bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation and Application of Reanalyzed Combined Data under Extreme Climate Conditions: A Case Study of a Typical Flood Event in the Jinsha River
Authors: Guo Dandan , Luo Chi , Xiang Jian , Cai Siyu
Published: February 2022

From 15 to 20 September 2016, precipitation extremes occurred in the middle and lower reaches of the Jinsha River, causing immense direct economic losses due to floods. The current research on extreme climate characteristics and the relationship between climate extremes and runoff extremes are based on a single data source. This is due to the uneven distribution of precipitation and temperature stations, which make it difficult to fully capture extreme climate events. In this paper, various internationally popular reanalysis datasets were introduced. Extreme climate indexes were computed using the merged datasets versus the meteorological station observations. The results showed that: (1) Comparative analysis of the extreme climate indexes of the reanalysis dataset and the data of traditional meteorological observation stations showed that most of the extreme precipitation indexes calculated by the various reanalysis of combined data exhibited good performances. Among the reanalyzed combined products, CMPA-H, CMADS, and GPM (IMERG) exhibited good performance while the performance of TRMM (TMPA) was slightly worse. The extreme temperature indexes, TXx and TNn, calculated based on the reanalysis of combined data showed a better consistency than the indexes calculated based on the observational data of meteorological stations. The CMADS temperature dataset exhibited a higher consistency with the data obtained from meteorological stations as well as the best accuracy (84% of the stations with the error value of TXx calculated from the CMADS dataset and observed data less than 3 °C). (2) The response of typical flood events to precipitation extremes were analyzed and evaluated; the spatial distribution of the precipitation in the combined dataset was used to quantitatively analyze the response of occurrence of typical flood events to precipitation extremes, and the typical flood events were found to be mainly caused by certain factors, such as lagging flood propagation in the upstream of the basin outlet. This study indicates that it is feasible to use the reanalyzed combined data products to calculate the extreme climate indexes of the Jinsha River Basin, especially in the upper reaches of the Yangtze River where there is a lack of meteorological observation stations.
Big Data Analytics in Supply Chain Management: A Systematic Literature Review and Research Directions
Authors: Lee In , Mangalaraj George
Published: February 2022

Big data analytics has been successfully used for various business functions, such as accounting, marketing, supply chain, and operations. Currently, along with the recent development in machine learning and computing infrastructure, big data analytics in the supply chain are surging in importance. In light of the great interest and evolving nature of big data analytics in supply chains, this study conducts a systematic review of existing studies in big data analytics. This study presents a framework of a systematic literature review from interdisciplinary perspectives. From the organizational perspective, this study examines the theoretical foundations and research models that explain the sustainability and performances achieved through the use of big data analytics. Then, from the technical perspective, this study analyzes types of big data analytics, techniques, algorithms, and features developed for enhanced supply chain functions. Finally, this study identifies the research gap and suggests future research directions.
Weighted Brain Network Analysis on Different Stages of Clinical Cognitive Decline
Authors: Abazid Majd , Houmani Nesma , Dorizzi Bernadette , Boudy Jerome , Mariani Jean , Kinugawa Kiyoka
Published: February 2022

This study addresses brain network analysis over different clinical severity stages of cognitive dysfunction using electroencephalography (EEG). We exploit EEG data of subjective cognitive impairment (SCI) patients, mild cognitive impairment (MCI) patients and Alzheimer’s disease (AD) patients. We propose a new framework to study the topological networks with a spatiotemporal entropy measure for estimating the connectivity. Our results show that functional connectivity and graph analysis are frequency-band dependent, and alterations start at the MCI stage. In delta, the SCI group exhibited a decrease of clustering coefficient and an increase of path length compared to MCI and AD. In alpha, the opposite behavior appeared, suggesting a rapid and high efficiency in information transmission across the SCI network. Modularity analysis showed that electrodes of the same brain region were distributed over several modules, and some obtained modules in SCI were extended from anterior to posterior regions. These results demonstrate that the SCI network was more resilient to neuronal damage compared to that of MCI and even more compared to that of AD. Finally, we confirm that MCI is a transitional stage between SCI and AD, with a predominance of high-strength intrinsic connectivity, which may reflect the compensatory response to the neuronal damage occurring early in the disease process.
Novel Nutraceutical Compounds in Alzheimer Prevention
Authors: Maccioni Ricardo Benjamin , Calfío Camila , González Andrea , Lüttges Valentina
Published: February 2022

Alzheimer’s disease (AD) incidence is increasing worldwide at an alarming rate. Considering this increase, prevention efforts, stemming from scientific research, health education, and public policies, are critical. Clinical studies evidenced that healthy lifestyles along with natural multitarget and disease-modifying agents have a preventative impact on AD or mitigate symptoms in diagnosed patients. The pathological alterations of AD start 30 years before symptoms, and it is essential to develop the capacity to detect those changes. In this regard, molecular biomarkers that detect early pathological manifestations are helpful. Based on markers data, early preventive interventions could reduce more than 40% of AD cases. Protective actions include exercise, shown to induce neurogenesis, cognitive stimulation, intellectual-social activity, and nutrition among others. Mediterranean diet, preprobiotics, and nutraceuticals containing bioactive molecules with antioxidant and anti-inflammatory properties are relevant. Antiprotein aggregation molecules whose mechanisms were described are important. Anti-inflammatory agents with anti-aggregation properties that help to control cognitive impairment, include quercetin, biocurcumin, rosemarinic acid, and Andean shilajit. Anthocyanidins, e.g., delphinidin, malvidin, and natural flavonoids, are also included. Quercetin and hydroxy-tyrosol are antiaging molecules and could have anti-AD properties. We emphasize the relevance of nutraceuticals as a main actor in the prevention and/or control of dementia and particularly AD.
CCN2 Binds to Tubular Epithelial Cells in the Kidney
Authors: Rayego-Mateos Sandra , Morgado-Pascual José Luis , Lavoz Carolina , Rodrigues-Díez Raúl R. , Márquez-Expósito Laura , Tejera-Muñoz Antonio , Tejedor-Santamaría Lucía , Rubio-Soto Irene , Marchant Vanessa , Ruiz-Ortega Marta
Published: February 2022

