bluuebunny/crossref_metadata_2025 huggingface dataset:
SARS-CoV-2 Infection: A Clinical and Histopathological Study in Pregnancy
Authors: Perna Angelica , Hay Eleonora , De Blasiis Paolo , La Verde Marco , Caprio Francesca , Torella Marco , Morlando Maddalena , Sellitto Carmine , Guerra Germano , Lucariello Angela , Baldi Alfonso , De Luca Antonio
Published: January 2023

During pregnancy, SARS-CoV-2 infection is associated with several adverse outcomes, including an increased risk of pre-eclampsia, preterm delivery, hypertensive disorders, gestational diabetes, and fetal growth restriction related to the development of placenta vascular abnormalities. We analyzed human placenta from full-term, uncomplicated pregnancies with SARS-CoV-2 infection during the first, second, or third trimesters of gestation. We studied, by the immunohistochemistry technique, the expression of CD34 and podoplanin (PDPN) as markers of vasculogenesis to find any differences. As secondary outcomes, we correlated maternal symptoms with placental histological alterations, including fibrin deposits, lymphocyte infiltration in the villi, edema, and thrombi. Our results showed a PDPN expression around the villous stroma as a plexiform network around the villous nucleus of fetal vessels; significant down-regulation was observed in the villous stroma of women infected during the third trimester. CD34 showed no changes in expression levels. During SARS-CoV-2 infection, the most common maternal symptoms were fever, anosmia, ageusia and asthenia, and the majority were treated with paracetamol, corticosteroids and azithromycin. Patients that required multiple symptomatic treatments evidenced a large amount of fibrin deposition in the villi. Certainly, PDPN plays a key role in healthy placental vasculogenesis and thus in its proper physiology, and SARS-CoV-2 surely alters its normal expression. Further studies are necessary to understand what mechanisms are being altered to try to avoid possible complications for both the mother and fetus in terms of the contagions that will still occur.
GT Transcription Factors of Rosa rugosa Thunb. Involved in Salt Stress Response
Authors: Wang Jianwen , Cheng Yufei , Shi Xinwei , Feng Liguo
Published: January 2023

Rosa rugosa was a famous aromatic plant while poor salt tolerance of commercial cultivars has hindered its culture in saline-alkali soil. In many plants, the roles of GT (or trihelix) genes in salt stresses responses have been emerging. In the wild R. rugosa, a total of 37 GTs (RrGTs) were grouped into GT-1, GT-2, GTγ, SH4, and SIP1 lineages. SIP1 lineage expanded by transposition. The motifs involved in the binding of GT cis-elements were conserved. Four RrGTs (RrGT11/14/16/18) significantly differentially expressed in roots or leaves under salt stress. The responsive patterns within 8 h NaCl treatment indicated that RrGTγ-4 (RrGT18) and RrGT-1 (RrGT16) were significantly induced by salt in roots of R. rugosa. Subcellular localizations of RrSIP1 (RrGT11) and RrGTγ-4 were on chloroplasts while RrGT-1 and RrSIP2 (RrGT14) located on cell nucleus. Regulation of ion transport could be the most important role of RrSIPs and RrGTγ-4. And RrGT-1 could be a halophytic gene with higher transcription abundance than glycophytic GT-1. These results provide key clue for further investigations of roles of RrGTs in salt stress response and would be helpful in the understanding the salt tolerance regulation mechanism of R. rugosa.
The Effects of Nordic Walking with Poles with an Integrated Resistance Shock Absorber on Red Blood Cell Distribution and Cardiorespiratory Efficiency in Postmenopausal Women—A Randomized Controlled Trial
Authors: Sobczak Katarzyna , Nowinka Paweł , Wochna Krystian , Domaszewska Katarzyna
Published: January 2023

Background: Age-related reduction in exercise capacity is manifested by a rapid development of fatigue. Research confirmed the adverse prognostic value of red blood cell distribution width (RDW-CV), an independent factor in heart failure, coronary heart disease and myocardial infarction. Physical exercise improves and helps to maintain cardiorespiratory fitness. The aim of our study was to examine the impact of 8 weeks’ Nordic walking training with classic poles (NW) and NW training with poles with an integrated resistance shock absorber (NW with RSA) on RDW-CV levels and to assess correlations between RDW-CV levels and cardiorespiratory performance in postmenopausal women. Methods: In this study, 32 postmenopausal women (NW-16, NW with RSA-16) participated in eight weeks of walking training. The mean age of women was 66.56 ± 4.23 year. and BMI 26.99 ± 3.86 kg/m2. At the beginning and at the end of the study, spirometry and exercise tests were performed. Haematological parameters were determined in the venous blood. Results: Statistical analysis of differences in post-training changes in the parameters between the groups studied showed a significant difference in change in body weight (∆body weight) (p < 0.05; ES: 0.778), BMI (∆BMI) (p < 0.05; ES: 0.778), waist circumference (∆WC) (p < 0.05; ES: 1.225) and (∆RDW-SD) (p < 0.05; ES: 1.215). There were no changes in electrocardiographic and spirometric parameters. Conclusions: Based on the findings from the present study, it can be assumed that endurance and resistance exercise can significantly reduce disease severity and mortality. A clinical analysis of RDW levels, together with other cardiological and biochemical parameters, can provide practical prognostic information relating to cardiovascular disease, mortality risk and treatment outcomes.
Retinal Structure Abnormalities in Parkinson’s Disease and Atypical Parkinsonism
Authors: Ma Xinxin , Li Shuhua , Zheng Bodi , Hu Lei , Liu Huijing , Wang Zheng , Wang Zhaoxia , Chen Haibo , Su Wen
Published: January 2023

