bluuebunny/crossref_metadata_2025 huggingface dataset:
Antigen-Specific T Cells and SARS-CoV-2 Infection: Current Approaches and Future Possibilities
Authors: Nova Zuzana , Zemanek Tomas , Botek Norbert
Published: December 2022

COVID-19, a significant global health threat, appears to be an immune-related disease. Failure of effective immune responses in initial stages of infection may contribute to development of cytokine storm and systemic inflammation with organ damage, leading to poor clinical outcomes. Disease severity and the emergence of new SARS-CoV-2 variants highlight the need for new preventative and therapeutic strategies to protect the immunocompromised population. Available data indicate that these people may benefit from adoptive transfer of allogeneic SARS-CoV-2-specific T cells isolated from convalescent individuals. This review first provides an insight into the mechanism of cytokine storm development, as it is directly related to the exhaustion of T cell population, essential for viral clearance and long-term antiviral immunity. Next, we describe virus-specific T lymphocytes as a promising and efficient approach for the treatment and prevention of severe COVID-19. Furthermore, other potential cell-based therapies, including natural killer cells, regulatory T cells and mesenchymal stem cells are mentioned. Additionally, we discuss fast and effective ways of producing clinical-grade antigen-specific T cells which can be cryopreserved and serve as an effective “off-the-shelf” approach for rapid treatment of SARS-CoV-2 infection in case of sudden patient deterioration.
Controlling Macrophage Polarization to Modulate Inflammatory Cues Using Immune-Switch Nanoparticles
Authors: Almeida Ana F. , Miranda Margarida S. , Vinhas Adriana , Gonçalves Ana I. , Gomes Manuela E. , Rodrigues Márcia T.
Published: December 2022

The persistence of inflammatory mediators in tissue niches significantly impacts regenerative outcomes and contributes to chronic diseases. Interleukin-4 (IL4) boosts pro-healing phenotypes in macrophages (Mφ) and triggers the activation of signal transducer and activator of transcription 6 (STAT6). Since the IL4/STAT6 pathway reduces Mφ responsiveness to inflammation in a targeted and precise manner, IL4 delivery offers personalized possibilities to overcome inflammatory events. Despite its therapeutic potential, the limited success of IL4-targeted delivery is hampered by inefficient vehicles. Magnetically assisted technologies offer precise and tunable nanodevices for the delivery of cytokines by combining contactless modulation, high tissue penetration, imaging features, and low interference with the biological environment. Although superparamagnetic iron oxide nanoparticles (SPION) have shown clinical applicability in imaging, SPION-based approaches have rarely been explored for targeted delivery and cell programming. Herein, we hypothesized that SPION-based carriers assist in efficient IL4 delivery to Mφ, favoring a pro-regenerative phenotype (M2φ). Our results confirmed the efficiency of SPION-IL4 and Mφ responsiveness to SPION-IL4 with evidence of STAT6-mediated polarization. SPION-IL4-treated Mφ showed increased expression of M2φ associated-mediators (IL10, ARG1, CCL2, IL1Ra) when compared to the well-established soluble IL4. The ability of SPION-IL4 to direct Mφ polarization using sophisticated magnetic nanotools is valuable for resolving inflammation and assisting innovative strategies for chronic inflammatory conditions.
The Graphical Studies of the Major Molecular Interactions for Neural Cell Adhesion Molecule (NCAM) Polysialylation by Incorporating Wenxiang Diagram into NMR Spectroscopy
Authors: Zhou Guo-Ping , Huang Ri-Bo
Published: December 2022

Polysialylation is a process of polysialic acid (polySia) addition to neural cell adhesion molecule (NCAM), which is associated with tumor cell migration and progression in many metastatic cancers and neurocognition. Polysialylation can be catalyzed by two highly homologous mammalian polysialyltransferases (polySTs), ST8Sia II (STX) and ST8Sia IV (PST). It has been proposed that two polybasic domains, polybasic region (PBR) and polysialyltransferase domain (PSTD) in polySTs, are possible binding sites for the intermolecular interactions of polyST–NCAM and polyST–polySia, respectively, as well as the intramolecular interaction of PSTD–PBR. In this study, Chou’s wenxiang diagrams of the PSTD and PBR are used to determine the key amino acids of these intermolecular and intramolecular interactions, and thus it may be helpful for the identification of the crucial amino acids in the polyST and for the understanding of the molecular mechanism of NCAM polysialylation by incorporating the wenxiang diagram and molecular modeling into NMR spectroscopy.
Isolation of TTF-1 Positive Circulating Tumor Cells for Single-Cell Sequencing by Using an Automatic Platform Based on Microfluidic Devices
Authors: Jou Hei-Jen , Ho Hsin-Cheng , Huang Kuan-Yeh , Chen Chen-Yang , Chen Sheng-Wen , Lo Pei-Hsuan , Huang Pin-Wen , Huang Chung-Er , Chen Ming
Published: December 2022

