bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-Wide Identification of DNA Binding with One Finger (Dof) Gene Family in Tartary Buckwheat (Fagopyrum tataricum) and Analysis of Its Expression Pattern after Exogenous Hormone Stimulation
Authors: Li Jing , Zhang Yuchuan , Xu Lei , Wang Chenyang , Luo Yan , Feng Shan , Yuan Yuhao , Yang Qinghua , Feng Baili
Published: January 2022

DNA binding with one finger (Dof) proteins have been proven to be involved in multiple biological processes. However, genome-wide identification of the Dof gene family has not been reported for Tartary buckwheat (Fagopyrum tataricum). In this study, 35 FtDof proteins were identified, and they could be divided into nine phylogenetic subgroups. Proteins within the same subgroup had similar gene structure and motif composition. Moreover, abundant cis-acting elements were present in the promoter regions of FtDof genes. Segmental duplication was the primary driving force for the evolution of the FtDof gene family. Synteny analysis indicated that Tartary buckwheat was closer to dicotyledons, and more orthologous Dof genes existed among them. The expression pattern of FtDofs in different tissues and at different fruit developmental stages varied. Different tissues contained several genes that were specifically expressed. FtDof expression was mainly upregulated under methyl jasmonate treatment and downregulated under other hormone treatments. Taken together, FtDofs may play important roles in the growth and development of Tartary buckwheat and in response to abiotic and biotic stresses. Therefore, the genome-wide identification and expression pattern analysis of the Tartary buckwheat Dof gene family lays a foundation for further exploration of the functional characteristics of FtDofs in the future.
Enzymatic Synthesis of Maltitol and Its Inhibitory Effect on the Growth of Streptococcus mutans DMST 18777
Authors: Haewpetch Patinya , Rudeekulthamrong Prakarn , Kaulpiboon Jarunee
Published: January 2022

This study aimed to synthesize maltitol using recombinant CGTase from Bacillus circulans A11 with β-cyclodextrin (β-CD) and sorbitol as a glucosyl donor and acceptor, respectively, and assess its antibacterial activity. Optimal conditions for producing the highest yield, 25.0% (w/w), were incubation of 1% (w/v) β-CD and sorbitol with 400 U/mL of CGTase in 20 mM phosphate buffer at pH 6.0 and 50 °C for 72 h. Subsequently, maltitol underwent large-scale production and was purified by HPLC. By mass spectrometry, the molecular weight of the synthesized maltitol was 379.08 daltons, corresponding exactly to that of standard maltitol. The relative sweetness of synthesized and standard maltitol was ~90% of that of sucrose. Spot assay on the agar plate showed that maltitol inhibited the growth of Streptococcus mutans DMST 18777 cells. In addition, the MIC and MBC values of synthesized and standard maltitol against S. mutans were also determined as 20 and 40 mg/mL, respectively. These results show that the synthesized maltitol can be produced at high yields and has the potential to be used as an anticariogenic agent in products such as toothpaste.
Biologically Relevant In Vitro 3D-Model to Study Bone Regeneration Potential of Human Adipose Stem Cells
Authors: van Santen Victor J. B. , Bastidas Coral Angela P. , Hogervorst Jolanda M. A. , Klein-Nulend Jenneke , Bakker Astrid D.
Published: January 2022

Standard cell cultures may not predict the proliferation and differentiation potential of human mesenchymal stromal cells (MSCs) after seeding on a scaffold and implanting this construct in a bone defect. We aimed to develop a more biologically relevant in vitro 3D-model for preclinical studies on the bone regeneration potential of MSCs. Human adipose tissue-derived mesenchymal stromal cells (hASCs; five donors) were seeded on biphasic calcium phosphate (BCP) granules and cultured under hypoxia (1% O2) for 14 days with pro-inflammatory TNFα, IL4, IL6, and IL17F (10 mg/mL each) added during the first three days, simulating the early stages of repair (bone construct model). Alternatively, hASCs were cultured on plastic, under 20% O2 and without cytokines for 14 days (standard cell culture). After two days, the bone construct model decreased total DNA (3.9-fold), COL1 (9.8-fold), and RUNX2 expression (19.6-fold) and metabolic activity (4.6-fold), but increased VEGF165 expression (38.6-fold) in hASCs compared to standard cultures. After seven days, the bone construct model decreased RUNX2 expression (64-fold) and metabolic activity (2.3-fold), but increased VEGF165 (54.5-fold) and KI67 expression (5.7-fold) in hASCs compared to standard cultures. The effect of the bone construct model on hASC proliferation and metabolic activity could be largely mimicked by culturing on BCP alone (20% O2, no cytokines). The effect of the bone construct model on VEGF165 expression could be mimicked by culturing hASCs under hypoxia alone (plastic, no cytokines). In conclusion, we developed a new, biologically relevant in vitro 3D-model to study the bone regeneration potential of MSCs. Our model is likely more suitable for the screening of novel factors to enhance bone regeneration than standard cell cultures.
Enzyme-Mediated Quenching of the Pseudomonas Quinolone Signal (PQS): A Comparison between Naturally Occurring and Engineered PQS-Cleaving Dioxygenases
Authors: Arranz San Martín Alba , Vogel Jan , Wullich Sandra C. , Quax Wim J. , Fetzner Susanne
Published: January 2022

