bluuebunny/crossref_metadata_2025 huggingface dataset:
Reconstruction of Soft Biological Tissues Using Laser Soldering Technology with Temperature Control and Biopolymer Nanocomposites
Authors: Gerasimenko Alexander Yu. , Morozova Elena A. , Ryabkin Dmitry I. , Fayzullin Alexey , Tarasenko Svetlana V. , Molodykh Victoria V. , Pyankov Evgeny S. , Savelyev Mikhail S. , Sorokina Elena A. , Rogalsky Alexander Y. , Shekhter Anatoly , Telyshev Dmitry V.
Published: May 2022

Laser soldering is a current biophotonic technique for the surgical recovery of the integrity of soft tissues. This technology involves the use of a device providing laser exposure to the cut edges of the wound with a solder applied. The proposed solder consisted of an aqueous dispersion of biopolymer albumin (25 wt.%), single-walled carbon nanotubes (0.1 wt.%) and exogenous indocyanine green chromophore (0.1 wt.%). Under laser exposure, the dispersion transforms into a nanocomposite due to the absorption of radiation and its conversion into heat. The nanocomposite is a frame structure of carbon nanotubes in a biopolymer matrix, which provides adhesion of the wound edges and the formation of a strong laser weld. A new laser device based on a diode laser (808 nm) has been developed to implement the method. The device has a temperature feedback system based on a bolometric infrared matrix sensor. The system determines the hottest area of the laser weld and adjusts the current supplied to the diode laser to maintain the preset laser heating temperature. The laser soldering technology made it possible to heal linear defects (cuts) in the skin of laboratory animals (rabbits) without the formation of a fibrotic scar compared to the control (suture material). The combined use of a biopolymer nanocomposite solder and a laser device made it possible to achieve a tensile strength of the laser welds of 4 ± 0.4 MPa. The results of the experiment demonstrated that the addition of single-walled carbon nanotubes to the solder composition leads to an increase in the ultimate tensile strength of the laser welds by 80%. The analysis of regenerative and morphological features in the early stages (1–3 days) after surgery revealed small wound gaps, a decrease in inflammation, the absence of microcirculatory disorders and an earlier epithelization of laser welds compared to the control. On the 10th day after the surgical operation, the laser weld was characterized by a thin cosmetic scar and a continuous epidermis covering the defect. An immunohistochemical analysis proved the absence of myofibroblasts in the area of the laser welds.
Community Vertical Composition of the Laguna Negra Hypersaline Microbial Mat, Puna Region (Argentinean Andes)
Authors: Boidi Flavia Jaquelina , Mlewski Estela Cecilia , Fernández Guillermo César , Flores María Regina , Gérard Emmanuelle , Farías María Eugenia , Gomez Fernando Javier
Published: May 2022

The Altiplano-Puna region is a high-altitude plateau in South America characterized by extreme conditions, including the highest UV incidence on Earth. The Laguna Negra is a hypersaline lake located in the Catamarca Province, northwestern Argentina, where stromatolites and other microbialites are found, and where life is mostly restricted to microbial mats. In this study, a particular microbial mat that covers the shore of the lake was explored, to unravel its layer-by-layer vertical structure in response to the environmental stressors therein. Microbial community composition was assessed by high-throughput 16S rRNA gene sequencing and pigment content analyses, complemented with microscopy tools to characterize its spatial arrangement within the mat. The top layer of the mat has a remarkable UV-tolerance feature, characterized by the presence of Deinococcus-Thermus and deinoxanthin, which might reflect a shielding strategy to cope with high UV radiation. Chloroflexi and Deltaproteobacteria were abundant in the second and third underlying layers, respectively. The bottom layer harbors copious Halanaerobiaeota. Subspherical aggregates composed of calcite, extracellular polymeric substances, abundant diatoms, and other microorganisms were observed all along the mat as the main structural component. This detailed study provides insights into the strategies of microbial communities to thrive under high UV radiation and hypersalinity in high-altitude lakes in the Altiplano-Puna region.
Meizi-Consuming Culture That Fostered the Sustainable Use of Plum Resources in Dali of China: An Ethnobotanical Study
Authors: Fan Yanxiao , Cheng Zhuo , Zhang Qing , Xiong Yong , Li Bingcong , Lu Xiaoping , He Liu , Jiang Xia , Tan Qi , Long Chunlin
Published: May 2022

Prunus mume has been cultivated for more than three millennia with important edible, ornamental, and medicinal value. Due to its sour taste, the Prunus mume fruit (called Meizi in Chinese and Ume in Japanese) is not very popular compared to other fruits. It is, however, a very favorite food for the Bai people living in Eryuan County, Dali of Yunnan, China. The local people are masters of making various local products with plum in different ways. In this research, we conducted field investigations in Eryuan County using ethnobotanical methods from August 2019 to July 2021, focusing on the Prunus mume (for its edible fruits). A total of 76 key informants participated in our semi-structured interviews. The survey recorded 37 species (and varieties) belonging to 11 families related to the Bai people’s Meizi-consuming culture. Among them, there are 14 taxa of plum resources, including one original species and 13 varieties. These 37 species are either used as substitutes for plum due to their similar taste or as seasonings to improve the sour taste of plum. The higher Cultural Food Significance Index value implies that Prunus mume, Chaenomeles speciosa, Phyllanthus emblica, Prunus salicina, and Chaenomeles cathayensis have high acceptance and use value in the Bai communities. Among the various local products traditionally made by the Bai people, carved plums, preserved plums, perilla-wrapped plums, and stewed plums are the most famous and popular categories in the traditional markets. Currently, the plum business based on the traditional Meizi-consuming culture of the Bai people is already one of Eryuan’s economic pillars. This study showed that plums play an important role in expressing the local cultural diversity, and they also help the local people by improving their livelihood through their edible value. In turn, for the sustainable use of plum resources, the Bai people positively manage local forests through a series of measures to protect the diversity of plum resources and related plant communities.
Effects of IGF-1 on the Three-Dimensional Culture of Ovarian Preantral Follicles and Superovulation Rates in Mice
Authors: Dai Shizhen , Zhang Hanxue , Yang Feng , Shang Wei , Zeng Shenming
Published: May 2022