We investigated retinal structure changes in patients with Parkinson’s disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and controls, and explored the value of this method in differential diagnosis. Spectral domain optical coherence tomography (SD-OCT) was used to measure peripapillary retinal nerve fiber layer (pRNFL) thickness, and macular thickness and volume. PSP patients showed higher temporal pRNFL thickness than PD and MSA patients. Peripapillary RNFL thickness could be used for discriminating PSP from MSA and PD. PD and MSA patients showed retinal thinning in the foveal center circle and nasal inner sectors compared to controls. Macular thickness and volume could be used for discriminating MSA from PD. There were negative correlations between disease duration and OCT parameters in PD, MSA, and PSP, independent of age, sex ratio, and the side of the eye. PD and atypical parkinsonism correlate with specific patterns of retina alterations. OCT could be a biomarker for differential diagnosis and progression evaluation of parkinsonian syndrome.
Retinal Pigment Epithelium Cell Development: Extrapolating Basic Biology to Stem Cell Research
Authors: Gupta Santosh , Lytvynchuk Lyubomyr , Ardan Taras , Studenovska Hana , Faura Georgina , Eide Lars , Znaor Ljubo , Erceg Slaven , Stieger Knut , Motlik Jan , Bharti Kapil , Petrovski Goran
Published: January 2023

The retinal pigment epithelium (RPE) forms an important cellular monolayer, which contributes to the normal physiology of the eye. Damage to the RPE leads to the development of degenerative diseases, such as age-related macular degeneration (AMD). Apart from acting as a physical barrier between the retina and choroidal blood vessels, the RPE is crucial in maintaining photoreceptor (PR) and visual functions. Current clinical intervention to treat early stages of AMD includes stem cell-derived RPE transplantation, which is still in its early stages of evolution. Therefore, it becomes essential to derive RPEs which are functional and exhibit features as observed in native human RPE cells. The conventional strategy is to use the knowledge obtained from developmental studies using various animal models and stem cell-based exploratory studies to understand RPE biogenies and developmental trajectory. This article emphasises such studies and aims to present a comprehensive understanding of the basic biology, including the genetics and molecular pathways of RPE development. It encompasses basic developmental biology and stem cell-based developmental studies to uncover RPE differentiation. Knowledge of the in utero developmental cues provides an inclusive methodology required for deriving RPEs using stem cells.
Graves’ Eye Disease: Clinical and Radiological Diagnosis
Authors: Hutchings Kasen R. , Fritzhand Seth J. , Esmaeli Bita , Koka Kirthi , Zhao Jiawei , Ahmed Salmaan , Debnam James Matthew
Published: January 2023

Graves’ disease is an autoimmune disorder in which hyperthyroidism results in various systematic symptoms, with about 30% of patients presenting with Graves’ eye disease (GED). The majority of patients with GED develop mild symptoms, including eyelid retraction, exposure of the globe, superior rectus–levator muscle complex inflammation, and fat expansion, leading to exophthalmos. More severe cases can result in extraocular muscle enlargement, restricted ocular movement, eyelid and conjunctival edema, and compression of the optic nerve leading to compressive optic neuropathy (CON). GED severity can be classified using the Clinical Activity Score, European Group on Graves’ Orbitopathy scale, NO SPECS Classification system, and VISA system. CT and MRI aid in the diagnosis of GED through the demonstration of orbital pathology. Several recent studies have shown that MRI findings correlate with disease severity and can be used to evaluate CON. Mild cases of GED can be self-limiting, and patients often recover spontaneously within 2–5 years. When medical treatment is required, immunomodulators or radiotherapy can be used to limit immunologic damage. Surgery may be needed to improve patient comfort, preserve the orbit, and prevent vision loss from optic nerve compression or breakdown of the cornea.
Secreted Frizzled Related Protein 5 (SFRP5) Serum Levels Are Decreased in Critical Illness and Sepsis and Are Associated with Short-Term Mortality
Authors: Hohlstein Philipp , Brozat Jonathan F. , Schuler Julia , Abu Jhaisha Samira , Pollmanns Maike R. , Bündgens Lukas , Wirtz Theresa H. , Yagmur Eray , Hamesch Karim , Weiskirchen Ralf , Tacke Frank , Trautwein Christian , Koch Alexander
Published: January 2023

Sepsis is a major health burden with insufficiently understood mechanisms of inflammation and immune paralysis, leading to a life-threatening critical illness. The secreted frizzled related protein 5 (SFRP5) acts as an anti-inflammatory adipokine by antagonizing the Wnt5a pathway. The aim of this study was to elucidate the role of SFRP5 in critical illness and sepsis and to determine its value as a prognostic biomarker for mortality. We analyzed SFRP5 serum concentrations of 223 critically ill patients at admission to a medical intensive care unit (ICU) and compared those to 24 healthy individuals. SFRP5 serum concentrations were significantly decreased in critical illness as compared to healthy controls (24.66 vs. 100 ng/mL, p = 0.029). Even lower serum concentrations were found in septic as compared to nonseptic critically ill patients (19.21 vs. 32.83 ng/mL, p = 0.031). SFRP5 concentrations correlated with liver disease, age, anti-inflammation, and metabolic parameters. Furthermore, patients with sepsis recovered levels of SFRP5 in the first week of ICU treatment. SFRP5 levels at admission predicted short-term mortality in critically ill but not in septic patients. This study points to the role of the anti-inflammatory mediator SFRP5 not only in sepsis but also in nonseptic critically ill patients and associates high levels of SFRP5 to worse outcomes, predominantly in nonseptic critically ill patients.
Rapid and Sensitive Diagnosis of COVID-19 Using an Electricity-Free Self-Testing System
Authors: Li Sheng , Guo Wenlong , Xiao Minmin , Chen Yulin , Luo Xinyi , Xu Wenfei , Zhou Jianhua , Wang Jiasi
Published: January 2023

