bluuebunny/crossref_metadata_2025 huggingface dataset:
Green Synthesis of Zinc Oxide Nanoparticles Using Salvia officinalis Leaf Extract and Their Photocatalytic and Antifungal Activities
Authors: Abomuti May Abdullah , Danish Ekram Y. , Firoz Ahmad , Hasan Nazim , Malik Maqsood Ahmad
Published: October 2021

The facile bio-fabrication of zinc oxide (ZnO) nanoparticles (NPs) is described in this study using an aqueous leaf extract of Salvia officinalis L. as an efficient stabilizing/capping agent. Biosynthesis of nanomaterials using phytochemicals present in the plants has received great attention and is gaining significant importance as a possible alternative to the conventional chemical methods. The properties of the bio-fabricated ZnONPs were examined by different techniques, such as UV-visible spectroscopy, X-ray diffraction spectroscopy (XRD), energy-dispersive X-ray spectroscopy (EDX), Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and thermogravimetric/differential scanning calorimetry analysis (TGA/DTG). The photocatalytic activity of ZnONPs was investigated against methyl orange (MO) under UV light irradiation. Under optimum experimental conditions, ZnONPs exhibited 92.47% degradation of MO. Furthermore, the antifungal activity of bio-fabricated ZnONPs was determined against different clinical Candida albicans isolates following standard protocols of broth microdilution and disc diffusion assay. The susceptibility assay revealed that ZnONPs inhibit the growth of all the tested fungal isolates at varying levels with MIC values ranging from 7.81 to 1.95 µg/mL. Insight mechanisms of antifungal action appeared to be originated via inhibition of ergosterol biosynthesis and the disruption of membrane integrity. Thus, it was postulated that bio-fabricated ZnONPs have sustainable applications in developing novel antifungal agents with multiple drug targets. In addition, ZnONPs show efficient photocatalytic efficiency without any significant catalytic loss after the catalyst was recycled and reused multiple times.
Identification and Biochemical Characterization of a Novel Hormone-Sensitive Lipase Family Esterase Est19 from the Antarctic Bacterium Pseudomonas sp. E2-15
Authors: Liu Xiaoyu , Zhou Mingyang , Xing Shu , Wu Tao , He Hailun , Bielicki John Kevin , Chen Jianbin
Published: October 2021

Esterases represent an important class of enzymes with a wide variety of industrial applications. A novel hormone-sensitive lipase (HSL) family esterase, Est19, from the Antarctic bacterium Pseudomonas sp. E2-15 is identified, cloned, and expressed. The enzyme possesses a GESAG motif containing an active serine (S) located within a highly conserved catalytic triad of Ser155, Asp253, and His282 residues. The catalytic efficiency (kcat/Km) of Est19 for the pNPC6 substrate is 148.68 s−1mM−1 at 40 °C. Replacing Glu154 juxtaposed to the critical catalytic serine with Asp (E154→D substitution) reduced the activity and catalytic efficiency of the enzyme two-fold, with little change in the substrate affinity. The wild-type enzyme retained near complete activity over a temperature range of 10–60 °C, while ~50% of its activity was retained at 0 °C. A phylogenetic analysis suggested that Est19 and its homologs may represent a new subfamily of HSL. The thermal stability and stereo-specificity suggest that the Est19 esterase may be useful for cold and chiral catalyses.
Glycoside Hydrolases and Glycosyltransferases from Hyperthermophilic Archaea: Insights on Their Characteristics and Applications in Biotechnology
Authors: Amin Khadija , Tranchimand Sylvain , Benvegnu Thierry , Abdel-Razzak Ziad , Chamieh Hala
Published: October 2021

Hyperthermophilic Archaea colonizing unnatural habitats of extremes conditions such as volcanoes and deep-sea hydrothermal vents represent an unmeasurable bioresource for enzymes used in various industrial applications. Their enzymes show distinct structural and functional properties and are resistant to extreme conditions of temperature and pressure where their mesophilic homologs fail. In this review, we will outline carbohydrate-active enzymes (CAZymes) from hyperthermophilic Archaea with specific focus on the two largest families, glycoside hydrolases (GHs) and glycosyltransferases (GTs). We will present the latest advances on these enzymes particularly in the light of novel accumulating data from genomics and metagenomics sequencing technologies. We will discuss the contribution of these enzymes from hyperthermophilic Archaea to industrial applications and put the emphasis on newly identifed enzymes. We will highlight their common biochemical and distinct features. Finally, we will overview the areas that remain to be explored to identify novel promising hyperthermozymes.
Altered O-glycomes of Renal Brush-Border Membrane in Model Rats with Chronic Kidney Diseases
Authors: Yu Aiying , Zhao Jingfu , Zhong Jieqiang , Wang Junyao , Yadav Shiv Pratap S. , Molitoris Bruce A. , Wagner Mark C. , Mechref Yehia
Published: October 2021

