bluuebunny/crossref_metadata_2025 huggingface dataset:
A Promising Intracellular Protein-Degradation Strategy: TRIMbody-Away Technique Based on Nanobody Fragment
Authors: Chen Gang , Kong Yu , Li You , Huang Ailing , Wang Chunyu , Zhou Shanshan , Yang Zhenlin , Wu Yanling , Ren Jianke , Ying Tianlei
Published: October 2021

Most recently, a technology termed TRIM-Away has allowed acute and rapid destruction of endogenous target proteins in cultured cells using specific antibodies and endogenous/exogenous tripartite motif 21 (TRIM21). However, the relatively large size of the full-size mAbs (150 kDa) results in correspondingly low tissue penetration and inaccessibility of some sterically hindered epitopes, which limits the target protein degradation. In addition, exogenous introduction of TRIM21 may cause side effects for treated cells. To tackle these limitations, we sought to replace full-size mAbs with the smaller format of antibodies, a nanobody (VHH, 15 kDa), and construct a new type of fusion protein named TRIMbody by fusing the nanobody and RBCC motif of TRIM21. Next, we introduced enhanced green fluorescent protein (EGFP) as a model substrate and generated αEGFP TRIMbody using a bispecific anti-EGFP (αEGFP) nanobody. Remarkably, inducible expression of αEGFP TRIMbody could specifically degrade intracellular EGFP in HEK293T cells in a time-dependent manner. By treating cells with inhibitors, we found that intracellular EGFP degradation by αEGFP TRIMbody relies on both ubiquitin–proteasome and autophagy–lysosome pathways. Taken together, these results suggested that TRIMbody-Away technology could be utilized to specifically degrade intracellular protein and could expand the potential applications of degrader technologies.
Cytokinin-Based Tissue Cultures for Stable Medicinal Plant Production: Regeneration and Phytochemical Profiling of Salvia bulleyana Shoots
Authors: Grzegorczyk-Karolak Izabela , Hnatuszko-Konka Katarzyna , Krzemińska Marta , Olszewska Monika A. , Owczarek Aleksandra
Published: October 2021

Salvia bulleyana is a rare Chinese medicinal plant that due to the presence of polyphenols lowers the risk of some chronic diseases especially those related to the cardiovascular system. The present study examines the organogenic competence of various combinations and concentrations of plant growth regulators to develop an efficient protocol for in vitro regeneration of S. bulleyana via leaf explants, maintaining the high production of active constituents. The purpose of the study was also to assess the possibilities of using a cytokinin-based regeneration to effectively produce therapeutic compounds. The adventitious shoot formation was observed through direct organogenesis on media with purine derivatives (meta-topolin, mT and benzylaminopurine, BAP), and through indirect organogenesis on media with urea derivatives (tidiazuron, TDZ and forchlorfenuron, CPPU). The highest regeneration frequency (95%) with 5.2 shoots per explant was obtained on leaves cultured on Murashige and Skoog (MS) medium containing 0.1 mg/L naphthalene-1-acetic acid (NAA) and 2 mg/L BAP. Following inter simple sequence repeat (ISSR) marker-based profiling, the obtained organogenic shoot lines revealed a similar banding pattern to the mother line, with total variability of 4.2–13.7%, indicating high level of genetic stability. The similar genetic profile of the studied lines translated into similar growth parameters. Moreover, HPLC analysis revealed no qualitative differences in the profile of bioactive metabolites; also, the total polyphenol content was similar for different lines, with the exception of the shoots obtained in the presence of CPPU that produced higher level of bioactive compounds. This is the first report of an effective and rapid in vitro organogenesis protocol for S. bulleyana, which can be efficiently employed for obtaining stable cultures rich in bioactive metabolites.
The Rationale for the Automation of a New Diagnostic Thermography Protocol to Confirm a Chronic-Low-Back-Pain Subtype Related to Nociplastic Pain
Authors: Skorupska Elzbieta , Dybek Tomasz
Published: October 2021

Gluteal syndrome (GS), a new low-back-pain subtype mimicking sciatica, has been included in the 11th Revision of the International Classification of Diseases (ICD-11). Low back pain is a symptom, not a disease, and the main problem associated with it is pain complexity. A plausible pain generator of gluteal syndrome is the central sensitization process and the therapeutic target area, which are trigger points located within the gluteal muscles. It has been hypothesized that dysregulated immune and autonomic nervous systems (ANS) are involved in central sensitization development. Changes in ANS regulation, mainly through the sympathetic branch, provoke nociceptor activation indirectly by a vasoconstriction–vasodilatation imbalance, or directly by sympathetic–nociceptor activation resulting in widespread pain, hyperalgesia, and allodynia. The minimally invasive procedure (MIP) uses thermography to confirm a completely new biological phenomenon, which suggests a pathological autonomic response to noxious stimuli and can possibly become an objective marker of some nociplastic pain subtypes related to trigger points. This review provides the biological and technical rationale for the automation of the MIP—a possible future diagnostic tool for an objective gluteal syndrome confirmation.
Link between History of Childhood Maltreatment and Emotion Dysregulation in Adults Suffering from Attention Deficit/Hyperactivity Disorder or Borderline Personality Disorder
Authors: Rüfenacht Eva , Pham Eléonore , Nicastro Rosetta , Dieben Karen , Hasler Roland , Weibel Sébastien , Perroud Nader
Published: October 2021

