bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting Class I-II-III PI3Ks in Cancer Therapy: Recent Advances in Tumor Biology and Preclinical Research
Authors: Thibault Benoît , Ramos-Delgado Fernanda , Guillermet-Guibert Julie
Published: January 2023

Phosphatidylinositol-3-kinase (PI3K) enzymes, producing signaling phosphoinositides at plasma and intracellular membranes, are key in intracellular signaling and vesicular trafficking pathways. PI3K is a family of eight enzymes divided into three classes with various functions in physiology and largely deregulated in cancer. Here, we will review the recent evidence obtained during the last 5 years on the roles of PI3K class I, II and III isoforms in tumor biology and on the anti-tumoral action of PI3K inhibitors in preclinical cancer models. The dependency of tumors to PI3K isoforms is dictated by both genetics and context (e.g., the microenvironment). The understanding of class II/III isoforms in cancer development and progression remains scarce. Nonetheless, the limited available data are consistent and reveal that there is an interdependency between the pathways controlled by all PI3K class members in their role to promote cancer cell proliferation, survival, growth, migration and metabolism. It is unknown whether this feature contributes to partial treatment failure with isoform-selective PI3K inhibitors. Hence, a better understanding of class II/III functions to efficiently inhibit their positive and negative interactions with class I PI3Ks is needed. This research will provide the proof-of-concept to develop combination treatment strategies targeting several PI3K isoforms simultaneously.
microRNAs in Liquid Biopsy: The Way to a Simple and Rapid Test for Early Colorectal Cancer Diagnosis?
Authors: Matis Serena , Poggi Alessandro , Benelli Roberto
Published: January 2023

About 15% of colorectal cancers (CRCs) are diagnosed as advanced, metastatic stage IV, a patient condition with an average survival of 2 [...]
Influence of Sex and Age on Site of Onset, Morphology, and Site of Metastasis in Colorectal Cancer: A Population-Based Study on Data from Four Italian Cancer Registries
Authors: Perotti Viviana , Fabiano Sabrina , Contiero Paolo , Michiara Maria , Musolino Antonio , Boschetti Lorenza , Cascone Giuseppe , Castelli Maurizio , Tagliabue Giovanna ,   Cancer Registries Working Group
Published: January 2023

The prognosis of colorectal cancer is affected by factors such as site of origin, tumor morphology, and metastasis at diagnosis, but also age and sex seem to play a role. This study aimed to investigate within the Italian population how sex and age interact in influencing certain aspects of the disease and how they affect patient survival, particularly in the metastatic cohort. Data from four cancer registries were collected, and patients were classified by sex and age (<50, 50–69, and >69 years). Two separate analyses were conducted: one for patients having right or left colon cancer with adenocarcinoma or mucinous morphology, and one for patients having metastases at diagnosis. Women showed significant differences in right colon cases from the youngest to oldest age group (36% vs. 45% vs. 60%). Men <50 years had a significantly higher mucinous carcinoma percentage than their female counterparts (22% vs. 11%), while in the oldest age group women had the highest percentage (15% vs. 11%). The metastatic pattern differed between men and women and by age. The three-year relative survival in the <50 age group was better for women than men, but this survival advantage was reversed in the oldest group. In conclusion, sex and age are factors that influence the biological and clinical characteristics of colorectal cancer, affecting the metastatic pattern as well as patient survival.
Metabolic Health, Mitochondrial Fitness, Physical Activity, and Cancer
Authors: Clemente-Suárez Vicente Javier , Martín-Rodríguez Alexandra , Redondo-Flórez Laura , Ruisoto Pablo , Navarro-Jiménez Eduardo , Ramos-Campo Domingo Jesús , Tornero-Aguilera José Francisco
Published: January 2023

Cancer continues to be a significant global health issue. Traditional genetic-based approaches to understanding and treating cancer have had limited success. Researchers are increasingly exploring the impact of the environment, specifically inflammation and metabolism, on cancer development. Examining the role of mitochondria in this context is crucial for understanding the connections between metabolic health, physical activity, and cancer. This study aimed to review the literature on this topic through a comprehensive narrative review of various databases including MedLine (PubMed), Cochrane (Wiley), Embase, PsychINFO, and CinAhl. The review highlighted the importance of mitochondrial function in overall health and in regulating key events in cancer development, such as apoptosis. The concept of “mitochondrial fitness” emphasizes the crucial role of mitochondria in cell metabolism, particularly their oxidative functions, and how proper function can prevent replication errors and regulate apoptosis. Engaging in high-energy-demanding movement, such as exercise, is a powerful intervention for improving mitochondrial function and increasing resistance to environmental stressors. These findings support the significance of considering the role of the environment, specifically inflammation and metabolism, in cancer development and treatment. Further research is required to fully understand the mechanisms by which physical activity improves mitochondrial function and potentially reduces the risk of cancer.
Implementing HRD Testing in Routine Clinical Practice on Patients with Primary High-Grade Advanced Ovarian Cancer
Authors: Heitz Florian , Ataseven Beyhan , Staniczok Claudia , Denkert Carsten , Rhiem Kerstin , Hahnen Eric , Heikaus Sebastian , Moubarak Malak , Welz Julia , Dagres Timoleon , Vrentas Vasilios , Bommert Mareike , Schneider Stephanie , Concin Nicole , Harter Philipp
Published: January 2023