Rapid and sensitive detection of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential for early diagnosis and effective treatment. Nucleic acid testing has been considered the gold standard method for the diagnosis of COVID-19 for its high sensitivity and specificity. However, the polymerase chain reaction (PCR)-based method in the central lab requires expensive equipment and well-trained personnel, which makes it difficult to be used in resource-limited settings. It highlights the need for a sensitive and simple assay that allows potential patients to detect SARS-CoV-2 by themselves. Here, we developed an electricity-free self-testing system based on reverse transcription loop-mediated isothermal amplification (RT-LAMP) that allows for rapid and accurate detection of SARS-CoV-2. Our system employs a heating bag as the heat source, and a 3D-printed box filled with phase change material (PCM) that successfully regulates the temperature for the RT-LAMP. The colorimetric method could be completed in 40 min and the results could be read out by the naked eye. A ratiometric measurement for exact readout was also incorporated to improve the detection accuracy of the system. This self-testing system is a promising tool for point-of-care testing (POCT) that enables rapid and sensitive diagnosis of SARS-CoV-2 in the real world and will improve the current COVID-19 screening efforts for control and mitigation of the pandemic.
Decreased ALFF and Functional Connectivity of the Thalamus in Vestibular Migraine Patients
Authors: Zhe Xia , Tang Min , Ai Kai , Lei Xiaoyan , Zhang Xiaoling , Jin Chenwang
Published: January 2023

Background: The thalamus has been reported to be associated with pain modulation and processing. However, the functional changes that occur in the thalamus of vestibular migraine (VM) patients remain unknown. Methods: In total, 28 VM patients and 28 healthy controls who were matched for age and sex underwent resting-state functional magnetic resonance imaging. They also responded to standardized questionnaires aimed at assessing the clinical features associated with migraine and vertigo. Differences in the amplitude of low-frequency fluctuation (ALFF) were analyzed and brain regions with altered ALFF in the two groups were used for further analysis of whole-brain functional connectivity (FC). The relationship between clusters and clinical features was investigated by correlation analyses. Results: The ALFF in the thalamus was significantly decreased in the VM group versus the control group. In the VM group, the ALFF in the left thalamus negatively correlated with VM episode frequency. Furthermore, the left thalamus showed significantly weaker FC than both regions of the medial prefrontal cortex, both regions of the anterior cingulum cortex, the left superior/middle temporal gyrus, and the left temporal pole in the VM group. Conclusions: The thalamus plays an important role in VM patients and it is suggested that connectivity abnormalities of the thalamocortical region contribute to abnormal pain information processing and modulation, transmission, and multisensory integration in patients with VM.
Working Memory Capacity Depends on Attention Control, but Not Selective Attention
Authors: Kotyusov Alexander I. , Kasanov Dauren , Kosachenko Alexandra I. , Gashkova Anastasia S. , Pavlov Yuri G. , Malykh Sergey
Published: January 2023

Working memory and attention are interrelated constructs that are sometimes even considered indistinguishable. Since attention is not a uniform construct, it is possible that different types of attention affect working memory capacity differently. To clarify this issue, we investigated the relationship between working memory capacity and various components of attention. The sample consisted of 136 healthy adult participants aged 18 to 37 years (M = 20.58, SD = 2.74). Participants performed tasks typically used to assess working memory (operation span, change detection, simple digit span, and adaptive digit span tasks), selective attention (visual search task), and attention control (Stroop and antisaccade tasks). We tested several models with working memory and attention, either as a unitary factor or being divided into selective attention and attention control factors. A confirmatory factor analysis showed that the model with three latent variables—working memory capacity, attention control, and selective attention—fit the data best. Results showed that working memory and attention are distinct but correlated constructs: working memory capacity was only related to attention control, whereas attention control was related to both constructs. We propose that differences in working memory capacity are determined only by the ability to maintain attention on the task, while differences in the ability to filter out non-salient distractors are not related to working memory capacity.
Assessing Factors That Influence Womenpreneurs’ Intention to Use Technology: A Structural Equation Modeling Approach
Authors: Jou Yung-Tsan , Shiang Wei-Jung , Silitonga Riana Magdalena , Adilah Muna , Halim Audrey Zebe Agathon
Published: January 2023

The growth of financial literacy is significant nowadays. Because of this, more people are becoming increasingly responsible in their financial planning, investments, and living expenses. In developing new technology, it is necessary to know the technological acceptance of the prospective users of the technology itself. This study aims to identify the primary factors influencing the technology acceptance levels of lower-middle socio-economic users for a digital financial literacy application. The proposed model in this research was developed based on UTAUT, TAM, and Usability model, and it consists of six primary constructs: (1) Performance Expectancy; (2) Effort Expectancy; (3) Social Influence; (4) Resources and Cost; (5) Satisfaction; (6) Behavior Intention. All the hypotheses used in this study were statistically measured using SmartPLS tools. This study found that because many lower-middle socio-economic users lack sufficient understanding of technology to properly utilize it, that a digital platform is not the right tool to teach them financial literacy.
Multi-Analytical Investigations of the Medieval Turkish Bath from Golești Open Air Museum
Authors: Dinu Monica , Ratoiu Lucian Cristian , Călin Camelia , Călin Gerard
Published: January 2023