Childhood maltreatment (CM) may have a long-term effect on emotion regulation. This study aimed to explore the relationship between CM and emotion dysregulation (ED) in a heterogeneous population. Four hundred seventy French-speaking outpatients (N = 279 ADHD, N = 70 BPD, N = 60 ADHD + BPD, N = 61 clinical controls) completed the Emotion Reactivity Scale (ERS), the Cognitive Emotional Regulation Questionnaire (CERQ), the Childhood Trauma Questionnaire (CTQ), and the Relationship Scales Questionnaire (RSQ). Reports of childhood maltreatment experiences were significantly associated with increased levels of emotion reactivity in all our groups and in the whole population, with a greater use of non-adaptive cognitive emotion regulation strategies and insecure attachment patterns. Emotional abuse showed the strongest effect. Further analysis indicated that an anxious attachment style significantly mediated the relationship between CM and the use of non-adaptive cognitive emotion regulation strategies and emotion reactivity. The results of our study suggest an impact of CM on ED and a potentially marked effect of emotional abuse. They also indicate a potentially mediating role of insecure attachment in the relationship between a history of childhood abuse and emotion reactivity and a higher use of non-adaptive cognitive emotion regulation strategies in adulthood.
Brain–Computer Interfacing Using Functional Near-Infrared Spectroscopy (fNIRS)
Authors: Paulmurugan Kogulan , Vijayaragavan Vimalan , Ghosh Sayantan , Padmanabhan Parasuraman , Gulyás Balázs
Published: October 2021

Functional Near-Infrared Spectroscopy (fNIRS) is a wearable optical spectroscopy system originally developed for continuous and non-invasive monitoring of brain function by measuring blood oxygen concentration. Recent advancements in brain–computer interfacing allow us to control the neuron function of the brain by combining it with fNIRS to regulate cognitive function. In this review manuscript, we provide information regarding current advancement in fNIRS and how it provides advantages in developing brain–computer interfacing to enable neuron function. We also briefly discuss about how we can use this technology for further applications.
Theoretical Model for a Highly Sensitive Near Infrared Biosensor Based on Bloch Surface Wave with Dirac Semimetal
Authors: Zheng Qiwen , Liu Yamei , Lu Wenguang , Dai Xiaoyu , Tian Haishan , Jiang Leyong
Published: October 2021

In this work, we present a theoretical model of a near-infrared sensitive refractive index biosensor based on the truncate 1D photonic crystal (1D PC) structure with Dirac semimetal. This highly sensitive near-infrared biosensor originates from the sharp reflectance peak caused by the excitation of Bloch surface wave (BSW) at the interface between the Dirac semimetal and 1D PC. The sensitivity of the biosensor model is sensitive to the Fermi energy of Dirac semimetal, the thickness of the truncate layer and the refractive index of the sensing medium. By optimizing the structural parameters, the maximum refractive index sensitivity of the biosensor model can surpass 17.4 × 103/RIU, which achieves a certain competitiveness compared to conventional surface plasmon resonance (SPR) or BSW sensors. Considering that bulk materials are easier to handle than two-dimensional materials in manufacturing facilities, we judge that 3D Dirac semimetal and its related devices will provide a strong competitor and alternative to graphene-based devices.
Oxygen Saturation Behavior by Pulse Oximetry in Female Athletes: Breaking Myths
Authors: Martín-Escudero Pilar , Cabanas Ana María , Fuentes-Ferrer Manuel , Galindo-Canales Mercedes
Published: October 2021

The myths surrounding women’s participation in sport have been reflected in respiratory physiology. This study aims to demonstrate that continuous monitoring of blood oxygen saturation during a maximal exercise test in female athletes is highly correlated with the determination of the second ventilatory threshold (VT2) or anaerobic threshold (AnT). The measurements were performed using a pulse oximeter during a maximum effort test on a treadmill on a population of 27 healthy female athletes. A common behavior of the oxygen saturation evolution during the incremental exercise test characterized by a decrease in saturation before the aerobic threshold (AeT) followed by a second significant drop was observed. Decreases in peripheral oxygen saturation during physical exertion have been related to the athlete’s physical fitness condition. However, this drop should not be a limiting factor in women’s physical performance. We found statistically significant correlations between the maximum oxygen uptake and the appearance of the ventilatory thresholds (VT1 and VT2), the desaturation time, the total test time, and between the desaturation time and the VT2. We observed a relationship between the desaturation time and the VT2 appearance. Indeed, a linear regression model between the desaturation time and the VT2 appearance can predict 80% of the values in our sample. Besides, we suggest that pulse oximetry is a simple, fairly accurate, and non-invasive technique for studying the physical condition of athletes who perform physical exertion.
Highly Efficient Purification of Recombinant VSV-∆G-Spike Vaccine against SARS-CoV-2 by Flow-Through Chromatography
Authors: Lerer Elad , Oren Ziv , Kafri Yaron , Adar Yaakov , Toister Einat , Cherry Lilach , Lupu Edith , Monash Arik , Levy Rona , Dor Eyal , Epstein Eyal , Levin Lilach , Girshengorn Meni , Natan Niva , Zichel Ran , Makovitzki Arik
Published: October 2021