The chemotherapy backbone for patients with high-grade advanced epithelial ovarian cancer (HG-AOC) is carboplatin and paclitaxel followed by a maintenance therapy either with bevacizumab, with a PARP inhibitor, or with a combination of both, which is defined by the presence of a homologous recombination deficiency (HRD) and by the BRCA1/2 status. This study included patients with a primary diagnosis of HG-AOC treated between December 2019 and December 2021. The HRD status was measured using the Myriad myChoice® test on all the patients with an indication for tumor HRD testing. Germline testing was conducted on all the patients using the TruRisk® panel as recommended by the national guidelines. HRD testing was requested for 190 patients, and, for 163 patients (85.8%), an HRD test result was available. An HRD test result could not be reported in 27 patients due to an insufficient tumor yield. The median time that it took to receive the HRD test results was 37 days (range of 8–97). In total, an HRD was present in 44.7% (73/163) of the patients based on a GIS ≥ 42 in 42.9% of the patients and based on a tumor BRCA1/2 mutation in 3 cases (all with a GIS < 42). The germline testing results were available for 148 patients, and, in 18 patients (12.2%), a deleterious germline mutation was detected. Of the 27 patients without sufficient HRD testing, BRCA1/2 germline testing results were available for 19 patients (70.4%), and a deleterious germline mutation was detected in 2 patients (7.4%). The implementation of HRD testing is feasible, and the results become available for treatment decisions in a timely manner for most patients. The prerequisite for HRD testing with the Myriad myChoice® test is a sufficient amount of tumor tissue. The cotesting of HRD and BRCA1/2 germline testing should be aimed for in order to enable optimal and timely treatment decisions on maintenance therapy as well as to test patients on whom the HRD test will not be evaluable.
Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection
Authors: Pchejetski Dmitri , Hunter Ewan , Dezfouli Mehrnoush , Salter Matthew , Powell Ryan , Green Jayne , Naithani Tarun , Koutsothanasi Christina , Alshaker Heba , Jaipuria Jiten , Connor Martin , Eldred-Evans David , Fiorentino Francesca , Ahmed Hashim , Akoulitchev Alexandre , Winkler Mathias
Published: January 2023

Background: Prostate cancer (PCa) has a high lifetime prevalence (one out of six men), but currently there is no widely accepted screening programme. Widely used prostate specific antigen (PSA) test at cut-off of 3.0 ng/mL does not have sufficient accuracy for detection of any prostate cancer, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance in some men with PCa. We have recently identified circulating chromosome conformation signatures (CCSs, Episwitch® PCa test) allowing PCa detection and risk stratification in line with standards of clinical PCa staging. The purpose of this study was to determine whether combining the Episwitch PCa test with the PSA test will increase its diagnostic accuracy. Methods: n = 109 whole blood samples of men enrolled in the PROSTAGRAM screening pilot study and n = 38 samples of patients with established PCa diagnosis and cancer-negative controls from Imperial College NHS Trust were used. Samples were tested for PSA, and the presence of CCSs in the loci encoding for of DAPK1, HSD3B2, SRD5A3, MMP1, and miRNA98 associated with high-risk PCa identified in our previous work. Results: PSA > 3 ng/mL alone showed a low positive predicted value (PPV) of 0.14 and a high negative predicted value (NPV) of 0.93. EpiSwitch alone showed a PPV of 0.91 and a NPV of 0.32. Combining PSA and Episwitch tests has significantly increased the PPV to 0.81 although reducing the NPV to 0.78. Furthermore, integrating PSA, as a continuous variable (rather than a dichotomised 3 ng/mL cut-off), with EpiSwitch in a new multivariant stratification model, Prostate Screening EpiSwitch (PSE) test, has yielded a remarkable combined PPV of 0.93 and NPV of 0.95 when tested on the independent combined cohort. Conclusions: Our results demonstrate that combining the standard PSA readout with circulating chromosome conformations (PSE test) allows for significantly enhanced PSA PPV and overall accuracy for PCa detection. The PSE test is accurate, rapid, minimally invasive, and inexpensive, suggesting significant screening diagnostic potential to minimise unnecessary referrals for expensive and invasive MRI and/or biopsy testing. Further extended prospective blinded validation of the new combined signature in a screening cohort with low cancer prevalence would be the recommended step for PSE adoption in PCa screening.
Mapping Resection Progress by Tool-Tip Tracking during Brain Tumor Surgery for Real-Time Estimation of Residual Tumor
Authors: Juvekar Parikshit , Torio Erickson , Bi Wenya Linda , Bastos Dhiego Chaves De Almeida , Golby Alexandra J. , Frisken Sarah F.
Published: January 2023

Surgical resection continues to be the primary initial therapeutic strategy in the treatment of patients with brain tumors. Computerized cranial neuronavigation based on preoperative imaging offers precision guidance during craniotomy and early tumor resection but progressively loses validity with brain shift. Intraoperative MRI (iMRI) and intraoperative ultrasound (iUS) can update the imaging used for guidance and navigation but are limited in terms of temporal and spatial resolution, respectively. We present a system that uses time-stamped tool-tip positions of surgical instruments to generate a map of resection progress with high spatial and temporal accuracy. We evaluate this system and present results from 80 cranial tumor resections. Regions of the preoperative tumor segmentation that are covered by the resection map (True Positive Tracking) and regions of the preoperative tumor segmentation not covered by the resection map (True Negative Tracking) are determined for each case. We compare True Negative Tracking, which estimates the residual tumor, with the actual residual tumor identified using iMRI. We discuss factors that can cause False Positive Tracking and False Negative Tracking, which underestimate and overestimate the residual tumor, respectively. Our method provides good estimates of the residual tumor when there is minimal brain shift, and line-of-sight is maintained. When these conditions are not met, surgeons report that it is still useful for identifying regions of potential residual.
Factors Influencing Residual Glandular Breast Tissue after Risk-Reducing Mastectomy in Genetically Predisposed Individuals Detected by MRI Mammography
Authors: Dietzel Frederic , Kolberg Leoni , Vesper Anne Sophie , Hoffmann Jürgen , Nestle-Krämling Carolin , Zwiefel Karin , Friebe Verena , Sawicki Lino M. , Bruckmann Nils Martin , Jannusch Kai , Morawitz Janna , Antoch Gerald , Fehm Tanja Natascha , Kirchner Julian , Mohrmann Svjetlana
Published: January 2023

