bluuebunny/crossref_metadata_2025 huggingface dataset:
Fungal Endophytes: Microfactories of Novel Bioactive Compounds with Therapeutic Interventions; A Comprehensive Review on the Biotechnological Developments in the Field of Fungal Endophytic Biology over the Last Decade
Authors: Gupta Aditi , Meshram Vineet , Gupta Mahiti , Goyal Soniya , Qureshi Kamal Ahmad , Jaremko Mariusz , Shukla Kamlesh Kumar
Published: June 2023

The seminal discovery of paclitaxel from endophytic fungus Taxomyces andreanae was a milestone in recognizing the immense potential of endophytic fungi as prolific producers of bioactive secondary metabolites of use in medicine, agriculture, and food industries. Following the discovery of paclitaxel, the research community has intensified efforts to harness endophytic fungi as putative producers of lead molecules with anticancer, anti-inflammatory, antimicrobial, antioxidant, cardio-protective, and immunomodulatory properties. Endophytic fungi have been a valuable source of bioactive compounds over the last three decades. Compounds such as taxol, podophyllotoxin, huperzine, camptothecin, and resveratrol have been effectively isolated and characterized after extraction from endophytic fungi. These findings have expanded the applications of endophytic fungi in medicine and related fields. In the present review, we systematically compile and analyze several important compounds derived from endophytic fungi, encompassing the period from 2011 to 2022. Our systematic approach focuses on elucidating the origins of endophytic fungi, exploring the structural diversity and biological activities exhibited by these compounds, and giving special emphasis to the pharmacological activities and mechanism of action of certain compounds. We highlight the tremendous potential of endophytic fungi as alternate sources of bioactive metabolites, with implications for combating major global diseases. This underscores the significant role that fungi can play in the discovery and development of novel therapeutic agents that address the challenges posed by prevalent diseases worldwide.
Factors Important in the Use of Fluorescent or Luminescent Probes and Other Chemical Reagents to Measure Oxidative and Radical Stress
Authors: Wardman Peter
Published: June 2023

Numerous chemical probes have been used to measure or image oxidative, nitrosative and related stress induced by free radicals in biology and biochemistry. In many instances, the chemical pathways involved are reasonably well understood. However, the rate constants for key reactions involved are often not yet characterized, and thus it is difficult to ensure the measurements reflect the flux of oxidant/radical species and are not influenced by competing factors. Key questions frequently unanswered are whether the reagents are used under ‘saturating’ conditions, how specific probes are for particular radicals or oxidants and the extent of the involvement of competing reactions (e.g., with thiols, ascorbate and other antioxidants). The commonest-used probe for ‘reactive oxygen species’ in biology actually generates superoxide radicals in producing the measured product in aerobic systems. This review emphasizes the need to understand reaction pathways and in particular to quantify the kinetic parameters of key reactions, as well as measure the intracellular levels and localization of probes, if such reagents are to be used with confidence.
Application of CRISPR Cas Systems for Biosensing
Authors: Liu Chung Chiun , Dai Yifan
Published: June 2023

The essential properties of a biosensor are its sensitivity and selectivity to detect, monitor and quantify the biomarker(s) for the interests of medicine [...]
Electrospun Nanofibers including Organic/Inorganic Nanohybrids: Polystyrene- and Clay-Based Architectures in Immunosensor Preparation for Serum Amyloid A
Authors: Evren Gizem , Er Eray , Yalcinkaya Esra Evrim , Horzum Nesrin , Odaci Dilek
Published: June 2023

Diagnostic techniques based on biomolecules have application potential that can be realized in many fields, such as disease diagnosis, bioprocess imaging, food/beverage industries, and environmental pollutant imaging. Successful surface immobilization of biomolecules is critical to increasing the stabilization, sensitivity, and selectivity of biomolecules used in bioassay systems. Nanofibers are good candidates for the immobilization of biomolecules owing to many advantages such as morphology and pore size. In this study, montmorillonite (MMT) clay is modified with poly(amidoamine) (PAMAM) generation 3 (PAMAMG3) and added to polystyrene (PS) solutions, following which PS/MMT-PAMAMG3 nanofibers are obtained using the electrospinning method. The nanofibers are obtained by testing PS% (wt%) and MMT-PAMAMG3% (wt%) ratios and characterized with scanning electron microscopy. Antiserum amyloid A antibody (Anti-SAA) is then conjugated to the nanofibers on the electrode surface via covalent bonds using a zero-length cross linker. Finally, the obtained selective surface is used for electrochemical determination of serum amyloid A (SAA) levels. The linear range of PS/MMT-PAMAM/Anti-SAA is between 1 and 200 ng/mL SAA, and the detection limit is 0.57 ng/mL SAA. The applicability of PS/MMT-PAMAMG3/Anti-SAA is investigated by taking measurements in synthetic saliva and serum both containing SAA.
Rapid and Quantitative Detection of Lung Cancer Biomarker ENOX2 Using a Novel Aptamer in an Electrochemical DNA-Based (E-DNA) Biosensor
Authors: Quansah Mary , Fetter Lisa , Fineran Autumn , Colling Haley V. , Silver Keaton , Rowland Teisha J. , Bonham Andrew J.
Published: June 2023