Cellular communication network-2 (CCN2), also called connective tissue growth factor (CTGF), is considered a fibrotic biomarker and has been suggested as a potential therapeutic target for kidney pathologies. CCN2 is a matricellular protein with four distinct structural modules that can exert a dual function as a matricellular protein and as a growth factor. Previous experiments using surface plasmon resonance and cultured renal cells have demonstrated that the C-terminal module of CCN2 (CCN2(IV)) interacts with the epidermal growth factor receptor (EGFR). Moreover, CCN2(IV) activates proinflammatory and profibrotic responses in the mouse kidney. The aim of this paper was to locate the in vivo cellular CCN2/EGFR binding sites in the kidney. To this aim, the C-terminal module CCN2(IV) was labeled with a fluorophore (Cy5), and two different administration routes were employed. Both intraperitoneal and direct intra-renal injection of Cy5-CCN2(IV) in mice demonstrated that CCN2(IV) preferentially binds to the tubular epithelial cells, while no signal was detected in glomeruli. Moreover, co-localization of Cy5-CCN2(IV) binding and activated EGFR was found in tubules. In cultured tubular epithelial cells, live-cell confocal microscopy experiments showed that EGFR gene silencing blocked Cy5-CCN2(IV) binding to tubuloepithelial cells. These data clearly show the existence of CCN2/EGFR binding sites in the kidney, mainly in tubular epithelial cells. In conclusion, these studies show that circulating CCN2(IV) can directly bind and activate tubular cells, supporting the role of CCN2 as a growth factor involved in kidney damage progression.
Interaction with the Assembly Chaperone Ump1 Promotes Incorporation of the β7 Subunit into Half-Proteasome Precursor Complexes Driving Their Dimerization
Authors: Zimmermann Jessica , Ramos Paula C. , Dohmen R. Jürgen
Published: February 2022

Biogenesis of the eukaryotic 20S proteasome core particle (PC) is a complex process assisted by specific chaperones absent from the active complex. The first identified chaperone, Ump1, was found in a precursor complex (PC) called 15S PC. Yeast cells lacking Ump1 display strong defects in the autocatalytic processing of β subunits, and consequently have lower proteolytic activity. Here, we dissect an important interaction of Ump1 with the β7 subunit that is critical for proteasome biogenesis. Functional domains of Ump1 and the interacting proteasome subunit β7 were mapped, and the functional consequences of their deletion or mutation were analyzed. Cells in which the first sixteen Ump1 residues were deleted display growth phenotypes similar to ump1∆, but massively accumulate 15S PC and distinct proteasome intermediate complexes containing the truncated protein. The viability of these cells depends on the transcription factor Rpn4. Remarkably, β7 subunit overexpression re-established viability in the absence of Rpn4. We show that an N-terminal domain of Ump1 and the propeptide of β7 promote direct interaction of the two polypeptides in vitro. This interaction is of critical importance for the recruitment of β7 precursor during proteasome assembly, a step that drives dimerization of 15S PCs and the formation of 20S CPs.
Association of Aneurysm Tissue Neutrophil Mediator Levels with Intraluminal Thrombus Thickness in Patients with Abdominal Aortic Aneurysm
Authors: Siennicka Aldona , Adamowicz Monika , Grzesch Natalie , Kłysz Magdalena , Woźniak Jarosław , Cnotliwy Miłosław , Galant Katarzyna , Jastrzębska Maria
Published: February 2022

An intraluminal thrombus (ILT), which accumulates large numbers of neutrophils, plays a key role in abdominal aortic aneurysm (AAA) pathogenesis. This study aimed to compare levels of selected neutrophil inflammatory mediators in thick and thin ILT, plus adjacent AAA walls, to determine whether levels depend on ILT thickness. Neutrophil mediator levels were analysed by enzyme-linked immunosorbent assays in thick and thin segments of ILT, plus adjacent aneurysm wall sections, taken from one aneurysm sac each from 36 AAA patients. In aneurysmal walls covered by thick ILT, neutrophil elastase and TNF-a levels were significantly higher, as were concentrations of IL-6, in thick ILT compared to thin layers. Positive correlations of NGAL, MPO, and neutrophil elastase were observed between thick ILT and the adjacent wall and thin ILT and the adjacent wall, suggesting that these mediators probably infiltrate thick AAA compartments as well as thin. These observations might support the idea that neutrophil mediators and inflammatory cytokines differentially accumulate in AAA tissues according to ILT thickness. The increased levels of neutrophil mediators within thicker AAA segments might suggest the existence of an intensified proinflammatory state that in turn presumably might preferentially weaken the AAA wall at that region.
Glycosylating Effectors of Legionella pneumophila: Finding the Sweet Spots for Host Cell Subversion
Authors: Belyi Yury , Levanova Nadya , Schroeder Gunnar N.
Published: February 2022

