in Modeling Polyglutamine Diseases Using Genome Editing Tools
Authors: Karwacka Marianna , Olejniczak Marta
Published: February 2022

Polyglutamine (polyQ) diseases, including Huntington’s disease, are a group of late-onset progressive neurological disorders caused by CAG repeat expansions. Although recently, many studies have investigated the pathological features and development of polyQ diseases, many questions remain unanswered. The advancement of new gene-editing technologies, especially the CRISPR-Cas9 technique, has undeniable value for the generation of relevant polyQ models, which substantially support the research process. Here, we review how these tools have been used to correct disease-causing mutations or create isogenic cell lines with different numbers of CAG repeats. We characterize various cellular models such as HEK 293 cells, patient-derived fibroblasts, human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs) and animal models generated with the use of genome-editing technology.
CNOT6: A Novel Regulator of DNA Mismatch Repair
Authors: Song Peng , Liu Shaojun , Liu Dekang , Keijzers Guido , Bakula Daniela , Duan Shunlei , de Wind Niels , Ye Zilu , Vakhrushev Sergey Y. , Scheibye-Knudsen Morten , Rasmussen Lene Juel
Published: February 2022

DNA mismatch repair (MMR) is a highly conserved pathway that corrects both base–base mispairs and insertion-deletion loops (IDLs) generated during DNA replication. Defects in MMR have been linked to carcinogenesis and drug resistance. However, the regulation of MMR is poorly understood. Interestingly, CNOT6 is one of four deadenylase subunits in the conserved CCR4-NOT complex and it targets poly(A) tails of mRNAs for degradation. CNOT6 is overexpressed in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and androgen-independent prostate cancer cells, which suggests that an altered expression of CNOT6 may play a role in tumorigenesis. Here, we report that a depletion of CNOT6 sensitizes human U2OS cells to N-methyl-N′nitro-N-nitrosoguanidine (MNNG) and leads to enhanced apoptosis. We also demonstrate that the depletion of CNOT6 upregulates MMR and decreases the mutation frequency in MMR-proficient cells. Furthermore, the depletion of CNOT6 increases the stability of mRNA transcripts from MMR genes, leading to the increased expression of MMR proteins. Our work provides insight into a novel CNOT6-dependent mechanism for regulating MMR.
Nuclear Localization Sequence of FGF1 Is Not Required for Its Intracellular Anti-Apoptotic Activity in Differentiated Cells
Authors: Lampart Agata , Sluzalska Katarzyna Dominika , Czyrek Aleksandra , Szerszen Aleksandra , Otlewski Jacek , Wiedlocha Antoni , Zakrzewska Malgorzata
Published: February 2022

Fibroblast growth factor 1 (FGF1) is considered primarily as a ligand for FGF surface receptors (FGFRs) through which it activates a number of cellular responses. In addition to its canonical mode of action, FGF1 can act intracellularly, before secretion or after internalization and translocation from the cell exterior. The role of FGF1 inside the cell is to provide additional protection against apoptosis and promote cell survival. The FGF1 protein contains a specific N-terminal nuclear localization sequence (NLS) that is essential for its efficient transport to the nucleus. Here, we investigated the role of this sequence in the anti-apoptotic response of FGF1. To this end, we produced recombinant FGF1 variants with mutated or deleted NLS and added them to apoptosis-induced cells in which FGFR1 was inactive, either as a result of chemical inhibition or kinase-dead mutation. After internalization, all FGF1 variants were able to protect the differentiated cells from serum starvation-induced apoptosis. To verify the results obtained for NLS mutants, we knocked down LRRC59, a protein that mediates the nuclear transport of FGF1. Upon LRRC59 silencing, we still observed a decrease in caspase 3/7 activity in cells treated exogenously with wild-type FGF1. In the next step, FGF1 variants with mutated or deleted NLS were expressed in U2OS cells, in which apoptosis was then induced by various factors (e.g., starvation, etoposide, staurosporine, anisomycin and actinomycin D). Experiments were performed in the presence of specific FGFR inhibitors to eliminate FGFR-induced signaling, potentially activated by FGF1 proteins released from damaged cells. Again, we found that the presence of NLS in FGF1 is not required for its anti-apoptotic activity. All NLS variants tested were able to act as wild type FGF1, increasing the cell viability and mitochondrial membrane potential and reducing the caspase 3/7 activity and PARP cleavage in cells undergoing apoptosis, both transiently and stably transfected. Our results indicate that the nuclear localization of FGF1 is not required for its intracellular anti-apoptotic activity in differentiated cells and suggest that the mechanism of the stress response differs according to the level of cell differentiation.
NAC Transcription Factor Family Regulation of Fruit Ripening and Quality: A Review
Authors: Liu Gang-Shuai , Li Hong-Li , Grierson Donald , Fu Da-Qi
Published: February 2022