This study reports a highly efficient, rapid one-step purification process for the production of the recombinant vesicular stomatitis virus-based vaccine, rVSV-∆G-spike (rVSV-S), recently developed by the Israel Institute for Biological Research (IIBR) for the prevention of COVID-19. Several purification strategies are evaluated using a variety of chromatography methods, including membrane adsorbers and packed-bed ion-exchange chromatography. Cell harvest is initially treated with endonuclease, clarified, and further concentrated by ultrafiltration before chromatography purification. The use of anion-exchange chromatography in all forms results in strong binding of the virus to the media, necessitating a high salt concentration for elution. The large virus and spike protein binds very strongly to the high surface area of the membrane adsorbents, resulting in poor virus recovery (<15%), while the use of packed-bed chromatography, where the surface area is smaller, achieves better recovery (up to 33%). Finally, a highly efficient chromatography purification process with CaptoTM Core 700 resin, which does not require binding and the elution of the virus, is described. rVSV-S cannot enter the inner pores of the resin and is collected in the flow-through eluent. Purification of the rVSV-S virus with CaptoTM Core 700 resulted in viral infectivity above 85% for this step, with the efficient removal of host cell proteins, consistent with regulatory requirements. Similar results were obtained without an initial ultrafiltration step.
Primer Binding Site (PBS) Profiling of Genetic Diversity of Natural Populations of Endemic Species Allium ledebourianum Schult.
Authors: Khapilina Oxana , Turzhanova Ainur , Danilova Alevtina , Tumenbayeva Asem , Shevtsov Vladislav , Kotukhov Yuri , Kalendar Ruslan
Published: October 2021

Endemic species are especially vulnerable to biodiversity loss caused by isolation or habitat specificity, small population size, and anthropogenic factors. Endemic species biodiversity analysis has a critically important global value for the development of conservation strategies. The rare onion Allium ledebourianum is a narrow-lined endemic species, with natural populations located in the extreme climatic conditions of the Kazakh Altai. A. ledebourianum populations are decreasing everywhere due to anthropogenic impact, and therefore, this species requires preservation and protection. Conservation of this rare species is associated with monitoring studies to investigate the genetic diversity of natural populations. Fundamental components of eukaryote genome include multiple classes of interspersed repeats. Various PCR-based DNA fingerprinting methods are used to detect chromosomal changes related to recombination processes of these interspersed elements. These methods are based on interspersed repeat sequences and are an effective approach for assessing the biological diversity of plants and their variability. We applied DNA profiling approaches based on conservative sequences of interspersed repeats to assess the genetic diversity of natural A. ledebourianum populations located in the territory of Kazakhstan Altai. The analysis of natural A. ledebourianum populations, carried out using the DNA profiling approach, allowed the effective differentiation of the populations and assessment of their genetic diversity. We used conservative sequences of tRNA primer binding sites (PBS) of the long-terminal repeat (LTR) retrotransposons as PCR primers. Amplification using the three most effective PBS primers generated 628 PCR amplicons, with an average of 209 amplicons. The average polymorphism level varied from 34% to 40% for all studied samples. Resolution analysis of the PBS primers showed all of them to have high or medium polymorphism levels, which varied from 0.763 to 0.965. Results of the molecular analysis of variance showed that the general biodiversity of A. ledebourianum populations is due to interpopulation (67%) and intrapopulation (33%) differences. The revealed genetic diversity was higher in the most distant population of A. ledebourianum LD64, located on the Sarymsakty ridge of Southern Altai. This is the first genetic diversity study of the endemic species A. ledebourianum using DNA profiling approaches. This work allowed us to collect new genetic data on the structure of A. ledebourianum populations in the Altai for subsequent development of preservation strategies to enhance the reproduction of this relict species. The results will be useful for the conservation and exploitation of this species, serving as the basis for further studies of its evolution and ecology.
Impact of Long-Rope Jumping on Monoamine and Attention in Young Adults
Authors: Yamashita Masatoshi , Yamamoto Takanobu
Published: October 2021

Previous research has shown that rope jumping improves physical health; however, little is known about its impact on brain-derived monoamine neurotransmitters associated with cognitive regulation. To address these gaps in the literature, the present study compared outcomes between 15 healthy participants (mean age, 23.1 years) after a long-rope jumping exercise and a control condition. Long-rope jumping also requires co-operation between people, attention, spatial cognition, and rhythm sensation. Psychological questionnaires were administered to both conditions, and Stroop task performance and monoamine metabolite levels in the saliva and urine were evaluated. Participants performing the exercise exhibited lower anxiety levels than those in the control condition. Saliva analyses showed higher 3-methoxy-4-hydroxyphenylglycol (a norepinephrine metabolite) levels, and urine analyses revealed higher 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindoleacetic acid (a serotonin metabolite) levels in the exercise condition than in the control. Importantly, urinary 5-hydroxyindoleacetic acid level correlated with salivary and urinary 3-methoxy-4-hydroxyphenylglycol levels in the exercise condition. Furthermore, cognitive results revealed higher Stroop performance in the exercise condition than in the control condition; this performance correlated with salivary 3-methoxy-4-hydroxyphenylglycol levels. These results indicate an association between increased 3-methoxy-4-hydroxyphenylglycol and attention in long-rope jumping. We suggest that long-rope jumping predicts central norepinephrinergic activation and related attention maintenance.
Abnormal Functional Network Topology and Its Dynamics during Sustained Attention Processing Significantly Implicate Post-TBI Attention Deficits in Children
Authors: Cao Meng , Halperin Jeffery M. , Li Xiaobo
Published: October 2021