The Golești Manor ensemble consists of architectural monuments dating back to the 17th, 18th, and 19th centuries, with ephemeral architecture roots from Phanariot times but also some pre- Brancovan influences. The Turkish steam bath is placed in the northeast of the enclosure, and it is thought to have been built by Stroe Leurdeanu. Although there are still original fragments of the old plaster that have been preserved, the Turkish bath has undergone several restorations through time, some of them poorly documented. Hyperspectral imaging (HSI) combined with LIBS were used in order to analyze the bricks and the mortars, evaluate their preservation state, map the original elements, and document and classify the interventions previously made. Based on the supervised classifications, several areas of interest were selected for LIBS elemental analysis, and multivariate data analysis was conducted in order to discriminate similar composition materials and to map the interventions and the original. By analyzing the variability of the spectral profiles, different algorithms were applied to the SWIR hyperspectral images in order to classify the main elements of the brickwork.
Influence of the Coupling Action of Flexural Load and Freezing–Thawing on the Chloride Diffusion of Marine High-Performance Concrete
Authors: Xiong Jianbo , Su Dagen , Wang Shengnian , Li Pengping , Zhang Xinxing , Zhang Zhijie , Zhong Mingfeng
Published: January 2023

The chloride diffusion of marine high-performance concrete under a couple of actions, flexural load and freezing–thawing, was investigated by a fast freezing and thawing test in NaCl solution. Concrete specimens of 100 × 100 × 515 mm were tested under bending load and 300 freeze–thaw cycles under the stress levels of 15%, 30%, and 50% of the ultimate fracture modulus. The change in the microstructure of the concrete was analyzed by SEM and MIP. The results indicated that the chloride diffusion coefficient of concrete under the coupling effect of flexural load and freezing–thawing or simple flexural load increased with the increasing in the flexural stress level, and the chloride diffusion coefficient was approximately exponential to the flexural stress level, as D = 0.8777e1.668σ for a couple of actions of flexural load and freezing–thawing, and D = 0.8336e1.3231σ for a simple flexural load. The resistance ability of concrete to chloride diffusion was reduced by the freezing–thawing procedures, the resisted ability dropped more severely under a couple of actions of flexural load and freezing–thawing than simple flexural load at the same stress level. Micro-cracks at the interfacial transition zone between the aggregate and the paste matrix in concrete was induced under a couple of actions of flexural load and freezing–thawing, which increased the average pore size and total pore volume, resulting in the modification of the pore size distribution in the concrete. The influence of a couple of actions of flexural load and freezing–thawing on the concrete was greater than that of simple flexural load.
Response Characteristics of Pre-Stressed Strand Cables Subjected to Low-Velocity Impact: Experiment Test
Authors: Wu Zhijie , Yang Yuchao , Hu Yachao , Liu Feng
Published: January 2023

This paper introduces some experimental data measured from 63 impact tests of pre−stressed strand cables. The test specimens consist of seven steel wires that have a length equivalent to 100 times the outside diameter. To ensure consistency with the engineering service status, the strand cables are fully installed in a specially designed device and are axially pre−stretched to 0% to 40% of the ultimate bearing capacity before being subjected to lateral impact. The mass of the indenter is 50.34 kg, and the maximum impact velocity reaches 13 m/s. Two dimensionless variables, axial force and input kinetic energy, are used to control the experimental parameters. The recorded test data show that input energy and pre−stress level are the key factors governing the impact behavior, which is mainly characterized by plastic deformation controlled by the combination of tension and flexure, and the dynamic fracture concentrated in the impact zone is controlled by the joint effects of compression, tension and shear. As the impact energy increases, the dynamic mode of the test specimen changes from elastic rebound to plastic deformation, and finally evolves into fracture of some or all steel wires, which correspond to slight, partial and total loss of pre−tension, respectively. An increase in the level of pre−stress will significantly reduce the critical displacement of the structural failure but has little effect on the critical failure energy. The present paper provides a basic experimental data and mechanical analysis framework for the analysis, design and evaluation of the mechanical behavior of strands under accidental lateral impact.
Treatment with Anti-HER2 Chimeric Antigen Receptor Tumor-Infiltrating Lymphocytes (CAR-TILs) Is Safe and Associated with Antitumor Efficacy in Mice and Companion Dogs
Authors: Forsberg Elin M. V. , Riise Rebecca , Saellström Sara , Karlsson Joakim , Alsén Samuel , Bucher Valentina , Hemminki Akseli E. , Olofsson Bagge Roger , Ny Lars , Nilsson Lisa M. , Rönnberg Henrik , Nilsson Jonas A.
Published: January 2023

