bluuebunny/crossref_metadata_2025 huggingface dataset:
Bridging the Gap: From Biomechanics and Functional Morphology of Plants to Biomimetic Developments
Authors: Speck Olga , Speck Thomas
Published: October 2021

During the last few decades, biomimetics has attracted increasing attention in both basic and applied research and in various fields of industry and building construction [...]
Malignancies and Biosensors: A Focus on Oral Cancer Detection through Salivary Biomarkers
Authors: Goldoni Riccardo , Scolaro Alessandra , Boccalari Elisa , Dolci Carolina , Scarano Antonio , Inchingolo Francesco , Ravazzani Paolo , Muti Paola , Tartaglia Gianluca
Published: October 2021

Oral cancer is among the deadliest types of malignancy due to the late stage at which it is usually diagnosed, leaving the patient with an average five-year survival rate of less than 50%. The booming field of biosensing and point of care diagnostics can, in this regard, play a major role in the early detection of oral cancer. Saliva is gaining interest as an alternative biofluid for non-invasive diagnostics, and many salivary biomarkers of oral cancer have been proposed. While these findings are promising for the application of salivaomics tools in routine practice, studies on larger cohorts are still needed for clinical validation. This review aims to summarize the most recent development in the field of biosensing related to the detection of salivary biomarkers commonly associated with oral cancer. An introduction to oral cancer diagnosis, prognosis and treatment is given to define the clinical problem clearly, then saliva as an alternative biofluid is presented, along with its advantages, disadvantages, and collection procedures. Finally, a brief paragraph on the most promising salivary biomarkers introduces the sensing technologies commonly exploited to detect oral cancer markers in saliva. Hence this review provides a comprehensive overview of both the clinical and technological advantages and challenges associated with oral cancer detection through salivary biomarkers.
Enhanced Plasmonic Biosensor Utilizing Paired Antibody and Label-Free Fe3O4 Nanoparticles for Highly Sensitive and Selective Detection of Parkinson’s α-Synuclein in Serum
Authors: Mandala Samuel Husin Surya , Liu Tai-Jan , Chen Chiung-Mei , Liu Kuo-Kang , Januar Mochamad , Chang Ying-Feng , Lai Chao-Sung , Chang Kuo-Hsuan , Liu Kou-Chen
Published: October 2021

Parkinson’s disease (PD) is an acute and progressive neurodegenerative disorder, and diagnosis of the disease at its earliest stage is of paramount importance to improve the life expectancy of patients. α-Synuclein (α-syn) is a potential biomarker for the early diagnosis of PD, and there is a great need to develop a biosensing platform that precisely detects α-syn in human body fluids. Herein, we developed a surface plasmon resonance (SPR) biosensor based on the label-free iron oxide nanoparticles (Fe3O4 NPs) and paired antibody for the highly sensitive and selective detection of α-syn in serum samples. The sensitivity of the SPR platform is enhanced significantly by directly depositing Fe3O4 NPs on the Au surface at a high density to increase the decay length of the evanescent field on the Au film. Moreover, the utilization of rabbit-type monoclonal antibody (α-syn-RmAb) immobilized on Au films allows the SPR platform to have a high affinity-selectivity binding performance compared to mouse-type monoclonal antibodies as a common bioreceptor for capturing α-syn molecules. As a result, the current platform has a detection limit of 5.6 fg/mL, which is 20,000-fold lower than that of commercial ELISA. The improved sensor chip can also be easily regenerated to repeat the α-syn measurement with the same sensitivity. Furthermore, the SPR sensor was applied to the direct analysis of α-syn in serum samples. By using a format of paired α-syn-RmAb, the SPR sensor provides a recovery rate in the range from 94.5% to 104.3% to detect the α-syn in diluted serum samples precisely. This work demonstrates a highly sensitive and selective quantification approach to detect α-syn in human biofluids and paves the way for the future development in the early diagnosis of PD.
Functional Connectivity at Rest between the Human Medial Posterior Parietal Cortex and the Primary Motor Cortex Detected by Paired-Pulse Transcranial Magnetic Stimulation
Authors: Breveglieri Rossella , Borgomaneri Sara , Filippini Matteo , De Vitis Marina , Tessari Alessia , Fattori Patrizia
Published: October 2021

The medial posterior parietal cortex (PPC) is involved in the complex processes of visuomotor integration. Its connections to the dorsal premotor cortex, which in turn is connected to the primary motor cortex (M1), complete the fronto-parietal network that supports important cognitive functions in the planning and execution of goal-oriented movements. In this study, we wanted to investigate the time-course of the functional connectivity at rest between the medial PPC and the M1 using dual-site transcranial magnetic stimulation in healthy humans. We stimulated the left M1 using a suprathreshold test stimulus to elicit motor-evoked potentials in the hand, and a subthreshold conditioning stimulus was applied over the left medial PPC at different inter-stimulus intervals (ISIs). The conditioning stimulus affected the M1 excitability depending on the ISI, with inhibition at longer ISIs (12 and 15 ms). We suggest that these modulations may reflect the activation of different parieto-frontal pathways, with long latency inhibitions likely recruiting polisynaptic pathways, presumably through anterolateral PPC.
Diffusion Tensor Imaging Changes Do Not Affect Long-Term Neurodevelopment following Early Erythropoietin among Extremely Preterm Infants in the Preterm Erythropoietin Neuroprotection Trial
Authors: Law Janessa B. , Comstock Bryan A. , Richards Todd L. , Traudt Christopher M. , Wood Thomas R. , Mayock Dennis E. , Heagerty Patrick J. , Juul Sandra E.
Published: October 2021