The NAC transcription factor (TF) family is one of the largest plant-specific TF families and its members are involved in the regulation of many vital biological processes during plant growth and development. Recent studies have found that NAC TFs play important roles during the ripening of fleshy fruits and the development of quality attributes. This review focuses on the advances in our understanding of the function of NAC TFs in different fruits and their involvement in the biosynthesis and signal transduction of plant hormones, fruit textural changes, color transformation, accumulation of flavor compounds, seed development and fruit senescence. We discuss the theoretical basis and potential regulatory models for NAC TFs action and provide a comprehensive view of their multiple roles in modulating different aspects of fruit ripening and quality.
MicroRNAs Associated with Chronic Mucus Hypersecretion in COPD Are Involved in Fibroblast–Epithelium Crosstalk
Authors: Tasena Hataitip , Timens Wim , van den Berge Maarten , van Broekhuizen Joy , Kennedy Brian K. , Hylkema Machteld N. , Brandsma Corry-Anke , Heijink Irene H.
Published: February 2022

We recently identified microRNAs (miRNAs) associated with chronic mucus hypersecretion (CMH) in chronic obstructive pulmonary disease (COPD), which were expressed in both airway epithelial cells and fibroblasts. We hypothesized that these miRNAs are involved in communication between fibroblasts and epithelium, contributing to airway remodeling and CMH in COPD. Primary bronchial epithelial cells (PBECs) differentiated at the air–liquid interface, and airway fibroblasts (PAFs) from severe COPD patients with CMH were cultured alone or together. RNA was isolated and miRNA expression assessed. miRNAs differentially expressed after co-culturing were studied functionally using overexpression with mimics in mucus-expressing human lung A549 epithelial cells or normal human lung fibroblasts. In PBECs, we observed higher miR-708-5pexpression upon co-culture with fibroblasts, and miR-708-5p expression decreased upon mucociliary differentiation. In PAFs, let-7a-5p, miR-31-5p and miR-146a-5p expression was significantly increased upon co-culture. miR-708-5p overexpression suppressed mucin 5AC (MUC5AC) secretion in A549, while let-7a-5poverexpression suppressed its target gene COL4A1 in lung fibroblasts. Our findings suggest that let-7a-5p, miR-31-5p and miR-146a-5p may be involved in CMH via fibroblasts–epithelium crosstalk, including extracellular matrix gene regulation, while airway epithelial expression of miR-708-5p may be involved directly, regulating mucin production. These findings shed light on miRNA-mediated mechanisms underlying CMH, an important symptom in COPD.
Appendicitis as a Leading Manifestation of Kawasaki Disease in Older Children
Authors: Huang Ya-Ning , Liu Lu-Hang , Chen Jeng-Jung , Tai Yu-Lin , Duh Yih-Cherng , Lin Chien-Yu
Published: February 2022

Kawasaki disease (KD) is a systematic inflammatory disease with multiple organ involvement. Timely diagnosis and prompt management are essential for successful treatment. KD, with an atypical presentation, remains a diagnostic challenge for physicians. We report a five-year-old boy who presented with appendicitis. An appendectomy was performed; however, his fever persisted. The boy was diagnosed with KD and intravenous immunoglobulin was administered. His symptoms resolved, and he had an uneventful recovery. Furthermore, we performed a literature review with 13 cases identified in the literature. Most cases were male, and the average age was older than typical for KD. In conclusion, KD may present with abdominal complaints and appendicitis may be a rare initial presentation of KD. Multidisciplinary cooperation and high awareness are warranted for timely diagnosis, especially in older children experiencing persistent fever after an appendectomy.
ICOS Gene Polymorphisms (IVS1 + 173 T/C and c. 1624 C/T) in Primary Sjögren’s Syndrome Patients: Analysis of ICOS Expression
Authors: García-Espinoza José Antonio , Muñoz-Valle José Francisco , García-Chagollán Mariel , Hernández-Bello Jorge , Palafox-Sánchez Claudia Azucena , López-Villalobos Erika Fabiola , Sánchez-Zuno Gabriela Athziri , Martínez-Bonilla Gloria Esther , Cerpa-Cruz Sergio , Carrillo-Ballesteros Francisco Josue , Oregon-Romero Edith
Published: February 2022

Background: Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease, which affects exocrine glands. T cell activation is a trigger mechanism in the immune response. Hyperreactivity of T cells and antibody production are features in pSS. ICOS can be critical in the pathogenesis of pSS. Methods: A total of 134 pSS patients and 134 control subjects (CS) were included. Genotyping was performed by PCR-RFLP. ICOS mRNA expression was quantified by real-time PCR, and CD4+ ICOS+ T cells were determined by flow cytometry. Results: The ICOS IVS1 + 173 T>C polymorphisms were not associated with susceptibility to pSS (p = 0.393, CI = 0.503–1.311). However, the c.1624 C>T polymorphism was associated with a reduction in the risk of development of pSS (p = 0.015, CI = 0.294–0.884). An increase in ICOS mRNA expression in patients was observed (3.7-fold). Furthermore, pSS patients showed an increase in membranal-ICOS expression (mICOS). High expression of mICOS (MFI) was associated with lymphocytic infiltration. Conclusions: The IVS1 + 173 polymorphism is not a genetic marker for the development of pSS, while c.1624 T allele was associated with a low risk. However, elevated mICOS expression in pSS patients with high lymphocytic infiltration was found. ICOS may have an important role in the immunopathogenesis of pSS and should be analyzed in T cell subsets in pSS patients as a possible disease marker.