The opportunistic pathogen Pseudomonas aeruginosa employs quorum sensing to govern the production of many virulence factors. Interference with quorum sensing signaling has therefore been put forward as an attractive approach to disarm this pathogen. Here, we analyzed the quorum quenching properties of natural and engineered (2-alkyl-)3-hydroxy-4(1H)-quinolone 2,4-dioxygenases (HQDs) that inactivate the P. aeruginosa signal molecule PQS (Pseudomonas quinolone signal; 2-heptyl-3-hydroxy-4(1H)-quinolone). When added exogenously to P. aeruginosa cultures, all HQDs tested significantly reduced the levels of PQS and other alkylquinolone-type secondary metabolites deriving from the biosynthetic pathway, such as the respiratory inhibitor 2-heptyl-4-hydroxyquinoline N-oxide. HQDs from Nocardia farcinica and Streptomyces bingchenggensis, which combine low KM values for PQS with thermal stability and resilience in the presence of P. aeruginosa exoproducts, respectively, attenuated production of the virulence factors pyocyanin and pyoverdine. A delay in mortality was observed when Galleria mellonella larvae were infected with P. aeruginosa suspensions treated with the S. bingchenggensis HQD or with inhibitors of alkylquinolone biosynthesis. Our data indicate that quenching of PQS signaling has potential as an anti-virulence strategy; however, an efficient anti-virulence therapy against P. aeruginosa likely requires a combination of agents addressing multiple targets.
The Role of Epigenetic Modifications in Abdominal Aortic Aneurysm Pathogenesis
Authors: Mangum Kevin , Gallagher Katherine , Davis Frank M.
Published: January 2022

Abdominal aortic aneurysm (AAA) is a life-threatening disease associated with high morbidity and mortality in the setting of acute rupture. Recently, advances in surgical and endovascular repair of AAA have been achieved; however, pharmaceutical therapies to prevent AAA expansion and rupture remain lacking. This highlights an ongoing need to improve the understanding the pathological mechanisms that initiate formation, maintain growth, and promote rupture of AAA. Over the past decade, epigenetic modifications, such as DNA methylation, posttranslational histone modifications, and non-coding RNA, have emerged as important regulators of cellular function. Accumulating studies reveal the importance of epigenetic enzymes in the dynamic regulation of key signaling pathways that alter cellular phenotypes and have emerged as major intracellular players in a wide range of biological processes. In this review, we discuss the roles and implications of epigenetic modifications in AAA animal models and their relevance to human AAA pathology.
Multi-Omics Analysis of Multiple Glucose-Sensing Receptor Systems in Yeast
Authors: Li Shuang , Li Yuanyuan , Rushing Blake R. , Harris Sarah E. , McRitchie Susan L. , Dominguez Daniel , Sumner Susan J. , Dohlman Henrik G.
Published: January 2022

The yeast Saccharomyces cerevisiae has long been used to produce alcohol from glucose and other sugars. While much is known about glucose metabolism, relatively little is known about the receptors and signaling pathways that indicate glucose availability. Here, we compare the two glucose receptor systems in S. cerevisiae. The first is a heterodimer of transporter-like proteins (transceptors), while the second is a seven-transmembrane receptor coupled to a large G protein (Gpa2) that acts in coordination with two small G proteins (Ras1 and Ras2). Through comprehensive measurements of glucose-dependent transcription and metabolism, we demonstrate that the two receptor systems have distinct roles in glucose signaling: the G-protein-coupled receptor directs carbohydrate and energy metabolism, while the transceptors regulate ancillary processes such as ribosome, amino acids, cofactor and vitamin metabolism. The large G-protein transmits the signal from its cognate receptor, while the small G-protein Ras2 (but not Ras1) integrates responses from both receptor pathways. Collectively, our analysis reveals the molecular basis for glucose detection and the earliest events of glucose-dependent signal transduction in yeast.
Biomarkers in Neurodegenerative Diseases
Authors: Ghosh Arnab
Published: January 2022

An increasing number of people are affected by various neurodegenerative diseases each year, impacting the quality of life of millions of people worldwide [...]
Association of Lipoproteins with Neutrophil Extracellular Traps in Patients with Abdominal Aortic Aneurysm
Authors: Brandau Annika , Ibrahim Nahla , Klopf Johannes , Hayden Hubert , Ozsvar-Kozma Maria , Afonyushkin Taras , Bleichert Sonja , Fuchs Lukas , Watzinger Viktoria , Nairz Verena , Manville Emely , Kessler Veronika , Stangl Herbert , Eilenberg Wolf , Neumayer Christoph , Brostjan Christine
Published: January 2022

Neutrophil extracellular traps (NETs) are DNA–protein structures released by neutrophils in response to various stimuli, including oxidized, low-density lipoprotein (oxLDL). Accumulating evidence suggests a role for NETs in the pathogenesis of abdominal aortic aneurysm (AAA). In this study, we investigated the potential association of lipoprotein particles and NETs in AAA in comparison to non-AAA control groups. The concentrations of neutrophil myeloperoxidase (MPO), the NET parameters citrullinated histone H3 (citH3) and circulating cell-free DNA (cfDNA), as well as of blood lipids were determined in plasma or serum of patients with AAA (n = 40), peripheral artery occlusive disease (PAD; n = 40) and healthy donors (n = 29). A sandwich ELISA detecting oxidized phosphatidylcholine in association with apolipoprotein B-100 (oxPL/apoB) was applied to measure oxidized phospholipids in circulation. The effect of lipoparticles on NET formation was tested using a DNA release assay with isolated human neutrophils. Plasma MPO, citH3 and cfDNA levels were significantly increased in AAA patients in comparison to healthy donors and PAD patients. Plasma concentrations of citH3 positively correlated with serum oxPL/apoB in AAA patients. In functional in vitro assays, the addition of oxLDL induced NET formation in pre-stimulated neutrophils. In conclusion, our data suggest a promoting role of oxLDL on NET formation in AAA patients.
In Vivo Activity of Metal Complexes Containing 1,10-Phenanthroline and 3,6,9-Trioxaundecanedioate Ligands against Pseudomonas aeruginosa Infection in Galleria mellonella Larvae
Authors: O’Shaughnessy Megan , Piatek Magdalena , McCarron Pauraic , McCann Malachy , Devereux Michael , Kavanagh Kevin , Howe Orla
Published: January 2022