We aimed to evaluate diffusion tensor imaging (DTI) in infants born extremely preterm, to determine the effect of erythropoietin (Epo) on DTI, and to correlate DTI with neurodevelopmental outcomes at 2 years of age for infants in the Preterm Erythropoietin Neuroprotection (PENUT) Trial. Infants who underwent MRI with DTI at 36 weeks postmenstrual age were included. Neurodevelopmental outcomes were evaluated by Bayley Scales of Infant and Toddler Development (BSID-III). Generalized linear models were used to assess the association between DTI parameters and treatment group, and then with neurodevelopmental outcomes. A total of 101 placebo- and 93 Epo-treated infants underwent MRI. DTI white matter mean diffusivity (MD) was lower in placebo- compared to Epo-treated infants in the cingulate and occipital regions, and occipital white matter fractional isotropy (FA) was lower in infants born at 24–25 weeks vs. 26–27 weeks. These values were not associated with lower BSID-III scores. Certain decreases in clustering coefficients tended to have lower BSID-III scores. Consistent with the PENUT Trial findings, there was no effect on long-term neurodevelopment in Epo-treated infants even in the presence of microstructural changes identified by DTI.
Similar CNV Neurodynamic Patterns between Sub- and Supra-Second Time Perception
Authors: Zhang Mingming , Zhang Keye , Zhou Xing , Zhan Bin , He Weiqi , Luo Wenbo
Published: October 2021

In the field of time psychology, the functional significance of the contingent negative variation (CNV) component in time perception and whether the processing mechanisms of sub- and supra-second are similar or different still remain unclear. In the present study, event-related potential (ERP) technology and classical temporal discrimination tasks were used to explore the neurodynamic patterns of sub- and supra-second time perception. In Experiment 1, the standard interval (SI) was fixed at 500 ms, and the comparison interval (CI) ranged from 200 ms to 800 ms. In Experiment 2, the SI was fixed at 2000 ms, and the CI ranged from 1400 ms to 2600 ms. Participants were required to judge whether the CI was longer or shorter than the SI. The ERP results showed similar CNV activity patterns in the two experiments. Specifically, CNV amplitude would be more negative when the CI was longer or closer to the memorized SI. CNV peak latency increased significantly until the CI reached the memorized SI. We propose that CNV amplitude might reflect the process of temporal comparison, and CNV peak latency might represent the process of temporal decision-making. To our knowledge, it is the first ERP task explicitly testing the two temporal scales, sub- and supra-second timing, in one study. Taken together, the present study reveals a similar functional significance of CNV between sub- and supra-second time perception.
Alterations in Leg Muscle Glucose Uptake and Inter-Limb Asymmetry after a Single Session of tDCS in Four People with Multiple Sclerosis
Authors: Fietsam Alexandra C. , Deters Justin R. , Workman Craig D. , Ponto Laura L. Boles , Rudroff Thorsten
Published: October 2021

Asymmetrical lower limb weakness is an early symptom and significant contributor to the progressive worsening of walking ability in people with multiple sclerosis (PwMS). Transcranial direct current stimulation (tDCS) may effectively increase neural drive to the more-affected lower limb and, therefore, increase symmetrical activation. Four PwMS (1 female, age range: 27–57) underwent one session each of 3 mA or SHAM tDCS over the motor cortex corresponding to their more-affected limb followed by 20 min of treadmill walking at a self-selected speed. Two min into the treadmill task, the subjects were injected with the glucose analog [18F]fluorodeoxyglucose (FDG). Immediately after treadmill walking, the subjects underwent whole-body positron emission tomography (PET) imaging. Glucose uptake (GU) values were compared between the legs, the spatial distribution of FDG was assessed to estimate glucose uptake heterogeneity (GUh), and GU asymmetry indices (AIs) were calculated. After tDCS, GU was altered, and GUh was decreased in various muscle groups in each subject. Additionally, AIs went from asymmetric to symmetric after tDCS in the subjects that demonstrated asymmetrical glucose uptake during SHAM. These results indicate that tDCS improved GU asymmetries, potentially from an increased neural drive and a more efficient muscle activation strategy of the lower limb in PwMS.
Genotype- and Age-Dependent Differences in Ultrasound Vocalizations of SPRED2 Mutant Mice Revealed by Machine Deep Learning
Authors: Hepbasli Denis , Gredy Sina , Ullrich Melanie , Reigl Amelie , Abeßer Marco , Raabe Thomas , Schuh Kai
Published: October 2021

Vocalization is an important part of social communication, not only for humans but also for mice. Here, we show in a mouse model that functional deficiency of Sprouty-related EVH1 domain-containing 2 (SPRED2), a protein ubiquitously expressed in the brain, causes differences in social ultrasound vocalizations (USVs), using an uncomplicated and reliable experimental setting of a short meeting of two individuals. SPRED2 mutant mice show an OCD-like behaviour, accompanied by an increased release of stress hormones from the hypothalamic–pituitary–adrenal axis, both factors probably influencing USV usage. To determine genotype-related differences in USV usage, we analyzed call rate, subtype profile, and acoustic parameters (i.e., duration, bandwidth, and mean peak frequency) in young and old SPRED2-KO mice. We recorded USVs of interacting male and female mice, and analyzed the calls with the deep-learning DeepSqueak software, which was trained to recognize and categorize the emitted USVs. Our findings provide the first classification of SPRED2-KO vs. wild-type mouse USVs using neural networks and reveal significant differences in their development and use of calls. Our results show, first, that simple experimental settings in combination with deep learning are successful at identifying genotype-dependent USV usage and, second, that SPRED2 deficiency negatively affects the vocalization usage and social communication of mice.
Recycling Crushed Waste Beer Bottle Glass in Fired Clay Bricks
Authors: Xin Yuecheng , Kurmus Halenur , Mohajerani Abbas , Dallol Yasmin , Lao Yunsha , Robert Dilan , Pramanik Biplob , Tran Phuong
Published: October 2021