Work over the past two decades clearly defined a significant role of glycosyltransferase effectors in the infection strategy of the Gram-negative, respiratory pathogen Legionella pneumophila. Identification of the glucosyltransferase effectors Lgt1-3, specifically modifying elongation factor eEF1A, disclosed a novel mechanism of host protein synthesis manipulation by pathogens and illuminated its impact on the physiological state of the target cell, in particular cell cycle progression and immune and stress responses. Recent characterization of SetA as a general O-glucosyltransferase with a wide range of targets including the proteins Rab1 and Snx1, mediators of membrane transport processes, and the discovery of new types of glycosyltransferases such as LtpM and SidI indicate that the vast effector arsenal might still hold more so-far unrecognized family members with new catalytic features and substrates. In this article, we review our current knowledge regarding these fascinating biomolecules and discuss their role in introducing new or overriding endogenous post-translational regulatory mechanisms enabling the subversion of eukaryotic cells by L. pneumophila.
HDAC Inhibition for Optimized Cellular Immunotherapy of NY-ESO-1-Positive Soft Tissue Sarcoma
Authors: Gong Wenjie , Wang Lei , Schubert Maria-Luisa , Kleist Christian , Neuber Brigitte , Wang Sanmei , Yang Mingya , Hückelhoven-Krauss Angela , Wu Depei , Schmitt Anita , Müller-Tidow Carsten , Shiku Hiroshi , Schmitt Michael , Sellner Leopold
Published: February 2022

Adoptive cell therapy with NY-ESO-1-specific T cells is a promising option for the treatment of soft tissue sarcoma (STS) but achieves only transient tumor control in the majority of cases. A strategy to optimize this cell therapeutic approach might be the modulation of the expression of the cancer-testis antigen NY-ESO-1 using histone deacetylase inhibitors (HDACis). In this study, the ex vivo effect of combining NY-ESO-1-specific T cells with the clinically approved pan HDACis panobinostat or vorionstat was investigated. Our data demonstrated that STS cells were sensitive to HDACis. Administration of HDACi prior to NY-ESO-1-specific T cells exerted enhanced lysis against the NY-ESO-1+ STS cell line SW982. This correlated with an increase in the NY-ESO-1 and HLA-ABC expression of SW982 cells, as well as increased CD25 expression on NY-ESO-1-specific T cells. Furthermore, the immune reactivity of NY-ESO-1-specific CD8+ T cells in terms of cytokine release was enhanced by HDACis. In summary, pretreatment with HDACis represents a potential means of enhancing the cytotoxic efficacy of NY-ESO-1-specific T cells against NY-ESO-1-positive STS.
Sodium Accumulation and Blood Capillary Rarefaction in the Skin Predispose Spontaneously Hypertensive Rats to Salt Sensitive Hypertension
Authors: Šilhavý Jan , Mlejnek Petr , Šimáková Miroslava , Liška František , Kubovčiak Jan , Sticová Eva , Pravenec Michal
Published: February 2022

Recent studies in humans and rats suggested that increased Na+ storage in the skin without parallel water retention may predispose to salt-sensitive hypertension. In the current studies, we compared tissue Na+ storage in salt sensitive spontaneously hypertensive rats (SHR) versus salt resistant normotensive Brown Norway (BN-Lx) rats. After salt loading (10 days drinking 1% NaCl solution), the SHR showed significant parallel increase in Na+-to-water as well as (Na++K+)-to-water ratios suggesting increased storage of osmotically inactive Na+ in the skin while no significant changes in skin electrolyte concentrations were observed in BN-Lx rats. SHR rats after salt treatment exhibited a nonsignificant decrease in skin blood capillary number (rarefaction) while BN-Lx rats showed significantly increased skin blood capillary density. Analysis of dermal gene expression profiles in BN-Lx rats after salt treatment showed significant up-regulation of genes involved in angiogenesis and proliferation of endothelial cells contrary to the SHR. Since the skin harbors most of the body’s resistance vessels it is possible that blood capillary rarefaction may lead to increased peripheral resistance and salt sensitivity in the SHR.
Lysine-PEGylated Cytochrome C with Enhanced Shelf-Life Stability
Authors: Santos João H. P. M. , Feitosa Valker A. , Meneguetti Giovanna P. , Carretero Gustavo , Coutinho João A. P. , Ventura Sónia P. M. , Rangel-Yagui Carlota O.
Published: February 2022

Cytochrome c (Cyt-c), a small mitochondrial electron transport heme protein, has been employed in bioelectrochemical and therapeutic applications. However, its potential as both a biosensor and anticancer drug is significantly impaired due to poor long-term and thermal stability. To overcome these drawbacks, we developed a site-specific PEGylation protocol for Cyt-c. The PEG derivative used was a 5 kDa mPEG-NHS, and a site-directed PEGylation at the lysine amino-acids was performed. The effects of the pH of the reaction media, molar ratio (Cyt-c:mPEG-NHS) and reaction time were evaluated. The best conditions were defined as pH 7, 1:25 Cyt-c:mPEG-NHS and 15 min reaction time, resulting in PEGylation yield of 45% for Cyt-c-PEG-4 and 34% for Cyt-c-PEG-8 (PEGylated cytochrome c with 4 and 8 PEG molecules, respectively). Circular dichroism spectra demonstrated that PEGylation did not cause significant changes to the secondary and tertiary structures of the Cyt-c. The long-term stability of native and PEGylated Cyt-c forms was also investigated in terms of peroxidative activity. The results demonstrated that both Cyt-c-PEG-4 and Cyt-c-PEG-8 were more stable, presenting higher half-life than unPEGylated protein. In particular, Cyt-c-PEG-8 presented great potential for biomedical applications, since it retained 30–40% more residual activity than Cyt-c over 60-days of storage, at both studied temperatures of 4 °C and 25 °C.
A Performance-Based Teleintervention for Adults in the Chronic Stage after Acquired Brain Injury: An Exploratory Pilot Randomized Controlled Crossover Study
Authors: Beit Yosef Aviva , Jacobs Jeremy Michael , Shames Jeffrey , Schwartz Isabella , Gilboa Yafit
Published: February 2022