Purpose: This study seeks to evaluate MR imaging morphological factors and other covariates that influence the presence of residual glandular tissue after risk-reducing mastectomy in patients with a familial predisposition. Methods: We analyzed women of a high-risk collective with pathogenic mutation (BRCA1 (n = 49), BRCA2 (n = 24), or further mutation (n = 9)). A total of 117 breasts were analyzed, 63 left and 54 right, from a cohort of 81 patients, who were on average 40 years old. The mean follow-up was 63 months (range 12–180 months, SD = 39.67). Retrospective analysis of MR imaging data from 2006–2022 of patients of a high-risk collective (all carriers of a pathogenic mutation) with contralateral (RRCM) or bilateral risk-reducing mastectomy (RRBM) was performed. In the image data the remaining skin flap thickness by distance measurements at eight equally distributed, clockwise points and the retromamillary area, as well as by volumetry of each breast, was elected. Residual glandular tissue was also volumetrized. In addition, patient-related covariates were recorded and their influence on postoperative residual glandular tissue and skin flap thickness was analyzed by uni- and multivariate regressions. Results: A significant association with postoperative residual glandular tissue was shown in multivariate analysis for the independent variables breast density, skin flap mean, and surgical method (all p-values < 0.01). A negatively significant association could be seen for the variables preoperative breast volume (p-values < 0.01) and surgeon experience (most p-values < 0.05–<0.1). Conclusion: Postoperative residual glandular tissue is an important tool for quantifying the risk of developing breast cancer after risk-reducing mastectomy. Different effects on residual glandular tissue were shown for the independent variables breast density, skin flap, surgical method, preoperative breast volume, and surgeon experience, so these should be considered in future surgical procedures preoperatively as well as postoperatively. Breast MRI has proven to be a suitable method to analyze the skin flap as well as the RGT.
Exploring the Past, Present, and Future of Anti-Angiogenic Therapy in Glioblastoma
Authors: Zhang Ashley B. , Mozaffari Khashayar , Aguirre Brian , Li Victor , Kubba Rohan , Desai Nilay C. , Wei Darren , Yang Isaac , Wadehra Madhuri
Published: January 2023

Glioblastoma, a WHO grade IV astrocytoma, constitutes approximately half of malignant tumors of the central nervous system. Despite technological advancements and aggressive multimodal treatment, prognosis remains dismal. The highly vascularized nature of glioblastoma enables the tumor cells to grow and invade the surrounding tissue, and vascular endothelial growth factor-A (VEGF-A) is a critical mediator of this process. Therefore, over the past decade, angiogenesis, and more specifically, the VEGF signaling pathway, has emerged as a therapeutic target for glioblastoma therapy. This led to the FDA approval of bevacizumab, a monoclonal antibody designed against VEGF-A, for treatment of recurrent glioblastoma. Despite the promising preclinical data and its theoretical effectiveness, bevacizumab has failed to improve patients’ overall survival. Furthermore, several other anti-angiogenic agents that target the VEGF signaling pathway have also not demonstrated survival improvement. This suggests the presence of other compensatory angiogenic signaling pathways that surpass the anti-angiogenic effects of these agents and facilitate vascularization despite ongoing VEGF signaling inhibition. Herein, we review the current state of anti-angiogenic agents, discuss potential mechanisms of anti-angiogenic resistance, and suggest potential avenues to increase the efficacy of this therapeutic approach.
Circulating Tumor Cell Enumeration for Serial Monitoring of Treatment Outcomes for Locally Advanced Esophageal Squamous Cell Carcinoma
Authors: Ko Josephine Mun Yee , Lam Ka On , Kwong Dora Lai Wan , Wong Ian Yu-Hong , Chan Fion Siu-Yin , Wong Claudia Lai-Yin , Chan Kwan Kit , Law Tsz Ting , Chiu Keith Wan Hang , Lam Candy Chi Shan , Wong Jean Chrysei , Fong Henry Chun Hung , Choy Faith Sin Fai , Lo Andy , Law Simon , Lung Maria Li
Published: January 2023

We aim to reveal the clinical significance and potential usefulness of dynamic monitoring of CTCs to track therapeutic responses and improve survival for advanced ESCC patients. Peripheral blood (PB) (n = 389) and azygos vein blood (AVB) (n = 13) samplings were recruited prospectively from 88 ESCC patients undergoing curative surgery from 2017 to 2022. Longitudinal CTC enumeration was performed with epithelial (EpCAM/pan-cytokeratins/MUC1) and mesenchymal (vimentin) markers at 12 serial timepoints at any of the pre-treatment, all of the post-treatments/pre-surgery, post-surgery follow-ups for 3-year, and relapse. Longitudinal real-time CTC analysis in PB and AVB suggests more CTCs are released early at pre-surgery and 3-month post-surgery into the circulation from the CTRT group compared to the up-front surgery group. High CTC levels at pre-treatments, 1-/3-month post-surgery, unfavorable changes of CTC levels between all post-treatment/pre-surgery and 1-month or 3-month post-surgery (Hazard Ratio (HR) = 6.662, p < 0.001), were independent prognosticators for curative treatment. The unfavorable pre-surgery CTC status was independent prognostic and predictive for neoadjuvant treatment efficacy (HR = 3.652, p = 0.035). The aggressive CTC clusters were more frequently observed in AVB compared to PB. Its role as an independent prognosticator with relapse was first reported in ESCC (HR = 2.539, p = 0.068). CTC clusters and longitudinal CTC monitoring provide useful prognostic information and potential predictive biomarkers to help guide clinicians in improving disease management.
Osimertinib Resistance: Molecular Mechanisms and Emerging Treatment Options
Authors: Gomatou Georgia , Syrigos Nikolaos , Kotteas Elias
Published: January 2023