Single-cell sequencing provides promising information in tumor evolution and heterogeneity. Even with the recent advances in circulating tumor cell (CTC) technologies, it remains a big challenge to precisely and effectively isolate CTCs for downstream analysis. The Cell RevealTM system integrates an automatic CTC enrichment and staining machine, an AI-assisted automatic CTC scanning and identification system, and an automatic cell picking machine for CTC isolation. H1975 cell line was used for the spiking test. The identification of CTCs and the isolation of target CTCs for genetic sequencing were performed from the peripheral blood of three cancer patients, including two with lung cancer and one with both lung cancer and thyroid cancer. The spiking test revealed a mean recovery rate of 81.81% even with extremely low spiking cell counts with a linear relationship between the spiked cell counts and the recovered cell counts (Y = 0.7241 × X + 19.76, R2 = 0.9984). The three cancer patients had significantly higher TTF-1+ CTCs than healthy volunteers. All target CTCs were successfully isolated by the Cell Picker machine for a subsequent genetic analysis. Six tumor-associated mutations in four genes were detected. The present study reveals the Cell RevealTM platform can precisely identify and isolate target CTCs and then successfully perform single-cell sequencing by using commercially available genetic devices.
Secretome Analysis of the Plant Biostimulant Bacteria Strains Bacillus subtilis (EB2004S) and Lactobacillus helveticus (EL2006H) in Response to pH Changes
Authors: Msimbira Levini A. , Subramanian Sowmyalakshmi , Naamala Judith , Antar Mohammed , Smith Donald L.
Published: December 2022

It is well-known that there is a high frequency of plant-growth-promoting strains in Bacillus subtilis and that these can be effective under both stressful and stress-free conditions. There are very few studies of this activity in the case of Lactobacillus helveticus. In this study, the effects of pH on the secretome (proteins) in the cell-free supernatants of two bacterial strains were evaluated. The bacteria were cultured at pH 5, 7 and 8, and their secretome profiles were analyzed, with pH 7 (optimal growth pH) considered as the “control”. The results showed that acidity (lower pH 5) diminishes the detectable production of most of the secretome proteins, whereas alkalinity (higher pH 8) increases the detectable protein production. At pH 5, five (5) new proteins were produced by L. helveticus, including class A sortase, fucose-binding lectin II, MucBP-domain-containing protein, SLAP-domain-containing protein and hypothetical protein LHEJCM1006_11110, whereas for B. subtilis, four (4) types of proteins were uniquely produced (p ≤ 0.05), including helicase-exonuclease AddAB subunit AddB, 5-methyltetrahydropteroyltriglutamate-homocysteine S-methyltransferase, a cluster of ABC-F family ATP-binding-cassette-domain-containing proteins and a cluster of excinuclease ABC (subunit B). At pH 8, Bacillus subtilis produced 56 unique proteins. Many of the detected proteins were involved in metabolic processes, whereas the others had unknown functions. The unique and new proteins with known and unknown functions suggest potential the acclimatization of the microbes to pH stress.
Deletion of TNF in Winnie-APCMin/+ Mice Reveals Its Dual Role in the Onset and Progression of Colitis-Associated Colorectal Cancer
Authors: Verna Giulio , Liso Marina , Cavalcanti Elisabetta , Armentano Raffaele , Miraglia Alessandro , Monsurrò Vladia , Chieppa Marcello , De Santis Stefania
Published: December 2022

Colorectal cancer (CRC) is among the best examples for depicting the relationship between inflammation and cancer. The introduction of new therapeutics targeting inflammatory mediators showed a marked decrease in the overall risk of CRC, although their chemopreventive potential is still debated. Specifically, a monoclonal antibody that blocks tumor necrosis factor (TNF), infliximab, increases CRC risk in inflammatory bowel disease patients. To address the axis between TNF and CRC development and progression, we depleted the Tnf from our previously established murine model of colitis-associated cancer (CAC), the Winnie-ApcMin/+ line. We characterized the new Winnie-APCMin/+-TNF-KO line through macroscopical and microscopical analyses. Surprisingly, the latter demonstrated that the deletion of Tnf in Winnie-ApcMin/+ mice resulted in an initial reduction in dysplastic lesion incidence in 5-week-old mice followed by a faster disease progression at 8 weeks. Histological data were confirmed by the molecular profiling obtained from both the real-time PCR analysis of the whole tissue and the RNA sequencing of the macrodissected tumoral lesions from Winnie-APCMin/+-TNF-KO distal colon at 8 weeks. Our results highlight that TNF could exert a dual role in CAC, supporting the promotion of neoplastic lesions onset in the early stage of the disease while inducing their reduction during disease progression.
Resveratrol-Mediated Reversal of Doxorubicin-Induced Osteoclast Differentiation
Authors: Poudel Sunil , Martins Gil , Cancela M. Leonor , Gavaia Paulo J.
Published: December 2022

Secondary osteoporosis has been associated with cancer patients undertaking Doxorubicin (DOX) chemotherapy. However, the molecular mechanisms behind DOX-induced bone loss have not been elucidated. Molecules that can protect against the adverse effects of DOX are still a challenge in chemotherapeutic treatments. We investigated the effect and mechanism of DOX in osteoclast differentiation and used the Sirt 1 activator resveratrol (RES) to counteract DOX-induced effects. RAW 264.7 cells were differentiated into osteoclasts under cotreatment with DOX and RES, alone or combined. RES treatment inhibited DOX-induced osteoclast differentiation, reduced the expression of osteoclast fusion marker Oc-stamp and osteoclast differentiation markers Rank, Trap, Ctsk and Nfatc1. Conversely, RES induced the upregulation of antioxidant genes Sod 1 and Nrf 2 while DOX significantly reduced the FoxM1 expression, resulting in oxidative stress. Treatment with the antioxidant MitoTEMPO did not influence DOX-induced osteoclast differentiation. DOX-induced osteoclastogenesis was studied using the cathepsin-K zebrafish reporter line (Tg[ctsk:DsRed]). DOX significantly increased ctsk signal, while RES cotreatment resulted in a significant reduction in ctsk positive cells. RES significantly rescued DOX-induced mucositis in this model. Additionally, DOX-exposed zebrafish displayed altered locomotor behavior and locomotory patterns, while RES significantly reversed these effects. Our research shows that RES prevents DOX-induced osteoclast fusion and activation in vitro and in vivo and reduces DOX-induced mucositis, while improving locomotion parameters.
Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker
Authors: Feng Jun , Chen Zhaowei , Liang Wei , Wei Zhongping , Ding Guohua
Published: December 2022