This pilot study aimed to investigate the initial effect of a remotely delivered performance-based client-centered intervention on activity performance and participation among adults in the chronic phase after acquired brain injury (ABI). Sixteen participants living at home with little to no assistance in basic daily activities were allocated into intervention or waitlist control groups. Assessments were conducted at the baseline, after the 3-month intervention/wait period, and at a 3-month follow-up. The primary outcomes were activity performance using the Canadian Occupational Performance Measure (COPM) and the Performance Quality Rating Scale (PQRS) and participation using the Mayo-Portland Adaptability Inventory-4 (MPAI-4). The intervention included weekly videoconferencing sessions using the Cognitive Orientation to Daily Occupational Performance approach (tele-CO-OP). The participants identified five functional goals, of which three were directly addressed. Wilcoxon signed-ranks test results showed no significant improvements in the control group at the end of the 3-month wait period. Pooled data from both groups showed significant improvements in COPM scores for trained and untrained goals following the intervention. Significant improvements were also found in the PQRS and MPAI-4 scores. Improvements were partially maintained at follow-up. Our preliminary results suggest that tele-CO-OP may positively impact the lives of adults after ABI who are coping with long-term disability.
Safety of Fingolimod in Patients with Multiple Sclerosis Switched from Natalizumab: Results from TRANSITION―A 2-Year, Multicenter, Observational, Cohort Study
Authors: Butzkueven Helmut , Giacomini Paul S. , Cohan Stanley , Ziemssen Tjalf , Sienkiewicz Daniel , Zhang Ying , Geissbühler Yvonne , Silva Diego , Tomic Davorka , Kropshofer Harald , Trojano Maria
Published: February 2022

Multiple sclerosis (MS) patients receiving natalizumab and who are at risk of developing progressive multifocal leukoencephalopathy (PML) often switch to other high-efficacy disease-modifying therapies including fingolimod as a risk mitigation strategy, which could impact treatment safety and effectiveness. The TRANSITION study aimed to evaluate the safety of fingolimod over two years in patients with MS after switching from natalizumab in a real-world setting. The safety and effectiveness were assessed by monitoring serious and other adverse events (SAEs, AEs). We assessed effectiveness by recording relapses, Expanded Disability Status Scale (EDSS) scores, and MRI activity. Of 637 patients enrolled, 505 completed the study (mean age, 42 years). Overall, 72.8% and 12.7% experienced AEs and SAEs respectively. The most common AEs were fatigue, headache, and urinary tract infection; no cases of PML were observed. Fingolimod treatment resulted in low disease activity. Patients with ≤8 weeks washout period had a markedly lower risk of relapses (4.5%) than those with >8 weeks (51.4%). In patients switching from natalizumab to fingolimod, no new safety signals with overall low relapse activity were observed in patients with washout latencies of ≤8 weeks before fingolimod initiation. Fingolimod was found to be safe and effective in patients transitioning from natalizumab.
Numerical Evaluation of the Effects of Transducer Displacement on Transcranial Focused Ultrasound in the Rat Brain
Authors: Seo Hyeon , Huh Hyungkyu , Lee Eun-Hee , Park Juyoung
Published: February 2022

Focused ultrasound is a promising therapeutic technique, as it involves the focusing of an ultrasonic beam with sufficient acoustic energy into a target brain region with high precision. Low-intensity ultrasound transmission by a single-element transducer is mostly established for neuromodulation applications and blood–brain barrier disruption for drug delivery. However, transducer positioning errors can occur without fine control over the sonication, which can affect repeatability and lead to reliability problems. The objective of this study was to determine whether the target brain region would be stable under small displacement (0.5 mm) of the transducer based on numerical simulations. Computed-tomography-derived three-dimensional models of a rat head were constructed to investigate the effects of transducer displacement in the caudate putamen (CP) and thalamus (TH). Using three different frequencies (1.1, 0.69, and 0.25 MHz), the transducer was displaced by 0.5 mm in each of the following six directions: superior, interior, anterior, posterior, left, and right. The maximum value of the intracranial pressure field was calculated, and the targeting errors were determined by the full-width-at-half-maximum (FWHM) overlap between the free water space (FWHMwater) and transcranial transmission (FWHMbase). When the transducer was positioned directly above the target region, a clear distinction between the target regions was observed, resulting in 88.3%, 81.5%, and 84.5% FWHMwater for the CP and 65.6%, 76.3%, and 64.4% FWHMwater for the TH at 1.1, 0.69, and 0.25 MHz, respectively. Small transducer displacements induced both enhancement and reduction of the peak pressure and targeting errors, compared with when the transducer was displaced in water. Small transducer displacement to the left resulted in the lowest stability, with 34.8% and 55.0% targeting accuracy (FWHMwater) at 1.1 and 0.69 MHz in the TH, respectively. In addition, the maximum pressure was reduced by up to 11% by the transducer displacement. This work provides the targeting errors induced by transducer displacements through a preclinical study and recommends that attention be paid to determining the initial sonication foci in the transverse plane in the cases of small animals.
Preferences of the Facade Composition in the Context of Its Regularity and Irregularity
Authors: Malewczyk Michał , Taraszkiewicz Antoni , Czyż Piotr
Published: February 2022