To overcome early cancer detection challenges, diagnostic tools enabling more sensitive, rapid, and noninvasive detection are necessary. An attractive cancer target for diagnostic blood tests is human Ecto-NOX disulfide–thiol exchanger 2 (ENOX2), expressed in most human cancer types and regularly shed into blood sera. Here, we developed an electrochemical DNA-based (E-DNA) biosensor that rapidly detects physiologically relevant levels of ENOX2. To identify ENOX2-binding aptamers that could potentially be used in a biosensor, recombinantly expressed ENOX2 was used as a binding target in an oligonucleotide library pull-down that generated a highly enriched ENOX2-binding aptamer. This candidate aptamer sensitively bound ENOX2 via gel mobility shift assays. To enable this aptamer to function in an ENOX2 E-DNA biosensor, the aptamer sequence was modified to adopt two conformations, one capable of ENOX2 binding, and one with disrupted ENOX2 binding. Upon ENOX2 introduction, a conformational shift to the ENOX2 binding state resulted in changed dynamics of a redox reporter molecule, which generated a rapid, significant, and target-specific electrical current readout change. ENOX2 biosensor sensitivity was at or below the diagnostic range. The ENOX2 E-DNA biosensor design presented here may enable the development of more sensitive, rapid, diagnostic tools for early cancer detection.
Selection for Reduced Fear of Humans Changes Brain and Cerebellum Size in Red Junglefowl in Line with Effects of Chicken Domestication
Authors: Gjøen Johanna , Cunha Felipe , Jensen Per
Published: June 2023

A central part of the domestication syndrome is a reduction in relative brain size. In chickens, it has previously been shown that domesticated birds have smaller relative brain mass, but larger relative mass of cerebellum, compared to their ancestors, the Red Junglefowl. It has been suggested that tameness may drive the domestication syndrome, so we examined the relationship between brain characteristics and tameness in 31 Red Junglefowl from lines divergently selected during ten generations for tameness. Our focus was on the whole brain, cerebellum, and the remainder of the brain. We used the isotropic fractionator technique to estimate the total number of cells in the cerebellum and differentiate between neurons and non-neuronal cells. We stained the cell nuclei with DAPI and performed cell counting using a fluorescence microscope. NeuN immunostaining was used to identify neurons. The absolute and relative masses of the brains and their regions were determined through weighing. Our analysis revealed that birds selected for low fear of humans (LF) had smaller relative brain mass compared to those selected for high fear of humans (HF). Sex had a significant impact only on the absolute size of the cerebellum, not its relative size. These findings support the notion that selection for increased tameness leads to an enlargement of the relative size of cerebellum in chickens consistent with comparisons of domesticated and ancestral chickens. Surprisingly, the HF birds had a higher density of neurons in the cerebellum compared to the LF line, despite having a smaller cerebellum overall. These findings highlight the intricate relationship between brain structure and behavior in the context of domestication.
Association between Citrullinated Histone H3 and White Matter Lesions Burden in Patients with Ischemic Stroke
Authors: Zhang Xiaohao , Li Yunzi , Huang Zhenqian , Chen Shuaiyu , E Yan , Zhang Yingdong , Wang Qingguang , Li Tingting
Published: June 2023

Introduction: Neutrophil extracellular traps play a role in the pathophysiology of stroke and are associated with severity and mortality. We aimed to investigate whether the citrullinated histone H3 (CitH3), a biomarker for neutrophil extracellular traps formation, is associated with the white matter lesion (WML) burden in ischemic stroke patients. Methods: Between September 2021 and April 2022, 322 patients were enrolled in this prospective observational cohort study. Serum CitH3 levels were measured after admission using an enzyme-linked immunosorbent assay. WMLs severity was graded according to the Fazekas scale and conceptually defined as mild (total Fazekas score 0–2) and severe (total Fazekas score 3–6). We used multivariable regression models to determine the relationship between CitH3 concentrations and the severity of WMLs burden. Results: One-hundred and forty-eight (46.0%) patients were diagnosed with severe WMLs burden after admission. Increased CitH3 levels (first quartile vs. fourth quartile of H3Cit, odds ratio, 3.311, 95% confidence interval, 1.336–8.027; p = 0.011) were independently associated with a greater WML burden in the fully adjusted multivariable model. Similar results were found when the H3Cit was analyzed as a continuous variable. Furthermore, the multiple-adjusted spline regression model showed a linear association between H3Cit levels and severe WMLs (P = 0.001 for linearity). Conclusions: In the present study, increased CitH3 levels were positively associated with extensive WMLs in ischemic stroke patients, indicating a role of neutrophil extracellular traps formation in the pathogenesis of WMLs.
Music Therapy for Gait and Speech Deficits in Parkinson’s Disease: A Mini-Review
Authors: Fan Leon , Hu Ellen Y. , Hey Grace E. , Hu Wei
Published: June 2023

Parkinson’s disease (PD) is a progressive central nervous system disease with a common motor symptom of gait disturbance in PD, which is more pronounced in the later stages. Although FDA-approved treatments, including dopaminergic pharmacotherapy, deep brain stimulation, and rehabilitation, have some benefits in improving gait dysfunction, a fair amount of advanced PD patients can develop a disability, social isolation, and high mortality and morbidity. Recently, clinicians and scientists have applied music to clinical therapy, namely music therapy. It has been used as a unique rehabilitation tool to improve PD-induced gait and speech disorders. Based on relevant studies in recent years, this paper reviews the published literature about music in treating gait disorders and speech problems in PD patients. Additionally, we discuss current studies’ limitations and emphasize the future potential research fields.
Task-Related Differences in End-Point Kinematics in School-Age Children with Typical Development
Authors: Mazzarella Julia , Richie Daniel , Chaudhari Ajit M. W. , Tudella Eloisa , Spees Colleen K. , Heathcock Jill C.
Published: June 2023