Insulin-like growth factor-1 (IGF-1) plays a crucial role during folliculogenesis, which has been demonstrated by previous research. However, the optimal IGF-1 dosage in the three-dimensional (3D) culture system is unknown. Mouse secondary follicles (140–150 µm) were cultured for 6 days within an alginate bead in a medium supplemented with 0 (G0), 5 ng/mL (G5), 10 ng/mL (G10), or 50 ng/mL IGF-1 (G50). Secretions of 17β-estradiol and progesterone were significantly increased in G10 and G50 (p < 0.05). However, G50 significantly inhibited follicular growth (p < 0.05), while G10 showed a higher oocyte maturation rate. Thus, the 10 ng/mL IGF-1 was used in subsequent experiments. IGF-1 enhanced the function of granulosa cells (GCs) by upregulating expressions of Star, Cyp19a1, Hsd3b1, Fshr, and Lhcgr. Oocyte secretory function was promoted by upregulating expressions of Bmp-15, Gdf-9, and Fgf-8. Addition of IGF-1 showed anti-apoptotic effect. However, G10 did not improve fertilization rate of MII oocytes compared to G0. In an intraperitoneal injection experiment in mice, IGF-1 significantly increased the number of ovulated oocytes (p < 0.05). In conclusion, 10 ng/mL IGF-1 can promote the production of mature oocytes in the 3D culture medium and injection of IGF-1 before superovulation increases the number of ovulated oocytes.
Whole-Transcriptome Analysis Identifies Gender Dimorphic Expressions of Mrnas and Non-Coding Rnas in Chinese Soft-Shell Turtle (Pelodiscus sinensis)
Authors: Zhu Junxian , Lei Luo , Chen Chen , Wang Yakun , Liu Xiaoli , Geng Lulu , Li Ruiyang , Chen Haigang , Hong Xiaoyou , Yu Lingyun , Wei Chengqing , Li Wei , Zhu Xinping
Published: May 2022

In aquaculture, the Chinese soft-shelled turtle (Pelodiscus sinensis) is an economically important species with remarkable gender dimorphism in its growth patterns. However, the underlying molecular mechanisms of this phenomenon have not been elucidated well. Here, we conducted a whole-transcriptome analysis of the female and male gonads of P. sinensis. Overall, 7833 DE mRNAs, 619 DE lncRNAs, 231 DE circRNAs, and 520 DE miRNAs were identified. Some “star genes” associated with sex differentiation containing dmrt1, sox9, and foxl2 were identified. Additionally, some potential genes linked to sex differentiation, such as bmp2, ran, and sox3, were also isolated in P. sinensis. Functional analysis showed that the DE miRNAs and DE ncRNAs were enriched in the pathways related to sex differentiation, including ovarian steroidogenesis, the hippo signaling pathway, and the calcium signaling pathway. Remarkably, a lncRNA/circRNA–miRNA–mRNA interaction network was constructed, containing the key genes associated with sex differentiation, including fgf9, foxl3, and dmrta2. Collectively, we constructed a gender dimorphism profile of the female and male gonads of P. sinensis, profoundly contributing to the exploration of the major genes and potential ncRNAs involved in the sex differentiation of P. sinensis. More importantly, we highlighted the potential functions of ncRNAs for gene regulation during sex differentiation in P. sinensis as well as in other turtles.
Multilocus Genotyping of ‘Candidatus Phytoplasma Solani’ Associated with Grapevine Bois Noir in Iran
Authors: Jamshidi Elham , Murolo Sergio , Ravari Sareh Baghaee , Salehi Mohammad , Romanazzi Gianfranco
Published: May 2022

Grapevine Bois noir (BN) is associated with ‘Candidatus Phytoplasma solani’. It has been recorded in vineyards throughout Europe as well as in different countries in Asia, where it now constitutes a threat to Iranian viticulture. BN is strictly dependent on ‘Ca. P. solani’ strains, wild host plants, and insect vectors. The molecular typing of ‘Ca. P. solani’, based on the nonribosomal gene tuf and the two hypervariable markers vmp1 and stamp, is valuable for the reconstruction and clarification of the pathways of BN spread. In this study, an RFLP analysis was performed on the vmp1 gene, and a single-nucleotide polymorphism analysis confirmed new vmp types in ‘Ca. P. solani’. A stamp gene phylogenetic analysis allowed us to distinguish between the new genotype infections in the grapevines and the ‘weeds’ Convolvulus arvensis and Erigeron bonariensis in Iranian vineyards, highlighting the close genetic relatedness of the strains of ‘Ca. P. solani’ found in Iran and Azerbaijan. The most common genotype in the grapevines was tuf b/V24/stamp III, which was associated with C. arvensis. This information contributes toward the identification of further routes of introduction of ‘Ca. P. solani’ in Iran to sustain the control measures for the management of BN.
Meroterpenoids Possibly Produced by a Bacterial Endosymbiont of the Tropical Basidiomycete Echinochaete brachypora
Authors: Hassan Khadija , Chepkirui Clara , Llanos-López Natalia Andrea , Matasyoh Josphat C. , Decock Cony , Marin-Felix Yasmina , Stadler Marc
Published: May 2022