Patients with metastatic melanoma have a historically poor prognosis, but recent advances in treatment options, including targeted therapy and immunotherapy, have drastically improved the outcomes for some of these patients. However, not all patients respond to available treatments, and around 50% of patients with metastatic cutaneous melanoma and almost all patients with metastases of uveal melanoma die of their disease. Thus, there is a need for novel treatment strategies for patients with melanoma that do not benefit from the available therapies. Chimeric antigen receptor-expressing T (CAR-T) cells are largely unexplored in melanoma. Traditionally, CAR-T cells have been produced by transducing blood-derived T cells with a virus expressing CAR. However, tumor-infiltrating lymphocytes (TILs) can also be engineered to express CAR, and such CAR-TILs could be dual-targeting. To this end, tumor samples and autologous TILs from metastasized human uveal and cutaneous melanoma were expanded in vitro and transduced with a lentiviral vector encoding an anti-HER2 CAR construct. When infused into patient-derived xenograft (PDX) mouse models carrying autologous tumors, CAR-TILs were able to eradicate melanoma, even in the absence of antigen presentation by HLA. To advance this concept to the clinic and assess its safety in an immune-competent and human-patient-like setting, we treated four companion dogs with autologous anti-HER2 CAR-TILs. We found that these cells were tolerable and showed signs of anti-tumor activity. Taken together, CAR-TIL therapy is a promising avenue for broadening the tumor-targeting capacity of TILs in patients with checkpoint immunotherapy-resistant melanoma.
CAR-T: What Is Next?
Authors: Chen Yi-Ju , Abila Bams , Mostafa Kamel Yasser
Published: January 2023

The year 2017 was marked by the Food and Drug Administration (FDA) approval of the first two chimeric antigen receptor-T (CAR-T) therapies. The approved indications were for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and for the treatment of patients up to 25 years of age with acute lymphoblastic leukemia (ALL) that is refractory or in a second or later relapse. Since then, extensive research activities have been ongoing globally on different hematologic and solid tumors to assess the safety and efficacy of CAR-T therapy for these diseases. Limitations to CAR-T therapy became apparent from, e.g., the relapse in up to 60% of patients and certain side effects such as cytokine release syndrome (CRS). This led to extensive clinical activities aimed at overcoming these obstacles, so that the use of CAR-T therapy can be expanded. Attempts to improve on efficacy and safety include changing the CAR-T administration schedule, combining it with chemotherapy, and the development of next-generation CAR-T therapies, e.g., through the use of CAR-natural killer (CAR-NK) and CAR macrophages (CAR-Ms). This review will focus on new CAR-T treatment strategies in hematologic malignancies, clinical trials aimed at improving efficacy and addressing side effects, the challenges that CAR-T therapy faces in solid tumors, and the ongoing research aimed at overcoming these challenges.
Patient Reported and Clinical Outcomes after High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Primary Central Nervous System Lymphoma
Authors: Beer Sina A. , Wirths Stefan , Vogel Wichard , Tabatabai Ghazaleh , Ernemann Ulrike , Merle David A. , Bethge Wolfgang , Möhle Robert , Lengerke Claudia
Published: January 2023

Primary central nervous system lymphomas (PCNSL) are rare and associated with an adverse prognosis. High-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT) improves progression free (PFS) and overall survival (OS) but neurocognition, performance status and quality of life (QoL) in patient-reported outcome (PRO) after HDC/ASCT remains underexplored. Especially elderly patients may insufficiently recover from this demanding therapy. Therefore, this single-center analysis investigated all PCNSL patients who received HDC/ASCT at the University Hospital Tübingen from 2006–2021 (n = 40, median age 60.5 years) in a retrospective manner. The 2-year PFS/OS was 78.7%/77.3%, respectively, without significant differences between the tested age-groups (≤60 vs. >60 years, p = 0.531/p = 0.334). Higher Thiotepa dosage was an independent predictor for better OS (p = 0.018). Additionally, a one-time prospective, cross-sectional analysis after HDC/ASCT in the same cohort was performed (n = 31; median follow-up 45 months). Here, the median ECOG improved by HDC/ASCT from 1 to 0 and mini-mental state examinations revealed unimpaired neurocognitive functioning (median 28 pts.). PRO data collected by EORTC QLQ-C30 showed a good QoL in both age groups with an average global health status (GHS) of 68.82% (≤60y: 64.72%, >60y: 74.14%). Together, our data indicate that HDC/ASCT is an effective therapy with respect to disease control, overall health status and quality of life, irrespective of patient age.
EGFR Pathway Expression Persists in Recurrent Glioblastoma Independent of Amplification Status
Authors: Dhawan Andrew , Manem Venkata S. K. , Yeaney Gabrielle , Lathia Justin D. , Ahluwalia Manmeet S.
Published: January 2023

Background: Glioblastoma mortality is driven by tumour progression or recurrence despite administering a therapeutic arsenal consisting of surgical resection, radiation, and alkylating chemotherapy. The genetic changes underlying tumour progression and chemotherapy resistance are poorly understood. Methods: In this study, we sought to define the relationship between EGFR amplification status, EGFR mRNA expression, and EGFR pathway activity. We compared RNA-sequencing data from matched primary and recurrent tumour samples (n = 40 patients, 20 with EGFR amplification). Results: In the setting of glioblastoma recurrence, the EGFR pathway was overexpressed regardless of EGFR-amplification status, suggesting a common genomic endpoint in recurrent glioblastoma, although EGFR amplification did associate with higher EGFR mRNA expression. Three of forty patients in the study cohort had EGFR-amplified tumours and received targeted EGFR therapy. Their molecular subtypes and clinical outcomes did not significantly differ from patients who received conventional chemotherapy. Conclusion: Our findings suggest that while the EGFR amplification may confer a unique molecular profile in primary glioblastoma, pathway analysis reveals upregulation of the EGFR pathway in recurrence, regardless of amplification status. As such, the EGFR pathway may be a key mediator of glioblastoma progression.
Efficacy and Safety of PD-1/PD-L1 Checkpoint Inhibitors versus Anti-PD-1/PD-L1 Combined with Other Therapies for Tumors: A Systematic Review
Authors: Zhang Yiru , Yao Qigu , Pan Yong , Fang Xinru , Xu Haoying , Zhao Tingxiao , Zhu Guangqi , Jiang Tianan , Li Shibo , Cao Hongcui
Published: January 2023