The aim of this study is to determine the preferences of Polish society towards building facades depending on the degree of the composition regularity of the facade elements. The subject matter is inspired by the authors’ observations in relation to the current architectural trends. The purposefulness of the conducted research results from several issues. Firstly, the reports of psychology and neurosciences clearly indicate the universality of certain preferences towards visual attributes of objects (e.g., in relation to abstract symmetric patterns), resulting from biological conditions. Secondly, residential, multi-family architecture is by definition designed for a wide group of anonymous users whose expectations must be met. One of the dimensions of the above-mentioned expectations is the visual dimension, partially dependent on the composition of the facade. In the course of the conducted research, it is shown that facades with a regular composition are assessed as more attractive than those with irregular compositions. Moreover, irregular facades evoked a negative effect of a significantly greater force than the positive effect in the case of regular facades. The above-described discoveries shed, in the authors’ opinion, a completely new light on the contemporary work of architects. It is extremely important to adapt the visual dimension of architecture to the expectations of its recipients, while taking care of its values and quality as a field of art.
Effectiveness of Selected Strain and Displacement Measurement Techniques in Civil Engineering
Authors: Szewczyk Piotr , Kudyba Piotr
Published: February 2022

The aim of this study was to assess how useful certain selected measurement techniques are in civil engineering. In this work, the focus was placed on the measurement of displacement and strain. Classical methods with an established position in the industry, such as electrical resistance strain gauge measurements and linear variable differential transducers (LVDT), were compared with modern techniques that do not require direct contact with the measured object, such as laser scanning and digital image correlation. A simply supported beam was bent in two types of tests. In the first test, a small load was applied on the beam, causing a slight deflection of the structure of approximately 0.5 mm. This enabled us to assess how effective the tested methods were, given the very precise measurement of the structure. In the second test, a much higher load was introduced, which caused displacement that can realistically be found in actual civil engineering structures. Ultimately, the model went through the plastic phase and was damaged. This enabled the measurement of displacement and strain that were much higher than those of the safe operating range of the structure. Based on conducted examinations, practical conclusions were drawn relative to the analyzed measurement methods.
Association between Sarcopenia and Immediate Complications and Mortality in Patients with Oral Cavity Squamous Cell Carcinoma Undergoing Surgery
Authors: Huang Chun-Hou , Lue Kun-Han , Chen Peir-Rorg , Hsieh Tsung-Cheng , Chou Yu-Fu
Published: February 2022

Sarcopenia negatively affects oncologic outcomes. However, studies have yet to reveal whether it is associated with postoperative complications and survival among patients with oral cavity squamous cell carcinoma (OSCC). This study retrospectively enrolled 592 patients undergoing primary OSCC surgery with available computed tomography (CT) images of their third cervical vertebrae (C3) within 30 days before surgery between January 2011 and December 2020. Preoperative sarcopenia, nutritional and frailty status, tumor characteristics, comorbidities, and inflammatory markers were assessed. The outcome variables included 30-day complications based on the Buzby and Dindo classification, reoperation, 5- and 8-year overall survival, and disease-free survival. A total of 318 (53.7%) had sarcopenia; of these patients, 217 (68.2%) presented with postoperative complications, and 48 (15.1%) underwent reoperations. Sarcopenia and higher systemic immune-inflammatory index were independently associated with local to systemic 30-day complications. Sarcopenia, advanced-stage disease, and extracapsular spread were correlated with 5- and 8-year survival. The presence of sarcopenia is associated with the 30-day complications and short- and long-term survival of patients who had OSCC and underwent surgery.
The Association between Patient Characteristics and the Efficacy and Safety of Selinexor in Diffuse Large B-Cell Lymphoma in the SADAL Study
Authors: Zijlstra Josée M. , Follows George , Casasnovas Rene-Olivier , Vermaat Joost S. P. , Kalakonda Nagesh , Choquet Sylvain , Hill Brian , Thieblemont Catherine , Cavallo Federica , Cruz Fatima De la , Kuruvilla John , Hamad Nada , Jaeger Ulrich , Caimi Paolo , Gurion Ronit , Warzocha Krzysztof , Bakhshi Sameer , Sancho Juan-Manuel , Schuster Michael , Egyed Miklos , Offner Fritz , Vassilakopoulos Theodoros P. , Samal Priyanka , Ku Matthew , Xu Jenny , Corona Kelly , Chamoun Kamal , Shah Jatin , Canales Miguel , Maerevoet Marie
Published: February 2022