Understanding whether and how children with typical development adapt their reaches for different functional tasks could inform a more targeted design of rehabilitation interventions to improve upper extremity function in children with motor disabilities. This prospective study compares timing and coordination of a reach-to-drink, reach-to-eat, and a bilateral reaching task in typically developing school-aged children. Average speed, straightness, and smoothness of hand movements were measured in a convenience sample of 71 children, mean age 8.77 ± 0.48 years. Linear mixed models for repeated measures compared the variables by task, phases of the reach, task x phase interactions, and dominant versus non-dominant hands. There were significant main effects for task and phase, significant task x phase interactions (p < 0.05), and a significant difference between the dominant and non-dominant hand for straightness. Hand movements were fastest and smoothest for the reach-to-eat task, and least straight for the bilateral reaching task. Hand movements were also straighter in the object transport phases than the prehension and withdrawal phases. These results indicate that children with typical development change their timing and coordination of reach based on the task they are performing. These results can inform the design of rehabilitation interventions targeting arm and hand function.
The Influence of the Prestressing Level of the Fully Threaded Anchor Bar on the Corrosion Rate
Authors: Zahuranec Michal , Koteš Peter , Kraľovanec Jakub
Published: June 2023

The article presents experimental research on the corrosion of prestressing steel bars with denotation CKT (fully threaded anchor bars), which are composed of high-quality prestressing steel of the grade Y 1050 (1050 MPa). The experiment was performed using an electrochemical accelerated test. The aspects of the electric current value influence, time dependence on the degree of corrosion, and especially the influence of the prestressing level in the prestressing steel bars on the degree of corrosion were observed and examined. The results of the experiment showed that if the sample was in a stressed state, its degree of corrosion increased. Specifically, for the maximal stress equal to 90% of the tensile strength, the corrosion degree was increased by approximately 7.3%, in comparison to the unstressed specimen. In this case, a 7.3% corrosion degree corresponds to a weight loss of 350 g. The theoretical degree of corrosion was calculated using Faraday’s Law, which allowed the prediction of a rough estimate of the corrosion degree obtained with known input data. The experimental results showed that there was no apparent difference in the corrosion morphology of the sample during the same time-dependent corrosion influence at the same prestressing level in the sample with the same electric current value.
Changes in Clay Hollow Block Geometry for Energy Efficiency Benefits—Thermal Simulation for Brazil
Authors: Gondim Ivo Almino , Sousa Hipólito , Bertini Alexandre
Published: June 2023

Masonry, which constitutes a large area of many buildings’ envelopes, represents important thermal performance and energy consumption functions. Clay hollow block geometry can influence these results. In this sense, this work aims to numerically evaluate the thermal properties and energy efficiency improvement provided by new geometries of clay blocks in the Brazilian context. Two commercial block geometries were selected, and new internal void geometries were proposed, maintaining approximately the same percentage of voids. The new formats were submitted to numerical simulation using Abaqus/CAE 2020 software, to obtain their thermal resistance. Finally, an energy simulation study was carried out in three housing typologies located in two Brazilian cities, Curitiba and Fortaleza, using EnergyPlus 9.2 software. Geometric changes resulted in reductions in thermal transmittance values of greater than 30% for the blocks and 20% for the walls. Regarding possible energy reduction, the study demonstrated that there is a non-significant reduction in values for periods of higher temperature (hottest month), in the evaluated schedule use, as well as a potential for savings (34% in the apartment typology for the coldest month) at lower temperatures. Findings of this study serve as a reference to discuss improvements in clay hollow brick geometry regarding energy efficiency and thermal comfort in the Brazilian context.
Research on the Architectural Features and Artistic Elements of Traditional Buildings in Different Regions of Jiangxi, China
Authors: Song Yingqiu , Liao Chenyue
Published: June 2023

Traditional buildings are a comprehensive manifestation of history, art, and architectural features, and are also a carrier of folk culture, traditional skills, and regional aesthetic tastes. This paper studies traditional buildings and arts from three regions of Jiangxi, including northern Jiangxi, southern Jiangxi, and central Jiangxi. Traditional buildings in Jiangxi Province flourished in the Ming and Qing Dynasties. As Jiangxi is located in the interior of China and is adjacent to many provinces, the architectural art of traditional buildings is greatly influenced by geographical location. Traditional buildings in northern Jiangxi are influenced by Huizhou architectural culture, while those in southern Jiangxi are influenced by Hakka culture. The patio-style buildings and high-lighting buildings that represent the local characteristics of Jiangxi are found exactly in central Jiangxi. The relatively diverse set of architectural features and artistic elements is due to a variety of intertwined regional cultures. Compared with those of the surrounding provinces, the economic level of Jiangxi is relatively underdeveloped, and the local architecture has accordingly formed a restrained, simple, and practical artistic style.
Optimization Model of Substation Building Envelope–Renewable Energy Utilization Based on Life-Cycle Minimum Carbon Emissions
Authors: Zhao Shuizhong , Zhu Yunxiang , Lou Ping , Hu Yuying , Xu Chenguan , Chen Yinhui
Published: June 2023