The kidney is a mitochondria-rich organ, and kidney diseases are recognized as mitochondria-related pathologies. Intact mitochondrial DNA (mtDNA) maintains normal mitochondrial function. Mitochondrial dysfunction caused by mtDNA damage, including impaired mtDNA replication, mtDNA mutation, mtDNA leakage, and mtDNA methylation, is involved in the progression of kidney diseases. Herein, we review the roles of mtDNA damage in different setting of kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD). In a variety of kidney diseases, mtDNA damage is closely associated with loss of kidney function. The level of mtDNA in peripheral serum and urine also reflects the status of kidney injury. Alleviating mtDNA damage can promote the recovery of mitochondrial function by exogenous drug treatment and thus reduce kidney injury. In short, we conclude that mtDNA damage may serve as a novel biomarker for assessing kidney injury in different causes of renal dysfunction, which provides a new theoretical basis for mtDNA-targeted intervention as a therapeutic option for kidney diseases.
Variations in Urinary Renin-Angiotensin-Aldosterone Component Concentrations in Paediatric IgA Vasculitis Nephritis
Authors: Chetwynd Andrew J. , Marro Julien , Northey Sarah J. , Hughes Daniel J. , Oni Louise
Published: December 2022

IgA Vasculitis (IgAV) is the most common form of vasculitis in children, and 1–2% of patients develop chronic kidney disease. In other forms of glomerulonephritis, there is strong evidence to support the role of the renin-angiotensin-aldosterone system (RAAS); however, data are lacking in IgAV nephritis. This study evaluated urinary RAAS components in children with IgA vasculitis, both with nephritis (IgAVN) and without nephritis (IgAVwoN). Urinary concentrations of renin, angiotensinogen and aldosterone were quantified using ELISAs. In total, 40 patients were included: IgAVN n = 9, IgAVwoN n = 17, HC n = 14, with a mean age of 8.3 ± 3.3 years. Urinary renin demonstrated no trend with nephritis. Urinary angiotensinogen was statistically significantly elevated in IgAV (1.18 ± 1.16 ng/mmol) compared to HC (0.28 ± 0.27 ng/mmol, p = 0.0015), and IgAVN (2.00 ± 1.22 ng/mmol) was elevated compared to IgAVwoN (0.74 ± 0.89 ng/mmol, p = 0.0492) and HC (p = 0.0233). Urinary aldosterone levels were significantly elevated in IgAV (1236 ± 1438 pg/mmol) compared to HC (73.90 ± 65.22 pg/mmol, p < 0.0001); this was most increased in IgAVwoN patients (1793 ± 1507 pg/mmol; IgAVN 183.30 ± 111.30 pg/mmol, p = 0.0035, HC p < 0.0001). As expected, the RAAS system is activated in patients with IgAVN and, more surprisingly, even in those without active nephritis. Further studies are needed to fully understand the role of the RAAS system in IgA vasculitis.
Uniformity Index as a Universal Air-Cooled Condenser Fan Performance Metric
Authors: Marincowitz Fredrik , Owen Michael , Muiyser Jacques , Holkers Peter
Published: December 2022

Ambient wind has a negative effect on mechanical forced-draft direct air-cooled steam condenser (ACC) fan volumetric performance, and increases dynamic fan blade loading. Investigating these effects directly using on-site measurement or numerical analysis is complicated, and most previous work has focused on only one effect at the expense of the other. In this study, fan axial velocity inflow uniformity is identified as a single metric offering the potential to holistically qualify ACC fan operation under windy conditions. A 3 × 6 fan cell ACC was modelled with CFD using a blade element theory-based fan model, and clear relationships between the fan inflow uniformity index and both fan volumetric performance and dynamic blade loading were observed in the results. The same relationships were observed in on-site test data collected at a single ACC fan, thus validating the numerical results. The uniformity index can be used in both numerical and experimental work as a means of investigating both fan volumetric performance and dynamic blade loading with less computational and measurement complexity; it also offers a potentially useful means of quantifying the severity of fan operating conditions, to assist with more reliable case-specific fan design and selection.
Efficacy of the PRESERFLO MicroShunt and a Meta-Analysis of the Literature
Authors: Pawiroredjo Shigeo S. M. , Bramer Wichor M. , Pawiroredjo Noemi D. , Pals Jan , Poelman Huub J. , de Vries Victor A. , Wolfs Roger C. W. , Ramdas Wishal D.
Published: December 2022