Waste glass is a readily available domestic material. Each year, around 257,000 tonnes of glass waste are produced in Victoria, and the majority is glass packings. Typically, mixed waste glass cullet is deposited in landfills due to the limited recycling techniques. As a result, landfills are facing a growing issue. Therefore, this study investigates the addition of waste beer bottle glass (BG) in fired clay bricks and examines the effects of varying firing temperatures on the physical and mechanical properties of the manufactured samples. Clay bricks containing 10% BG at a firing temperature of 950 °C depicted similar compressive strength results (41 MPa) to the control samples (42 MPa). The results of all tested bricks were found to be below the water absorption limit of 17%. The thermal conductivity of the bricks incorporating BG was investigated, and it was found that the thermal performance improved with the decreasing firing temperature. Moreover, an initial rate of absorption (IRA), XRD, and XRF analysis was conducted. The experimental results have been discussed and compared with the recommended acceptable properties for standard bricks.
Assessment of Seismic Building Vulnerability Using Rapid Visual Screening Method through Web-Based Application for Malaysia
Authors: Kassem Moustafa Moufid , Beddu Salmia , Ooi Jun Hao , Tan Chee Ghuan , Mohamad El-Maissi Ahmad , Mohamed Nazri Fadzli
Published: October 2021

Rapid visual screening is a quick and simple approach often used by researchers to estimate the seismic vulnerability of buildings in an area. In this study, preliminary seismic vulnerability assessment of 500 buildings situated at Northern and Eastern George Town, Malaysia, was carried out by utilizing a modified FEMA-154 (2002) method that suits Malaysian conditions. Data were collected from online sources via Google Maps and Google Earth instead of traditional surveying data collection through street screening. The seismic assessment analysis of this study was based on the RVS performance score and the damage state classification for each building typology. This approach generates, for each building, a final performance score based on governing parameters such as structural resisting system, height, structural irregularities, building age, and soil type. The findings revealed the immediate need for effective seismic mitigation strategies, as 90% of the studied buildings required a further detailed analyses to pinpoint their exact seismic vulnerability performance. Most of the surveyed buildings were predicted to experience moderate-to-substantial damage, with 220 out of 500 being classed as damage state 2 (D2) and damage state 3 (D3). A GIS map, “RVS Malaysian Form-George Town Area”, was generated via ArcGIS and shared with the public to provide vital information for further research.
Critical Factors Affecting Team Work Efficiency in BIM-Based Collaborative Design: An Empirical Study in China
Authors: Wang Jiayuan , Yuan Zikui , He Zhilin , Zhou Fuping , Wu Zezhou
Published: October 2021

Building information modeling (BIM) can theoretically facilitate collaboration among diverse design participants in construction projects, but in practice, its implementation tends to prolong the design period. Existing literature has examined some technical and managerial causes of this problem but still lacks an overall coverage of related factors. This study aims to identify the comprehensive factors affecting the teamwork efficiency in China’s BIM-based collaborative design, and to investigate the critical factors and their interactions. Based on the input-process-output theory, this study initially established a hypothetical model. Potential factors were further identified through the literature review and semi-structured interviews. Questionnaire survey was conducted, and structural equation modeling was used for analysis. The results indicated that the team cooperation atmosphere is the most significant factor, followed by the collaborators’ learning ability, comfort of the working environment, BIM software function, and the characteristics and arrangement of the design task (CADT). Besides, the CADT negatively affects the teamwork efficiency through the human interaction process, while other factors exert positive impacts by affecting both the personal work process and the human interaction process. The findings can help design units to determine the management focus of BIM-based collaborative design and prioritize the allocation of limited resources accordingly to maximize teamwork efficiency.
Erratum: Rodriguez et al. Substance P Antagonism as a Novel Therapeutic Option to Enhance Efficacy of Cisplatin in Triple Negative Breast Cancer and Protect PC12 Cells against Cisplatin-Induced Oxidative Stress and Apoptosis. Cancers 2021, 13, 3871
Authors: Rodriguez Emma , Pei Guangsheng , Zhao Zhongming , Kim Sang T. , German Alexis , Robinson Prema
Published: October 2021

One contributor’s name was missing in the original version of the authorship of the paper [...]
PROTECT: Prospective Phase-II-Trial Evaluating Adaptive Proton Therapy for Cervical Cancer to Reduce the Impact on Morbidity and the Immune System
Authors: Corbeau Anouk , Nout Remi A. , Mens Jan Willem M. , Horeweg Nanda , Godart Jérémy , Kerkhof Ellen M. , Kuipers Sander C. , van Poelgeest Mariette I. E. , Kroep Judith R. , Boere Ingrid A. , van Doorn Helena C. , Hoogeman Mischa S. , van der Heide Uulke A. , Putter Hein , Welters Marij J. P. , van der Burg Sjoerd H. , Creutzberg Carien L. , de Boer Stephanie M.
Published: October 2021