Maximizing the carbon reduction in substations with minimum cost investments can be achieved by taking advantage of the potential of substations in terms of the envelope and renewable energy, which is significant in promoting carbon reduction in substations. Therefore, firstly, the relationship between building cost–energy consumption–carbon emissions is explored, and then the global optimal calculation model of substation envelope–renewable energy is established, with the lowest life-cycle carbon emission of the substation as the optimization goal. Finally, the validity of the model is verified based on a case study of a typical 110 kV outdoor substation. The model calculation results show that, without considering the cost constraint, Harbin has the highest maximum carbon reduction of 180,350 kg, which is 25.15% and 13.74% higher than the maximum carbon reduction in Shanghai and Haikou, respectively. Furthermore, based on the comparison of the cost and benefits of each carbon reduction technology, a prioritization of various carbon reduction technologies is given for each climate zone. The model established in this paper can provide the optimal configuration of substation carbon reduction technologies with different incremental cost constraints, and provide a reference for the low-carbon design of substations.
Interpreting Housing Prices with a MultidisciplinaryApproach Based on Nature-Inspired Algorithms and Quantum Computing
Authors: De Paola Pierfrancesco , Previtera Simone , Manganelli Benedetto , Forte Fabiana , Del Giudice Francesco Paolo
Published: June 2023

Current technology still does not allow the use of quantum computers for broader and individual uses; however, it is possible to simulate some of its potentialities through quantum computing. Quantum computing can be integrated with nature-inspired algorithms to innovatively analyze the dynamics of the real estate market or any other economic phenomenon. With this main aim, this study implements a multidisciplinary approach based on the integration of quantum computing and genetic algorithms to interpret housing prices. Starting from the principles of quantum programming, the work applies genetic algorithms for the marginal price determination of relevant real estate characteristics for a particular segment of Naples’ real estate market. These marginal prices constitute the quantum program inputs to provide, as results, the purchase probabilities corresponding to each real estate characteristic considered. The other main outcomes of this study consist of a comparison of the optimal quantities for each real estate characteristic as determined by the quantum program and the average amounts of the same characteristics but relative to the real estate data sampled, as well as the weights of the same characteristics obtained with the implementation of genetic algorithms. With respect to the current state of the art, this study is among the first regarding the application of quantum computing to interpretation of selling prices in local real estate markets.
Numerical Analysis on the Behavior of Floating Geogrid-Encased Stone Column Improved Foundation
Authors: Cheng Ye , Cai Xiaocong , Mo Haizhao , Gu Meixiang
Published: June 2023

The ordinary (OSC) and geosynthetic-encased stone column (ESC) with different bearing strata significantly influenced its behavior. The paper established seven models for studying the behavior of floating stone columns using the finite difference method (FDM). The effect of geogrid and column length on the load-settlement behavior, bulging deformation, failure mode, and load transfer coefficient were also analyzed based on proposal models. The results showed that the bearing capacity of F-OSCs and F-ESCs increased with the increase in column and encasement length, respectively, and a critical length (i.e., 4D, where D was the column diameter) was found in settlement improvement. The bulging deformation was significant in F-OSCs and was observed at the top of a long column and the full length of a short column. The geogrid encasement could constrain the OSC to decrease the bulging deformation. The failure mode in F-OSCs was mainly a punching failure with bulging deformation for a short column (e.g., less than 4D), and was relative to the vertical pressure for a long column. The failure mode in F-ESCs was a punching failure, and the punching degree increased with an increase in encasement length. The load transfer coefficient of F-OSCs or F-ESCs was relatively stable as the column length increased to a critical value (e.g., 4D) or the encasement length increased to a critical value (e.g., 4D).
The Impact of Urban Street Network on Land Value: Correlate Syntactical Premises to the Land Price
Authors: Abdulla Hawnaz Magid , Ibrahim Muammal Alaaddin , Al-Hinkawi Wahda Shuker
Published: June 2023

Recent literature has highlighted the critical issue of urban land value and cost; properly assessing land use costs, particularly for residential and commercial purposes, is crucial in influencing urban development and investments. Therefore, the objective of this research is to create a model for land pricing that considers the urban street networks and hierarchy; by analyzing the spatial plan of the city using space syntax and evaluating the economic impact on land value, the study aims to identify the factors that influence land prices. Furthermore, the study intends to investigate the correlation between urban spatial networks, street hierarchy, and land price to create a predictive model for urban spatial land pricing. Ultimately, the study has successfully built a model for predicting the price of urban land. The case selected is evaluated and compared in three aspects of the analysis, including the urban axial assessments and urban street width, to find out their impacts on the real estate’s land price in the context of the land use distributions, which are predominantly residential and commercial types of uses. Depth map X8, SPSS, and QGIS 3.16 were used for the study evaluations and assessments. The study found that land prices are influenced by factors such as integration, connectivity, and street width. Commercial zones with good integration and wider roads tend to command higher prices, while narrow local roads generally have lower prices. This result can enhance future urban design regarding urban economy improvements and land costs.
Experimental Study on the Structural Performance of Reinforced Truss Concrete Composite Slabs during and after Fire
Authors: Li Bing , Li Zhengshang , Chen Zhijun , Yang Zhoulin , Zhang Yang
Published: June 2023