Selinexor, an oral selective inhibitor of nuclear export, was evaluated in the Phase 2b SADAL study in patients with diffuse large B-cell lymphoma (DLBCL) who previously received two to five prior systemic regimens. In post hoc analyses, we analyzed several categories of patient characteristics (age, renal function, DLBCL subtype, absolute lymphocyte count, transplant status, number of prior lines of therapy, refractory status, Ann Arbor disease stage, and lactate dehydrogenase) at baseline, i.e., during screening procedures, to determine their potential contributions to the efficacy (overall response rate [ORR], duration of response [DOR], overall survival [OS]) and tolerability of selinexor. Across most categories of characteristics, no significant difference was observed in ORR or DOR. OS was significantly longer for patients < 65 vs. ≥ 65 years, and for those with lymphocyte counts ≥ 1000/µL vs. < 1000/µL or lactate dehydrogenase ≤ ULN vs. > ULN. The most common adverse events (AEs) across the characteristics were thrombocytopenia and nausea, and similar rates of grade 3 AEs and serious AEs were observed. With its oral administration, novel mechanism of action, and consistency in responses in heavily pretreated patients, selinexor may help to address an important unmet clinical need in the treatment of DLBCL.
Efficacy of Immune Checkpoint Inhibitors against Advanced or Metastatic Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis
Authors: Park Eun-Joo , Park Hyo-Jung , Kim Kyung-Won , Suh Chong-Hyun , Yoo Changhoon , Chae Young-Kwang , Tirumani Sree Harsha , Ramaiya Nikhil H.
Published: February 2022

We performed a systematic review and meta-analysis of the treatment efficacy of immune checkpoint inhibitors (ICIs) in advanced/metastatic neuroendocrine neoplasms (NENs). MEDLINE and EMBASE were searched to identify studies that provide data on treatment response and/or survival outcomes of advanced/metastatic NEN patients treated with ICIs. The overall response rate (ORR) was pooled using a random-effects model. Meta-regression was performed to explore factors influencing the ORR. Individual patient data (IPD) meta-analysis of survival was performed using stratified Cox regression. Ten studies (464 patients) were included. The overall pooled ORR was 15.5% (95% confidence interval (CI), 9.5–24.3%), and it varied according to the primary site (thoracic, 24.7%; gastro–entero–pancreatic, 9.5%), tumor differentiation (poorly differentiated, 22.7%; well-differentiated, 10.4%), and drug regimen (combination, 25.3%; monotherapy, 10.1%). All these variables significantly influenced the ORR. Tumor differentiation was associated with both overall survival and progression-free survival (hazard ratio of poorly differentiated tumors, 4.2 (95% CI, 2.0–8.7) and 2.6 (95% CI, 1.6–4.4), respectively). Thus, the treatment efficacy of ICIs for advanced/metastatic NENs varied according to primary site, tumor differentiation, and drug regimen. Poorly differentiated NENs showed a better ORR than well-differentiated NENs but had a negative impact on survival.
Association between Pre-Existing Sleep Disorders and Survival Rates of Patients with Breast Cancer
Authors: Chen Yen-Chang , Chen Wan-Ming , Chiang Ming-Feng , Shia Ben-Chang , Wu Szu-Yuan
Published: February 2022

PURPOSE: To investigate the effects of pre-existing sleep disorders on the survival outcomes of women receiving standard treatments for breast invasive ductal carcinoma (IDC). METHODS: We recruited patients from the Taiwan Cancer Registry Database who had received surgery for clinical stage I–III breast IDC. The Cox proportional hazards model was used to analyze all-cause mortality. We categorized the patients into those with and without sleep disorders (Groups 1 and 2, respectively) through propensity score matching. RESULTS: In the multivariate Cox regression analysis, the adjusted hazard ratio for all-cause mortality for Group 1 compared with Group 2 was 1.51 (95% confidence interval: 1.19, 1.91; p < 0.001). CONCLUSION: Our study demonstrated that the sleep disorder group had poorer survival rates than the non-sleep disorder group in breast cancer. Therefore, patients should be screened and evaluated for pre-existing sleep disorders prior to breast surgery, with such disorders serving as a predictor of survival in patients with breast cancer. Future studies may investigate the survival benefits of pharmacological and behavioral treatments for sleep problems in patients with breast cancer.
Genetics of Heritable Thoracic Aortic Disease
Authors: Papatheodorou Efstathios , Degiannis Dimitrios , Anastasakis Aris
Published: February 2022

Genetic testing plays an increasing diagnostic and prognostic role in the management of patients with heritable thoracic aortic disease (HTAD). The identification of a specific variant can establish or confirm the diagnosis of syndromic HTAD, dictate extensive evaluation of the arterial tree in HTAD with known distal vasculature involvement and justify closer follow-up and earlier surgical intervention in HTAD with high risk of dissection of minimal or normal aortic size. Evolving phenotype–genotype correlations lead us towards more precise and individualized management and treatment of patients with HTAD. In this review, we present the latest evidence regarding the role of genetics in patients with HTAD.
Synthesis and Characterization of Supported Pd Catalysts for Potential Application in Glycerol Electro-Oxidation
Authors: Ngwenya Talent , Nombona Nolwazi , Shozi Mzamo
Published: February 2022