Drug-resistant Pseudomonas aeruginosa is rapidly developing resulting in a serious global threat. Immunocompromised patients are specifically at risk, especially those with cystic fibrosis (CF). Novel metal complexes incorporating 1,10-phenanthroline (phen) ligands have previously demonstrated antibacterial and anti-biofilm effects against resistant P. aeruginosa from CF patients in vitro. Herein, we present the in vivo efficacy of {[Cu(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (Cu-tdda-phen), {[Mn(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (Mn-tdda-phen) and [Ag2(3,6,9-tdda)(phen)4]·EtOH (Ag-tdda-phen) (tddaH2 = 3,6,9-trioxaundecanedioic acid). Individual treatments of these metal-tdda-phen complexes and in combination with the established antibiotic gentamicin were evaluated in vivo in larvae of Galleria mellonella infected with clinical isolates and laboratory strains of P. aeruginosa. G. mellonella were able to tolerate all test complexes up to 10 µg/larva. In addition, the immune response was affected by stimulation of immune cells (hemocytes) and genes that encode for immune-related peptides, specifically transferrin and inducible metallo-proteinase inhibitor. The amalgamation of metal-tdda-phen complexes and gentamicin further intensified this response at lower concentrations, clearing a P. aeruginosa infection that were previously resistant to gentamicin alone. Therefore this work highlights the anti-pseudomonal capabilities of metal-tdda-phen complexes alone and combined with gentamicin in an in vivo model.
Brain Tumor Classification Using a Combination of Variational Autoencoders and Generative Adversarial Networks
Authors: Ahmad Bilal , Sun Jun , You Qi , Palade Vasile , Mao Zhongjie
Published: January 2022

Brain tumors are a pernicious cancer with one of the lowest five-year survival rates. Neurologists often use magnetic resonance imaging (MRI) to diagnose the type of brain tumor. Automated computer-assisted tools can help them speed up the diagnosis process and reduce the burden on the health care systems. Recent advances in deep learning for medical imaging have shown remarkable results, especially in the automatic and instant diagnosis of various cancers. However, we need a large amount of data (images) to train the deep learning models in order to obtain good results. Large public datasets are rare in medicine. This paper proposes a framework based on unsupervised deep generative neural networks to solve this limitation. We combine two generative models in the proposed framework: variational autoencoders (VAEs) and generative adversarial networks (GANs). We swap the encoder–decoder network after initially training it on the training set of available MR images. The output of this swapped network is a noise vector that has information of the image manifold, and the cascaded generative adversarial network samples the input from this informative noise vector instead of random Gaussian noise. The proposed method helps the GAN to avoid mode collapse and generate realistic-looking brain tumor magnetic resonance images. These artificially generated images could solve the limitation of small medical datasets up to a reasonable extent and help the deep learning models perform acceptably. We used the ResNet50 as a classifier, and the artificially generated brain tumor images are used to augment the real and available images during the classifier training. We compared the classification results with several existing studies and state-of-the-art machine learning models. Our proposed methodology noticeably achieved better results. By using brain tumor images generated artificially by our proposed method, the classification average accuracy improved from 72.63% to 96.25%. For the most severe class of brain tumor, glioma, we achieved 0.769, 0.837, 0.833, and 0.80 values for recall, specificity, precision, and F1-score, respectively. The proposed generative model framework could be used to generate medical images in any domain, including PET (positron emission tomography) and MRI scans of various parts of the body, and the results show that it could be a useful clinical tool for medical experts.
Antibacterial and Immunomodulatory Properties of Acellular Wharton’s Jelly Matrix
Authors: Dubus Marie , Scomazzon Loïc , Chevrier Julie , Ledouble Charlotte , Baldit Adrien , Braux Julien , Gindraux Florelle , Boulagnon Camille , Audonnet Sandra , Colin Marius , Rammal Hassan , Mauprivez Cédric , Kerdjoudj Halima
Published: January 2022

Of all biologic matrices, decellularized tissues have emerged as a promising tool in the field of regenerative medicine. Few empirical clinical studies have shown that Wharton’s jelly (WJ) of the human umbilical cord promotes wound closure and reduces wound-related infections. In this scope, we herein investigated whether decellularized (DC)-WJ could be used as an engineered biomaterial. In comparison with devitalized (DV)-WJ, our results showed an inherent effect of DC-WJ on Gram positive (S. aureus and S. epidermidis) and Gram negative (E. coli and P. aeruginosa) growth and adhesion. Although DC-WJ activated the neutrophils and monocytes in a comparable magnitude to DV-WJ, macrophages modulated their phenotypes and polarization states from the resting M0 phenotype to the hybrid M1/M2 phenotype in the presence of DC-WJ. M1 phenotype was predominant in the presence of DV-WJ. Finally, the subcutaneous implantation of DC-WJ showed total resorption after three weeks of implantation without any sign of foreign body reaction. These significant data shed light on the potential regenerative application of DC-WJ in providing a suitable biomaterial for tissue regenerative medicine and an ideal strategy to prevent wound-associated infections.
Analyzing Modeled Torque Profiles to Understand Scale-Dependent Active Muscle Responses in the Hip Joint
Authors: Young Fletcher R. , Chiel Hillel J. , Tresch Matthew C. , Heckman Charles J. , Hunt Alexander J. , Quinn Roger D.
Published: January 2022