Standard fire resistance tests and post-fire tests on residual mechanical properties were carried out on two four-edge simply supported reinforced truss concrete two-way composite slabs with wide seam splicing (“integral seam”) and close seam splicing (“separated seam”), and the effects of the different splicing forms on the mechanical properties of the reinforced truss concrete composite slabs during and after exposure to high temperatures were explored. The results indicate that there are significant differences in terms of crack developments, moisture loss times on the slab surface, spalling characteristics of the bottom of the slab and cross-section temperature gradients of concrete and steel reinforcement along the thickness direction between the wide seam spliced reinforced truss concrete composite two-way slab (referred to as “S1 composite slab”) and the close seam spliced reinforced truss concrete composite two-way slab (referred to as “S2 composite slab”) in the fire test. This is mainly due to differences in the splicing forms and structural measures of the prefabricated base slabs at joints, which led to changes in the heat transfer path at the joints. As the temperature at the close seam can be released quickly, the stiffness recovery of the S2 composite slab is significantly greater than the stiffness weakening due to the thermal hysteresis of the concrete, so the deflection of the S2 composite slab recovers immediately after the fire stops. Overall, both the S1 and S2 composite slabs exhibit two-way high temperature deformation characteristics. The post-fire residual static load tests show that the static load-carrying capacity of the S1 composite slab is 12.08% higher than that of the S2 composite slab and the ultimate displacement is 8.74% lower than that of the S2 composite slab. It is appropriate to calculate the residual load capacities of the S1 and S2 composite slabs after the fire as a one-way slab.
MCAK Inhibitors Induce Aneuploidy in Triple-Negative Breast Cancer Models
Authors: Smith John C. , Husted Stefan , Pilrose Jay , Ems-McClung Stephanie C. , Stout Jane R. , Carpenter Richard L. , Walczak Claire E.
Published: June 2023

Standard of care for triple-negative breast cancer (TNBC) involves the use of microtubule poisons such as paclitaxel, which are proposed to work by inducing lethal levels of aneuploidy in tumor cells. While these drugs are initially effective in treating cancer, dose-limiting peripheral neuropathies are common. Unfortunately, patients often relapse with drug-resistant tumors. Identifying agents against targets that limit aneuploidy may be a valuable approach for therapeutic development. One potential target is the microtubule depolymerizing kinesin, MCAK, which limits aneuploidy by regulating microtubule dynamics during mitosis. Using publicly available datasets, we found that MCAK is upregulated in triple-negative breast cancer and is associated with poorer prognoses. Knockdown of MCAK in tumor-derived cell lines caused a two- to five-fold reduction in the IC50 for paclitaxel, without affecting normal cells. Using FRET and image-based assays, we screened compounds from the ChemBridge 50 k library and discovered three putative MCAK inhibitors. These compounds reproduced the aneuploidy-inducing phenotype of MCAK loss, reduced clonogenic survival of TNBC cells regardless of taxane-resistance, and the most potent of the three, C4, sensitized TNBC cells to paclitaxel. Collectively, our work shows promise that MCAK may serve as both a biomarker of prognosis and as a therapeutic target.
Immunotherapy in Biliary Tract Cancers: Current Standard-of-Care and Emerging Strategies
Authors: Lo Justin H. , Agarwal Rajiv , Goff Laura W. , Heumann Thatcher R.
Published: June 2023

Biliary tract cancers (BTCs), comprising intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder adenocarcinoma, continue to be challenging to manage. Conventional chemotherapy regimens for advanced disease are limited in both options and benefits, and more effective perioperative regimens are also needed. Over the last decade, immunotherapy has had a profound impact on the management of many solid tumor types, particularly in using immune checkpoint inhibition to enable a tumor-directed T cell response. Immunotherapy administered on its own has had limited utility in BTCs, in part due to a hostile immune microenvironment and the relative infrequency of biomarker-based tumor-agnostic indications for immunotherapy. However, immunotherapy in conjunction with chemotherapy, molecularly targeted therapies, and/or anti-angiogenic therapies has gained traction, supported by evidence that these agents can impart favorable immunomodulatory effects on the tumor microenvironment. The TOPAZ-1 trial led to the first BTC-specific immunotherapy approval, establishing the combination of durvalumab with gemcitabine and cisplatin as the preferred first-line treatment for advanced or metastatic disease. Recently, the KEYNOTE-966 trial showed positive results for the combination of pembrolizumab with gemcitabine and cisplatin in the same setting, adding further evidence for the addition of immune checkpoint inhibition to the standard chemotherapy backbone. Meanwhile, advances in the molecular profiling of BTCs has contributed to the recent proliferation of molecularly targeted therapeutics for the subset of BTCs harboring alterations in IDH1, FGFR2, MAP kinase signaling, HER2, and beyond, and there has been great interest in investigating combinations of these agents with immunotherapy. Emerging immunotherapy strategies beyond immune checkpoint inhibition are also being studied in BTCs, and these include immunostimulatory receptor agonists, Wnt signaling modulators, adoptive cell therapy, and cancer vaccines. A large number of trials are underway to explore promising new combinations and immune-targeted strategies, offering opportunities to expand the role of immunotherapy in BTC management in the near future.
Expression Analysis of hsa-miR-181a-5p, hsa-miR-143-3p, hsa-miR-132-3p and hsa-miR-23a-3p as Biomarkers in Colorectal Cancer—Relationship to the Body Mass Index
Authors: Tesolato Sofía Elena , González-Gamo Daniel , Barabash Ana , Claver Paula , de la Serna Sofía Cristina , Domínguez-Serrano Inmaculada , Dziakova Jana , de Juan Carmen , Torres Antonio José , Iniesta Pilar
Published: June 2023