The development of tyrosine kinase inhibitors (TKIs) targeting the mutant epidermal growth factor receptor (EGFR) protein initiated the success story of targeted therapies in non-small-cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR-TKI, is currently indicated as first-line therapy in patients with NSCLC with sensitizing EGFR mutations, as second-line therapy in patients who present the resistance-associated mutation T790M after treatment with previous EGFR-TKIs, and as adjuvant therapy for patients with early stage resected NSCLC, harboring EGFR mutations. Despite durable responses in patients with advanced NSCLC, resistance to osimertinib, similar to other targeted therapies, inevitably develops. Understanding the mechanisms of resistance, including both EGFR-dependent and -independent molecular pathways, as well as their therapeutic potential, represents an unmet need in thoracic oncology. Interestingly, differential resistance mechanisms develop when osimertinib is administered in a first-line versus second-line setting, indicating the importance of selection pressure and clonal evolution of tumor cells. Standard therapeutic approaches after progression to osimertinib include other targeted therapies, when a targetable genetic alteration is detected, and cytotoxic chemotherapy with or without antiangiogenic and immunotherapeutic agents. Deciphering the when and how to use immunotherapeutic agents in EGFR-positive NSCLC is a current challenge in clinical lung cancer research. Emerging treatment options after progression to osimertinib involve combinations of different therapeutic approaches and novel EGFR-TKI inhibitors. Research should also be focused on the standardization of liquid biopsies in order to facilitate the monitoring of molecular alterations after progression to osimertinib.
Candidate Genes and Pathways in Cervical Cancer: A Systematic Review and Integrated Bioinformatic Analysis
Authors: Elias Marjanu Hikmah , Das Srijit , Abdul Hamid Nazefah
Published: January 2023

Cervical cancer is the leading cause of cancer-related death among women in developing countries. However, no comprehensive molecular mechanism for cervical cancer has been established, as many studies were small-cohort studies conducted with small sample sizes. A thorough literature search was performed using the PubMed, Scopus, EBSCOhost, and Science Direct databases. Medical Subject Heading (MeSH) terms such as “Uterine Cervical Neoplasms” and “gene expression” were used as the keywords in all fields. A total of 4027 studies were retrieved, and only clinical studies, which used the microarray method to identify differentially expressed genes (DEGs) in the cervical tissue of cervical cancer patients, were selected. Following the screening, 6 studies were selected and 1128 DEGs were extracted from the data. Sixty-two differentially expressed genes from at least two studies were selected for further analysis by DAVID, STRING, and Cytoscape software. In cervical cancer pathogenesis, three significant clusters with high intermolecular interactions from the Protein–Protein Interaction (PPI) network complex revealed three major molecular mechanisms, including cell signaling, cell cycle, and cell differentiation. Subsequently, eight genes were chosen as the candidate genes based on their involvement in the relevant gene ontology (GO) and their interaction with other genes in the PPI network through undirected first neighbor nodes. The present systematic review improves our understanding of the molecular mechanism of cervical cancer and the proposed genes that can be used to expand the biomarker panel in the screening for cervical cancer. The targeted genes may be beneficial for the development of better treatment strategies.
Lipase Production by Yarrowia lipolytica in Solid-State Fermentation Using Amazon Fruit By-Products and Soybean Meal as Substrate
Authors: Carvalho Aparecida Selsiane Sousa , Sales Júlio Cesar Soares , Nascimento Felipe Valle do , Ribeiro Bernardo Dias , Souza Carlos Eduardo Conceição de , Lemes Ailton Cesar , Coelho Maria Alice Zarur
Published: January 2023