Objective: In recent years, the anti-programmed cell death protein-1 and its ligand (PD-1/PD-L1) or combination therapies have been recommended as an alternative emerging choice of treatment for oncology patients. However, the efficacy and adverse events of different combination strategies for the treatment of tumors remain controversial. Methods: PubMed, Embase, Cochrane Library, the American Society of Clinical Oncology (ASCO), and the European Society of Medicine Oncology (ESMO) were searched from database inception until 16 February 2022. The endpoints of objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were analyzed from different treatment schemes and tumor types. The protocol was registered in PROSPERO (CRD42022328927). Results: This meta-analysis included forty-eight eligible studies. Combination therapy has improved ORR (RR = 1.40, p < 0.001), DCR (RR = 1.22, p < 0.001), and PFS (the median survival ratio (MSR) was estimated to be 1.475 p < 0.001) compared to anti-PD-1/PD-L1 but had no significant benefit on OS (MSR was estimated to be 1.086 p = 0.117). Besides, combination treatment strategies are more toxic in any grade AEs (RR = 1.13, p < 0.001) and grade 3–5 AEs (RR = 1.81, p < 0.001). Conclusions: Treatment with PD-1/PD-L1 inhibitors in combination with other antitumor therapies improve patients’ ORR, DCR, and PFS compared to anti-PD-1/PD-L1. However, it is regrettable that there is no benefit to OS and an increased risk of AEs in combinatorial therapies.
Alternations of Lipoprotein Profiles in the Plasma as Biomarkers of Huntington’s Disease
Authors: Chang Kuo-Hsuan , Cheng Mei-Ling , Lo Chi-Jen , Fan Chun-Ming , Wu Yih-Ru , Chen Chiung-Mei
Published: January 2023

Alterations in lipid composition and disturbed lipoprotein metabolism are involved in the pathomechanism of Huntington’s disease (HD). Here, we measured 112 lipoprotein subfractions and components in the plasma of 20 normal controls, 24 symptomatic (sympHD) and 9 presymptomatic (preHD) HD patients. Significant changes were found in 30 lipoprotein subfractions and components in all HD patients. Plasma levels of total cholesterol (CH), apolipoprotein (Apo)B, ApoB-particle number (PN), and components of low-density lipoprotein (LDL) were lower in preHD and sympHD patients. Components of LDL4, LDL5, LDL6 and high-density lipoprotein (HDL)4 demonstrated lower levels in preHD and sympHD patients compared with controls. Components in LDL3 displayed lower levels in sympHD compared with the controls, whereas components in very low-density lipoprotein (VLDL)5 were higher in sympHD patients compared to the controls. The levels of components in HDL4 and VLDL5 demonstrated correlation with the scores of motor assessment, independence scale or functional capacity of Unified Huntington’s Disease Rating Scale. These findings indicate the potential of components of VLDL5, LDL3, LDL4, LDL5 and HDL4 to serve as the biomarkers for HD diagnosis and disease progression, and demonstrate substantial evidence of the involvement of lipids and apolipoproteins in HD pathogenesis.
Transcriptomic and Functional Evidence That miRNA193a-3p Inhibits Lymphatic Endothelial Cell (LEC) and LEC + MCF-7 Spheroid Growth Directly and by Altering MCF-7 Secretome
Authors: Azzarito Giovanna , Henry Margit , Rotshteyn Tamara , Leeners Brigitte , Dubey Raghvendra K.
Published: January 2023

MicroRNA 193a-3p (miR193a-3p) is a short non-coding RNA with tumor suppressor properties. Breast cancer (BC) progression is governed by active interaction between breast cancer cells, vascular (V)/lymphatic (L) endothelial cells (ECs), and BC secretome. We have recently shown that miR193a-3p, a tumor suppressor miRNA, inhibits MCF-7 BC cell-driven growth of VECs via direct antimitogenic actions and alters MCF-7 secretome. Since LEC-BC cross-talk plays a key role in BC progression, we investigated the effects of miR193a-3p on MCF-7 secretome and estradiol-mediated growth effects in LECs and LEC + MCF-7 spheroids, and delineated the underlying mechanisms. Transfection of LECs with miR193a-3p, as well as secretome from MCF-7 transfected cells, inhibited LEC growth, and these effects were mimicked in LEC + MCF-7 spheroids. Moreover, miR193a-3p inhibited ERK1/2 and Akt phosphorylation in LECs and LEC + MCF-7 spheroids, which are importantly involved in promoting cancer development and metastasis. Treatment of LECs and LEC + MCF-7 spheroids with estradiol (E2)-induced growth, as well as ERK1/2 and Akt phosphorylation, and was abrogated by miR193a-3p and secretome from MCF-7 transfected cells. Gene expression analysis (GEA) in LEC + MCF-7 spheroids transfected with miR193a-3p showed significant upregulation of 54 genes and downregulation of 73 genes. Pathway enrichment analysis of regulated genes showed significant modulation of several pathways, including interferon, interleukin/cytokine-mediated signaling, innate immune system, ERK1/2 cascade, apoptosis, and estrogen receptor signaling. Transcriptomic analysis showed downregulation in interferon and anti-apoptotic and pro-growth molecules, such as IFI6, IFIT1, OSA1/2, IFITM1, HLA-A/B, PSMB8/9, and PARP9, which are known to regulate BC progression. The cytokine proteome array of miR193a-3p transfected MCF secretome and confirmed the upregulation of several growth inhibitory cytokines, including IFNγ, Il-1a, IL-1ra, IL-32, IL-33, IL-24, IL-27, cystatin, C-reactive protein, Fas ligand, MIG, and sTIM3. Moreover, miR193a-3p alters factors in MCF-7 secretome, which represses ERK1/2 and Akt phosphorylation, induces pro-apoptotic protein and apoptosis in LECs, and downregulates interferon-associated proteins known to promote cancer growth and metastasis. In conclusion, miR193a-3p can potentially modify the tumor microenvironment by altering pro-growth BC secretome and inhibiting LEC growth, and may represent a therapeutic molecule to target breast tumors/cancer.
Early Neurobehavioral Characterization of the CD Mouse Model of Williams–Beuren Syndrome
Authors: Giannoccaro Silvia , Ferraguto Celeste , Petroni Valeria , Marcelly Coline , Nogues Xavier , Campuzano Victoria , Pietropaolo Susanna
Published: January 2023