A mycelial culture of the African basidiomycete Echinochaete cf. brachypora was studied for biologically active secondary metabolites, and four compounds were isolated from its crude extract derived from shake flask fermentations, using preparative high-performance liquid chromatography (HPLC). The pure metabolites were identified using extensive nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HR-MS). Aside from the new metabolites 1-methoxyneomarinone (1) and (E)-3-methyl-5-(-12,13,14-trimethylcyclohex-10-en-6-yl)pent-2-enoic acid (4), the known metabolites neomarinone (2) and fumaquinone (4) were obtained. Such compounds had previously only been reported from Actinobacteria but were never isolated from the cultures of a fungus. This observation prompted us to evaluate whether the above metabolites may actually have been produced by an endosymbiontic bacterium that is associated with the basidiomycete. We have indeed been able to characterize bacterial 16S rDNA in the fungal mycelia, and the production of the metabolites stopped when the fungus was sub-cultured on a medium containing antibacterial antibiotics. Therefore, we have found strong evidence that compounds 1–4 are not of fungal origin. However, the endofungal bacterium was shown to belong to the genus Ralstonia, which has never been reported to produce similar metabolites to 1–4. Moreover, we failed to obtain the bacterial strain in pure culture to provide final proof for its identity. In any case, the current report is the first to document that polyporoid Basidiomycota are associated with endosymbionts and constitutes the first report on secondary metabolites from the genus Echinochaete.
Metformin Induces Resistance of Cancer Cells to the Proteasome Inhibitor Bortezomib
Authors: Schlesser Camille , Meul Thomas , Stathopoulos Georgios , Meiners Silke
Published: May 2022

The anti-diabetic drug metformin is currently tested for the treatment of hematological and solid cancers. Proteasome inhibitors, e.g., Bortezomib, are approved for the treatment of multiple myeloma and mantle cell lymphoma but are also studied for lung cancer therapy. We here analyzed the interaction of the two drugs in two cell lines, namely the mantle cell lymphoma Jeko-1 and the non-small-cell lung cancer (NSCLC) H1299 cells, using proliferation and survival assays, native-gel analysis for proteasome activity and assembly, and expression analysis of proteasome assembly factors. Our results demonstrate that metformin treatment induces resistance of cancer cells to the proteasome inhibitor Bortezomib by impairing the activity and assembly of the 26S proteasome complexes. These effects of metformin on proteasome inhibitor sensitivity in cancer cells are of potential relevance for patients that receive proteasome inhibitor therapy.
Molecular Mechanisms of Peritoneal Membrane Pathophysiology
Authors: Zarogiannis Sotirios G. , Schmitt Claus Peter
Published: May 2022

The peritoneal membrane is the largest internal membrane of the human body, having a surface area that approximates the surface area of the skin [...]
Classical and Unexpected Effects of Ultra-Micronized PEA in Neuromuscular Function
Authors: Cifelli Pierangelo , Ruffolo Gabriele , Ceccanti Marco , Cambieri Chiara , Libonati Laura , Palma Eleonora , Inghilleri Maurizio
Published: May 2022

Recently, the endocannabinoid system has attracted growing attention from the scientific community for its involvement in homeostatic and pathological processes as they pertains to human physiology. Among the constituents of the endocannabinoid system, the molecule palmitoyl ethanolamide has particularly been studied for its ability to reduce several inflammatory processes involving the central nervous system. Here, we reviewed published literature and summarized the main targets of the palmitoyl ethanolamide, along with its unique possible mechanisms for restoring correct functioning of the central nervous system. Moreover, we have highlighted a less-known characteristic of palmitoyl ethanolamide, namely its ability to modulate the function of the neuromuscular junction by binding to acetylcholine receptors in different experimental conditions. Indeed, there are several studies that have highlighted how ultra-micronized palmitoyl ethanolamide is an interesting nutraceutical support for the treatment of pathological neuromuscular conditions, specifically when the normal activity of the acetylcholine receptor is altered. Although further multicentric clinical trials are needed to confirm the efficacy of ultra-micronized palmitoyl ethanolamide in improving symptoms of neuromuscular diseases, all the literature reviewed here strongly supports the ability of this endocannabinoid-like molecule to modulate the acetylcholine receptors thus resulting as a valid support for the treatment of human neuromuscular diseases.
Discovery of a Novel Antimicrobial Peptide, Temporin-PKE, from the Skin Secretion of Pelophylax kl. esculentus, and Evaluation of Its Structure-Activity Relationships
Authors: Lin Yaxian , Jiang Yangyang , Zhao Ziwei , Lu Yueyang , Xi Xinping , Ma Chengbang , Chen Xiaoling , Zhou Mei , Chen Tianbao , Shaw Chris , Wang Lei
Published: May 2022