Ceria-supported Pd catalysts encompassing oxides of Cu, Co, and Fe were synthesized and characterized using XRD, TEM, SEM-EDX, TPR, BET, and Raman. After the incorporation of the metal oxides, the surface area and pore volume of the ceria support decreased. XRD showed the presence of the metal oxide phases as well as the support, CeO2. TPR showed that the bimetallic catalyst had improved reducibility compared to the monometallic Pd/CeO2. TEM images showed irregular-shaped particles with an average size distribution of 2–10 nm. SEM-EDX showed that the metal oxides were evenly distributed over the surface of the support. The electro-oxidation of glycerol in an alkaline environment was evaluated using cyclic voltammetry, and the products formed were identified and quantified using GC-MS. Glyceric acid was the dominant product over Pd-CuO/CeO2, while glyceraldehyde and dihydroxyacetone were dominant over Pd-Co3O4/CeO2 and Pd-Fe2O3/CeO2, respectively.
A Kinetic Study of Photocatalytic Degradation of Phenol over Titania–Silica Mixed Oxide Materials under UV Illumination
Authors: Yohi Shivatharsiny , Wu Chia-Ming , Koodali Ranjit T.
Published: February 2022

A set of titania–silica mixed oxide materials were prepared by a cosolvent-induced gelation method using ethanol and toluene as solvent and cosolvent, respectively. These materials were extensively characterized by utilizing several characterization techniques and assessed for phenol degradation under UV illumination. The degradation of phenol follows first-order kinetics, and fragmented products formed during the phenol degradation were qualitatively identified by using high performance liquid Chromatographic (HPLC) and atomic pressure chemical ionization mass spectroscopic (APCI-MS) techniques. The complete mineralization of phenol was further evidenced by the measurement of the total organic contents that remained in the solution after irradiation. The pore diameter of the materials was found to be the key factor for phenol degradation, whereas surface area and pore volume play a role among the mixed oxide materials. In addition, in the mixed oxide system there was an inverse correlation obtained with the particle size of the materials and the degradation efficiency. The smaller particle size of titania in the mixed oxide material was found to be a requirement for an effective degradation of phenol.
Evidence of Adult Features and Functions of Hepatocytes Differentiated from Human Induced Pluripotent Stem Cells and Self-Organized as Organoids
Authors: Messina Antonietta , Luce Eléanor , Benzoubir Nassima , Pasqua Mattia , Pereira Ulysse , Humbert Lydie , Eguether Thibaut , Rainteau Dominique , Duclos-Vallée Jean-Charles , Legallais Cécile , Dubart-Kupperschmitt Anne
Published: February 2022

Background: Human-induced pluripotent stem cell-derived hepatocytes (iHeps) have been shown to have considerable potential in liver diseases, toxicity, and pharmacological studies. However, there is a growing need to obtain iHeps that are truly similar to primary adult hepatocytes in terms of morphological features and functions. We generated such human iHeps, self-assembled as organoids (iHep-Orgs). Methods: iPSC-derived hepatoblasts were self-assembled into spheroids and differentiated into mature hepatocytes modulating final step of differentiation. Results: In about four weeks of culture, the albumin secretion levels and the complete disappearance of α-fetoprotein from iHep-Orgs suggested the acquisition of a greater degree of maturation than those previously reported. The expression of apical transporters and bile acid secretion evidenced the acquisition of complex hepatocyte polarity as well as the development of a functional and well-defined bile canalicular network confirmed by computational analysis. Activities recorded for CYP450, UGT1A1, and alcohol dehydrogenase, response to hormonal stimulation, and glucose metabolism were also remarkable. Finally, iHep-Orgs displayed a considerable ability to detoxify pathological concentrations of lactate and ammonia. Conclusions: With features similar to those of primary adult hepatocytes, the iHep-Orgs thus produced could be considered as a valuable tool for the development and optimization of preclinical and clinical applications.
Hereditary Ovarian Carcinoma: Cancer Pathogenesis Looking beyond BRCA1 and BRCA2
Authors: Samuel David , Diaz-Barbe Alexandra , Pinto Andre , Schlumbrecht Matthew , George Sophia
Published: February 2022

Besides BRCA1 and BRCA2, several other inheritable mutations have been identified that increase ovarian cancer risk. Surgical excision of the fallopian tubes and ovaries reduces ovarian cancer risk, but for some non-BRCA hereditary ovarian cancer mutations the benefit of this intervention is unclear. The fallopian tubes of women with hereditary ovarian cancer mutations provide many insights into the early events of carcinogenesis and process of malignant transformation. Here we review cancer pathogenesis in hereditary cases of ovarian cancer, the occurrence of pre-invasive lesions and occult carcinoma in mutation carriers and their clinical management.
Understanding the Links among Maternal Diet, Myelination, and Depression: Preclinical and Clinical Overview
Authors: Smaga Irena
Published: February 2022

Depression is one of the most common mental disorders in the general population, and multiple mechanisms are involved in the etiology of this disease, including myelination. According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, maternal diet affects the lifetime of the individual during adulthood and may contribute to the development of neuropsychiatric disorders. Additionally, the intensive processes of myelination contribute to the development of the central nervous system in the perinatal period, while any alterations during this crucial process providing the physiological functioning of neurons may lead to neuropsychiatric disorders in the next generation. The present review summarizes the current knowledge on the role of the myelin-related changes in depression, as well as the crosstalk among maternal malnutrition, myelination, and depression in preclinical and clinical settings.
Dynamic Spatiotemporal Expression Pattern of the Senescence-Associated Factor p16Ink4a in Development and Aging
Authors: Safwan-Zaiter Hasan , Wagner Nicole , Michiels Jean-François , Wagner Kay-Dietrich
Published: February 2022