External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a very effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient’s quality of life (QoL) and ability to complete treatment or undergo adjuvant therapies. Intensity modulated proton therapy (IMPT) enables a significant dose reduction in organs at risk (OAR), when compared to that of standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). However, clinical studies evaluating whether IMPT consequently reduces side effects for LACC are lacking. The PROTECT trial is a nonrandomized prospective multicenter phase-II-trial comparing clinical outcomes after IMPT or IMRT/VMAT in LACC. Thirty women aged >18 years with a histological diagnosis of LACC will be included in either the IMPT or IMRT/VMAT group. Treatment includes EBRT (45 Gy in 25 fractions of 1.8 Gy), concurrent five weekly cisplatin (40 mg/m2), and 3D image (MRI)-guided adaptive brachytherapy. The primary endpoint is pelvic bones Dmean and mean bowel V15Gy. Secondary endpoints include dosimetric parameters, oncological outcomes, health-related QoL, immune response, safety, and tolerability. This study provides the first data on the potential of IMPT to reduce OAR dose in clinical practice and improve toxicity and QoL for patients with LACC.
Added Value of Tomoelastography for Characterization of Pancreatic Neuroendocrine Tumor Aggressiveness Based on Stiffness
Authors: Gültekin Emin , Wetz Christoph , Braun Jürgen , Geisel Dominik , Furth Christian , Hamm Bernd , Sack Ingolf , Marticorena Garcia Stephan R.
Published: October 2021

Purpose: To evaluate the diagnostic performance of tomoelastography in differentiating pancreatic neuroendocrine tumors (PNETs) from healthy pancreatic tissue and to assess the prediction of tumor aggressiveness by correlating PNET stiffness with PET derived asphericity. Methods: 13 patients with PNET were prospectively compared to 13 age-/sex-matched heathy volunteers (CTR). Multifrequency MR elastography was combined with tomoelastography-postprocessing to provide high-resolution maps of shear wave speed (SWS in m/s). SWS of pancreatic neuroendocrine tumor (PNET-T) were compared with nontumorous pancreatic tissue in patients with PNET (PNET-NT) and heathy pancreatic tissue (CTR). The diagnostic performance of tomoelastography was evaluated by ROC-AUC analysis. PNET-SWS correlations were calculated with Pearson’s r. Results: SWS was higher in PNET-T (2.02 ± 0.61 m/s) compared to PNET-NT (1.31 ± 0.18 m/s, p < 0.01) and CTR (1.26 ± 0.09 m/s, p < 0.01). An SWS-cutoff of 1.46 m/s distinguished PNET-T from PNET-NT (AUC = 0.89; sensitivity = 0.85; specificity = 0.92) and a cutoff of 1.49 m/s differentiated pancreatic tissue of CTR from PNET-T (AUC = 0.96; sensitivity = 0.92; specificity = 1.00). The SWS of PNET-T was positively correlated with PET derived asphericity (r = 0.81; p = 0.01). Conclusions: Tomoelastography provides quantitative imaging markers for the detection of PNET and the prediction of greater tumor aggressiveness by increased stiffness.
Serum CXCL8 and Its Specific Receptor (CXCR2) in Gastric Cancer
Authors: Pawluczuk Elżbieta , Łukaszewicz-Zając Marta , Gryko Mariusz , Kulczyńska-Przybik Agnieszka , Mroczko Barbara
Published: October 2021

Gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide. This malignancy is usually diagnosed at an advanced stage. Therefore, novel biomarkers useful in the early detection of GC are sorely needed. Some authors suggest the role of chemokines and their specific receptors in GC pathogenesis. The aim of the study was to investigate whether serum CXCL8 and its receptor (CXCR2) might be considered as potential candidates for biomarkers in the diagnosis and prognosis of GC. The study included 98 subjects: 64 GC patients and 34 healthy volunteers. CXCL8 and CXCR2 concentrations were assessed by the enzyme-linked immunosorbent assay (ELISA) method. Serum CXCL8 and CXCR2 concentrations were significantly higher in GC patients than in healthy controls, similar to the well-established tumor marker (CA19-9) and marker of inflammation (CRP). Diagnostic sensitivity of CXCL8 was the highest among all proteins tested and increased for the combined assessment with CA19-9. The area under the ROC curve for CXCL8 was higher than those for CXCR2 and classical tumor markers. Serum CXCL8 levels were indicated as a significant risk factor of GC occurrence. Our findings suggest that serum CXCL8 is a promising candidate for a biomarker in GC diagnosis and might be used as a significant predictor of GC risk.
A Targeted Approach to Post-Mastectomy Pain and Persistent Pain following Breast Cancer Treatment
Authors: Chang Philip J. , Asher Arash , Smith Sean R.
Published: October 2021

Persistent pain following treatment for breast cancer is common and often imprecisely labeled as post-mastectomy pain syndrome (PMPS). PMPS is a disorder with multiple potential underlying causes including intercostobrachial nerve injury, intercostal neuromas, phantom breast pain, and pectoralis minor syndrome. Adding further complexity to the issue are various musculoskeletal pain syndromes including cervical radiculopathy, shoulder impingement syndrome, frozen shoulder, and myofascial pain that may occur concurrently and at times overlap with PMPS. These overlapping pain syndromes may be difficult to separate from one another, but precise diagnosis is essential, as treatment for each pain generator may be distinct. The purpose of this review is to clearly outline different pain sources based on anatomic location that commonly occur following treatment for breast cancer, and to provide tailored and evidence-based recommendations for the evaluation and treatment of each disorder.
Clinical Significance of Plasma CD9-Positive Exosomes in HIV Seronegative and Seropositive Lung Cancer Patients
Authors: Dimitrakopoulos Foteinos-Ioannis , Kottorou Anastasia E. , Rodgers Kristen , Sherwood John Timothy , Koliou Georgia-Angeliki , Lee Beverly , Yang Andrew , Brahmer Julie Renee , Baylin Stephen B. , Yang Stephen C. , Orita Hajime , Hulbert Alicia , Brock Malcolm V.
Published: October 2021