Traumatic brain injury (TBI) is highly prevalent in children. Attention deficits are among the most common and persistent post-TBI cognitive and behavioral sequalae that can contribute to adverse outcomes. This study investigated the topological properties of the functional brain network for sustained attention processing and their dynamics in 42 children with severe post-TBI attention deficits (TBI-A) and 47 matched healthy controls. Functional MRI data during a block-designed sustained attention task was collected for each subject, with each full task block further divided into the pre-, early, late-, and post-stimulation stages. The task-related functional brain network was constructed using the graph theoretic technique. Then, the sliding-window-based method was utilized to assess the dynamics of the topological properties in each stimulation stage. Relative to the controls, the TBI-A group had significantly reduced nodal efficiency and/or degree of left postcentral, inferior parietal, inferior temporal, and fusiform gyri and their decreased stability during the early and late-stimulation stages. The left postcentral inferior parietal network anomalies were found to be significantly associated with elevated inattentive symptoms in children with TBI-A. These results suggest that abnormal functional network characteristics and their dynamics associated with the left parietal lobe may significantly link to the onset of the severe post-TBI attention deficits in children.
The Department of Veterans Affairs Gulf War Veterans’ Illnesses Biorepository: Supporting Research on Gulf War Veterans’ Illnesses
Authors: Brady Christopher B. , Robey Ian , Stein Thor D. , Huber Bertrand R. , Riley Jessica , Abdul Rauf Nazifa , Spencer Keith R. , Walt Gabriel , Adams Latease , Averill James G. , Walker Sean , McKee Ann C. , Thomson Stephen P. , Kowall Neil W.
Published: October 2021

Aims: To introduce a resource supporting research on Gulf War illness (GWI) and related disorders, the Gulf War Veterans’ Illnesses Biorepository (GWVIB). Methods: Gulf War era veterans (GWVs) are recruited nationally and enrolled via telephone and email/postal mail. Enrolled veterans receive annual telephone and mail follow-up to collect health data until their passing. A postmortem neuropathological examination is performed, and fixed and frozen brain and spinal cord samples are banked to support research. Investigators studying GWI and related disorders may request tissue and data from the GWVIB. Results: As of September 2021, 127 GWVs from 39 states were enrolled; 60 met the criteria for GWI, and 14 met the criteria for chronic multisymptom illness (CMI). Enrollees have been followed up to six years. Postmortem tissue recoveries were performed on 14 GWVs. The most commonly found neuropathologies included amyotrophic lateral sclerosis, chronic traumatic encephalopathy, and Lewy body disease. Tissue was of good quality with an average RNA integrity number of 5.8 (SD = 1.0) and ≥4.8 in all of the cases. Discussion: The availability of health data and high-quality CNS tissue from this well-characterized GWV cohort will support research on GWI and related disorders affecting GWVs. Enrollment is ongoing.
Reduced Axon Calibre in the Associative Striatum of the Sapap3 Knockout Mouse
Authors: Lousada Eliana , Boudreau Mathieu , Cohen-Adad Julien , Nait Oumesmar Brahim , Burguière Eric , Schreiweis Christiane
Published: October 2021

Pathological repetitive behaviours are a common feature of various neuropsychiatric disorders, including compulsions in obsessive–compulsive disorder or tics in Gilles de la Tourette syndrome. Clinical research suggests that compulsive-like symptoms are related to associative cortico-striatal dysfunctions, and tic-like symptoms to sensorimotor cortico-striatal dysfunctions. The Sapap3 knockout mouse (Sapap3-KO), the current reference model to study such repetitive behaviours, presents both associative as well as sensorimotor cortico-striatal dysfunctions. Previous findings point to deficits in both macro-, as well as micro-circuitry, both of which can be affected by neuronal structural changes. However, to date, structural connectivity has not been analysed. Hence, in the present study, we conducted a comprehensive structural characterisation of both associative and sensorimotor striatum as well as major cortical areas connecting onto these regions. Besides a thorough immunofluorescence study on oligodendrocytes, we applied AxonDeepSeg, an open source software, to automatically segment and characterise myelin thickness and axon area. We found that axon calibre, the main contributor to changes in conduction speed, is specifically reduced in the associative striatum of the Sapap3-KO mouse; myelination per se seems unaffected in associative and sensorimotor cortico-striatal circuits.
Framework to Evaluate Quality Performance of Green Building Delivery: Project Brief and Design Stage
Authors: Raouf Ayman , Al-Ghamdi Sami
Published: October 2021