Bacterial resistance against antibiotics has led to increasing numbers of treatment failures, and AMPs are widely accepted as becoming potential alternatives due to their advantages. Temporin-PKE is a novel peptide extracted from the skin secretion of Pelophylax kl. esculentus and it displays a strong activity against Gram-positive bacteria, with an extreme cytotoxicity. Incorporating positively charged residues and introducing D-amino acids were the two main strategies adopted for the modifications. The transformation of the chirality of Ile could reduce haemolytic activity, and an analogue with appropriate D-isoforms could maintain antimicrobial activity and stability. The substitution of hydrophobic residues could bring about more potent and broad-spectrum antimicrobial activities. The analogues with Lys were less harmful to the normal cells and their stabilities remained at similarly high levels compared to temporin-PKE. The optimal number of charges was three, and the replacement on the polar face was a better choice. Temporin-PKE-3K exerted dually efficient functions includingstrong antimicrobial and anticancer activity. This analogue showed a reduced possibility for inducing resistance in MRSA and Klebsiella pneumoniae, a rather strong antimicrobial activity in vivo, and it exhibited the highest therapeutic index such that temporin-PKE-3K has the potential to be developed as a clinical drug.
A Novel Augmented Reality Mobile-Based Application for Biomechanical Measurement
Authors: Basiratzadeh Shahin , Lemaire Edward D. , Baddour Natalie
Published: May 2022

Human posture and range of motion (ROM) measurements are important health indicators for identifying abnormalities from various disorders (e.g., scoliosis, musculoskeletal disorders, pain syndromes). A viable real-time mobile application for measuring body posture and ROM is currently lacking. To address this need, a novel Android smartphone augmented-reality-based application was developed and evaluated to enable real-time AprilTag2 marker measurement at the point of patient contact (Biomechanical Augmented Reality-Marker, BAR-M). Mobile app performance was evaluated on a body opponent bag (BOB) and 15 healthy participants by comparing smartphone app and Vicon motion analysis output (pelvis, shoulder, arm, torso angles). A Samsung Galaxy smartphone recorded live video, calculated AprilTag orientations and angle of “a line connecting the center of two tags”, and displayed outcomes in real time. For the BOB test, the absolute difference between Vicon and smartphone angles were 0.09° ± 0.05° for hip, 0.09° ± 0.06° for shoulder, and 0.69° for arm abduction. For the participant test, the absolute mean angle differences were 1.70° ± 0.23° for hip, 1.34° ± 0.27° for shoulder, and 11.18° ± 3.68° for arm abduction. Overall, the app obtained valid and reliable angle measurements for postural and ROM assessments using the smartphone’s front camera. Arm abduction results were affected by clothing movement that caused Vicon markers to move differently from AprilTag markers. Thus, with appropriate measurement methods, this real-time smartphone app is a viable tool to facilitate immediate clinical decision making based on human posture and ROM assessments.
Neuronal and Neuroaxonal Damage Cerebrospinal Fluid Biomarkers in Autoimmune Encephalitis Associated or Not with the Presence of Tumor
Authors: Vakrakou Aigli G. , Tzartos John S. , Strataki Eleni , Boufidou Fotini , Dimou Eleni , Pyrgelis Efstratios-Stylianos , Constantinides Vasilios C. , Paraskevas George P. , Kapaki Elisabeth
Published: May 2022

The aim of this study was to evaluate the association of neuronal damage biomarkers (neurofilament light chain (NFL) and total tau protein (T-tau)) in the CSF of patients with autoimmune encephalitis (AE) with the presence of an underlying malignancy and to determine correlations with patient characteristics. The study comprised 21 patients with encephalitis associated with antibodies against intracellular (n = 11) and surface/synaptic antigens (extracellular, n = 10) and non-inflammatory disease controls (n = 10). Patients with AE associated with intracellular antigens had increased CSF-NFL (p = 0.003) but not T-tau levels compared to controls. When adjusted for age, CSF-NFL but not CSF-T-tau was higher in patients with encephalitis associated with intracellular antigens as compared to those with encephalitis associated with extracellular antigens (p = 0.032). Total tau and NFL levels were not significantly altered in patients with encephalitis associated with extracellular antigens compared to controls. NFL in the total cohort correlated with neurological signs of cerebellar dysfunction, peripheral neuropathy, presence of CV2 positivity, presence of an underlying tumor and a more detrimental clinical outcome. AE patients with abnormal MRI findings displayed higher NFL levels compared to those without, albeit with no statistical significance (p = 0.07). Using receiver operating characteristic curve analysis, CSF-NFL levels with a cut-off value of 969 pg/mL had a sensitivity and specificity of 100% and 76.19%, respectively, regarding the detection of underlying malignancies. Our findings suggest that neuronal integrity is preserved in autoimmune encephalitis associated with extracellular antigens and without the presence of tumor. However, highly increased NFL is observed in AE associated with intracellular antigens and presence of an underlying tumor. CSF-NFL could potentially be used as a diagnostic biomarker of underlying malignancies in the clinical setting of AE.
Rifaximin Improves Spatial Learning and Memory Impairment in Rats with Liver Damage-Associated Neuroinflammation
Authors: Leone Paola , Mincheva Gergana , Balzano Tiziano , Malaguarnera Michele , Felipo Vicente , Llansola Marta
Published: May 2022