Recently, the role of exosomes in the progression of both cancer and HIV (human immunodeficiency virus) has been described. This study investigates the clinical significance of CD9-positive plasma exosomes in lung cancer patients, healthy individuals, and HIV-positive patients with or without lung cancer. Using a verified with transmission electron microscopy double-sandwich ELISA technique, plasma-derived exosomes were isolated and quantified from 210 lung cancer patients (including 44 metastatic patients with progressive disease after chemotherapy), 49 healthy controls, 20 patients with pulmonary granulomas, 19 HIV+ patients with lung cancer, 31 HIV+ patients without cancer, and 3 HIV+ patients with pulmonary granulomas. Plasma exosome concentrations differed between healthy controls, patients with immunocompetent pulmonary granulomas and patients with lung cancer even after chemotherapy (p < 0.001). Lung cancer patients after chemotherapy had lower exosome concentrations compared to patients with untreated lung cancer or granuloma (p < 0.001 for both). HIV+ patients without lung cancer had significantly higher exosome concentrations compared to HIV+ patients with lung cancer (p = 0.016). Although exosome concentrations differed between all different lung cancer histologies and healthy controls (p < 0.001 for all histologies), adjusted statistical significance was oµy retained for patients with granulomas and SCLC (Small-cell lung cancer, p < 0.001). HIV-induced immunodeficient patients with or without lung cancer had lower plasma exosomes compared to immunocompetent granuloma and lung cancer patients (p < 0.001). Finally, higher plasma exosomes were associated both on univariate (p = 0.044), and multivariate analysis (p = 0.040) with a better 3-year survival in stage II and III NSCLC (Non-small-cell lung carcinoma) patients. In conclusion, our study shows that CD9-positive plasma exosomes are associated with both lung cancer and HIV, prior chemotherapy, as well as with survival, suggesting a possible prognostic value.
SIRT3 and Metabolic Reprogramming Mediate the Antiproliferative Effects of Whey in Human Colon Cancer Cells
Authors: D’Onofrio Nunzia , Martino Elisa , Balestrieri Anna , Mele Luigi , Neglia Gianluca , Balestrieri Maria Luisa , Campanile Giuseppe
Published: October 2021

Emerging strategies to improve healthy aging include dietary interventions as a tool to promote health benefits and reduce the incidence of aging-related comorbidities. The health benefits of milk are also linked to its richness in betaines and short-chain acylcarnitines, which act synergistically in conferring anticancer, anti-inflammatory, and antioxidant properties. Whey, despite being a dairy by-product, still has a considerable content of bioactive betaines and acylcarnitines. Here, we investigated the anticancer properties of whey from Mediterranean water buffalo (Bubalus bubalis) milk by testing its antiproliferative effects in colorectal cancer (CRC) cells HT-29, HCT 116, LoVo and SW480. Results indicated that treatment with whey for 72 h inhibited cell proliferation (p < 0.001), induced cell cycle arrest, and apoptosis via caspase-3 activation, and modulated cell metabolism by limiting glucose uptake and interfering with mitochondrial energy metabolism with the highest effects observed in HT-29 and HCT 116 cells. At molecular level, these effects were accompanied by upregulation of sirtuin 3 (SIRT3) (p < 0.01) and peroxisome proliferator-activated receptor (PPAR)-γ expression (p < 0.001), and downregulation of lactate dehydrogenase A (LDHA) (p < 0.01), sterol regulatory-element binding protein 1 (SREBP1) (p < 0.05), and PPAR-α (p < 0.01). Transient SIRT3 gene silencing blocked the effects of whey on the LDHA, PPAR-γ, and PPAR-α protein expressions (p < 0.01) suggesting that the whey capacity of perturbating the metabolic homeostasis in CRC cell lines is mediated by SIRT3.
Breast Cancer Drug Approvals Issued by EMA: A Review of Clinical Trials
Authors: Duranti Simona , Fabi Alessandra , Filetti Marco , Falcone Rosa , Lombardi Pasquale , Daniele Gennaro , Franceschini Gianluca , Carbognin Luisa , Palazzo Antonella , Garganese Giorgia , Paris Ida , Scambia Giovanni , Pietragalla Antonella
Published: October 2021

Breast cancer represents the first cause of cancer worldwide and the leading cause of cancer mortality for women. Therefore, new therapies are needed to improve the prognosis of women diagnosed with this disease. In this review, we summarize the new drug indications for the treatment of breast cancer approved by European Medicines Agency between January 2015 and June 2021. In particular, we analyzed the clinical trials results leading to approvals and their update (when available), according to setting (localized and locally advanced or metastatic) and clinical features (hormone receptor positive, HER2 positive, triple negative, BRCA 1/2 mutation). The aim of this paper is to describe the clinical benefit obtained with the new indications.
FOXA1: A Pioneer of Nuclear Receptor Action in Breast Cancer
Authors: Seachrist Darcie D. , Anstine Lindsey J. , Keri Ruth A.
Published: October 2021