Design quality considers the extent to which the owner’s requirements are accurately synthesized into conformance specifications and drawings for the construction team to execute. Expected superior performance and sustainability of a green building require diligence in design to ensure its specifications are accurately stipulated. Several studies reported mismatches between expected and actual performances in green buildings that were attributed to poor design. This study thus revisits the design process and proposes a framework to map the quality activities in the project brief and design stages using the integration definition for function modeling (IDEFO) process. Semi-structured interviews and a focus group validated the framework and revealed issues in the current design practice that cause insufficient design solutions. Additionally, project delivery systems were discussed, with conditions for improving their suitability. This research contribution elucidates recommended quality activities necessary for green buildings, which often are not implemented in the construction industry, to ultimately ensure that green buildings are properly designed to meet sustainability objectives.
Assessment of Green Building Materials’ Attributes to Achieve Sustainable Building Façades Using AHP
Authors: Mayhoub Marwa , El Sayad Zeyad , Ali Ahmed , Ibrahim Mona
Published: October 2021

The need to enhance the performance of building façades and mitigate adverse environmental impacts has promoted the hypothesis of integrating green materials towards sustainable buildings. Façade designers tend to select building materials based on their green characteristics (origin) or green performance; however, this study highlights the importance of integrating both into the decision process. The main objective is to develop a new assessment process for selecting green building façade materials based on green performance and green originality. Furthermore, the evaluation framework considers four green building rating systems as a reference to allocate credits for the relevant criteria. Applying the proposed criteria in this study helps maximize the points for accreditation when incorporating green building materials in building façades. Moreover, the Analytic Hierarchy Process (AHP) is used to assign the proposed criteria’s weighting importance based on the four rating systems’ average points. After that, performing sensitivity analysis to identify each criterion’s influence is conducted. The study concluded that involving minimum levels of adverse impacts is the preferable criteria regarding the green origin concept. As for the green performance, promoting the performance of indoor air quality is the most favorable selection criteria.
Modeling the Impact of Building-Level Flood Mitigation Measures Made Possible by Early Flood Warnings on Community-Level Flood Loss Reduction
Authors: Nofal Omar M. , van de Lindt John W. , Cutler Harvey , Shields Martin , Crofton Kevin
Published: October 2021

The growing number of flood disasters worldwide and the subsequent catastrophic consequences of these events have revealed the flood vulnerability of communities. Flood impact predictions are essential for better flood risk management which can result in an improvement of flood preparedness for vulnerable communities. Early flood warnings can provide households and business owners additional time to save certain possessions or products in their buildings. This can be accomplished by elevating some of the water-sensitive components (e.g., appliances, furniture, electronics, etc.) or installing a temporary flood barrier. Although many qualitative and quantitative flood risk models have been developed and highlighted in the literature, the resolution used in these models does not allow a detailed analysis of flood mitigation at the building- and community level. Therefore, in this article, a high-fidelity flood risk model was used to provide a linkage between the outputs from a high-resolution flood hazard model integrated with a component-based probabilistic flood vulnerability model to account for the damage for each building within the community. The developed model allowed to investigate the benefits of using a precipitation forecast system that allows a lead time for the community to protect its assets and thereby decreasing the amount of flood-induced losses.
Shaking Table Tests and Validation of Multi-Modal Sensing and Damage Detection Using Smartphones
Authors: Han Ruicong , Zhao Xuefeng
Published: October 2021

Structural health monitoring (SHM) systems using modal- and vibration-based methods, particularly wireless systems, have been widely investigated in relation to the monitoring of damage states in civil infrastructures such as bridges and buildings. Unlike many current efforts in developing wireless sensors, one can instead leverage the suite of sensors, network transmission, data storage, and embedded processing capabilities built into modern smartphones for SHM. The objective of this work was to assess and validate the use of smartphones for the monitoring of artificial damage states in a three-story steel frame model subjected to shaking table-induced earthquake excitations. The steel frame was a 2D structure with six rotary viscous dampers installed at the beam–column joints, which were used for simulating different damage states at their respective locations; the columns were also replaced with ones of reduced cross-sectional areas to further emulate damage. In addition to instrumenting the frame with conventional tethered sensors, Apple iPhones (pre-loaded with customized smartphone apps to record acceleration and inter-story displacement) were also installed. Shaking table tests were then conducted on the undamaged and damaged frames, while conventional sensors’ and smartphones’ responses were collected and compared. Wavelet packet decomposition was employed to analyze the acceleration data to detect damage in two different cases. Structural displacements were also computed from acceleration measurements and compared with displacement measurements to further validate the quality of smartphone sensor measurements.
The Impact of Entrepreneurship on Economic Growth within a City
Authors: Huang Xiaoyan , Chen Yuli
Published: October 2021

Entrepreneurship usually takes place in innovative systems, mostly in cities. Cities, with unique features, may alter the impact of entrepreneurship. This paper employs multiple regression models to assess the impact of entrepreneurship on economic growth, considering the moderation effect of the city context. We use Gross Domestic Product (GDP) as the dependent variable and government spending, labor, fixed and financial capital and entrepreneurship as the independent variables. The data are from the 2003–2017 yearbooks of Zhaoqing, Shantou and Meizhou (three cities with distinct cultural and geographic features in Guangdong, China). We conclude that (1) the three cities’ GDPs highly rely on traditional factors of production (i.e., government spending, labor and fixed and financial capital) rather than entrepreneurship and (2) the city context of Meizhou is relatively unsupportive of its entrepreneurship contributing to the GDP, in comparison with that of Zhaoqing and Shantou. This study adds to the literature by empirically assessing and comparing three cities’ entrepreneurship development in China; it also informs scholars and practitioners of the moderation effect of the city context.
Discovery of a Potent and Highly Isoform-Selective Inhibitor of the Neglected Ribosomal Protein S6 Kinase Beta 2 (S6K2)
Authors: Gerstenecker Stefan , Haarer Lisa , Schröder Martin , Kudolo Mark , Schwalm Martin P. , Wydra Valentin , Serafim Ricardo A. M. , Chaikuad Apirat , Knapp Stefan , Laufer Stefan , Gehringer Matthias
Published: October 2021