Background: Recent studies on the PRESERFLO MicroShunt suggest that it may be effective in lowering intraocular pressure (IOP); however, the number of studies on this device remains limited. Therefore, we assessed the efficacy of the PRESERFLO MicroShunt in patients with glaucoma and performed a meta-analysis of published results. Methods: Prospective study including all patients that underwent PRESERFLO MicroShunt surgery from 2018 onwards. Sub-analyses were performed for cataract-combined procedures. To compare our results, we performed a systematic review and meta-analysis. IOP, IOP-lowering medication and surgical complications reported in the retrieved studies were assessed. Results: A total of 72 eyes underwent PRESERFLO-implant surgery (59 as standalone procedure and 13 as cataract-combined procedure). No significant differences were found in IOP and IOP-lowering medication between both groups. The mean ± standard deviation IOP and IOP-lowering medications of both groups taken together declined from 21.72 ± 8.35 to 15.92 ± 8.54 mmHg (p < 0.001, 26.7% reduction) and 3.40 to 0.93 (p < 0.001, 72.6% reduction) at 1 year follow-up, respectively. Secondary surgeries were required in 19.4% of eyes, the majority (71.4%) within 6 months. The meta-analysis including 14 studies (totaling 1213 PRESERFLO MicroShunt surgeries) from the systematic review showed a mean preoperative IOP and IOP-lowering medication of 22.28 ± 5.38 and 2.97 ± 1.07, respectively. The three-years postoperative pooled mean was (weighted mean difference, 95% CI) 11.07 (10.27 [8.23–12.32], p < 0.001) mmHg and 0.91 (1.77 [1.26–2.28], p < 0.001) for IOP and IOP-lowering medication, respectively. The most common reported complication was hypotony (2–39%). Conclusion: The PRESERFLO MicroShunt is effective and safe in lowering IOP and the number of IOP-lowering medications.
Elemental Dynamics in Hair Accurately Predict Future Autism Spectrum Disorder Diagnosis: An International Multi-Center Study
Authors: Austin Christine , Curtin Paul , Arora Manish , Reichenberg Abraham , Curtin Austen , Iwai-Shimada Miyuki , Wright Robert O. , Wright Rosalind J. , Remnelius Karl Lundin , Isaksson Johan , Bölte Sven , Nakayama Shoji F.
Published: December 2022

Autism spectrum disorder (ASD) is a neurodevelopmental condition diagnosed in approximately 2% of children. Reliance on the emergence of clinically observable behavioral patterns only delays the mean age of diagnosis to approximately 4 years. However, neural pathways critical to language and social functions develop during infancy, and current diagnostic protocols miss the age when therapy would be most effective. We developed non-invasive ASD biomarkers using mass spectrometry analyses of elemental metabolism in single hair strands, coupled with machine learning. We undertook a national prospective study in Japan, where hair samples were collected at 1 month and clinical diagnosis was undertaken at 4 years. Next, we analyzed a national sample of Swedish twins and, in our third study, participants from a specialist ASD center in the US. In a blinded analysis, a predictive algorithm detected ASD risk as early as 1 month with 96.4% sensitivity, 75.4% specificity, and 81.4% accuracy (n = 486; 175 cases). These findings emphasize that the dynamics in elemental metabolism are systemically dysregulated in autism, and these signatures can be detected and leveraged in hair samples to predict the emergence of ASD as early as 1 month of age.
Local Resection in Choroidal Melanoma: A Review
Authors: Caminal Josep Maria , Lorenzo Daniel , Gutierrez Cristina , Slocker Andrea , Piulats Josep Maria , Cobos Estefania , Garcia-Bru Pere , Morwani Rahul , Santamaria Juan Francisco , Arias Luis
Published: December 2022

Surgical resection is widely used to treat small tumours located in the iris and the ciliary body, due to the accessibility of these sites. By contrast, surgical removal of choroidal tumours is substantially more challenging, which is why this procedure is performed only at specialised centres. In the present article, we review the literature on surgical resection of choroidal tumours, which can be performed as endoresection (ab interno) or transscleral resection (ab externo). An important aim of this review is to describe and compare the two approaches in terms of visual outcomes, survival rates, and complications. Both approaches are indicated for the removal of large tumours (thickness > 8 mm) with small base diameters. Surgical resection of the tumour allows clinicians to obtain valuable histopathologic and cytogenetic data from the specimen and eliminates the risks associated with radiotherapy. However, both of these surgical approaches are technically challenging procedures involving the risk of severe early and late postoperative complications.
Bipolar Disorder and Bone Mineral Density Z-Scores in Relation to Clinical Characteristics and Lithium Medication
Authors: Lassas Anders , Norrback Karl-fredrik , Adolfsson Rolf , Maripuu Martin
Published: December 2022

Bipolar disorder is associated with a long range of medical comorbidities, including migraine, diabetes, and cardiovascular disease. Bipolar disorder has also been associated with an increased risk of bone fractures. Osteoporosis is a reduction in bone mineral density, which leads to an increased risk for fragility fractures. Currently there is limited research on the association between bipolar disorder and osteoporosis. We aimed to study the association between high and low bone mineral density in relation to disease and treatment history in a sample of bipolar patients. We found that bipolar patients with high bone mineral density were more often on lithium medication, had a more active lifestyle and expressed lower current disease burden. Low mineral density was not associated with any of the addressed aspects of disease and treatment history. In conclusion our results support that patients on lithium treatment have higher bone mineral density; further studies are needed to address if lithium medication causes an increase in bone mineral density, and lowers the risk of bone fractures in bipolar disorder.
Nonlinear Relationship between Temporomandibular Joint Disc Displacement Distance and Disc Length: A Magnetic Resonance Imaging Analysis
Authors: Zhang Qinlanhui , Ye Zheng , Wu Yange , Zhu Yufan , Liu Jiaqi , Yang Wenke , Ye Chengxinyue , Lau Rui Han Sophie , Wang Jun , Xiong Xin
Published: December 2022