Animal locomotion is influenced by a combination of constituent joint torques (e.g., due to limb inertia and passive viscoelasticity), which determine the necessary muscular response to move the limb. Across animal size-scales, the relative contributions of these constituent joint torques affect the muscular response in different ways. We used a multi-muscle biomechanical model to analyze how passive torque components change due to an animal’s size-scale during locomotion. By changing the size-scale of the model, we characterized emergent muscular responses at the hip as a result of the changing constituent torque profile. Specifically, we found that activation phases between extensor and flexor torques to be opposite between small and large sizes for the same kinematic motion. These results suggest general principles of how animal size affects neural control strategies. Our modeled torque profiles show a strong agreement with documented hindlimb torque during locomotion and can provide insights into the neural organization and muscle activation behavior of animals whose motion has not been extensively documented.
The Evaluation of Microshear Bond Strength of Resin Cements to Titanium Using Different Surface Treatment Methods: An In Vitro Study
Authors: Nakhaei Mohammadreza , Bozorgmehr Neda , Rajati Haghi Hamidreza , Bagheri Hossein , Rangrazi Abdolrasoul
Published: January 2022

This study attempted to investigate the effect of sandblasting and H2O2 treatments on the microshear bond strength of two commercially available resin cements. A total of 90 cube-shaped specimens of commercially pure titanium (cp-Ti) were divided into two groups of Panavia and MHA cements (n = 45). Samples of the Panavia group were randomly divided into three subgroups of 15 samples, including subgroups (no treatment, aluminum oxide sandblasting, and immersion in 35% hydrogen peroxide solution with halogen light). Once the treatment was completed, Panavia V5 was applied on the cp-Ti surface by a Tygon tube. The 45 specimens of the MHA cement group were randomly divided into three subgroups (n = 15) similarly to the Panavia group. Then, the MHA was applied on the surface of cp-Ti. A universal testing machine was used to measure and examine the microshear bond strength of cement to cp-Ti subsequent to the step of thermocycling. According to results, in the Panavia cement group, the SBS of sandblasting treatment was significantly higher than that of the H2O2 treatment subgroup (p < 0.05), which displayed a significantly higher SBS than that of the no-treatment subgroup (p < 0.001). In regard to the MHA group, the SBS of the H2O2 treatment subgroup was significantly lower than that of the sandblasting treatment subgroup (p < 0.001), whereas there were no significant differences between the SBS of the no treatment and H2O2 treatment subgroups (p = 0.35). Considering the comparison between Panavia and MHA cases, there were no significant differences observed among the no-treatment subgroups (p = 0.34), as well as the sandblasting treatment subgroups (p = 0.67), while the SBS of the H2O2 treatment subgroup in Panavia cement was higher than that of the H2O2 subgroup in MHA cement (p < 0.001). In conclusion, in both Panavia V5 and MHA cements, sandblasting treatment could improve the bond strength between the titanium surface. However, H2O2 treatment proved to be capable of enhancing the bond strength of Panavia V5 cement without causing any positive effects on the bond strength of MHA cement.
Development and In-Depth Characterization of Bacteria Repellent and Bacteria Adhesive Antibody-Coated Surfaces Using Optical Waveguide Biosensing
Authors: Farkas Eniko , Tarr Robert , Gerecsei Tamás , Saftics Andras , Kovács Kinga Dóra , Stercz Balazs , Domokos Judit , Peter Beatrix , Kurunczi Sandor , Szekacs Inna , Bonyár Attila , Bányai Anita , Fürjes Péter , Ruszkai-Szaniszló Szilvia , Varga Máté , Szabó Barnabás , Ostorházi Eszter , Szabó Dóra , Horvath Robert
Published: January 2022

Bacteria repellent surfaces and antibody-based coatings for bacterial assays have shown a growing demand in the field of biosensors, and have crucial importance in the design of biomedical devices. However, in-depth investigations and comparisons of possible solutions are still missing. The optical waveguide lightmode spectroscopy (OWLS) technique offers label-free, non-invasive, in situ characterization of protein and bacterial adsorption. Moreover, it has excellent flexibility for testing various surface coatings. Here, we describe an OWLS-based method supporting the development of bacteria repellent surfaces and characterize the layer structures and affinities of different antibody-based coatings for bacterial assays. In order to test nonspecific binding blocking agents against bacteria, OWLS chips were coated with bovine serum albumin (BSA), I-block, PAcrAM-g-(PMOXA, NH2, Si), (PAcrAM-P) and PLL-g-PEG (PP) (with different coating temperatures), and subsequent Escherichia coli adhesion was monitored. We found that the best performing blocking agents could inhibit bacterial adhesion from samples with bacteria concentrations of up to 107 cells/mL. Various immobilization methods were applied to graft a wide range of selected antibodies onto the biosensor’s surface. Simple physisorption, Mix&Go (AnteoBind) (MG) films, covalently immobilized protein A and avidin–biotin based surface chemistries were all fabricated and tested. The surface adsorbed mass densities of deposited antibodies were determined, and the biosensor;s kinetic data were evaluated to divine the possible orientations of the bacteria-capturing antibodies and determine the rate constants and footprints of the binding events. The development of affinity layers was supported by enzyme-linked immunosorbent assay (ELISA) measurements in order to test the bacteria binding capabilities of the antibodies. The best performance in the biosensor measurements was achieved by employing a polyclonal antibody in combination with protein A-based immobilization and PAcrAM-P blocking of nonspecific binding. Using this setting, a surface sensitivity of 70 cells/mm2 was demonstrated.
Parkinson’s Disease in Light of the COVID-19 Pandemic
Authors: Drelich-Zbroja Anna , Cheda Mateusz , Kuczyńska Maryla , Dąbrowska Izabela , Kopyto Ewa , Halczuk Izabela
Published: January 2022