The ribosomal protein S6 kinase beta 2 (S6K2) is thought to play an important role in malignant cell proliferation, but is understudied compared to its closely related homolog S6 kinase beta 1 (S6K1). To better understand the biological function of S6K2, chemical probes are needed, but the high similarity between S6K2 and S6K1 makes it challenging to selectively address S6K2 with small molecules. We were able to design the first potent and highly isoform-specific S6K2 inhibitor from a known S6K1-selective inhibitor, which was merged with a covalent inhibitor engaging a cysteine located in the hinge region in the fibroblast growth factor receptor kinase (FGFR) 4 via a nucleophilic aromatic substitution (SNAr) reaction. The title compound shows a high selectivity over kinases with an equivalently positioned cysteine, as well as in a larger kinase panel. A good stability towards glutathione and Nα-acetyl lysine indicates a non-promiscuous reactivity pattern. Thus, the title compound represents an important step towards a high-quality chemical probe to study S6K2-specific signaling.
Overcoming Resistance to Immunotherapy in Advanced Cutaneous Squamous Cell Carcinoma
Authors: García-Sancha Natalia , Corchado-Cobos Roberto , Bellido-Hernández Lorena , Román-Curto Concepción , Cardeñoso-Álvarez Esther , Pérez-Losada Jesús , Orfao Alberto , Cañueto Javier
Published: October 2021

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans, and is now responsible for as many deaths as melanoma. Immunotherapy has changed the therapeutic landscape of advanced CSCC after the FDA approval of anti-PD1 molecules for the treatment of locally advanced and metastatic CSCC. However, roughly 50% of patients will not respond to this systemic treatment and even those who do respond can develop resistance over time. The etiologies of primary and secondary resistance to immunotherapy involve changes in the neoplastic cells and the tumor microenvironment. Indirect modulation of immune system activation with new therapies, such as vaccines, oncolytic viruses, and new immunotherapeutic agents, and direct modulation of tumor immunogenicity using other systemic treatments or radiotherapy are now under evaluation in combined regimens. The identification of predictors of response is an important area of research. In this review, we focus on the features associated with the response to immunotherapy, and the evaluation of combination treatments and new molecules, a more thorough knowledge of which is likely to improve the survival of patients with advanced CSCC.
KLF4 Induces Mesenchymal–Epithelial Transition (MET) by Suppressing Multiple EMT-Inducing Transcription Factors
Authors: Subbalakshmi Ayalur Raghu , Sahoo Sarthak , McMullen Isabelle , Saxena Aaditya Narayan , Venugopal Sudhanva Kalasapura , Somarelli Jason A. , Jolly Mohit Kumar
Published: October 2021

Epithelial–Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial to mesenchymal (EMT) or from mesenchymal to epithelial (MET) phenotypes. Both these processes are modulated by multiple transcription factors acting in concert. While EMT-inducing transcription factors (TFs)—TWIST1/2, ZEB1/2, SNAIL1/2/3, GSC, and FOXC2—are well-characterized, the MET-inducing TFs are relatively poorly understood (OVOL1/2 and GRHL1/2). Here, using mechanism-based mathematical modeling, we show that transcription factor KLF4 can delay the onset of EMT by suppressing multiple EMT-TFs. Our simulations suggest that KLF4 overexpression can promote a phenotypic shift toward a more epithelial state, an observation suggested by the negative correlation of KLF4 with EMT-TFs and with transcriptomic-based EMT scoring metrics in cancer cell lines. We also show that the influence of KLF4 in modulating the EMT dynamics can be strengthened by its ability to inhibit cell-state transitions at the epigenetic level. Thus, KLF4 can inhibit EMT through multiple parallel paths and can act as a putative MET-TF. KLF4 associates with the patient survival metrics across multiple cancers in a context-specific manner, highlighting the complex association of EMP with patient survival.
Genomic Risk Factors for Cervical Cancer
Authors: Ramachandran Dhanya , Dörk Thilo
Published: October 2021

Cervical cancer is the fourth common cancer amongst women worldwide. Infection by high-risk human papilloma virus is necessary in most cases, but not sufficient to develop invasive cervical cancer. Despite a predicted genetic heritability in the range of other gynaecological cancers, only few genomic susceptibility loci have been identified thus far. Various case-control association studies have found corroborative evidence for several independent risk variants at the 6p21.3 locus (HLA), while many reports of associations with variants outside the HLA region remain to be validated in other cohorts. Here, we review cervical cancer susceptibility variants arising from recent genome-wide association studies and meta-analysis in large cohorts and propose 2q14 (PAX8), 17q12 (GSDMB), and 5p15.33 (CLPTM1L) as consistently replicated non-HLA cervical cancer susceptibility loci. We further discuss the available evidence for these loci, knowledge gaps, future perspectives, and the potential impact of these findings on precision medicine strategies to combat cervical cancer.
CDKN2A-Mutated Pancreatic Ductal Organoids from Induced Pluripotent Stem Cells to Model a Cancer Predisposition Syndrome
Authors: Merkle Jessica , Breunig Markus , Schmid Maximilian , Allgöwer Chantal , Krüger Jana , Melzer Michael K. , Bens Susanne , Siebert Reiner , Perkhofer Lukas , Azoitei Ninel , Seufferlein Thomas , Heller Sandra , Meier Matthias , Müller Martin , Kleger Alexander , Hohwieler Meike
Published: October 2021