The pioneering function of FOXA1 establishes estrogen-responsive transcriptomes in luminal breast cancer. Dysregulated FOXA1 chromatin occupancy through focal amplification, mutation, or cofactor recruitment modulates estrogen receptor (ER) transcriptional programs and drives endocrine-resistant disease. However, ER is not the sole nuclear receptor (NR) expressed in breast cancers, nor is it the only NR for which FOXA1 serves as a licensing factor. Receptors for androgens, glucocorticoids, and progesterone are also found in the majority of breast cancers, and their functions are also impacted by FOXA1. These NRs interface with ER transcriptional programs and, depending on their activation level, can reprogram FOXA1-ER cistromes. Thus, NR interplay contributes to endocrine therapy response and resistance and may provide a vulnerability for future therapeutic benefit in patients. Herein, we review what is known regarding FOXA1 regulation of NR function in breast cancer in the context of cell identity, endocrine resistance, and NR crosstalk in breast cancer progression and treatment.
Landscape of 4D Cell Interaction in Hodgkin and Non-Hodgkin Lymphomas
Authors: Hartmann Sylvia , Scharf Sonja , Steiner Yvonne , Loth Andreas G. , Donnadieu Emmanuel , Flinner Nadine , Poeschel Viola , Angel Stephanie , Bewarder Moritz , Bein Julia , Brunnberg Uta , Bozzato Alessandro , Schick Bernhard , Stilgenbauer Stephan , Bohle Rainer M. , Thurner Lorenz , Hansmann Martin-Leo
Published: October 2021

Profound knowledge exists about the clinical, morphologic, genomic, and transcriptomic characteristics of most lymphoma entities. However, information is currently lacking on the dynamic behavior of malignant lymphomas. This pilot study aimed to gain insight into the motility of malignant lymphomas and bystander cells in 20 human lymph nodes. Generally, B cells were faster under reactive conditions compared with B cells in malignant lymphomas. In contrast, PD1-positive T cells did not show systematic differences in velocity between reactive and neoplastic conditions in general. However, lymphomas could be divided into two groups: one with fast PD1-positive T cells (e.g., Hodgkin lymphoma and mantle cell lymphoma; means 8.4 and 7.8 µm/min) and another with slower PD1-positive T cells (e.g., mediastinal grey zone lymphoma; mean 3.5 µm/min). Although the number of contacts between lymphoma cells and PD1-positive T cells was similar in different lymphoma types, important differences were observed in the duration of these contacts. Among the lymphomas with fast PD1-positive T cells, contacts were particularly short in mantle cell lymphoma (mean 54 s), whereas nodular lymphocyte-predominant Hodgkin lymphoma presented prolonged contact times (mean 6.1 min). Short contact times in mantle cell lymphoma were associated with the largest spatial displacement of PD1-positive cells (mean 12.3 µm). Although PD1-positive T cells in nodular lymphocyte-predominant Hodgkin lymphoma were fast, they remained in close contact with the lymphoma cells, in line with a dynamic immunological synapse. This pilot study shows for the first time systematic differences in the dynamic behavior of lymphoma and bystander cells between different lymphoma types.
Novel Non-Immunologic Agents for Relapsed and Refractory Multiple Myeloma: A Review Article
Authors: Bobin Arthur , Gruchet Cécile , Guidez Stéphanie , Gardeney Hélène , Nsiala Makunza Laly , Vonfeld Mathilde , Lévy Anthony , Cailly Laura , Sabirou Florence , Systchenko Thomas , Moya Niels , Leleu Xavier
Published: October 2021

Novel treatments are needed to address the lack of options for patients with relapsed or refractory multiple myeloma. Even though immunotherapy-based treatments have revolutionized the field in recent years, offering new opportunities for patients, there is still no curative therapy. Thus, non-immunologic agents, which have proven effective for decades, are still central to the treatment of multiple myeloma, especially for advanced disease. Building on their efficacy in myeloma, the development of proteasome inhibitors and immunomodulatory drugs has been pursued, and has led to the emergence of a novel generation of agents (e.g., carfilzomib, ixazomib, pomalidomide). The use of alkylating agents is decreasing in most treatment regimens, but melflufen, a peptide-conjugated alkylator with a completely new mechanism of action, offers interesting opportunities. Moreover, with the identification of novel targets, new drug classes have entered the myeloma armamentarium, such as XPO1 inhibitors (selinexor), HDAC inhibitors (panobinostat), and anti-BCL-2 agents (venetoclax). New pathways are still being explored, especially the possibility of a mutation-driven strategy, as biomarkers and targeted treatments are increasing. Though multiple myeloma is still considered incurable, the treatment options are expanding and are progressively becoming more diverse, largely because of the continuous development of non-immunologic agents.
Identification of Biochemical and Molecular Markers of Early Aging in Childhood Cancer Survivors
Authors: Ravera Silvia , Vigliarolo Tiziana , Bruno Silvia , Morandi Fabio , Marimpietri Danilo , Sabatini Federica , Dagnino Monica , Petretto Andrea , Bartolucci Martina , Muraca Monica , Biasin Eleonora , Haupt Riccardo , Zecca Marco , Fagioli Franca , Cilloni Daniela , Podestà Marina , Frassoni Francesco
Published: October 2021