Williams–Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a chromosomic microdeletion (7q11.23). WBS has been modeled by a mouse line having a complete deletion (CD) of the equivalent mouse locus. This model has been largely used to investigate the etiopathological mechanisms of WBS, although pharmacological therapies have not been identified yet. Surprisingly, CD mice were so far mainly tested in adulthood, despite the developmental nature of WBS and the critical relevance of early timing for potential treatments. Here we provide for the first time a phenotypic characterization of CD mice of both sexes during infancy and adolescence, i.e., between birth and 7 weeks of age. CD pups of both sexes showed reduced body growth, delayed sensory development, and altered patterns of ultrasonic vocalizations and exploratory behaviors. Adolescent CD mice showed reduced locomotion and acoustic startle response, and altered social interaction and communication, the latter being more pronounced in female mice. Juvenile CD mutants of both sexes also displayed reduced brain weight, cortical and hippocampal dendritic length, and spine density. Our findings highlight the critical relevance of early neurobehavioral alterations as biomarkers of WBS pathology, underlying the importance of adolescence for identifying novel therapeutic targets for this neurological disorder.
Light-Enhanced Cytotoxicity of Doxorubicin by Photoactivation
Authors: Greco Giulia , Ulfo Luca , Turrini Eleonora , Marconi Alessia , Costantini Paolo Emidio , Marforio Tainah Dorina , Mattioli Edoardo Jun , Di Giosia Matteo , Danielli Alberto , Fimognari Carmela , Calvaresi Matteo
Published: January 2023

The combination of photodynamic therapy with chemotherapy (photochemotherapy, PCT) can lead to additive or synergistic antitumor effects. Usually, two different molecules, a photosensitizer (PS) and a chemotherapeutic drug are used in PCT. Doxorubicin is one of the most successful chemotherapy drugs. Despite its high efficacy, two factors limit its clinical use: severe side effects and the development of chemoresistance. Doxorubicin is a chromophore, able to absorb light in the visible range, making it a potential PS. Here, we exploited the intrinsic photosensitizing properties of doxorubicin to enhance its anticancer activity in leukemia, breast, and epidermoid carcinoma cells, upon irradiation. Light can selectively trigger the local generation of reactive oxygen species (ROS), following photophysical pathways. Doxorubicin showed a concentration-dependent ability to generate peroxides and singlet oxygen upon irradiation. The underlying mechanisms leading to the increase in its cytotoxic activity were intracellular ROS generation and the induction of necrotic cell death. The nuclear localization of doxorubicin represents an added value for its use as a PS. The use of doxorubicin in PCT, simultaneously acting as a chemotherapeutic agent and a PS, may allow (i) an increase in the anticancer effects of the drug, and (ii) a decrease in its dose, and thus, its dose-related adverse effects.
Grapevine-Associated Lipid Signalling Is Specifically Activated in an Rpv3 Background in Response to an Aggressive P. viticola Pathovar
Authors: Laureano Gonçalo , Santos Catarina , Gouveia Catarina , Matos Ana Rita , Figueiredo Andreia
Published: January 2023

Vitis vinifera L. is highly susceptible to the biotrophic pathogen Plasmopara viticola. To control the downy mildew disease, several phytochemicals are applied every season. Recent European Union requirements to reduce the use of chemicals in viticulture have made it crucial to use alternative and more sustainable approaches to control this disease. Our previous studies pinpoint the role of fatty acids and lipid signalling in the establishment of an incompatible interaction between grapevine and P. viticola. To further understand the mechanisms behind lipid involvement in an effective defence response we have analysed the expression of several genes related to lipid metabolism in three grapevine genotypes: Chardonnay (susceptible); Regent (tolerant), harbouring an Rpv3-1 resistance loci; and Sauvignac (resistant) that harbours a pyramid of Rpv12 and Rpv3-1 resistance loci. A highly aggressive P. viticola isolate was used (NW-10/16). Moreover, we have characterised the grapevine phospholipases C and D gene families and monitored fatty acid modulation during infection. Our results indicate that both susceptible and resistant grapevine hosts did not present wide fatty acid or gene expression modulation. The modulation of genes associated with lipid signalling and fatty acids seems to be specific to Regent, which raises the hypothesis of being specifically linked to the Rpv3 loci. In Sauvignac, the Rpv12 may be dominant concerning the defence response, and, thus, this genotype may present the activation of other pathways rather than lipid signalling.
Antimycobacterial Activity of Sida hermaphrodita (L.) Rusby (Malvaceae) Seed Extract
Authors: Lewtak Kinga , Czaplewska Paulina , Wydrych Jerzy , Keller Radosław , Nowicka Aldona , Skrzypiec Krzysztof , Fiołka Marta Julia
Published: January 2023