Patients with non-alcoholic fatty liver disease (NAFLD) may show mild cognitive impairment. Neuroinflammation in the hippocampus mediates cognitive impairment in rat models of minimal hepatic encephalopathy (MHE). Treatment with rifaximin reverses cognitive impairment in a large proportion of cirrhotic patients with MHE. However, the underlying mechanisms remain unclear. The aims of this work were to assess if rats with mild liver damage, as a model of NAFLD, show neuroinflammation in the hippocampus and impaired cognitive function, if treatment with rifaximin reverses it, and to study the underlying mechanisms. Mild liver damage was induced with carbon-tetrachloride. Infiltration of immune cells, glial activation, and cytokine expression, as well as glutamate receptors expression in the hippocampus and cognitive function were assessed. We assessed the effects of daily treatment with rifaximin on the alterations showed by these rats. Rats with mild liver damage showed hippocampal neuroinflammation, reduced membrane expression of glutamate N-methyl-D-aspartate (NMDA) receptor subunits, and impaired spatial memory. Increased C-C Motif Chemokine Ligand 2 (CCL2), infiltration of monocytes, microglia activation, and increased tumor necrosis factor α (TNFα) were reversed by rifaximin, that normalized NMDA receptor expression and improved spatial memory. Thus, rifaximin reduces neuroinflammation and improves cognitive function in rats with mild liver damage, being a promising therapy for patients with NAFLD showing mild cognitive impairment.
Influence of Molecular Structures on Fluorescence of Flavonoids and Their Detection in Mammalian Cells
Authors: De Ranjit , Jo Kyung Won , Kim Kyong-Tai
Published: May 2022

Flavonoids are being increasingly applied for the treatment of various diseases due to their anti-cancer, anti-oxidant, anti-inflammatory, and anti-viral properties. However, it is often challenging to detect their presence in cells and tissues through bioimaging, as most of them are not fluorescent or are too weak to visualize. Here, fluorescence possibilities of nine naturally occurring analogous flavonoids have been investigated through UV/visible spectroscopy, molecular structure examination, fluorescent images in mammalian cells and their statistical analysis employing aluminum chloride and diphenylboric acid 2-aminoethyl ester as fluorescence enhancers. It is found that, in order to form a stable fluorescent complex with an enhancer, flavonoids should have a keto group at C4 position and at least one -OH group at C3 or C5 position. Additionally, the presence of a double bond at C2–C3 can stabilize extended quinonoid structure at the cinnamoyl moiety, which thereby enhances the complex stability. A possible restriction to the free rotation of ring B around C1′–C2 single bond can contribute to the further enhancement of fluorescence. Thus, these findings can act as a guide for distinguishing flavonoids capable of exhibiting fluorescence from thousands of their analogues. Finally, using this technique, flavonoids are detected in neuroblastoma cells and their time course assay is conducted via fluorescence imaging. Their cellular uptake efficiency is found to be high and differential in nature and their distribution throughout the cytoplasm is clearly detected.
The Role of Salvage in the Management of Patients with Sinonasal Squamous Cell Carcinoma
Authors: Kacorzyk Urszula , Rutkowski Tomasz Wojciech
Published: May 2022

Objectives: This paper presents and discusses the rate and outcome of salvage according to various factors for patients with sinonasal squamous cell carcinoma (SNSCC). Methods: Data of 79 patients treated radically due to SNSCC between 2000 and 2016 in the National Cancer Research Institute, Gliwice branch, were analyzed. Surgery was the primary treatment in 63 (79%) of patients. The ratio, type, and effectiveness of salvage was assessed and correlated with prognostic factors. Probabilities of overall survival (OS), local control (LC), nodal control (NC), and locoregional control (LRC) were assessed and compared between the groups. Results: The 5-year LC, NC, and LRC survival rates were 62%, 75%, and 53%, respectively. The 5-year OS rate was 51%. In 34 (43%) patients, treatment failure was reported, and salvage was performed in 17 (50%) of them. It was shown that patients after any salvage had significantly longer 2- and 3-year OS rates when compared to patients with no salvage: 52% vs. 7% and 38% vs. 0%, respectively (p = 0.004). Two- and three-year OS rates for patients after effective and ineffective salvage were 83% vs. 33% and 83% vs. 11%, respectively (p = 0.02). For patients with effective salvage, OS did not differ significantly when compared to the OS of primarily cured patients (p = 0.6). Conclusions: For SNSCC patients after treatment failure, salvage is possible in half of the cases and can improve their overall survival even if not finally successful. Moreover, effective salvage can compensate for the failure and give the same ultimate OS as in primarily cured patients.
Thymidylate Synthase Overexpression Drives the Invasive Phenotype in Colon Cancer Cells
Authors: Ciszewski Wojciech M. , Chmielewska-Kassassir Małgorzata , Wozniak Lucyna A. , Sobierajska Katarzyna
Published: May 2022