Patient-derived induced pluripotent stem cells (iPSCs) provide a unique platform to study hereditary disorders and predisposition syndromes by resembling germline mutations of affected individuals and by their potential to differentiate into nearly every cell type of the human body. We employed plucked human hair from two siblings with a family history of cancer carrying a pathogenic CDKN2A variant, P16-p.G101W/P14-p.R115L, to generate patient-specific iPSCs in a cancer-prone ancestry for downstream analytics. The differentiation capacity to pancreatic progenitors and to pancreatic duct-like organoids (PDLOs) according to a recently developed protocol remained unaffected. Upon inducible expression of KRASG12Dusing a piggyBac transposon system in CDKN2A-mutated PDLOs, we revealed structural and molecular changes in vitro, including disturbed polarity and epithelial-to-mesenchymal (EMT) transition. CDKN2A-mutated KRASG12DPDLO xenotransplants formed either a high-grade precancer lesion or a partially dedifferentiated PDAC-like tumor. Intriguingly, P14/P53/P21 and P16/RB cell-cycle checkpoint controls have been only partly overcome in these grafts, thereby still restricting the tumorous growth. Hereby, we provide a model for hereditary human pancreatic cancer that enables dissection of tumor initiation and early development starting from patient-specific CDKN2A-mutated pluripotent stem cells.
A Systems Approach to Interrogate Gene Expression Patterns in African American Men Presenting with Clinically Localized Prostate Cancer
Authors: Hardiman Gary , Savage Stephen J. , Hazard E. Starr , da Silveira Willian A. , Morgan Rebecca , Harris Adam , Jefferson Melanie S. , Wilson Robert C. , Caulder Susan , Ambrose Linda , Frey Lewis , Wolf Bethany , Gattoni-Celli Sebastiano , Hughes Halbert Chanita
Published: October 2021

An emerging theory about racial differences in cancer risk and outcomes is that psychological and social stressors influence cellular stress responses; however, limited empirical data are available on racial differences in cellular stress responses among men who are at risk for adverse prostate cancer outcomes. In this study, we undertook a systems approach to examine molecular profiles and cellular stress responses in an important segment of African American (AA) and European American (EA) men: men undergoing prostate biopsy. We assessed the prostate transcriptome with a single biopsy core via high throughput RNA sequencing (RNA-Seq). Transcriptomic analyses uncovered impacted biological pathways including PI3K-Akt signaling pathway, Neuroactive ligand-receptor interaction pathway, and ECM-receptor interaction. Additionally, 187 genes mapping to the Gene Ontology (GO) terms RNA binding, structural constituent of ribosome, SRP-dependent co-translational protein targeting to membrane and the biological pathways, translation, L13a-mediated translational silencing of Ceruloplasmin expression were differentially expressed (DE) between EA and AA. This signature allowed separation of AA and EA patients, and AA patients with the most severe clinical characteristics. AA patients with elevated expression levels of this genomic signature presented with higher Gleason scores, a greater number of positive core biopsies, elevated dehydroepiandrosterone sulfate levels and serum vitamin D deficiency. Protein-protein interaction (PPI) network analysis revealed a high degree of connectivity between these 187 proteins.
Inducible Liver Cancer Models in Transgenic Zebrafish to Investigate Cancer Biology
Authors: Lee Ai Qi , Li Yan , Gong Zhiyuan
Published: October 2021

Primary liver cancer is one of the most prevalent and deadly cancers, which incidence continues to increase while treatment response remains poor; thus, in-depth understanding of tumour events is necessary to develop more effective therapies. Animal models for liver cancer are powerful tools to reach this goal. Over the past decade, our laboratory has established multiple oncogene transgenic zebrafish lines that can be robustly induced to develop liver cancer. Histological, transcriptomic and molecular analyses validate the use of these transgenic zebrafish as experimental models for liver cancer. In this review, we provide a comprehensive summary of our findings with these inducible zebrafish liver cancer models in tumour initiation, oncogene addiction, tumour microenvironment, gender disparity, cancer cachexia, drug screening and others. Induced oncogene expression causes a rapid change of the tumour microenvironment such as inflammatory responses, increased vascularisation and rapid hepatic growth. In several models, histologically-proven carcinoma can be induced within one week of chemical inducer administration. Interestingly, the induced liver tumours show the ability to regress when the transgenic oncogene is suppressed by the withdrawal of the chemical inducer. Like human liver cancer, there is a strong bias of liver cancer severity in male zebrafish. After long-term tumour progression, liver cancer-bearing zebrafish also show symptoms of cancer cachexia such as muscle-wasting. In addition, the zebrafish models have been used to screen for anti-metastasis drugs as well as to evaluate environmental toxicants in carcinogenesis. These findings demonstrated that these inducible zebrafish liver cancer models provide rapid and convenient experimental tools for further investigation of fundamental cancer biology, with the potential for the discovery of new therapeutic approaches.
New Advances in Liquid Biopsy Technologies for Anaplastic Lymphoma Kinase (ALK)—Positive Cancer
Authors: Villa Matteo , Sharma Geeta G. , Manfroni Chiara , Cortinovis Diego , Mologni Luca
Published: October 2021