Survival rates of childhood cancer patients have improved over the past four decades, although cancer treatments increase the risk of developing chronic diseases typical of aging. Thus, we aimed to identify molecular/metabolic cellular alterations responsible for early aging in childhood cancer survivors (CCS). Biochemical, proteomic, and molecular biology analyses were conducted on mononuclear cells (MNCs) isolated from peripheral blood of 196 CCS, the results being compared with those obtained on MNCs of 154 healthy subjects. CCS-MNCs showed inefficient oxidative phosphorylation associated with low energy status, and increased lipid peroxidation and lactate fermentation compared with age-matched normal controls. According to a mathematical model based on biochemical parameters, CCS-MNCs showed significantly higher metabolic ages than their real ages. The dysfunctional metabolism of CCS-MNCs is associated with lower expression levels of genes and proteins involved in mitochondrial biogenesis and metabolism regulation, such as CLUH, PGC1-alpha, and SIRT6 in CCS, not observed in the age-matched healthy or elderly subjects. In conclusion, our study identified some biochemical and molecular alterations possibly contributing to the pathophysiology of aging and metabolic deficiencies in CCS. These results identify new targets for pharmacological interventions to restore mitochondrial function, slowing down the aging-associated pathologies in CCS.
Mutational Characterization of Cutaneous Melanoma Supports Divergent Pathways Model for Melanoma Development
Authors: Millán-Esteban David , Peña-Chilet María , García-Casado Zaida , Manrique-Silva Esperanza , Requena Celia , Bañuls José , López-Guerrero Jose Antonio , Rodríguez-Hernández Aranzazu , Traves Víctor , Dopazo Joaquín , Virós Amaya , Kumar Rajiv , Nagore Eduardo
Published: October 2021

According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being BRAF. The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included NF1, ROS1, GNA11, and RAC1. We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.
Comprehensive Analysis of VEGFR2 Expression in HPV-Positive and -Negative OPSCC Reveals Differing VEGFR2 Expression Patterns
Authors: Uzun Senem , Korkmaz Yüksel , Wuerdemann Nora , Arolt Christoph , Puladi Behrus , Siefer Oliver G. , Dönmez Hanife G. , Hufbauer Martin , Akgül Baki , Klussmann Jens P. , Huebbers Christian U.
Published: October 2021

VEGF signaling regulated by the vascular endothelial growth factor receptor 2 (VEGFR2) plays a decisive role in tumor angiogenesis, initiation and progression in several tumors including HNSCC. However, the impact of HPV-status on the expression of VEGFR2 in OPSCC has not yet been investigated, although HPV oncoproteins E6 and E7 induce VEGF-expression. In a series of 56 OPSCC with known HPV-status, VEGFR2 expression patterns were analyzed both in blood vessels from tumor-free and tumor-containing regions and within tumor cells by immunohistochemistry using densitometry. Differences in subcellular colocalization of VEGFR2 with endothelial, tumor and stem cell markers were determined by double-immunofluorescence imaging. Immunohistochemical results were correlated with clinicopathological data. HPV-infection induces significant downregulation of VEGFR2 in cancer cells compared to HPV-negative tumor cells (p = 0.012). However, with respect to blood vessel supply, the intensity of VEGFR2 staining differed only in HPV-positive OPSCC and was upregulated in the blood vessels of tumor-containing regions (p < 0.0001). These results may suggest different routes of VEGFR2 signaling depending on the HPV-status of the OPSCC. While in HPV-positive OPSCC, VEGFR2 might be associated with increased angiogenesis, in HPV-negative tumors, an autocrine loop might regulate tumor cell survival and invasion.
Facile and Rapid Synthesis of Durable SSZ-13 Catalyst Using Choline Chloride Template for Methanol-to-Olefins Reaction
Authors: Lin Xiongchao , Yang Sasha , Li Xiaojia , Wang Caihong , Wang Yonggang
Published: October 2021

In the current study, a facile and rapid synthesis approach for a SSZ-13 catalyst using choline chloride (CC) as a template was proposed, and the catalytic performance for the methanol-to-olefins (MTO) reaction was examined. With a proper amount of CC addition (i.e., m(CC)/m(SiO2) = 0.14), uniform and homogeneously distributed cubic SSZ-13 crystals were obtained within 4 h with lower aggregation. The synthesized catalyst demonstrated excellent porous features with a total specific surface area and mesopore volume of 641.71 m2·g−1 and 0.04 cm3·g−1, respectively. The optimized strong and weak acid sites on SSZ-13 were obtained by regulating the m(CC)/m(SiO2) ratio. The less strong acid sites and a larger amount of weak acid sites in the synthesized catalyst were conducive to the catalytic performance of the MTO reaction under a lower reaction temperature (450 °C). The appropriate acidity and well-developed pore structure of synthesized SSZ-13 could also slow down the carbon deposition rate and, thus, significantly improve the catalytic lifetime of the catalyst. The methanol conversion rate and initial selectivity of light olefin using the synthesized catalyst could maintain over 95% and 50%, respectively, and a lifetime of 172 min was achieved. Although the low olefin selectivity of the synthesized SSZ-13 catalyst was slightly lower than that of the purchased one, its desirable features were thought to have good potential for industrial application.
Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons
Authors: Ting Hsiao-Chien , Yang Hui-I , Harn Horng-Jyh , Chiu Ing-Ming , Su Hong-Lin , Li Xiang , Chen Mei-Fang , Ho Tsung-Jung , Liu Ching-Ann , Tsai Yung-Jen , Chiou Tzyy-Wen , Lin Shinn-Zong , Chang Chia-Yu
Published: October 2021