The production of polyunsaturated fatty acids from fish oil, which is related to various health benefits including effects against cardiovascular diseases, antihypertensive, anticancer, antioxidant, antidepression, anti-aging, and anti-arthritis effects, among others, can be advantageously performed through the application of lipase. However, the high cost associated with enzyme production can make the process unfeasible and thus alternative substrates should be investigated to solve these problems. This research aimed to produce lipase by Yarrowia lipolytica IMUFRJ50682 in solid-state fermentation using by-products of the food processing industry (andiroba oil cake and soybean meal) and verify the potential application in the initial hydrolysis of fish oil to further produce polyunsaturated fatty acids in a suitable process. A screening was carried out for the analysis of andiroba oil cake and soybean meal combinations in different proportions (0:100 to 100:0, respectively) at 48 h of the fermentation process. Afterward, the solid matrix composed by soybean meal and andiroba oil cake was supplemented with soy oil and Tween 80 to improve the lipase activity. The enzymatic extract was characterized in relation to the protein profile by electrophoresis. Finally, the enzymatic extract and the solid biocatalyst produced were applied to evaluate the potential hydrolysis of the fish oil in an initial study. Maximum lipolytic activity (63.7 U·g−1) was achieved using andiroba oil cake and soybean meal (50:50) after 24 h of fermentation. Soybean oil 1.5% and Tween 80 (0.001%) in an emulsion provided an increase of 1.5-fold (82.52 U·g−1) in the enzyme activity. The electrophoretic analysis demonstrated a band between 37 and 40 kDa that may be related to lipase and a band of 75 kDa referring to the α subunit of the β-conglycinin present in soybean meal. After 48 h, the solid biocatalyst showed a higher degree of hydrolysis (DH) (71.0%) than the enzymatic extract (61.5%). The solid biocatalyst was stable during storage at room temperature for 7 months. The production of lipases using Amazon fruit by-product and soybean meal in solid-state fermentation is viable as well as the application of the extract and solid biocatalyst in the initial application for the hydrolysis of fish oil to further produce polyunsaturated fatty acids in an industrially suited process.
Ionic Liquid Modified SPION@Chitosan as a Novel and Reusable Superparamagnetic Catalyst for Green One-Pot Synthesis of Pyrido[2,3-d]pyrimidine-dione Derivatives in Water
Authors: Sayahi Mohammad Hosein , Sepahdar Asma , Bazrafkan Farokh , Dehghani Farzaneh , Mahdavi Mohammad , Bahadorikhalili Saeed
Published: January 2023

In this paper, the chitosan-functionalized ionic liquid is modified with superparamagnetic iron oxide nanoparticles to form a novel and reusable catalyst (SPION@CS-IL), which was carried out using an ultrasonic promoted approach. Transmission electron microscopy (TEM), vibrating-sample magnetometer (VSM), energy-dispersive X-ray spectroscopy (EDX), Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRD), energy-dispersive X-ray spectroscopy (EDX), and thermogravimetric analysis (TGA) are some of the techniques that are used to fully characterize SPION@CS-IL. The created nanoparticles were discovered to be a reusable heterogeneous superparamagnetic catalyst for the environmentally friendly one-pot synthesis of pyrido[2,3-d]pyrimidine derivatives using a simple three-component reaction approach involving thiobarbituric acid, 4-hydroxy coumarin, and various aromatic aldehydes. The method is studied by performing the reaction under ultrasonic irradiation, while the approach is a “green” method, it uses water as the solvent. The isolated yields of the synthesized products are very advantageous. The catalyst has outstanding reusability and is easily removed from the products via filtration (5 runs). Short reaction times, low catalyst loadings, the nanocatalyst’s capacity to be recycled five times, and the absence of harmful chemical reagents are all significant benefits of this environmentally benign process.
The Application of Two-Phase Catalytic System in Enantioselective Separation of Racemic (R,S)-1-Phenylethanol
Authors: Chałupka Joanna , Dulęba Jacek , Sikora Adam , Siódmiak Tomasz , Marszałł Michał Piotr
Published: January 2023

Kinetic resolution is one of the methods which allows obtaining enantiomerically pure compounds. In the study presented herein, enantioselective biotransformations of (R,S)-1-phenylethanol were performed with the use of various catalytic systems containing ionic liquids and n-heptane or toluene as a reaction medium, vinyl acetate or isopropenyl acetate as an acetylating agent, and lipases from Burkholderia cepacia or Candida rugosa. The conducted studies proved that the use of Burkholderia cepacia lipase, vinyl acetate, and n-heptane with [EMIM][BF4] allows obtaining enantiomerically pure 1-phenylethyl acetate, with the enantiomeric excess of products eep = 98.9%, conversion c = 40.1%, and high value of enantioselectivity E > 200. Additionally, the use of ionic liquids allowed us to reuse enzyme in 5 reaction cycles, ensuring the high operational stability of the protein.
Partially Reduced Ni-NiO-TiO2 Photocatalysts for Hydrogen Production from Methanol–Water Solution
Authors: Drobná Helena , Meinhardová Vendula , Dubnová Lada , Kozumplíková Kateřina , Reli Martin , Kočí Kamila , Čapek Libor
Published: January 2023

The study compares the photocatalytic behavior of TiO2, NiO-TiO2, and Ni-NiO-TiO2 photocatalysts in photocatalytic hydrogen production from methanol–water solution. TiO2 and NiO-TiO2 photocatalysts with theoretical NiO loading of 0.5, 1.0, and 3.0 wt. % of NiO were prepared by the sol–gel method. The Ni-NiO-TiO2 photocatalysts were prepared by partial reduction of NiO-TiO2 in hydrogen at 450 °C. The Ni-NiO-TiO2 photocatalysts showed significantly higher hydrogen production than the NiO-TiO2 photocatalysts. The structural, textural, redox, and optical properties of all of the prepared photocatalysts were studied by using XRD, SEM, N2- adsorption, XPS, H2-TPR, and DRS. Attention is focused on the contribution of Ni loading, the surface composition (Ni2+, the lattice O2− species, and OH groups), the distribution of Ni species (dispersed NiO species, crystalline NiO phase, and the metallic Ni0 species), oxygen vacancies, TiO2 modification, the TiO2 crystallite size, and the specific surface area.
Use of Bioprinted Lipases in Microwave-Assisted Esterification Reactions
Authors: Carvalho de Melo Jéssica Jéssi , Passos da Silva Gardenia Laís , Mota Danyelle Andrade , de Souza Brandão Luma Mirely , de Souza Ranyere Lucena , Pereira Matheus M. , Lima Álvaro Silva , Soares Cleide Mara Faria
Published: January 2023