In this review we attempt to collate the existing scientific evidence regarding the possible role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the pathophysiology of Parkinson’s disease (PD), as well as to investigate the impact of PD/parkinsonism on the clinical course of the viral infection itself. Since etiology of PD is not completely understood, various studies suggest different potential links between coronavirus disease 2019 (COVID-19) and PD. Suggested connections include, among others, similar prodromal symptoms, renin–angiotensin–aldosterone system involvement, or gut microbiome dysbiosis participation. Despite the initial assumptions that, as a mainly elderly population suffering from rigidity of respiratory muscles, impairment of cough reflex, and dyspnea, PD patients would be more susceptible to viral infection, and would experience a more aggressive course of COVID-19, the published scientific reports contain mutually exclusive data that require further investigation and meta-analysis.
Performance of Modern Passive Stack Ventilation in a Retrofitted Nordic Apartment Building
Authors: Kravchenko Ilia , Kosonen Risto , Jokisalo Juha , Kilpeläinen Simo
Published: January 2022

The paper analyses the performance of a five-storey apartment building equipped with modern passive stack ventilation in Nordic conditions. The passive stack ventilation system was retrofitted in 2019, and novel self-regulating air inlet devices with filters were equipped. The building was simulated with IDA ICE software, where the model of the self-regulating terminal units was developed using manufacturer product data. Several case scenarios were created to analyze the effects of poor maintenance, improved airtightness, and window opening on the system performance. For the analysis, one-room and three-room apartments on the second and fifth floors have been chosen. The CO2 concentration and indoor air temperature were analyzed and compared with EN 16798-1 standard guidelines. The results show a significant effect of poor maintenance and possibility to open windows on the CO2 concentration. The results also show a trend for the one-room apartments to overheat despite having a higher air change rate than the three-room apartments. The three-room apartments tolerate over-heating, although they are much more sensitive to poor maintenance. Furthermore, the apartments on the fifth floor are even more sensitive to poor maintenance, and three-room apartments there showed warning levels of CO2. Improving the envelope airtightness does not benefit the IAQ of the apartments.
Initial Evaluation of Therapy Response after Adjuvant Radioiodine Therapy in Patients with Early-Stage Papillary Thyroid Cancer—Does Time Matter?
Authors: Grawe Freba , Cramm Yuri , Fabritius Matthias P. , Ruebenthaler Johannes , Koehler Viktoria F. , Ilhan Harun , Bartenstein Peter , Wenter Vera , Todica Andrei
Published: January 2022

Background: The aim was to assess ablation success after initial radioiodine (RAI) therapy in early-stage PTC patients and compare outcomes of first diagnostic control after 6 and 9 months (6m/9m-DC) to examine whether time could possibly avoid unnecessary overtreatment. Methods: There were 353 patients who were matched regarding age, sex, and tumor stage and divided in two groups depending on time of first DC (6m- and 9m-DC). Therapy response was defined as thyroglobulin level <0.5 ng/mL, no pathological uptake in the diagnostic I-131 whole-body scintigraphy (WBS), and no further RAI therapy courses. The 6m-DC group was further divided into endogenously and exogenously stimulated TSH before RAI therapy and compared regarding outcome. Results: No significant differences were found between 6m-DC vs. 9m-DC regarding I-131 uptake in WBS (p = n.s.), Tg levels (p = n.s.), re-therapy rates (p = n.s.), and responder rates (p = n.s.). Significantly less relevant pathological I-131 uptake was found in WBS (p = 0.006) in endogenously compared to exogenously stimulated 6m-DC patients, resulting in lower re-therapy (p = 0.028) and higher responder rates (p = 0.001). Conclusion: DC at 6 months after RAI therapy and stimulation with recombinant human thyroid-stimulating hormone (rhTSH) represent the most balanced solution. Particularly regarding quality of life and mental relief of patients, early DC with rhTSH represents sufficient and convenient assessment of ablation success.
Novel Cellular Therapies for Hepatocellular Carcinoma
Authors: Roddy Harriet , Meyer Tim , Roddie Claire
Published: January 2022

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Most patients present with advanced disease, and current gold-standard management using tyrosine kinase inhibitors or immune checkpoint inhibitors (ICIs) offers modest clinical benefit. Cellular immune therapies targeting HCC are currently being tested in the laboratory and in clinical trials. Here, we review the landscape of cellular immunotherapy for HCC, defining antigenic targets, outlining the range of cell therapy products being applied in HCC (such as CAR-T and TCR-T), and exploring how advanced engineering solutions may further enhance this therapeutic approach.
NSAIDs Overcome PIK3CA Mutation-Mediated Resistance to EGFR Inhibition in Head and Neck Cancer Preclinical Models
Authors: Li Hua , Peyser Noah D. , Zeng Yan , Ha Patrick K. , Johnson Daniel E. , Grandis Jennifer R.
Published: January 2022