Amyotrophic lateral sclerosis (ALS) is a progressive nervous system disease that causes motor neuron (MN) degeneration and results in patient death within a few years. To recapitulate the cytopathies of ALS patients’ MNs, SOD1G85R mutant and corrected SOD1G85G isogenic-induced pluripotent stem cell (iPSC) lines were established. Two SOD1 mutant ALS (SOD1G85R and SOD1D90A), two SOD1 mutant corrected (SOD1G85G and SOD1D90D), and one sporadic ALS iPSC lines were directed toward MNs. After receiving ~90% purity for MNs, we first demonstrated that SOD1G85R mutant ALS MNs recapitulated ALS-specific nerve fiber aggregates, similar to SOD1D90A ALS MNs in a previous study. Moreover, we found that both SOD1 mutant MNs showed ALS-specific neurite degenerations and neurotransmitter-induced calcium hyperresponsiveness. In a small compound test using these MNs, we demonstrated that gastrodin, a major ingredient of Gastrodia elata, showed therapeutic effects that decreased nerve fiber cytopathies and reverse neurotransmitter-induced hyperresponsiveness. The therapeutic effects of gastrodin applied not only to SOD1 ALS MNs but also to sporadic ALS MNs and SOD1G93A ALS mice. Moreover, we found that coactivation of the GSK3β and IGF-1 pathways was a mechanism involved in the therapeutic effects of gastrodin. Thus, the coordination of compounds that activate these two mechanisms could reduce nerve fiber cytopathies in SOD1 ALS MNs. Interestingly, the therapeutic role of GSK3β activation on SOD1 ALS MNs in the present study was in contrast to the role previously reported in research using cell line- or transgenic animal-based models. In conclusion, we identified in vitro ALS-specific nerve fiber and neurofunctional markers in MNs, which will be useful for drug screening, and we used an iPSC-based model to reveal novel therapeutic mechanisms (including GSK3β and IGF-1 activation) that may serve as potential targets for ALS therapy.
Structural Equation Modeling (SEM) Analysis of Sequence Variation and Green Plant Regeneration via Anther Culture in Barley
Authors: Bednarek Piotr Tomasz , Orłowska Renata , Mańkowski Dariusz Rafał , Oleszczuk Sylwia , Zebrowski Jacek
Published: October 2021

The process of anther culture involves numerous abiotic stresses required for cellular reprogramming, microspore developmental switch, and plant regeneration. These stresses affect DNA methylation patterns, sequence variation, and the number of green plants regenerated. Recently, in barley (Hordeum vulgare L.), mediation analysis linked DNA methylation changes, copper (Cu2+) and silver (Ag+) ion concentrations, sequence variation, β-glucans, green plants, and duration of anther culture (Time). Although several models were used to explain particular aspects of the relationships between these factors, a generalized complex model employing all these types of data was not established. In this study, we combined the previously described partial models into a single complex model using the structural equation modeling approach. Based on the evaluated model, we demonstrated that stress conditions (such as starvation and darkness) influence β-glucans employed by cells for glycolysis and the tricarboxylic acid cycle. Additionally, Cu2+ and Ag+ ions affect DNA methylation and induce sequence variation. Moreover, these ions link DNA methylation with green plants. The structural equation model also showed the role of time in relationships between parameters included in the model and influencing plant regeneration via anther culture. Utilization of structural equation modeling may have both scientific and practical implications, as it demonstrates links between biological phenomena (e.g., culture-induced variation, green plant regeneration and biochemical pathways), and provides opportunities for regulating these phenomena for particular biotechnological purposes.
Mitochondrial Phospholipid Homeostasis Is Regulated by the i-AAA Protease PaIAP and Affects Organismic Aging
Authors: Löser Timo , Joppe Aljoscha , Hamann Andrea , Osiewacz Heinz D.
Published: October 2021

Mitochondria are ubiquitous organelles of eukaryotic organisms with a number of essential functions, including synthesis of iron-sulfur clusters, amino acids, lipids, and adenosine triphosphate (ATP). During aging of the fungal aging model Podospora anserina, the inner mitochondrial membrane (IMM) undergoes prominent morphological alterations, ultimately resulting in functional impairments. Since phospholipids (PLs) are key components of biological membranes, maintenance of membrane plasticity and integrity via regulation of PL biosynthesis is indispensable. Here, we report results from a lipidomic analysis of isolated mitochondria from P. anserina that revealed an age-related reorganization of the mitochondrial PL profile and the involvement of the i-AAA protease PaIAP in proteolytic regulation of PL metabolism. The absence of PaIAP enhances biosynthesis of characteristic mitochondrial PLs, leads to significant alterations in the acyl composition of the mitochondrial signature PL cardiolipin (CL), and induces mitophagy. These alterations presumably cause the lifespan increase of the PaIap deletion mutant under standard growth conditions. However, PaIAP is required at elevated temperatures and for degradation of superfluous CL synthase PaCRD1 during glycolytic growth. Overall, our study uncovers a prominent role of PaIAP in the regulation of PL homeostasis in order to adapt membrane plasticity to fluctuating environmental conditions as they occur in nature.
Drosophila Dendritic Arborisation Neurons: Fantastic Actin Dynamics and Where to Find Them
Authors: Kilo Lukas , Stürner Tomke , Tavosanis Gaia , Ziegler Anna B.
Published: October 2021

Neuronal dendrites receive, integrate, and process numerous inputs and therefore serve as the neuron’s “antennae”. Dendrites display extreme morphological diversity across different neuronal classes to match the neuron’s specific functional requirements. Understanding how this structural diversity is specified is therefore important for shedding light on information processing in the healthy and diseased nervous system. Popular models for in vivo studies of dendrite differentiation are the four classes of dendritic arborization (c1da–c4da) neurons of Drosophila larvae with their class-specific dendritic morphologies. Using da neurons, a combination of live-cell imaging and computational approaches have delivered information on the distinct phases and the time course of dendrite development from embryonic stages to the fully developed dendritic tree. With these data, we can start approaching the basic logic behind differential dendrite development. A major role in the definition of neuron-type specific morphologies is played by dynamic actin-rich processes and the regulation of their properties. This review presents the differences in the growth programs leading to morphologically different dendritic trees, with a focus on the key role of actin modulatory proteins. In addition, we summarize requirements and technological progress towards the visualization and manipulation of such actin regulators in vivo.