In this study, a comparative evaluation was performed in batch esterification reactions under conventional heating (CH) and assisted by microwave irradiation (MW) using bioprinted lipases. Microwave-irradiation-assisted reactions generally provide higher productivities and improve synthesis performance in terms of increased rate and reduced reaction times, resulting in higher interest yields in less time. Productivity was calculated with the enzymes: Burkholderia cepacia lipase (BCL), Candida rugosa lipase (CRL), and porcine pancreas lipase (PPL) using different fatty acids (lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0), and oleic acid (18:1)) and alcohols at a molar ratio of 1:8. The microwave reactor was operated at a temperature of 45 °C, and power varied between 50 W and 200 W. Bioprinted BCL (bBCL) showed the highest productivity among the tested lipases. In the reaction with the best result, bBCL with lauric acid under MW, the reaction time decreased from 24 h (CH) to 25 min (MW) and the productivity increased 33 times compared with the reactions under CH. The increase in productivity demonstrates its activation that occurred as a result of conformational changes of the enzyme in the bioprinting process, confirmed by Fourier transform infrared (FTIR) spectrometric analysis, which reduces the content of bBCL α-helix with lauric acid. The biocatalyst showed high operational stability over eight cycles, while losing only 19% of its initial activity with half-life times of 12.8 batches. The storage time was five weeks, maintaining ≈80% activity. The results demonstrate the prospect of a new enzymatic route to obtain hyperactive catalysts, with the use of bioprinted lipases in esterification reactions under microwave irradiation, for the synthesis of esters with a view to large-scale industrial application.
Comparison of Four Immobilization Methods for Different Transaminases
Authors: Heinks Tobias , Montua Nicolai , Teune Michelle , Liedtke Jan , Höhne Matthias , Bornscheuer Uwe T. , Fischer von Mollard Gabriele
Published: January 2023

Biocatalytic syntheses often require unfavorable conditions, which can adversely affect enzyme stability. Consequently, improving the stability of biocatalysts is needed, and this is often achieved by immobilization. In this study, we aimed to compare the stability of soluble and immobilized transaminases from different species. A cysteine in a consensus sequence was converted to a single aldehyde by the formylglycine-generating enzyme for directed single-point attachment to amine beads. This immobilization was compared to cross-linked enzyme aggregates (CLEAs) and multipoint attachments to glutaraldehyde-functionalized amine- and epoxy-beads. Subsequently, the reactivity and stability (i.e., thermal, storage, and solvent stability) of all soluble and immobilized transaminases were analyzed and compared under different conditions. The effect of immobilization was highly dependent on the type of enzyme, the immobilization strategy, and the application itself, with no superior immobilization technique identified. Immobilization of HAGA-beads often resulted in the highest activities of up to 62 U/g beads, and amine beads were best for the hexameric transaminase from Luminiphilus syltensis. Furthermore, the immobilization of transaminases enabled its reusability for at least 10 cycles, while maintaining full or high activity. Upscaled kinetic resolutions (partially performed in a SpinChemTM reactor) resulted in a high conversion, maintained enantioselectivity, and high product yields, demonstrating their applicability.
Insights into Synergy of Copper and Acid Sites for Selective Catalytic Reduction of NO with Ammonia over Zeolite Catalysts
Authors: Zhao Wenyi , Shen Menglin , Zhu Yueran , Ren Xudong , Li Xingang
Published: January 2023

Herein, we report the function of copper sites in Cu-SSZ-13, Cu-ZSM-5 and Cu-Beta catalysts with the same Si/Al ratio (14) and Cu/Al ratio (0.4) on selective catalytic reduction of NO with NH3 (NH3-SCR) and reveal the relationship between active sites (Cu sites, acid sites) and catalytic activity. The results show that the amount of isolated Cu2+ ions in the catalysts directly determines the formation of strong Lewis acid sites and reaction intermediate NO3− ions, thus affecting the low-temperature SCR performance, while the amount of highly stable Cu+ ions and Brønsted acid sites is related to the high-temperature SCR performance of the catalysts. Consequently, it contains enough isolated Cu2+ ions, highly stable Cu+ ions and Brønsted acid sites, which endows Cu-SSZ-13 with excellent NH3-SCR activity.
Magnetic CLEAs of β-Galactosidase from Aspergillus oryzae as a Potential Biocatalyst to Produce Tagatose from Lactose
Authors: de Freitas Lucas A. , de Sousa Marylane , Ribeiro Laiza B. , de França Ítalo W. L. , Gonçalves Luciana R. B.
Published: January 2023

β-galactosidase is an enzyme capable of hydrolysing lactose, used in various branches of industry, mainly the food industry. As the efficient industrial use of enzymes depends on their reuse, it is necessary to find an effective method for immobilisation, maintaining high activity and stability. The present work proposes cross-linked magnetic cross-linked enzyme aggregates (mCLEAs) to prepare heterogeneous biocatalysts of β-galactosidase. Different concentrations of glutaraldehyde (0.6%, 1.0%, 1.5%), used as a cross-linking agent, were studied. The use of dextran-aldehyde as an alternative cross-linking agent was also evaluated. The mCLEAs presented increased recovered activity directly related to the concentration of glutaraldehyde. Modifications to the protocol to prepare mCLEAs with glutaraldehyde, adding a competitive inhibitor or polymer coating, have not been effective in increasing the recovered activity of the heterogeneous biocatalysts or its thermal stability. The biocatalyst prepared using dextran-aldehyde presented 73.6% recovered activity, aside from substrate affinity equivalent to the free enzyme. The thermal stability at 60 °C was higher for the biocatalyst prepared with glutaraldehyde (mCLEA-GLU-1.5) than the one produced with dextran-aldehyde (mCLEA-DEX), and the opposite happened at 50 °C. Results obtained for lactose hydrolysis, the use of its product to produce a rare sugar (D-tagatose) and operational and storage stability indicate that heterogeneous biocatalysts have adequate characteristics for industrial use.
Electrocatalytic Oxygen Reduction to Hydrogen Peroxide on Graphdiyne-Based Single-Atom Catalysts: First-Principles Studies
Authors: Lian Kangkang , Wan Qiang , Jiang Rong , Lin Sen
Published: January 2023