Epidermal growth factor receptor (EGFR) inhibitors are approved by the Food and Drug Administration (FDA) but remain under active clinical investigation for the treatment of both newly diagnosed and recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Despite EGFR expression in the majority of HNSCC tumors, the levels of total or phosphorylated EGFR have not consistently been correlated with a response to EGFR targeting agents. The lack of predictive biomarkers represents a major obstacle to successful use of these drugs. Activation of phosphatidylinositol 3-kinase (PI3K) signaling by mutation of the PIK3CA oncogene represents a plausible mechanism for EGFR inhibitor drug resistance. We compared the impact of EGFR inhibitors, alone or in combination with non-steroidal anti-inflammatory drugs (NSAIDs), in preclinical HNSCC models harboring mutant versus wild-type PIK3CA. Our results demonstrate additive or synergistic effects of NSAIDs and EGFR inhibitors in vitro and in vivo in PIK3CA-mutated HNSCC models. These findings suggest that the addition of NSAIDs to EGFR inhibitors for the treatment of HNSCC may represent a promising therapeutic strategy in PIK3CA-mutated cancers.
Pathological Response in the Breast and Axillary Lymph Nodes after Neoadjuvant Systemic Treatment in Patients with Initially Node-Positive Breast Cancer Correlates with Disease Free Survival: An Exploratory Analysis of the GeparOcto Trial
Authors: Gerber Bernd , Schneeweiss Andreas , Möbus Volker , Golatta Michael , Tesch Hans , Krug David , Hanusch Claus , Denkert Carsten , Lübbe Kristina , Heil Jörg , Huober Jens , Ataseven Beyhan , Klare Peter , Hahn Markus , Untch Michael , Kast Karin , Jackisch Christian , Thomalla Jörg , Seither Fenja , Blohmer Jens-Uwe , Rhiem Kerstin , Fasching Peter A. , Nekljudova Valentina , Loibl Sibylle , Kühn Thorsten
Published: January 2022

Background: The conversion of initially histologically confirmed axillary lymph node-positive (pN+) to ypN0 after neoadjuvant systemic treatment (NAST) is an important prognostic factor in breast cancer (BC) patients and may influence surgical de-escalation strategies. We aimed to determine pCR rates in lymph nodes (pCR-LN), the breast (pCR-B), and both (tpCR) in women who present with pN+ BC, to assess predictors for response and the impact of pCR-LN, pCR-B, and tpCR on invasive disease-free survival (iDFS). Methods: Retrospective, exploratory analysis of 242 patients with pN+ at diagnosis from the multicentric, randomized GeparOcto trial. Results: Of 242 patients with initially pN+ disease, 134 (55.4%) had a pCR-LN, and 109 (45.0%) a pCR-B. Of the 109 pCR-B patients, 9 (8.3%) patients had involved LN, and 100 (41.3%) patients had tpCR. Those with involved LN still had a bad prognosis. As expected, pCR-B and intrinsic subtypes (TNBC and HER2+) were identified as independent predictors of pCR-LN. pCR-LN (ypN0; hazard ratio 0.42; 95%, CI 0.23–0.75; p = 0.0028 for iDFS) was the strongest independent prognostic factor. Conclusions: In initially pN+ patients undergoing NAST, the conversion to ypN0 is of high prognostic value. Surgical axillary staging after NAST is still essential in these patients to offer tailored treatment.
Pancreatic Cancer Organoids in the Field of Precision Medicine: A Review of Literature and Experience on Drug Sensitivity Testing with Multiple Readouts and Synergy Scoring
Authors: Mäkinen Lotta , Vähä-Koskela Markus , Juusola Matilda , Mustonen Harri , Wennerberg Krister , Hagström Jaana , Puolakkainen Pauli , Seppänen Hanna
Published: January 2022

Pancreatic ductal adenocarcinoma (PDAC) is a silent killer, often diagnosed late. However, it is also dishearteningly resistant to nearly all forms of treatment. New therapies are urgently needed, and with the advent of organoid culture for pancreatic cancer, an increasing number of innovative approaches are being tested. Organoids can be derived within a short enough time window to allow testing of several anticancer agents, which opens up the possibility for functional precision medicine for pancreatic cancer. At the same time, organoid model systems are being refined to better mimic the cancer, for example, by incorporation of components of the tumor microenvironment. We review some of the latest developments in pancreatic cancer organoid research and in novel treatment design. We also summarize our own current experiences with pancreatic cancer organoid drug sensitivity and resistance testing (DSRT) in 14 organoids from 11 PDAC patients. Our data show that it may be necessary to include a cell death read-out in ex vivo DSRT assays, as metabolic viability quantitation does not capture actual organoid killing. We also successfully adapted the organoid platform for drug combination synergy discovery. Lastly, live organoid culture 3D confocal microscopy can help identify individual surviving tumor cells escaping cell death even during harsh combination treatments. Taken together, the organoid technology allows the development of novel precision medicine approaches for PDAC, which paves the way for clinical trials and much needed new treatment options for pancreatic cancer patients.
Lotus (Nelumbo nucifera Gaertn.) and Its Bioactive Phytocompounds: A Tribute to Cancer Prevention and Intervention
Authors: Bishayee Anupam , Patel Palak A. , Sharma Priya , Thoutireddy Shivani , Das Niranjan
Published: January 2022