Objective: to explore the association between the distance of disc displacement and disc morphology in patients with temporomandibular disorders (TMDs). Methods: a total of 717 joints in 473 subjects were enrolled in this cross-sectional study. The magnetic resonance imaging (MRI) of each patient was evaluated for temporomandibular joint (TMJ) disc morphology classification and position. The distance of the disc displacement and disc length were measured for smoothing spline prediction. A stratified analysis was performed based on the types of disc positions. The disc width and length-width ratio (L/W) were also measured. Descriptive statistics, one-way analysis of variance, smoothing spline analysis, threshold analysis, and two piecewise linear regression were performed to investigate the association between the displacement distance and length of discs. Results: the differences in displacement distance among morphological categories and among different disc positions were statistically significant. Nonlinear relationships were found between distance and length in all subjects. Two turning points of distance (−1.8 mm and 1.7 mm) were found, dividing the curve into three segments. Disc width and L/W were significantly different among discs in the three segments of the curve. The correlation coefficient (β) for the three segments were as follows: −0.6 [95% confidence interval (CI) = −0.9 to −0.3, p < 0.001], 0.0 (95% CI = −0.1 to 0.0, p = 0.027), and −0.7 (95% CI = −0.8 to −0.7, p < 0.001). Nonlinear relationships were also found between the distance and length in cases with anterior disc displacement (ADD), anterior disc displacement with reduction (ADDWR), and without reduction (ADDWoR). Conclusion: the turning points of the disc displacement distance may be considered as a potential reference value for high-risk disc deformation and ADD. Disc length decreases sharply with anterior disc displacement when the disc displacement distance is over 1.7 mm. Prospective and long-term studies are required to clarify the natural course of the disc at different stages of the regression curve.
Peak Plasma Levels of mtDNA Serve as a Predictive Biomarker for COVID-19 in-Hospital Mortality
Authors: Edinger Fabian , Edinger Sophia , Koch Christian , Markmann Melanie , Hecker Matthias , Sander Michael , Schneck Emmanuel
Published: December 2022

Several predictive biomarkers for coronavirus disease (COVID-19)-associated mortality in critically ill patients have been described. Although mitochondrial DNA (mtDNA) is elevated in patients with COVID-19, the association with coagulation function and its predictive power for mortality is unclear. Accordingly, this study investigates the predictive power of mtDNA for in-hospital mortality in critically ill patients with COVID-19, and whether combining it with thromboelastographic parameters can increase its predictive performance. This prospective explorative study included 29 patients with COVID-19 and 29 healthy matched controls. mtDNA encoding for NADH dehydrogenase 1 (ND1) was quantified using a quantitative polymerase chain reaction analysis, while coagulation function was evaluated using thromboelastometry and impedance aggregometry. Receiver operating characteristic (ROC) curves were used for the prediction of in-hospital mortality. Within the first 24 h, the plasma levels of mtDNA peaked significantly (controls: 65 (28–119) copies/µL; patients: 281 (110–805) at t0, 403 (168–1937) at t24, and 467 (188–952) copies/µL at t72; controls vs. patients: p = 0.02 at t0, p = 0.03 at t24, and p = 0.44 at t72). The mtDNA levels at t24 showed an excellent predictive performance for in-hospital mortality (area under the ROC curve: 0.90 (0.75–0.90)), which could not be improved by the combination with thromboelastometric or aggregometric parameters. Critically ill patients with COVID-19 present an early increase in the plasma levels of ND1 mtDNA, lasting over 24 h. They also show impairments in platelet function and fibrinolysis, as well as hypercoagulability, but these do not correlate with the plasma levels of fibrinogen. The peak plasma levels of mtDNA can be used as a predictive biomarker for in-hospital mortality; however, the combination with coagulation parameters does not improve the predictive validity.
Remarkable Remission Rate and Long-Term Efficacy of Upfront Metronomic Chemotherapy in Elderly and Frail Patients, with Diffuse Large B-Cell Lymphoma
Authors: Bocci Guido , Pelliccia Sabrina , Orlandi Paola , Caridi Matteo , Banchi Marta , Musuraca Gerardo , Di Napoli Arianna , Bianchi Maria , Patti Caterina , Anticoli-Borza Paola , Battistini Roberta , Casaroli Ivana , Lanzolla Tiziana , Tafuri Agostino , Cox Maria
Published: December 2022