The electrocatalytic oxygen reduction reaction (2e− ORR) via a two-electron process is a promising pathway for the production of hydrogen peroxide (H2O2). Here, we systematically investigated the 2e− ORR process on graphdiyne (GDY) supported single transition metal atoms (TM1@GDY) using density functional theory (DFT) calculations. Among the 23 TM1@GDY catalysts, Pt1@GDY showed the best performance for the H2O2 product with an overpotential as low as 0.15 V. The electronic structure analysis, on the one hand, elucidates that the electron transfer between Pt1@GDY and the adsorbed O2 facilitates the activation of O2, and, on the other hand, reveals that the high 2e− ORR activity of Pt1@GDY lies in the transfer of electrons from the filled Pt-3d orbitals to the 2p antibonding orbitals of OOH*, which effectively activates the O–O bond. This work provides insights to design efficient electrocatalysts for H2O2 generation.
Unveiling the Photocatalytic Activity of Carbon Dots/g-C3N4 Nanocomposite for the O-Arylation of 2-Chloroquinoline-3-carbaldehydes
Authors: Manjupriya Ravichandran , Roopan Selvaraj Mohana
Published: January 2023

Visible-light-active, organic, heterogeneous photocatalysts offer an ecologically friendly and sustainable alternative to traditional metal-based catalysts. In this work, we report the microwave synthesis of nanocarbon dots (CDs), loaded with graphitic carbon nitride (g-C3N4). The fabricated nanocomposite was shown to exhibit various properties, such as the Schottky heterojunction. The optical properties, functional group analysis, surface morphology, crystallinity, chemical stability, electronic properties, and pore size distribution of the synthesized nanocomposite were analyzed by Ultraviolet-Diffuse Reflectance Spectroscopy (UV-DRS), Photoluminescence (PL), Fourier Transform Infrared Spectroscopy (FTIR), Transmission Electron Microscopy (TEM), X-Ray Diffraction (XRD), Zeta potential, X-Ray Photoelectron Spectroscopy (XPS), and Brunauer–Emmett–Teller (BET). Until now, to the best of our knowledge, there have been no reports published on the light-assisted synthesis of O-arylation of 2-chloroquinoline-3-carbaldehyde. Therefore, we explored the photocatalytic activity of the fabricated nanocomposite in the production of the O-arylated 2-chloroquinoline-3-carbaldehyde. This facile technique uses a blue LED light source as a non-conventional source and operates under moderate conditions, resulting in useful O-arylated products. The experimental data shows the good recyclability of the catalyst for up to five cycles without a loss in catalytic activity, a simple operational protocol, easy recoverability of the catalyst, and good product yields (65–90%) within 12–24 h. Additionally, the preliminary mechanistic investigations are discussed. The results show that the phenoxy and quinoline-3-carbaldehyde radicals generated upon blue LED irradiation during the course of the reaction are responsible for C-O bond formation, which results in O-arylation. The present study clearly indicates that 0D/2D nanocomposites have a bright future as metal-free, heterogeneous photocatalysts suitable for organic reactions.
The Breakthroughs and Caveats of Using Human Pluripotent Stem Cells in Modeling Alzheimer’s Disease
Authors: Sahlgren Bendtsen Katja Maria , Hall Vanessa Jane
Published: January 2023

Modeling Alzheimer’s disease (AD) using human-induced pluripotent stem cells (iPSCs) is a field now spanning 15 years. Developments in the field have shown a shift in using simple 2D cortical neuron models to more advanced tri-cultures and 3D cerebral organoids that recapitulate more features of the disease. This is largely due to development and optimization of new cell protocols. In this review, we highlight recent major breakthroughs in the AD field and the implications this has in modeling AD using iPSCs (AD-iPSCs). To date, AD-iPSCs have been largely used to recapitulate and study impaired amyloid precursor protein (APP) processing and tau phosphorylation in both familial and sporadic AD. AD-iPSCs have also been studied for varying neuronal and glial dysfunctions. Moreover, they have been useful for discovering new molecular mechanisms, such as identifying proteins that bridge APP processing with tau phosphorylation and for identifying molecular pathways that bridge APP processing dysfunction with impaired cholesterol biosynthesis. Perhaps the greatest use of AD-iPSCs has been in discovering compounds via drug screening, that reduce amyloid beta (Aβ) in neurons, such as the anti-inflammatory compound, cromolyn, and antiparasitic drugs, avermectins. In addition, high content screening using AD-iPSCs has led to the identification of statins that can reduce levels of phosphorylated tau (p-Tau) in neurons. Some of these compounds have made it through to testing in human clinical trials. Improvements in omic technologies including single cell RNA sequencing and proteomics as well as advances in production of iPSC-cerebral organoids and tri-cultures is likely to result in the further discovery of new drugs and treatments for AD. Some caveats remain in the field, including, long experimental conditions to create mature neurons, high costs of media that limit research capabilities, and a lack of reproducibility using current iPSC-cerebral organoid protocols. Despite these current limitations, AD-iPSCs remain an excellent cellular model for studying AD mechanisms and for drug discovery.
Computational Approach to Drug Penetration across the Blood-Brain and Blood-Milk Barrier Using Chromatographic Descriptors
Authors: Karolina Wanat , Agata Rojek , Elżbieta Brzezińska
Published: January 2023