Cancer cells are characterized by high genetic instability, that favors tumor relapse. The identification of the genetic causes of relapse can direct next-line therapeutic choices. As tumor tissue rebiopsy at disease progression is not always feasible, noninvasive alternative methods are being explored. Liquid biopsy is emerging as a non-invasive, easy and repeatable tool to identify specific molecular alterations and monitor disease response during treatment. The dynamic follow-up provided by this analysis can provide useful predictive information and allow prompt therapeutic actions, tailored to the genetic profile of the recurring disease, several months before radiographic relapse. Oncogenic fusion genes are particularly suited for this type of analysis. Anaplastic Lymphoma Kinase (ALK) is the dominant driver oncogene in several tumors, including Anaplastic Large-Cell Lymphoma (ALCL), Non-Small Cell Lung Cancer (NSCLC) and others. Here we review recent findings in liquid biopsy technologies, including ctDNA, CTCs, exosomes, and other markers that can be investigated from plasma samples, in ALK-positive cancers.
Serum Epiplakin Might Be a Potential Serodiagnostic Biomarker for Bladder Cancer
Authors: Shimura Soichiro , Matsumoto Kazumasa , Shimizu Yuriko , Mochizuki Kohei , Shiono Yutaka , Hirano Shuhei , Koguchi Dai , Ikeda Masaomi , Sato Yuichi , Iwamura Masatsugu
Published: October 2021

Tumor markers that can be detected at an early stage are needed. Here, we evaluated the epiplakin expression levels in sera from patients with bladder cancer (BC). Using a micro-dot blot array, we evaluated epiplakin expression levels in 60 patients with BC, 20 patients with stone disease, and 28 healthy volunteers. The area under the curve (AUC) and best cut-off point were calculated using receiver-operating characteristic (ROC) analysis. Serum epiplakin levels were significantly higher in patients with BC than in those with stone disease (p = 0.0013) and in healthy volunteers (p < 0.0001). The AUC-ROC level for BC was 0.78 (95% confidence interval (CI) = 0.69–0.87). Using a cut-off point of 873, epiplakin expression levels exhibited 68.3% sensitivity and 79.2% specificity for BC. However, the serum epiplakin levels did not significantly differ by sex, age, pathological stage and grade, or urine cytology. We performed immunohistochemical staining using the same antibody on another cohort of 127 patients who underwent radical cystectomy. Univariate and multivariate analysis results showed no significant differences between epiplakin expression, clinicopathological findings, and patient prognoses. Our results showed that serum epiplakin might be a potential serodiagnostic biomarker in patients with BC.
Evaluation of Angiogenesis-Related Genes as Prognostic Biomarkers of Bevacizumab Treated Ovarian Cancer Patients: Results from the Phase IV MITO16A/ManGO OV-2 Translational Study
Authors: Califano Daniela , Gallo Daniela , Rampioni Vinciguerra Gian Luca , De Cecio Rossella , Arenare Laura , Signoriello Simona , Russo Daniela , Ferrandina Gabriella , Citron Francesca , Losito Nunzia Simona , Gargiulo Piera , Simeon Vittorio , Scambia Giovanni , Cecere Sabrina Chiara , Montella Marco , Colombo Nicoletta , Tognon Germana , Bignotti Eliana , Zannoni Gian Franco , Canzonieri Vincenzo , Ciucci Alessandra , Spina Anna , Scognamiglio Giosuè , Del Sesto Michele , Schettino Clorinda , Piccirillo Maria Carmela , Perrone Francesco , Chiodini Paolo , Pignata Sandro , Baldassarre Gustavo
Published: October 2021

Background. Epithelial ovarian cancer (EOC) is a rare, highly lethal disease. In a subset of high grade EOC patients, maintenance therapy with the antiangiogenic drug Bevacizumab (BEV) is a valuable option. To date, no validated predictive or prognostic biomarkers exist for selecting EOC patients that might benefit from BEV treatment. Methods. Immunohistochemistry and RT-qPCR evaluated the expression of seven angiogenesis-related proteins and of a twelve microRNAs angio-signature in EOC patients, treated in first line with chemotherapy plus BEV (MITO16A/ManGO OV-2 phase IV trial). Centralized statistical analyses assessed the associations between each biomarker, clinical prognostic factors and survival outcomes. Results. High miR-484 expression was associated with longer progression-free and overall survival. Notably, the combined expression of miR-484 and its target VEGFB identified a subset of patients that might mostly benefit from BEV treatment. No other significant correlations were found between the other analyzed biomarkers and patients’ survival. The application of a shrinkage procedure to adjust for over-fitting hazard ratio estimates reduced the association significance. Conclusions. The analysis of angiogenesis related biomarkers in EOC patients homogenously treated with BEV in first line provides novel insight in their prognostic value and suggests that some of them might merit to be tested as predictive markers of drug activity in dedicated randomized trials.