The upfront treatment of very elderly and frail patients with diffuse large B-cell lymphoma (DLBCL) is still a matter of debate. Herein, we report results of the metronomic all-oral DEVEC [prednisolone/deltacortene®, vinorelbine (VNR), etoposide (ETO), cyclophosphamide] combined with i.v. rituximab (R). This schedule was administered as a first line therapy in 22 elderly/frail DLBCL subjects (median age = 84.5 years). In 17/22 (77%) patients, the Elderly-IPI-score was high. After a median follow-up of 24 months, 15 patients had died: seven (50%) for causes unrelated to DLBCL or its treatment, six (40%) for progression, and two (13%) for multiorgan failure. Six treatment-pertinent serious-adverse-events occurred. At the end of induction, 14/22 (64%) achieved complete remission; overall survival and event-free survival at 24 months were both 54% (95% CI = 32–72%), while the disease-free survival was 74% (95% CI = 48–88%). Furthermore, antiproliferative and proapoptotic assays were performed on DLBCL/OCI-LY3 cell-line using metronomic VNR and ETO and their combination. Both metronomic VNR and ETO had concentration-dependent antiproliferative (IC50 = 0.036 ± 0.01 nM and 7.9 ± 3.6 nM, respectively), and proapoptotic activities in DLBCL cells. Co-administration of the two drugs showed a strong synergism (combination index < 1 and dose reduction index > 1) against cell proliferation and survival. This low-dose schedule seems to compare favourably with intravenous-CHEMO protocols used in the same subset. Indeed, the high synergism shown by metronomic VRN+ETO in in vitro studies, explains the remarkable clinical responses and it allows significant dose reductions.
The Development of a Gleason Score-Related Gene Signature for Predicting the Prognosis of Prostate Cancer
Authors: Yimamu Yiliyasi , Yang Xu , Chen Junxin , Luo Cheng , Xiao Wenyang , Guan Hongyu , Wang Daohu
Published: December 2022

The recurrence of prostate cancer (PCa) is intrinsically linked to increased mortality. The goal of this study was to develop an efficient and reliable prognosis prediction signature for PCa patients. The training cohort was acquired from The Cancer Genome Atlas (TCGA) dataset, while the validation cohort was obtained from the Gene Expression Omnibus (GEO) dataset (GSE70769). To explore the Gleason score (GS)-based prediction signature, we screened the differentially expressed genes (DEGs) between low- and high-GS groups, and then univariate Cox regression survival analysis and multiple Cox analyses were performed sequentially using the training cohort. The testing cohort was used to evaluate and validate the prognostic model’s effectiveness, accuracy, and clinical practicability. In addition, the correlation analyses between the risk score and clinical features, as well as immune infiltration, were performed. We constructed and optimized a valid and credible model for predicting the prognosis of PCa recurrence using four GS-associated genes (SFRP4, FEV, COL1A1, SULF1). Furthermore, ROC and Kaplan–Meier analysis revealed a higher predictive efficiency for biochemical recurrence (BCR). The results showed that the risk model was an independent prognostic factor. Moreover, the risk score was associated with clinical features and immune infiltration. Finally, the risk model was validated in a testing cohort. Our data support that the GS-based four-gene signature acts as a novel signature for predicting BCR in PCa patients.
Eryptosis in Patients with Chronic Kidney Disease: A Possible Relationship with Oxidative Stress and Inflammatory Markers
Authors: Clementi Anna , Virzì Grazia , Milan Manani Sabrina , Battaglia Giovanni , Ronco Claudio , Zanella Monica
Published: December 2022

Background. Eryptosis is the programmed death of red blood cells; it may contribute to worsening anemia in chronic kidney disease (CKD). In this clinical condition, different factors induce eryptosis, such as oxidative stress, energy depletion and uremic toxins. In our study, we investigated if the progression of CKD may influence erythrocyte death levels and its relationship with oxidative stress and inflammation. Methods. We evaluated eryptosis levels in 25 CKD patients (five for each stage), as well as markers of oxidative stress and inflammation: myeloperoxidase (MPO), copper/zinc superoxide dismutase (Cu/Zn SOD) and interleukin-6 (IL-6) were evaluated in plasma samples. Results. Higher cell death rate was reported in the highest CKD stages (p < 0.05). Furthermore, we divided CKD patients into two groups (eGFR< or ≥60 mL/min/1.73 m2). Patients with eGFR < 60 mL/min/1.73 m2 had higher eryptosis levels (p < 0.001). MPO, CU/Zn SOD and IL-6 resulted significantly differently between groups (p < 0.001). Significant positive correlations were reported between eryptosis and MPO (Spearman’s rho = 0.77, p = 0.01) and IL-6 (Spearman’s rho = 0.52, p = 0.05) and Cu/Zn SOD. Spearman’s rho = 0.6, p = 0.03). Conclusions. In patients with CKD, different factors are involved in the pathogenesis of eryptosis, in particular uremic toxins and oxidative stress and inflammatory markers. The progressive impairment of renal function may be associated with the increase in eryptosis levels, probably due to the accumulation of oxidative stress factors, inflammatory cytokines and uremic toxins.
Early Reconstruction Delivered Better Outcomes for Severe Open Fracture of Lower Extremities: A 15-Year Retrospective Study
Authors: Cao Zheming , Li Cheng , He Jiqiang , Qing Liming , Yu Fang , Wu Panfeng , Tang Juyu
Published: December 2022