Thymidylate synthase (TYMS) is the crucial enzymatic precursor for DNA biosynthesis and, therefore, the critical target for numerous types of chemotherapy, including the most frequently applied agent in colon cancer treatment 5-fluorouracil (5-FU). TYMS also seems to be associated with cancer metastasis and acquiring mesenchymal character by tumor cells during epithelial–mesenchymal transition (EMT). Based on that knowledge, we decided to investigate the role of TYMS in the modulation of invasive ability in colon cancer cells, where its effect on cancer metastasis has not been studied in detail before. We employed colon cancer cells isolated from different stages of tumor development, cells undergoing EMT, and TYMS overexpressing cells. The elongation ratio, cell migration, invasion assay, and MMP-7 secretion were applied to analyze the cell behavior. Important epithelial and mesenchymal markers characteristic of EMT were examined at the protein level by Western blot assay. Overall, our study showed a correlation between TYMS level and invasion ability in colon cancer cells and, above all, a crucial role of TYMS in the EMT regulation. We postulate that chemotherapeutics that decrease or inhibit TYMS expression could increase the effectiveness of the therapy in patients with colon cancer, especially in the metastatic stage.
Prognostic Role of Systemic Inflammatory Markers in Patients Undergoing Surgical Resection for Oral Squamous Cell Carcinoma
Authors: Cho Uiju , Sung Yeoun-Eun , Kim Min-Sik , Lee Youn-Soo
Published: May 2022

Background: A high platelet–lymphocyte ratio (PLR) is a marker of systemic inflammation and, together with the neutrophil–lymphocyte ratio (NLR), is associated with poor outcomes in several cancers. We investigated the prognostic value of PLR and other systemic inflammatory markers, such as NLR, systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI), in oral squamous cell carcinoma (OSCC) patients undergoing surgical resection. Methods: We derived PLR, NLR, SII, and SIRI from a retrospective chart review of 269 consecutive OSCC patients. The complete blood count examined in the immediate preoperative period was used to compute PLR, NLR, SII, and SIRI. We analyzed the relationship between these systemic inflammatory markers and the clinicopathologic characteristics, disease-specific survival (DSS), and progression-free survival (PFS) of patients. Results: In the univariate analysis, high PLR and SII were significantly associated with worse DSS and PFS (all p < 0.05). In the multivariate analysis, PLR (HR 2.36, 95% CI 1.28–4.36 for DSS; HR 1.80, 95% CI 1.06–3.06 for PFS) was an independent predictor of survival outcomes. When PLR was analyzed as a continuous variable, the relationship between the outcome and preoperative PLR was not monotonically linear. In the subgroup analysis, PLR was more strongly associated with DSS and PFS in patients who were male, had stage III/IV OSCC, or had lymph node metastasis. Conclusion: Our data suggest that in OSCC patients, the pretreatment PLR is an independent predictor of DSS and PFS. The PLR is a readily available biomarker that will improve prognostication and risk stratification in OSCC.
Automatic Segmentation of Retinal Fluid and Photoreceptor Layer from Optical Coherence Tomography Images of Diabetic Macular Edema Patients Using Deep Learning and Associations with Visual Acuity
Authors: Hsu Huan-Yu , Chou Yu-Bai , Jheng Ying-Chun , Kao Zih-Kai , Huang Hsin-Yi , Chen Hung-Ruei , Hwang De-Kuang , Chen Shih-Jen , Chiou Shih-Hwa , Wu Yu-Te
Published: May 2022

Diabetic macular edema (DME) is a highly common cause of vision loss in patients with diabetes. Optical coherence tomography (OCT) is crucial in classifying DME and tracking the results of DME treatment. The presence of intraretinal cystoid fluid (IRC) and subretinal fluid (SRF) and the disruption of the ellipsoid zone (EZ), which is part of the photoreceptor layer, are three crucial factors affecting the best corrected visual acuity (BCVA). However, the manual segmentation of retinal fluid and the EZ from retinal OCT images is laborious and time-consuming. Current methods focus only on the segmentation of retinal features, lacking a correlation with visual acuity. Therefore, we proposed a modified U-net, a deep learning algorithm, to segment these features from OCT images of patients with DME. We also correlated these features with visual acuity. The IRC, SRF, and EZ of the OCT retinal images were manually labeled and checked by doctors. We trained the modified U-net model on these labeled images. Our model achieved Sørensen–Dice coefficients of 0.80 and 0.89 for IRC and SRF, respectively. The area under the receiver operating characteristic curve (ROC) for EZ disruption was 0.88. Linear regression indicated that EZ disruption was the factor most strongly correlated with BCVA. This finding agrees with that of previous studies on OCT images. Thus, we demonstrate that our segmentation network can be feasibly applied to OCT image segmentation and assist physicians in assessing the severity of the disease.
Genetic Profiling of Glucocorticoid (NR3C1) and Mineralocorticoid (NR3C2) Receptor Polymorphisms before Starting Therapy with Androgen Receptor Inhibitors: A Study of a Patient Who Developed Toxic Myocarditis after Enzalutamide Treatment
Authors: Morales Manuel , Martín-Vasallo Pablo , Ávila Julio
Published: May 2022

Enzalutamide is a nonsteroidal inhibitor of the androgen receptor (AR) signaling pathway and is used to treat patients with metastatic castration-resistant prostate cancer. However, the risk of cardiovascular-related hospitalization in patients with no contraindications for the use of enzalutamide is about 1–2%. To date, the underlying molecular basis of this has not been established. The androgen receptor, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are nuclear receptors that share structural similarities and have closely related DNA-binding sites and coregulators. In non-epithelial cells, a fine balance of the activities of these receptors is essential to ensure correct cellular function. In this study, we present a molecular characterization of these nuclear receptors in a prostate cancer patient who developed congestive heart failure after enzalutamide treatment. White cell RNAseq revealed a homozygous rs5522 MR polymorphism and both the rs143711342 and rs56149945 GR polymorphisms, carried in different alleles. No different specific splice isoforms were detected. Recent research suggests that AR inhibition by enzalutamide makes available a coregulator that specifically interacts with the rs5522-mutated MR, increasing its activity and producing adverse effects on cardiovascular health. We suggest an evaluation of the MR rs5522 polymorphism before starting therapy with AR inhibitors.
Biomimetic Incremental Domain Generalization with a Graph Network for Surgical Scene Understanding
Authors: Seenivasan Lalithkumar , Islam Mobarakol , Ng Chi-Fai , Lim Chwee Ming , Ren Hongliang
Published: May 2022