Cancer is one of the major leading causes of death worldwide. Accumulating evidence suggests a strong relationship between specific dietary habits and cancer development. In recent years, a food-based approach for cancer prevention and intervention has been gaining tremendous attention. Among diverse dietary and medicinal plants, lotus (Nelumbo nucifera Gaertn., family Nymphaeaceae), also known as Indian lotus, sacred lotus or Chinese water lily, has the ability to effectively combat this disease. Various parts of N. nucifera have been utilized as a vegetable as well as an herbal medicine for more than 2000 years in the Asian continent. The rhizome and seeds of N. nucifera represent the main edible parts. Different parts of N. nucifera have been traditionally used to manage different disorders, such as fever, inflammation, insomnia, nervous disorders, epilepsy, hypertension, cardiovascular diseases, obesity, and hyperlipidemia. It is believed that numerous bioactive components, including alkaloids, polyphenols, terpenoids, steroids, and glycosides, are responsible for its various biological and pharmacological activities, such as antioxidant, anti-inflammatory, immune-modulatory, antiviral, hepatoprotective, cardioprotective, and hypoglycemic activities. Nevertheless, there is no comprehensive review with an exclusive focus on the anticancer attributes of diverse phytochemicals from different parts of N. nucifera. In this review, we have analyzed the effects of N. nucifera extracts, fractions and pure compounds on various organ-specific cancer cells and tumor models to understand the cancer-preventive and therapeutic potential and underlying cellular and molecular mechanisms of action of this interesting medicinal and dietary plant. In addition, the bioavailability, pharmacokinetics, and possible toxicity of N. nucifera-derived phytochemicals, as well as current limitations, challenges and future research directions, are also presented.
Incidence and Risk Factors of Cancer in the Anal Transitional Zone and Ileal Pouch following Surgery for Ulcerative Colitis and Familial Adenomatous Polyposis
Authors: Le Cosquer Guillaume , Buscail Etienne , Gilletta Cyrielle , Deraison Céline , Duffas Jean-Pierre , Bournet Barbara , Tuyeras Géraud , Vergnolle Nathalie , Buscail Louis
Published: January 2022

Proctocolectomy with ileal pouch-anal anastomosis is the intervention of choice for ulcerative colitis and familial adenomatous polyposis requiring surgery. One of the long-term complications is pouch cancer, having a poor prognosis. The risk of high-grade dysplasia and cancer in the anal transitional zone and ileal pouch after 20 years is estimated to be 2 to 4.5% and 3 to 10% in ulcerative colitis and familial polyposis, respectively. The risk factors for ulcerative colitis are the presence of pre-operative dysplasia or cancer, disease duration > 10 years and severe villous atrophy. For familial polyposis, the risk factors are the number of pre-operative polyps > 1000, surgery with stapled anastomosis and the duration of follow-up. In the case of ulcerative colitis, a pouchoscopy should be performed annually if one of the following is present: dysplasia and cancer at surgery, primary sclerosing cholangitis, villous atrophy and active pouchitis (every 5 years without any of these factors). In the case of familial polyposis, endoscopy is recommended every year including chromoendoscopy. Even if anal transitional zone and ileal pouch cancers seldom occur following proctectomy for ulcerative colitis and familial adenomatous polyposis, the high mortality rate associated with this complication warrants endoscopic monitoring.
Landscape of Epidermal Growth Factor Receptor Heterodimers in Brain Metastases
Authors: Lim Malcolm , Nguyen Tam H. , Niland Colleen , Reid Lynne E. , Jat Parmjit S. , Saunus Jodi M. , Lakhani Sunil R.
Published: January 2022

HER2+ breast cancer patients have an elevated risk of developing brain metastases (BM), despite adjuvant HER2-targeted therapy. The mechanisms underpinning this reduced intracranial efficacy are unclear. We optimised the in situ proximity ligation assay (PLA) for detection of the high-affinity neuregulin-1 receptor, HER2-HER3 (a key target of pertuzumab), in archival tissue samples and developed a pipeline for high throughput extraction of PLA data from fluorescent microscope image files. Applying this to a large BM sample cohort (n = 159) showed that BM from breast, ovarian, lung and kidney cancers have higher HER2-HER3 levels than other primary tumour types (melanoma, colorectal and prostate cancers). HER2 status, and tumour cell membrane expression of pHER2(Y1221/1222) and pHER3(Y1222) were positively, but not exclusively, associated with HER2-HER3 frequency. In an independent cohort (n = 78), BM had significantly higher HER2-HER3 levels than matching primary tumours (p = 0.0002). For patients who had two craniotomy procedures, HER2-HER3 dimer levels were lower in the consecutive lesion (n = 7; p = 0.006). We also investigated the effects of trastuzumab and pertuzumab on five different heterodimers in vitro: HER2-EGFR, HER2-HER4, HER2-HER3, HER3-HER4, HER3-EGFR. Treatment significantly altered the absolute frequencies of individual complexes in SKBr3 and/or MDA-MB-361 cells, but in the presence of neuregulin-1, the overall distribution was not markedly altered, with HER2-HER3 and HER2-HER4 remaining predominant. Together, these findings suggest that markers of HER2 and HER3 expression are not always indicative of dimerization, and that pertuzumab may be less effective at reducing HER2-HER3 dimerization in the context of excess neuregulin.
Palladium-Catalyzed Domino Cycloisomerization/Double Condensation of Acetylenic Acids with Dinucleophiles
Authors: Conde Nerea , Herrero María Teresa , Urgoitia Garazi , SanMartin Raul
Published: January 2022

Metal-catalyzed cascade processes based on hydrofunctionalization of alkynes are receiving much more attention because of their potential to provide advantageous approaches to otherwise synthetically challenging compounds. An alternative catalyst system has been found for the domino cycloisomerization/cyclocondensation reaction involving acetylenic acids and heterodinucleophiles. A CNN pincer palladium(II) complex, acting as a homogeneous catalyst, provides the corresponding polyheterocycles with a higher substrate/catalyst ratio. Other palladium sources were also tested and discarded, and a number of mechanistic studies including poisoning assays, kinetic plots, TEM images, XRD spectra and UPLC-MS analysis of reaction intermediates were conducted in order to shed light on the role of this pincer catalyst and the catalytic cycle involved in the cascade reaction. As a result, a more nuanced mechanism is tentatively proposed.
A Single-Cell Omics Network Model of Cell Crosstalk during the Formation of Primordial Follicles
Authors: Wang Qian , Dong Ang , Jiang Libo , Griffin Christopher , Wu Rongling
Published: January 2022