This work aims to investigate the expression levels of four preselected miRNAs previously linked to cancer and/or obesity, with the purpose of finding potential biomarkers in the clinical management of CRC developed by patients showing different BMI values. We analyzed samples from a total of 65 subjects: 43 affected by CRC and 22 without cancer. Serum and both subcutaneous and omental adipose tissues (SAT and OAT) were investigated, as well as tumor and non-tumor colorectal tissues in the case of the CRC patients. The relative expression (2−∆∆Ct) levels of 4 miRNAs (hsa-miR-181a-5p, hsa-miR-143-3p, has-miR-132-3p and hsa-miR-23a-3p) were measured by RT-qPCR. Serum, SAT and OAT expression levels of these miRNAs showed significant differences between subjects with and without CRC, especially in the group of overweight/obese subjects. In CRC, serum levels of hsa-miR-143-3p clearly correlated with their levels in both SAT and OAT, independently of the BMI group. Moreover, hsa-miR-181a-5p could be considered as a biomarker in CRC patients with BMI ≥ 25 Kg/m2 and emerges as a tumor location marker. We conclude that both adiposity and CRC induce changes in the expression of the miRNAs investigated, and hsa-miR-143-3p and hsa-miR-181a-5p expression analysis could be useful in the clinical management of CRC.
Presenting Symptoms in Newly Diagnosed Myeloma, Relation to Organ Damage, and Implications for Symptom-Directed Screening: A Secondary Analysis from the Tackling Early Morbidity and Mortality in Myeloma (TEAMM) Trial
Authors: Bowcock Stella , Atkin Catherine , Iqbal Gulnaz , Pratt Guy , Yong Kwee , Neal Richard D. , Planche Tim , Karunanithi Kamaraj , Jenkins Stephen , Stern Simon , Arnott Sarah , Toth Peter , Wandroo Farooq , Dunn Janet , Drayson Mark T.
Published: June 2023

Multiple myeloma (MM) patients risk diagnostic delays and irreversible organ damage. In those with newly diagnosed myeloma, we explored the presenting symptoms to identify early signals of MM and their relationships to organ damage. The symptoms were recorded in patients’ own words at diagnosis and included diagnostic time intervals. Those seen by a haematologist >6 months prior to MM diagnosis were classified as precursor disease (PD). Most (962/977) patients provided data. Back pain (38%), other pain (31%) and systemic symptoms (28%) predominated. Patients rarely complain of ‘bone pain’, simply ‘pain’. Vertebral fractures are under-recognised as pathological and are the predominant irreversible organ damage (27% of patients), impacting the performance status (PS) and associated with back pain (odds ratio (OR) 6.14 [CI 4.47–8.44]), bone disease (OR 3.71 [CI 1.88–7.32]) and age >65 years (OR 1.58 [CI 1.15–2.17]). Renal failure is less frequent and associated with gastrointestinal symptoms (OR 2.23 [CI1.28–3.91]), age >65 years (OR 2.14 [CI1.28–3.91]) and absence of back pain (OR 0.44 [CI 0.29–0.67]). Patients with known PD (n = 149) had fewer vertebral fractures (p = 0.001), fewer adverse features (p = 0.001), less decline in PS (p = 0.001) and a lower stage (p = 0.04) than 813 with de novo MM. Our data suggest subgroups suitable for trials of ‘symptom-directed’ screening: those with back pain, unexplained pain, a general decline in health or low-impact vertebral compression fractures.
Recent Advances in Transcription Factors Biomarkers and Targeted Therapies Focusing on Epithelial–Mesenchymal Transition
Authors: Chuang Kai-Ting , Chiou Shyh-Shin , Hsu Shih-Hsien
Published: June 2023

Transcription factors involve many proteins in the process of transactivating or transcribing (none-) encoded DNA to initiate and regulate downstream signals, such as RNA polymerase. Their unique characteristic is that they possess specific domains that bind to specific DNA element sequences called enhancer or promoter sequences. Epithelial–mesenchymal transition (EMT) is involved in cancer progression. Many dysregulated transcription factors—such as Myc, SNAIs, Twists, and ZEBs—are key drivers of tumor metastasis through EMT regulation. This review summarizes currently available evidence related to the oncogenic role of classified transcription factors in EMT editing and epigenetic regulation, clarifying the roles of the classified conserved transcription factor family involved in the EMT and how these factors could be used as therapeutic targets in future investigations.
Impact of Signet-Ring Cell Histology in the Management of Patients with Non-Metastatic Gastric Cancer: Results from a Retrospective Multicenter Analysis Comparing FLOT Perioperative Chemotherapy vs. Surgery Followed by Adjuvant Chemotherapy
Authors: Giampieri Riccardo , Baleani Maria Giuditta , Bittoni Alessandro , Rastelli Francesca , Catalano Vincenzo , Del Prete Michela , Chiorrini Silvia , Pinterpe Giada , Graziano Francesco , Giorgi Francesca Chiara , Bisonni Renato , Silva Rosarita , Alessandroni Paolo , Mencarini Lara , Berardi Rossana
Published: June 2023