Surgical scene understanding is a key barrier for situation-aware robotic surgeries and the associated surgical training. With the presence of domain shifts and the inclusion of new instruments and tissues, learning domain generalization (DG) plays a pivotal role in expanding instrument–tissue interaction detection to new domains in robotic surgery. Mimicking the ability of humans to incrementally learn new skills without forgetting their old skills in a similar domain, we employ incremental DG on scene graphs to predict instrument–tissue interaction during robot-assisted surgery. To achieve incremental DG, incorporate incremental learning (IL) to accommodate new instruments and knowledge-distillation-based student–teacher learning to tackle domain shifts in the new domain. Additionally, we designed an enhanced curriculum by smoothing (E-CBS) based on Laplacian of Gaussian (LoG) and Gaussian kernels, and integrated it with the feature extraction network (FEN) and graph network to improve the instrument–tissue interaction performance. Furthermore, the FEN’s and graph network’s logits are normalized by temperature normalization (T-Norm), and its effect in model calibration was studied. Quantitative and qualitative analysis proved that our incrementally-domain generalized interaction detection model was able to adapt to the target domain (transoral robotic surgery) while retaining its performance in the source domain (nephrectomy surgery). Additionally, the graph model enhanced by E-CBS and T-Norm outperformed other state-of-the-art models, and the incremental DG technique performed better than the naive domain adaption and DG technique.
Selective Detection of Alkaline Phosphatase Activity in Environmental Water Samples by Copper Nanoclusters Doped Lanthanide Coordination Polymer Nanocomposites as the Ratiometric Fluorescent Probe
Authors: Li Xin , Wang Xiaoling , Guo Wei , Wang Yunfei , Hua Qing , Tang Feiyan , Luan Feng , Tian Chunyuan , Zhuang Xuming , Zhao Lijun
Published: May 2022

In this paper, a novel, accurate, sensitive and rapid ratiometric fluorescent sensor was fabricated using a copper nanoclusters@infinite coordination polymer (ICP), specifically, terbium ion-guanosine 5’-disodium (Cu NCs@Tb-GMP) nanocomposites as the ratiometric fluorescent probe, to detect alkaline phosphatase (ALP) in water. The fluorescence probe was characterized by scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, and Fourier transform infrared spectroscopy. The experimental results showed that, compared with Tb-GMP fluorescent sensors, Cu ratiometric fluorescent sensors based on NCs encapsulated in Tb-GMP had fewer experimental errors and fewer false-positive signals and were more conducive to the sensitive and accurate detection of ALP. In addition, the developed fluorescent probe had good fluorescence intensity, selectivity, repeatability and stability. Under optimized conditions, the ratiometric fluorescent sensor detected ALP in the range of 0.002–2 U mL−1 (R2 = 0.9950) with a limit of detection of 0.002 U mL−1, and the recovery of ALP from water samples was less than 108.2%. These satisfying results proved that the ratiometric fluorescent probe has good application prospects and provides a new method for the detection of ALP in real water samples.
Brush-like Polymer Prodrug with Aggregation-Induced Emission Features for Precise Intracellular Drug Tracking
Authors: Naghibi Sanaz , Sabouri Soheila , Hong Yuning , Jia Zhongfan , Tang Youhong
Published: May 2022

In this study, a brush-like polymer with aggregation-induced emission (AIE) features was synthesized for drug delivery and intracellular drug tracking. The polymer consisting of tetraphenylethene (TPE) chain-end as well as oligo-poly (ethylene glycol) (PEG) and hydrazine functionalities was successfully synthesized through copper (0)-mediated reversible-deactivation radical polymerization (Cu0-mediated RDRP). Anticancer drug doxorubicin (DOX) was conjugated to the polymer and formed a prodrug named TPE-PEGA-Hyd-DOX, which contains 11% DOX. The hydrazone between DOX and polymer backbone is a pH-sensitive linkage that can control the release of DOX in slightly acidic conditions, which can precisely control the DOX release rate. The drug release of 10% after 96 h in normal cell environments compared with about 40% after 24 h in cancer cell environments confirmed the influence of the hydrazone bond. The ratiometric design of fluorescent intensities with peaks at 410 nm (emission due to AIE feature of TPE) and 600 nm (emission due to ACQ feature of DOX) provides an excellent opportunity for this product as a precise intracellular drug tracker. Cancer cells confocal microscopy showed negligible DOX solution uptake, but an intense green emission originated from prodrug uptake. Moreover, a severe red emission in the DOX channel confirmed a promising level of drug release from the prodrug in the cytoplasm. The merged images of cancer cells confirmed the high performance of the TPE-PEGA-Hyd-DOX compound in the viewpoints of cellular uptake and drug release. This polymer prodrug successfully demonstrates low cytotoxicity in healthy cells and high performance in killing cancer cells.
A Novel Classification Model for Lower-Grade Glioma Patients Based on Pyroptosis-Related Genes
Authors: Shen Yusheng , Chi Hao , Xu Ke , Li Yandong , Yin Xisheng , Chen Shi , Yang Qian , He Miao , Zhu Guohua , Li Xiaosong
Published: May 2022