Drug penetration through biological barriers is an important aspect of pharmacokinetics. Although the structure of the blood-brain and blood-milk barriers is different, a connection can be found in the literature between drugs entering the central nervous system (CNS) and breast milk. This study was created to reveal such a relationship with the use of statistical modelling. The basic physicochemical properties of 37 active pharmaceutical compounds (APIs) and their chromatographic retention data (TLC and HPLC) were incorporated into calculations as molecular descriptors (MDs). Chromatography was performed in a thin layer format (TLC), where the plates were impregnated with bovine serum albumin to mimic plasma protein binding. Two columns were used in high performance liquid chromatography (HPLC): one with immobilized human serum albumin (HSA), and the other containing an immobilized artificial membrane (IAM). Statistical methods including multiple linear regression (MLR), cluster analysis (CA) and random forest regression (RF) were performed with satisfactory results: the MLR model explains 83% of the independent variable variability related to CNS bioavailability; while the RF model explains up to 87%. In both cases, the parameter related to breast milk penetration was included in the created models. A significant share of reversed-phase TLC retention values was also noticed in the RF model.
Inhibition of Abl Kinase by Imatinib Can Rescue the Compromised Barrier Function of 22q11.2DS Patient-iPSC-Derived Blood–Brain Barriers
Authors: Li Yunfei , Sun Zhixiong , Zhu Huixiang , Sun Yan , Shteyman David B. , Markx Sander , Leong Kam W. , Xu Bin , Fu Bingmei M.
Published: January 2023

We have previously established that the integrity of the induced blood–brain barrier (iBBB) formed by brain microvascular endothelial cells derived from the iPSC of 22q11.2 DS (22q11.2 Deletion Syndrome, also called DiGeorge Syndrome) patients is compromised. We tested the possibility that the haploinsufficiency of CRKL, a gene within the 22q11.2 DS deletion region, contributes to the deficit. The CRKL is a major substrate of the Abl tyrosine kinase, and the Abl/CRKL signaling pathway is critical for endothelial barrier functions. Imatinib, an FDA-approved drug, inhibits Abl kinase and has been used to treat various disorders involving vascular leakages. To test if imatinib can restore the compromised iBBB, we treated the patient’s iBBB with imatinib. After treatment, both trans-endothelial electrical resistance and solute permeability returned to comparable levels of the control iBBB. Correspondingly, changes in tight junctions and endothelial glycocalyx of the iBBB were also restored. Western blotting showed that imatinib increased the level of active forms of the CRKL protein. A transcriptome study revealed that imatinib up-regulated genes in the signaling pathways responsible for the protein modification process and down-regulated those for cell cycling. The KEGG pathway analysis further suggested that imatinib improved the gene expression of the CRKL signaling pathway and tight junctions, which agrees with our expectations and the observations at protein levels. Our results indicate that the 22q11.2DS iBBB is at least partially caused by the haploinsufficiency of CRKL, which can be rescued by imatinib via its effects on the Abl/CRKL signaling pathway. Our findings uncover a novel disease mechanism associated with 22q11.2DS.
Mercury Chloride Affects Band 3 Protein-Mediated Anionic Transport in Red Blood Cells: Role of Oxidative Stress and Protective Effect of Olive Oil Polyphenols
Authors: Perrone Pasquale , Spinelli Sara , Mantegna Gianluca , Notariale Rosaria , Straface Elisabetta , Caruso Daniele , Falliti Giuseppe , Marino Angela , Manna Caterina , Remigante Alessia , Morabito Rossana
Published: January 2023

Mercury is a toxic heavy metal widely dispersed in the natural environment. Mercury exposure induces an increase in oxidative stress in red blood cells (RBCs) through the production of reactive species and alteration of the endogenous antioxidant defense system. Recently, among various natural antioxidants, the polyphenols from extra-virgin olive oil (EVOO), an important element of the Mediterranean diet, have generated growing interest. Here, we examined the potential protective effects of hydroxytyrosol (HT) and/or homovanillyl alcohol (HVA) on an oxidative stress model represented by human RBCs treated with HgCl2 (10 µM, 4 h of incubation). Morphological changes as well as markers of oxidative stress, including thiobarbituric acid reactive substance (TBARS) levels, the oxidation of protein sulfhydryl (-SH) groups, methemoglobin formation (% MetHb), apoptotic cells, a reduced glutathione/oxidized glutathione ratio, Band 3 protein (B3p) content, and anion exchange capability through B3p were analyzed in RBCs treated with HgCl2 with or without 10 μM HT and/or HVA pre-treatment for 15 min. Our data show that 10 µM HT and/or HVA pre-incubation impaired both acanthocytes formation, due to 10 µM HgCl2, and mercury-induced oxidative stress injury and, moreover, restored the endogenous antioxidant system. Interestingly, HgCl2 treatment was associated with a decrease in the rate constant for SO42− uptake through B3p as well as MetHb formation. Both alterations were attenuated by pre-treatment with HT and/or HVA. These findings provide mechanistic insights into benefits deriving from the use of naturally occurring polyphenols against oxidative stress induced by HgCl2 on RBCs. Thus, dietary supplementation with polyphenols might be useful in populations exposed to HgCl2 poisoning.