Background: FLOT perioperative chemotherapy represents the standard of care in non-metastatic gastric cancer patients. Signet-ring cell positivity is associated with a worse prognosis in patients with gastric cancer treated with chemotherapy. Comparison between FLOT perioperative chemotherapy vs. surgery followed by adjuvant chemotherapy based on signet-ring cell positivity is lacking. The aim of the analysis was to compare perioperative FLOT with adjuvant chemotherapy in gastric cancer patients stratified by signet-ring cell positivity. Methods: We conducted a retrospective multicenter analysis based on disease-free survival (DFS) and overall survival (OS) in patients with gastric cancer who received perioperative chemotherapy with a FLOT regimen and compared their survival with a historical cohort of patients treated with adjuvant chemotherapy, matched by cT and cN stage and by tumor histological features. Results: Seventy-six patients were enrolled and 24 (32%) were signet-ring cell positive. At a median follow-up time of 39 months, the median DFS was 26.3 months and the median OS was 37.3 months. Signet-ring cell positivity was associated with a shorter OS (median OS: 20.4 vs. 46.9 months, HR: 3.30, 95%CI: 1.56–6.99, p = 0.0018) and DFS (mDFS: 15.2 vs. 38.6 months, HR: 3.18, 95%CI: 1.55–6.54, p = 0.0016). This was confirmed by multivariate analysis for DFS (Exp(B): 2.55) and OS (Exp(B): 2.68). After propensity score matching, statistically significant shorter DFS (HR: 3.30, 95%CI: 1.50–7.35, p = 0.003) and OS (HR: 5.25, 95%CI: 2.18–12–68, p = 0.0002) were observed for patients with signet-ring cell positivity who received perioperative treatment vs. those who received surgery followed by adjuvant chemotherapy. Conclusions: Signet-ring positivity was associated with shorter DFS and OS in patients who received perioperative treatment with FLOT compared with surgery followed by adjuvant therapy. These data suggest that for patients with signet-ring cell histology, FLOT perioperative treatment might not always be the best choice of treatment, and further research should be focused on this group of patients.
A Concise Review of Multicomponent Reactions Using Novel Heterogeneous Catalysts under Microwave Irradiation
Authors: Damera Thirupathi , Pagadala Ramakanth , Rana Surjyakanta , Jonnalagadda Sreekantha Babu
Published: June 2023

Multi-component reactions for the construction of heterocycles have been fascinated by microwave energy as an alternative technique of heating, owing to the advantages over traditional reflux methods. The heterogeneous catalysts contribute significantly towards recycling, harmless, easy filtration, catalyst preparation, more life span, abundance, and product yields. With novel and creative uses in organic and peptide synthesis, polymer chemistry, material sciences, nanotechnology, and biological processes, the usage of microwave energy has rapidly increased during the past 20 years. This article covers multicomponent reactions involving construction of chromenes, pyridines, pyrroles, triazoles, pyrazoles, tetrazoles, trans and cis julolidines using heterogeneous catalysts under microwave. It provides an overview of contemporary microwave-assisted heterogeneous catalytic reactions. Microwave chemistry is now an established technology with several advantages regarding reaction rate and production yield, improving energy savings as confirmed by many applications. Due to the widespread curiosity in medicinal chemistry, the heterogeneously catalysed construction of heterocycles under microwave irradiation is explored to reduce time and energy. By considering various aspects of economy, eco-friendly, and user-friendly factors, this review focuses on recent advances in the multi-component construction of heterocycles using heterogeneous catalysts under microwave irradiation. This review also discusses the benefits and limitations of reaction conditions and yields from the literature reports for the past five years.
Use of Deep Eutectic Solvents in Plastic Depolymerization
Authors: Paparella Andrea Nicola , Perrone Serena , Salomone Antonio , Messa Francesco , Cicco Luciana , Capriati Vito , Perna Filippo Maria , Vitale Paola
Published: June 2023

Polymeric materials are widely used in every human endeavor (bottles, clothes, containers, toys, tools, etc.) due to their unique properties of chemical and mechanical resistance. They are, however, almost non-biodegradable, and their chemical recycling into monomers is difficult and costly, thereby allowing their accumulation into the environment. This review highlights recent advances in the use of deep eutectic solvents (DESs) as catalysts and/or green solvents in plastics degradation, with the aim of designing greener processes for polymers’ chemical recycling, by reusing their monomers. These greener processes, in combination with other catalytic approaches, are aimed at introducing plastics as feedstock into the synthesis of other materials, according to the circular economy principles.
The Src-Family Kinases SRC and BLK Contribute to the CLDN6-Adhesion Signaling
Authors: Ichikawa-Tomikawa Naoki , Sugimoto Kotaro , Kashiwagi Korehito , Chiba Hideki
Published: June 2023

Cell adhesion molecules, including integrins, cadherins, and claudins (CLDNs), are known to activate Src-family kinases (SFKs) that organize a variety of physiological and pathological processes; however, the underlying molecular basis remains unclear. Here, we identify the SFK members that are coupled with the CLDN6-adhesion signaling. Among SFK subtypes, BLK, FGR, HCK, and SRC were highly expressed in F9 cells and concentrated with CLDN6 along cell borders during epithelial differentiation. Immunoprecipitation assay showed that BLK and SRC, but not FGR or HCK, form a complex with CLDN6 via the C-terminal cytoplasmic domain. We also demonstrated, by pull-down assay, that recombinant BLK and SRC proteins directly bind to the C-terminal cytoplasmic domain of CLDN6 (CLDN6C). Unexpectedly, both recombinant SFK proteins recognized the CLDN6C peptide in a phosphotyrosine-independent manner. Furthermore, by comparing phenotypes of F9:Cldn6:Blk−/− and F9:Cldn6:Src−/− cells with those of wild-type F9 and F9:Cldn6 cells, we revealed that BLK and SRC are essential for CLDN6-triggered cellular events, namely epithelial differentiation and the expression of retinoid acid receptor target genes. These results indicate that selective SFK members appear to participate in the CLDN-adhesion signaling.
A Shared Pathogenic Mechanism for Valproic Acid and SHROOM3 Knockout in a Brain Organoid Model of Neural Tube Defects
Authors: Takla Taylor N. , Luo Jinghui , Sudyk Roksolana , Huang Joy , Walker John Clayton , Vora Neeta L. , Sexton Jonathan Z. , Parent Jack M. , Tidball Andrew M.
Published: June 2023