Background: The principle of early flap reconstruction for high-grade traumatic lower-extremity injuries established in 1986 by Godina has been widely accepted. However, the lack of an orthoplastic center in China makes early reconstruction not accessible for all patients with a Gustilo IIIB fracture. This study aimed to analyze the impact of timing on outcomes in lower-extremity traumatic free-flap reconstruction. Methods: A retrospective review identified 394 free-flap reconstructions performed from January 2005 to January 2020 for Gustilo IIIB tibial fractures. Patients were stratified based on the number of debridements: two times or less (early) and more than two times (delayed). The interval between injury and reconstruction, surgery time, hemorrhage volume, length of hospitalization (LoS), wound and bone healing time, flap outcomes, and function restoration were examined based on times of debridement. Results: The mean interval between injury and flap reconstruction in the early-repair group with 6.15 ± 1.82 postoperative days (PODs) was significantly shorter than that of the delayed-repair group with 16.46 ± 4.09 PODs (p < 0.001). The flap harvest time, reconstructive time, and intraoperative blood loss were also significantly less in the early-repair group compared to the delayed-repair group. Interestingly, we observed an 8.20% enlargement of wound size due to multiple debridements in the delayed-repair group. Most importantly, the early-repair group had better outcomes with a decreased risk of total or partial flap necrosis, lower incidence of flap complications, and fewer overall late complications than the delayed-repair group. In addition, the LoS, as well as wound and bone healing time, were notably shorter in the early-repair group. Furthermore, 4.85% of cases in the delayed-repair group experienced additional operations on bone, while no additional operations were performed in the early-repair group. All cases in both groups obtained satisfying functional results, while the early-repair group showed better functional recovery. Conclusions: Early repair with free flaps performed within two instances of debridement had superior outcomes when compared with delayed reconstruction after multiple debridements, consistent with Godina’s findings. We recommended early referral to a higher-level hospital with orthoplastic capabilities after an aggressive and thorough initial debridement carried out by senior surgeons.
Influence of Sea Surface Temperature in the Tropics on the Antarctic Sea Ice during Global Warming
Authors: Alekseev Genrikh , Vyazilova Anastasiia , Smirnov Alexander
Published: December 2022

Sea ice extent in the Antarctica, unlike in the Arctic, did not show a decrease until 2016 under observed global warming. The aim of the study is to explain this climatic phenomenon based on the idea of joint dynamics of the Southern Ocean oceanic structures—the Antarctic polar front, the boundary of the maximum sea ice extent and atmospheric structures—Intratropical Convection Zone (ITCZ) and the Hadley circulation. ERA5 reanalysis and HadISST data were used as well as the sea ice database for the period 1979–2021. The effect of SST at low latitudes of the North Atlantic on the position of the Antarctic polar front and the maximum sea ice extent has been established. The SST in the same area of the North Atlantic has an opposite effect on the sea ice extent in the Arctic. The impact of the SST on the sea ice is mediated through the ITCZ and the Hadley circulation. The obtained results confirmed the key role of the SST at the low latitudes of the North Atlantic in the development of multidirectional trends in changes in the Arctic and the Antarctic ice cover in 1979–2016.
Analytical Solutions of Steady a Seepage Field for Deep-Buried Tunnel with Grouting Ring Considering Anisotropic Flow
Authors: Chen Qizhi , Liang Luju , Zou Baoping , Xu Changjie , Kong Bowen , Ma Jingyuan
Published: December 2022

Difficulties related to seepage are frequently encountered in tunnel design and construction, especially in deep-buried tunnels. Nowadays, analytical solutions of steady seepage fields for deep-buried tunnel usually assume that the surrounding rock mass is homogeneous. In this study, analytical solutions of a steady seepage field for a deep-buried tunnel with grouting ring considering anisotropic flow are proposed. The proposed analytical solutions are verified by numerical simulations and parameter analysis are carried out. Results show that the seepage field of surrounding rocks around the deep buried circular tunnel is no longer uniformly distributed and presents elliptical distribution. The change of permeability coefficient of the lining structure has a great influence on the hydraulic head when the difference between permeability coefficient of lining structure and surrounding rock is not very large. The results show that the size of the grouting ring has more significant influence on the grouting effect.
AXL and MET Tyrosine Kinase Receptors Co-Expression as a Potential Therapeutic Target in Malignant Pleural Mesothelioma
Authors: Zito Marino Federica , Della Corte Carminia Maria , Ciaramella Vincenza , Erra Stefania , Ronchi Andrea , Fiorelli Alfonso , Vicidomini Giovanni , Santini Mario , Scognamiglio Giosuè , Morgillo Floriana , Ciardiello Fortunato , Franco Renato , Accardo Marina
Published: December 2022

Malignant pleural mesothelioma (MPM) is a highly lethal malignancy that unfortunately cannot benefit from molecularly targeted therapies. Although previous results showed the pivotal role of various receptor tyrosine kinases (RTKs) in MPM tumorigenesis, the treatment with a single inhibitor targeting one specific RTK has been shown to be ineffective in MPM patients. The main aim of the present study was to investigate the potential role of AXL and MET receptors in MPM and the possible efficacy of treatment with AXL and MET multitarget inhibitors. Immunohistochemical and FISH analyses were performed in a wide series of formalin-fixed paraffin-embedded MPM samples to detect the expression of two receptors and the potential gene amplification. In vitro studies were performed to evaluate putative correlations between the target’s expression and the cell sensitivity to AXL-MET multitarget inhibitors. In our series, 10.4% of cases showed a co-expression of AXL and MET, regardless of their ligand expression, and the gene amplification. Furthermore, our in vitro results suggest that the concomitant pharmacological inhibition of AXL and MET may affect the proliferative and aggressiveness of MPM cells. In conclusion, the subset of MPM patients with AXL-MET co-activation could benefit from treatment with specific multitarget inhibitors.
Comparison of Surgical Outcomes of Adnexectomy by Vaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) Versus Single-Port Access (SPA) Surgery
Authors: Jung Jihee , Noh Joseph J. , Jeon Jungeun , Chang Chi-Son , Kim Tae-Joong
Published: December 2022