Recent studies demonstrated that pyroptosis plays a crucial role in shaping the tumor-immune microenvironment. However, the influence of pyroptosis on lower-grade glioma regarding immunotherapy and targeted therapy is still unknown. This study analyzed the variations of 33 pyroptosis-related genes in lower-grade glioma and normal tissues. Our study found considerable genetic and expression alterations in heterogeneity among lower-grade gliomas and normal brain tissues. There are two pyroptosis phenotypes in lower-grade glioma, and they exhibited differences in cell infiltration characteristics and clinical characters. Then, a PyroScore model using the lasso-cox method was constructed to measure the level of pyroptosis in each patient. PyroScore can refine the lower-grade glioma patients with a stratified prognosis and a distinct tumor immune microenvironment. Pyscore may also be an effective factor in predicting potential therapeutic benefits. In silico analysis showed that patients with a lower PyroScore are expected to be more sensitive to targeted therapy and immunotherapy. These findings may enhance our understanding of pyroptosis in lower-grade glioma and might help optimize risk stratification for the survival and personalized management of lower-grade glioma patients.
Stance Phase Gait Training Post Stroke Using Simultaneous Transcranial Direct Current Stimulation and Motor Learning-Based Virtual Reality-Assisted Therapy: Protocol Development and Initial Testing
Authors: Salameh Ahlam , McCabe Jessica , Skelly Margaret , Duncan Kelsey Rose , Chen Zhengyi , Tatsuoka Curtis , Bikson Marom , Hardin Elizabeth C. , Daly Janis J. , Pundik Svetlana
Published: May 2022

Gait deficits are often persistent after stroke, and current rehabilitation methods do not restore normal gait for everyone. Targeted methods of focused gait therapy that meet the individual needs of each stroke survivor are needed. Our objective was to develop and test a combination protocol of simultaneous brain stimulation and focused stance phase training for people with chronic stroke (>6 months). We combined Transcranial Direct Current Stimulation (tDCS) with targeted stance phase therapy using Virtual Reality (VR)-assisted treadmill training and overground practice. The training was guided by motor learning principles. Five users (>6 months post-stroke with stance phase gait deficits) completed 10 treatment sessions. Each session began with 30 min of VR-assisted treadmill training designed to apply motor learning (ML)-based stance phase targeted practice. During the first 15 min of the treadmill training, bihemispheric tDCS was simultaneously delivered. Immediately after, users completed 30 min of overground (ML)-based gait training. The outcomes included the feasibility of protocol administration, gait speed, Timed Up and Go (TUG), Functional Gait Assessment (FGA), paretic limb stance phase control capability, and the Fugl–Meyer for lower extremity coordination (FMLE). The changes in the outcome measures (except the assessments of stance phase control capability) were calculated as the difference from baseline. Statistically and clinically significant improvements were observed after 10 treatment sessions in gait speed (0.25 ± 0.11 m/s) and FGA (4.55 ± 3.08 points). Statistically significant improvements were observed in TUG (2.36 ± 3.81 s) and FMLE (4.08 ± 1.82 points). A 10-session intervention combining tDCS and ML-based task-specific gait rehabilitation was feasible and produced clinically meaningful improvements in lower limb function in people with chronic gait deficits after stroke. Because only five users tested the new protocol, the results cannot be generalized to the whole population. As a contribution to the field, we developed and tested a protocol combining brain stimulation and ML-based stance phase training for individuals with chronic stance phase deficits after stroke. The protocol was feasible to administer; statistically and/or clinically significant improvements in gait function across an array of gait performance measures were observed with this relatively short treatment protocol.
Cardiac–Brain Dynamics Depend on Context Familiarity and Their Interaction Predicts Experience of Emotional Arousal
Authors: Mishra Sudhakar , Srinivasan Narayanan , Tiwary Uma Shanker
Published: May 2022

Our brain continuously interacts with the body as we engage with the world. Although we are mostly unaware of internal bodily processes, such as our heartbeats, they may be influenced by and in turn influence our perception and emotional feelings. Although there is a recent focus on understanding cardiac interoceptive activity and interaction with brain activity during emotion processing, the investigation of cardiac–brain interactions with more ecologically valid naturalistic emotional stimuli is still very limited. We also do not understand how an essential aspect of emotions, such as context familiarity, influences affective feelings and is linked to statistical interaction between cardiac and brain activity. Hence, to answer these questions, we designed an exploratory study by recording ECG and EEG signals for the emotional events while participants were watching emotional movie clips. Participants also rated their familiarity with the stimulus on the familiarity scale. Linear mixed effect modelling was performed in which the ECG power and familiarity were considered as predictors of EEG power. We focused on three brain regions, including prefrontal (PF), frontocentral (FC) and parietooccipital (PO). The analyses showed that the interaction between the power of cardiac activity in the mid-frequency range and the power in specific EEG bands is dependent on familiarity, such that the interaction is stronger with high familiarity. In addition, the results indicate that arousal is predicted by cardiac–brain interaction, which also depends on familiarity. The results support emotional theories that emphasize context dependency and interoception. Multimodal studies with more realistic stimuli would further enable us to understand and predict different aspects of emotional experience.