Neural tube defects (NTDs), including anencephaly and spina bifida, are common major malformations of fetal development resulting from incomplete closure of the neural tube. These conditions lead to either universal death (anencephaly) or severe lifelong complications (spina bifida). Despite hundreds of genetic mouse models of neural tube defect phenotypes, the genetics of human NTDs are poorly understood. Furthermore, pharmaceuticals, such as antiseizure medications, have been found clinically to increase the risk of NTDs when administered during pregnancy. Therefore, a model that recapitulates human neurodevelopment would be of immense benefit to understand the genetics underlying NTDs and identify teratogenic mechanisms. Using our self-organizing single rosette cortical organoid (SOSR-COs) system, we have developed a high-throughput image analysis pipeline for evaluating the SOSR-CO structure for NTD-like phenotypes. Similar to small molecule inhibition of apical constriction, the antiseizure medication valproic acid (VPA), a known cause of NTDs, increases the apical lumen size and apical cell surface area in a dose-responsive manner. GSK3β and HDAC inhibitors caused similar lumen expansion; however, RNA sequencing suggests VPA does not inhibit GSK3β at these concentrations. The knockout of SHROOM3, a well-known NTD-related gene, also caused expansion of the lumen, as well as reduced f-actin polarization. The increased lumen sizes were caused by reduced cell apical constriction, suggesting that impingement of this process is a shared mechanism for VPA treatment and SHROOM3-KO, two well-known causes of NTDs. Our system allows the rapid identification of NTD-like phenotypes for both compounds and genetic variants and should prove useful for understanding specific NTD mechanisms and predicting drug teratogenicity.
Patterned Arteriole-Scale Vessels Enhance Engraftment, Perfusion, and Vessel Branching Hierarchy of Engineered Human Myocardium for Heart Regeneration
Authors: Kant Rajeev J. , Dwyer Kiera D. , Lee Jang-Hoon , Polucha Collin , Kobayashi Momoka , Pyon Stephen , Soepriatna Arvin H. , Lee Jonghwan , Coulombe Kareen L. K.
Published: June 2023

Heart regeneration after myocardial infarction (MI) using human stem cell-derived cardiomyocytes (CMs) is rapidly accelerating with large animal and human clinical trials. However, vascularization methods to support the engraftment, survival, and development of implanted CMs in the ischemic environment of the infarcted heart remain a key and timely challenge. To this end, we developed a dual remuscularization-revascularization therapy that is evaluated in a rat model of ischemia-reperfusion MI. This study details the differentiation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for engineering cardiac tissue containing patterned engineered vessels 400 μm in diameter. Vascularized engineered human myocardial tissues (vEHMs) are cultured in static conditions or perfused in vitro prior to implantation and evaluated after two weeks. Immunohistochemical staining indicates improved engraftment of hiPSC-CMs in in vitro-perfused vEHMs with greater expression of SMA+ vessels and evidence of inosculation. Three-dimensional vascular reconstructions reveal less tortuous and larger intra-implant vessels, as well as an improved branching hierarchy in in vitro-perfused vEHMs relative to non-perfused controls. Exploratory RNA sequencing of explanted vEHMs supports the hypothesis that co-revascularization impacts hiPSC-CM development in vivo. Our approach provides a strong foundation to enhance vEHM integration, develop hierarchical vascular perfusion, and maximize hiPSC-CM engraftment for future regenerative therapy.
Role of Chondroitin Sulfate Proteoglycan 5 in Steroid-Induced Cataract
Authors: Yoo Woong-Sun , Seong Hyemin , Song Chieun , Choi Mee-Young , Lee Bina , Eom Youngsub , Kim Hae-Jin , Yun Seung Pil , Kim Seong-Jae
Published: June 2023

Steroid-induced cataracts (SIC) are defined as cataracts associated with the administration of corticosteroids. Long-term glucocorticoid treatment for inflammatory diseases reportedly increases the risk of SIC, and steroids can induce cataracts by disrupting ocular growth factor balance or homeostasis. In this study, we verified the effect of chondroitin sulfate proteoglycan 5 (CSPG5) using dexamethasone (dexa)-treated human lens epithelial (HLE-B3) cells and the lens epithelium from the anterior capsule of SIC patients obtained during cataract surgery. CSPG5 expression increased in the lens epithelium of SIC patients. The downregulation of CSPG5 suppressed the dexa-induced epithelial–mesenchymal transition (EMT)-related protein expression and motility in HLE-B3 cells. The disruption of the transcription factors EZH2 and B-Myb downregulated CSPG5, dexa-induced fibronectin expression, and cell migration in HLE-B3 cells, reaffirming that CSPG5 expression regulates EMT in lens epithelial cells. Taken together, these results indicate that the steroid-induced effects on lens epithelial cells are mediated via alterations in CSPG5 expression. Therefore, our study emphasizes the potential of CSPG5 as a therapeutic target for the prevention and treatment of SIC.