The objective of the present pilot study is to compare operative outcomes between vaginal natural orifice transluminal endoscopic surgery (vNOTES) and single-port access (SPA) adnexectomy. Subjects were patients who underwent adnexectomy for benign adnexal disease, from November 2019 to May 2021. A total of 12 patients underwent vNOTES adnexectomy, and 55 patients received SPA laparoscopic adnexectomy. All surgeries were performed by one surgeon. In order to balance the baseline characteristics of the patients, 1:2 matching was performed. The vNOTES group demonstrated a low postoperative pain score within 12 h after surgery. They also required less use of analgesic medications postoperatively. Other surgical outcomes were comparable between the two groups. This study showed that vNOTES adnexectomy has comparable surgical outcomes to SPA.
A Historical Misconception in Clinical Trials of Drugs for Cancer—Age Grouping
Authors: Chen Jingyu , Yao Lan , Alamoudi Abdulmohsin J. , Aleya Lotfi , Gu Weikuan
Published: December 2022

In clinical trials of cancer drugs, grouping by age is a very common grouping method, as it can allow for a visual comparison of the different pharmaceutical responses in patients at different age stages. Under the guidance of this thinking, many researchers use age grouping when studying clinical cancer drugs. However, even people at the same age may be at different stages in their lives, such as individuals who are going through puberty, menopause/andropause, or intermediate transition, as well as childhood and old age, affected by factors such as hormone levels, immune responses, ethnic groups, and regions. Every individual has different cancer symptoms and responses to drugs; therefore, the experimental effect of life stage grouping will be more obvious and clearer. Not only does this conclusion apply to cancer drugs, but it also applies to clinical trials for other diseases. In addition, this does not mean that age grouping should be completely abandoned. Life stage is a more general interval that can be further divided into life stage groups according to the age of the patients. Based on the principal law of lifespan (PLOSP), age trends in life stages also need to be updated from time to time. To date, life stage grouping has not been discussed systematically and has not been used as a grouping method for cancer patients. In this paper, life stage grouping is discussed as one of the important grouping categories in cancer clinical trials.
The Long-Term Risk Familiarity Effect on Courier Services’ Digital Branding during the COVID-19 Crisis
Authors: Sakas Damianos P. , Kamperos Ioannis Dimitrios G. , Terzi Marina C.
Published: December 2022

The explosion of e-commerce creates new opportunities for courier companies to thrive, making the industry one of the success stories, due to its sustainability and resilience during the pandemic. As customers become more familiar with COVID-19, they adopt new online purchasing behaviors toward branding preferences. The purpose of this paper is to analyze the impact of risk familiarization on courier companies’ digital branding. This paper investigates the application of the psychometric paradigm by Fischhoff ho suggested risk novelty as a key factor for the level of risk perception. Five big companies with global trading activities were selected and analyzed on a three-period time: the year before, the first year, and the second year of the COVID-19 pandemic, by using passive crowdsourcing data. The results indicate that after the first year of the pandemic, online customers’ risk perception of COVID-19 hazards decreased, and consumers returned to their pre-COVID-19 behavior regarding brand preference. However, the dramatic escalation of new infections caused by new COVID-19 mutations reversed their online purchasing attitude from non-branded to branded preferences. The outcomes of the research can be used by scientists and supply chain risk managers to redefine risk mitigation strategies, COVID-related information marketing strategies and innovation investments within the industry. The research further introduces dynamic simulation modeling to be used as a risk management tool in favor of courier companies’ proper resource allocation and digital optimization.
The Whole Is More than Its Parts: A Multidimensional Construct of Values in Consumer Information Search Behavior on SNS
Authors: Kol Ofrit , Levy Shalom
Published: December 2022

The notion of consumer values has been a key factor in understanding consumer behavior and has attracted the attention of various scholars in e-commerce. The aims of this study are to conceptualize a multidimensional construct of consumer information value (CIV) on social network sites (SNS), to examine the construct empirically, and to investigate the nature of its relationships with consumer information search behavior, i.e., the use of information channels on SNS. Quantitative research was conducted using a representative sample of 612 Facebook users. The use of a higher-order construct and structural equation modeling procedures reveals that the following five value constructs—Economic, Psychological, Social, Functional and Hedonic values—are significant facets of the CIV. It suggests that the CIV model is a powerful tool that directly explains consumer information search behavior and has better explanatory power than the sum of its parts.
Immunoglobulin A and Physiologic Correlates of Well-Being in Asian Elephants
Authors: Moresco Anneke , Prado Natalia , Davis Maura , Schreier Amy L. , Readyhough Taylor S. , Joseph Sharon , Gray Charlie , Brown Janine L.
Published: December 2022

Zoological institutions aim to continually improve the lives of the animals under their stewardship. To this end, bull elephants are now increasingly maintained in all-male groups to mimic social conditions observed in the wild. While cortisol is the most frequently used “stress” biomarker, secretory immunoglobulin A (sIgA) as a measure of health and positive affect, and the social hormone, oxytocin, are increasingly viewed as additional markers of welfare. The introduction of a pair of bull elephants to an existing group of three bull elephants at Denver Zoo presented an opportunity to assess sIgA, oxytocin and cortisol in response to the socialization process. In this study, sIgA varied greatly between individuals and did not correlate with cortisol but did correlate with salivary oxytocin. sIgA and oxytocin concentrations differed the most between social and solo situations during the introduction period compared to before bulls were introduced, and after a stable group had been formed. In contrast to findings in some species, sIgA and oxytocin were higher when housed alone than socially. Nonetheless, these results suggest that sIgA and oxytocin may be involved in social engagement and establishment of new social dynamics, and thus provide more insight into overall welfare states.