The current prevalence of such lifestyle diseases as mycobacteriosis and tuberculosis is a result of the growing resistance of microorganisms to the available antibiotics and their significant toxicity. Therefore, plants can successfully become a source of new therapeutic agents. The aim of this study was to investigate the effect of protein extract from Sida hermaphrodita seeds on the morphology, structure, and viability of Mycobacterium smegmatis and to carry out proteomic characterization of the protein extract. The analyses were carried out using fluorescence and transmission microscopy, atomic force microscopy, and spectroscopy. The proteomic studies were performed using liquid chromatography coupled to tandem mass spectrometry. The studies showed that the seed extract applied at concentrations of 50–150 µg/mL exerted a statistically significant effect on M. smegmatis cells, that is, a reduction of the viability of the bacteria and induction of changes in the structure of the mycobacterial cell wall. Additionally, the SEM analysis confirmed that the extract did not have a cytotoxic or cytopathic effect on fibroblast cells. The proteomic analysis revealed the presence of structural, storage, and enzymatic proteins and peptides in the extract, which are typical for seeds. Proteins and peptides with antimicrobial activity identified as vicillins and lipid-transporting proteins were also determined in the protein profile of the extract.
DEHP Decreases Steroidogenesis through the cAMP and ERK1/2 Signaling Pathways in FSH-Stimulated Human Granulosa Cells
Authors: Tesic Biljana , Samardzija Nenadov Dragana , Tomanic Tamara , Fa Nedeljkovic Svetlana , Milatovic Stevan , Stanic Bojana , Pogrmic-Majkic Kristina , Andric Nebojsa
Published: January 2023

DEHP is an endocrine disruptor that interferes with the function of the female reproductive system. Several studies suggested that DEHP affects steroidogenesis in human and rodent granulosa cells (GC). Some studies have shown that DEHP can also affect the FSH-stimulated steroidogenesis in GC; however, the mechanism by which DEHP affects hormone-challenged steroidogenesis in human GC is not understood. Here, we analyzed the mechanism by which DEHP affects steroidogenesis in the primary culture of human cumulus granulosa cells (hCGC) stimulated with FSH. Cells were exposed to DEHP and FSH for 48 h, and steroidogenesis and the activation of cAMP and ERK1/2 were analyzed. The results show that DEHP decreases FSH-stimulated STAR and CYP19A1 expression, which is accompanied by a decrease in progesterone and estradiol production. DEHP lowers cAMP production and CREB phosphorylation in FSH but not cholera toxin- and forskolin-challenged hCGC. DEHP was not able to decrease steroidogenesis in cholera toxin- and forskolin-stimulated hCGC. Furthermore, DEHP decreases FSH-induced ERK1/2 phosphorylation. The addition of EGF rescued ERK1/2 phosphorylation in FSH- and DEHP-treated hCGC and prevented a decrease in steroidogenesis in the FSH- and DEHP-treated hCGC. These results suggest that DEHP inhibits the cAMP and ERK1/2 signaling pathways, leading to the inhibition of steroidogenesis in the FSH-stimulated hCGC.
Preoperative Radiochemotherapy in Rectal Cancer: Is There an Impact of Oxaliplatin on Pathologic Complete Response and Survival Rates under “Real World“ Conditions?
Authors: Grabenbauer Alexander , Aigner Thomas , Göbel Holger , Leibl Bernhard J. , Lamberti Christof , Grabenbauer Gerhard G. , Distel Luitpold V.
Published: January 2023

This study aimed to evaluate the benefit of additional administration of oxaliplatin during fluorouracil-based neoadjuvant radiochemotherapy (nRCT) in terms of pathologic complete remission (pCR), disease-free survival (DFS), and overall survival (OS) in patients with advanced rectal cancer. Between 2006 and 2021, 669 patients (pts) were diagnosed with locally advanced rectal cancer, of whom a total of 414 pts with nRCT were identified and included in the study. A total of 283 pts were treated by nRCT using concurrent chemotherapy with fluorouracil or capecitabine; 131 pts were treated using a combination of fluorouracil or capecitabine and oxaliplatin. Propensity score matching analyses (PSM) with 114 pts in each group were used to balance the patients’ characteristics. OS, DFS, pCR-rate, and potential prognostic factors were compared between the two groups. The median follow-up time was 59.5 weeks in the fluorouracil-group and 43 weeks in the fluorouracil/oxaliplatin group (p = 0.003). After PSM, the pCR-rate (including sustained clinical complete remission) was 27% (31/114 pts) in the fluorouracil/oxaliplatin group and 16% (18/114 pts) in the fluorouracil-group (p = 0.033). There was no difference between these two groups for both 10-year OS and DFS neither before nor after PSM, respectively (OS: 72.6% vs. 55.4%, p = 0.066, and 67.8% vs. 55.1%, p = 0.703, and DFS: 44.8% vs. 46.8%, p = 0.134, and 44.7% vs. 42.3%, p = 0.184). Multivariate analysis identified regression grading according to Dworak grade 4 (HR: 0.659; CI: 0.471–0.921; p = 0.015) and age over 60 years (HR: 2.231; CI: 1.245–4.001; p = 0.007) as independent predictors for OS. In conclusion, the addition of oxaliplatin to fluorouracil during nRCT significantly improved pCR-rate without having an impact on survival.