The fate of fetal germ cells (FGCs) in primordial follicles is largely determined by how they interact with the surrounding granulosa cells. However, the molecular mechanisms underlying this interactive process remain poorly understood. Here, we develop a computational model to characterize how individual genes program and rewire cellular crosstalk across FGCs and somas, how gene regulatory networks mediate signaling pathways that functionally link these two cell types, and how different FGCs diversify and evolve through cooperation and competition during embryo development. We analyze single-cell RNA-seq data of human female embryos using the new model, identifying previously uncharacterized mechanisms behind follicle development. The majority of genes (70%) promote FGC–soma synergism, only with a small portion (4%) that incur antagonism; hub genes function reciprocally between the FGC network and soma network; and germ cells tend to cooperate between different stages of development but compete in the same stage within a developmental embryo. Our network model could serve as a powerful tool to unravel the genomic signatures that mediate folliculogenesis from single-cell omics data.
Sézary Syndrome: Different Erythroderma Morphological Features with Proposal for a Clinical Score System
Authors: Roccuzzo Gabriele , Giordano Silvia , Avallone Gianluca , Rubatto Marco , Canonico Silvia , Funaro Ada , Ortolan Erika , Senetta Rebecca , Fava Paolo , Fierro Maria Teresa , Ribero Simone , Quaglino Pietro
Published: January 2022

Sézary syndrome is a rare subtype of cutaneous T-cell lymphoma characterized by erythroderma, peripheral lymphadenopathies, and circulating atypical cerebriform T-cells. To date, no definite staging system has been developed for these patients. In this retrospective analysis of the archive of the Dermatological Clinic of the University of Turin, Italy, erythrodermic SS patients were classified according to clinical records and photographs into three main presentations: erythematous, infiltrated, or melanodermic. The pattern of erythroderma was found to be associated with disease outcome, as better survivals were recorded in patients with erythematous and infiltrative erythroderma. Patients in the melanodermic group, though less represented in our investigation, seemed to show a worse trend in survival. According to this preliminary evidence, a new prognostic classification, with a revised score specific for Sézary syndrome patients, can be proposed to usefully integrate the current staging system. The correlation displayed in our research will be hopefully confirmed by prospective studies with larger cohorts, with the aim of identifying significant prognostic features in this subset of cutaneous T-cell lymphoma patients.
Sarcopenia Is a Cause and Consequence of Metabolic Dysregulation in Aging Humans: Effects of Gut Dysbiosis, Glucose Dysregulation, Diet and Lifestyle
Authors: Daily James W. , Park Sunmin
Published: January 2022

Skeletal muscle mass plays a critical role in a healthy lifespan by helping to regulate glucose homeostasis. As seen in sarcopenia, decreased skeletal muscle mass impairs glucose homeostasis, but it may also be caused by glucose dysregulation. Gut microbiota modulates lipopolysaccharide (LPS) production, short-chain fatty acids (SCFA), and various metabolites that affect the host metabolism, including skeletal muscle tissues, and may have a role in the sarcopenia etiology. Here, we aimed to review the relationship between skeletal muscle mass, glucose homeostasis, and gut microbiota, and the effect of consuming probiotics and prebiotics on the development and pathological consequences of sarcopenia in the aging human population. This review includes discussions about the effects of glucose metabolism and gut microbiota on skeletal muscle mass and sarcopenia and the interaction of dietary intake, physical activity, and gut microbiome to influence sarcopenia through modulating the gut–muscle axis. Emerging evidence suggests that the microbiome can regulate both skeletal muscle mass and function, in part through modulating the metabolisms of short-chain fatty acids and branch-chain amino acids that might act directly on muscle in humans or indirectly through the brain and liver. Dietary factors such as fats, proteins, and indigestible carbohydrates and lifestyle interventions such as exercise, smoking, and alcohol intake can both help and hinder the putative gut–muscle axis. The evidence presented in this review suggests that loss of muscle mass and function are not an inevitable consequence of the aging process, and that dietary and lifestyle interventions may prevent or delay sarcopenia.
Protective Effects of Curcumin in Cardiovascular Diseases—Impact on Oxidative Stress and Mitochondria
Authors: Cox Fiona Frederike , Misiou Angelina , Vierkant Annika , Ale-Agha Niloofar , Grandoch Maria , Haendeler Judith , Altschmied Joachim
Published: January 2022

Cardiovascular diseases (CVDs) contribute to a large part of worldwide mortality. Similarly, two of the major risk factors for these diseases, aging and obesity, are also global problems. Aging, the gradual decline of body functions, is non-modifiable. Obesity, a modifiable risk factor for CVDs, also predisposes to type 2 diabetes mellitus (T2DM). Moreover, it affects not only the vasculature and the heart but also specific fat depots, which themselves have a major impact on the development and progression of CVDs. Common denominators of aging, obesity, and T2DM include oxidative stress, mitochondrial dysfunction, metabolic abnormalities such as altered lipid profiles and glucose metabolism, and inflammation. Several plant substances such as curcumin, the major active compound in turmeric root, have been used for a long time in traditional medicine and for the treatment of CVDs. Newer mechanistic, animal, and human studies provide evidence that curcumin has pleiotropic effects and attenuates numerous parameters which contribute to an increased risk for CVDs in aging as well as in obesity. Thus, curcumin as a nutraceutical could hold promise in the prevention of CVDs, but more standardized clinical trials are required to fully unravel its potential.