A plethora of factors have been attributed to underly aging, including oxidative stress, telomere shortening and cellular senescence. Several studies have shown a significant role of the cyclin-dependent kinase inhibitor p16ink4a in senescence and aging. However, its expression in development has been less well documented. Therefore, to further clarify a potential role of p16 in development and aging, we conducted a developmental expression study of p16, as well as of p19ARF and p21, and investigated their expression on the RNA level in brain, heart, liver, and kidney of mice at embryonic, postnatal, adult, and old ages. P16 expression was further assessed on the protein level by immunohistochemistry. Expression of p16 was highly dynamic in all organs in embryonic and postnatal stages and increased dramatically in old mice. Expression of p19 and p21 was less variable and increased to a moderate extent at old age. In addition, we observed a predominant expression of p16 mRNA and protein in liver endothelial cells versus non-endothelial cells of old mice, which suggests a functional role specifically in liver endothelium of old subjects. Thus, p16 dynamic spatiotemporal expression might implicate p16 in developmental and physiological processes in addition to its well-known function in the build-up of senescence.
Comprehensive Analysis of the ILCs and Unconventional T Cells in Virus Infection: Profiling and Dynamics Associated with COVID-19 Disease for a Future Monitoring System and Therapeutic Opportunities
Authors: Lo Presti Elena , De Gaetano Andrea , Pioggia Giovanni , Gangemi Sebastiano
Published: February 2022

This review is a comprehensive analysis of the effects of SARS-CoV-2 infection on Unconventional T cells and innate lymphoid cells (ILCs). COVID-19 affected patients show dysregulation of their adaptive immune systems, but many questions remain unsolved on the behavior of Unconventional cells and ILCs during infection, considering their role in maintaining homeostasis in tissue. Therefore, we highlight the differences that exist among the studies in cohorts of patients who in general were categorized considering symptoms and hospitalization. Moreover, we make a critical analysis of the presence of particular clusters of cells that express activation and exhausted markers for each group in order to bring out potential diagnostic factors unconsidered before now. We also focus our attention on studies that take into consideration recovered patients. Indeed, it could be useful to determine Unconventional T cells’ and ILCs’ frequencies and functions in longitudinal studies because it could represent a way to monitor the immune status of SARS-CoV-2-infected subjects. Possible changes in cell frequencies or activation profiles could be potentially useful as prognostic biomarkers and for future therapy. Currently, there are no efficacious therapies for SARS-CoV-2 infection, but deep studies on involvement of Unconventional T cells and ILCs in the pathogenesis of COVID-19 could be promising for targeted therapies.
Transcriptomic Response to Acidosis Reveals Its Contribution to Bone Metastasis in Breast Cancer Cells
Authors: Yamagata Ana Sayuri , Freire Paula Paccielli , Jones Villarinho Nícolas , Teles Ramon Handerson Gomes , Francisco Kelliton José Mendonça , Jaeger Ruy Gastaldoni , Freitas Vanessa Morais
Published: February 2022

Bone is the most common site of metastasis in breast cancer. Metastasis is promoted by acidosis, which is associated with osteoporosis. To investigate how acidosis could promote bone metastasis, we compared differentially expressed genes (DEGs) in MDA-MB-231 cancer cells in acidosis, bone metastasis, and bone metastatic tumors. The DEGs were identified using Biojupies and GEO2R. The expression profiles were assessed with Morpheus. The overlapping DEGs between acidosis and bone metastasis were compared to the bulk of the DEGs in terms of the most important genes and enriched terms using CytoHubba and STRING. The expression of the genes in this overlap filtered by secreted proteins was assessed in the osteoporosis secretome. The analysis revealed that acidosis-associated transcriptomic changes were more similar to bone metastasis than bone metastatic tumors. Extracellular matrix (ECM) organization would be the main biological process shared between acidosis and bone metastasis. The secretome genes upregulated in acidosis, bone metastasis, and osteoporosis-associated mesenchymal stem cells are enriched for ECM organization and angiogenesis. Therefore, acidosis may be more important in the metastatic niche than in the primary tumor. Acidosis may contribute to bone metastasis by promoting ECM organization. Untreated osteoporosis could favor bone metastasis through the increased secretion of ECM organization proteins.
Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV
Authors: Misko Albert L. , Weinstock Laura D. , Sankar Sitara B. , Furness Amanda , Grishchuk Yulia , Wood Levi B.
Published: February 2022

Background: Mucolipidosis IV (MLIV) is an autosomal recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by a loss of function of the lysosomal channel transient receptor potential mucolipin-1 and is associated with an early pro-inflammatory brain phenotype, including increased cytokine expression. The goal of the current study was to determine whether blood cytokines are linked to motor dysfunction in patients with MLIV and reflect brain inflammatory changes observed in an MLIV mouse model. Methods: To determine the relationship between blood cytokines and motor function, we collected plasma from MLIV patients and parental controls concomitantly with assessment of motor function using the Brief Assessment of Motor Function and Modified Ashworth scales. We then compared these profiles with cytokine profiles in brain and plasma samples collected from the Mcoln1−/− mouse model of MLIV. Results: We found that MLIV patients had prominently increased cytokine levels compared to familial controls and identified profiles of cytokines correlated with motor dysfunction, including IFN-γ, IFN-α2, and IP-10. We found that IP-10 was a key differentiating factor separating MLIV cases from controls based on data from human plasma, mouse plasma, and mouse brain. Conclusions: Our data indicate that MLIV is characterized by increased blood cytokines, which are strongly related to underlying neurological and functional deficits in MLIV patients. Moreover, our data identify the interferon pro-inflammatory axis in both human and mouse signatures, suggesting that interferon signaling is an important aspect of MLIV pathology.