Chronic kidney disease (CKD) is defined as a decrease in renal function or glomerular filtration rate (GFR), and proteinuria is often present. Proteinuria increases with age and can be caused by glomerular and/or proximal tubule (PT) alterations. PT cells have an apical brush border membrane (BBM), which is a highly dynamic, organized, and specialized membrane region containing multiple glycoproteins required for its functions including regulating uptake, secretion, and signaling dependent upon the physiologic state. PT disorders contribute to the dysfunction observed in CKD. Many glycoprotein functions have been attributed to their N- and O-glycans, which are highly regulated and complex. In this study, the O-glycans present in rat BBMs from animals with different levels of kidney disease and proteinuria were characterized and analyzed using liquid chromatography tandem mass spectrometry (LC–MS/MS). A principal component analysis (PCA) documented that each group has distinct O-glycan distributions. Higher fucosylation levels were observed in the CKD and diabetic groups, which may contribute to PT dysfunction by altering physiologic glycoprotein interactions. Fucosylated O-glycans such as 1-1-1-0 exhibited higher abundance in the severe proteinuric groups. These glycomic results revealed that differential O-glycan expressions in CKD progressions has the potential to define the mechanism of proteinuria in kidney disease and to identify potential therapeutic interventions.
Over-Dose Lithium Toxicity as an Occlusive-like Syndrome in Rats and Gastric Pentadecapeptide BPC 157
Authors: Strbe Sanja , Gojkovic Slaven , Krezic Ivan , Zizek Helena , Vranes Hrvoje , Barisic Ivan , Strinic Dean , Orct Tatjana , Vukojevic Jaksa , Ilic Spomenko , Lovric Eva , Muzinic Darija , Kolenc Danijela , Filipčić Igor , Zoricic Zoran , Marcinko Darko , Boban Blagaic Alenka , Skrtic Anita , Seiwerth Sven , Sikiric Predrag
Published: October 2021

Due to endothelial impairment, high-dose lithium may produce an occlusive-like syndrome, comparable to permanent occlusion of major vessel-induced syndromes in rats; intracranial, portal, and caval hypertension, and aortal hypotension; multi-organ dysfunction syndrome; brain, heart, lung, liver, kidney, and gastrointestinal lesions; arterial and venous thrombosis; and tissue oxidative stress. Stable gastric pentadecapeptide BPC 157 may be a means of therapy via activating loops (bypassing vessel occlusion) and counteracting major occlusion syndromes. Recently, BPC 157 counteracted the lithium sulfate regimen in rats (500 mg/kg/day, ip, for 3 days, with assessment at 210 min after each administration of lithium) and its severe syndrome (muscular weakness and prostration, reduced muscle fibers, myocardial infarction, and edema of various brain areas). Subsequently, BPC 157 also counteracted the lithium-induced occlusive-like syndrome; rapidly counteracted brain swelling and intracranial (superior sagittal sinus) hypertension, portal hypertension, and aortal hypotension, which otherwise would persist; counteracted vessel failure; abrogated congestion of the inferior caval and superior mesenteric veins; reversed azygos vein failure; and mitigated thrombosis (superior mesenteric vein and artery), congestion of the stomach, and major hemorrhagic lesions. Both regimens of BPC 157 administration also counteracted the previously described muscular weakness and prostration (as shown in microscopic and ECG recordings), myocardial congestion and infarction, in addition to edema and lesions in various brain areas; marked dilatation and central venous congestion in the liver; large areas of congestion and hemorrhage in the lung; and degeneration of proximal and distal tubules with cytoplasmic vacuolization in the kidney, attenuating oxidative stress. Thus, BPC 157 therapy overwhelmed high-dose lithium intoxication in rats.
Psoriasis as an Immune-Mediated and Inflammatory Systemic Disease: From Pathophysiology to Novel Therapeutic Approaches
Authors: Campanati Anna , Marani Andrea , Martina Emanuela , Diotallevi Federico , Radi Giulia , Offidani Annamaria
Published: October 2021

Psoriasis is an immune-mediated inflammatory disease, with a chronic relapsing-remitting course, which affects 2–3% of the worldwide population. The progressive acquisitions of the inflammatory pathways involved in the development of psoriasis have led to the identification of the key molecules of the psoriatic inflammatory cascade. At the same time, psoriasis therapy has radically evolved with the introduction of target molecules able to modify the natural history of the disease, acting specifically on these inflammatory pathways. For these reasons, biologics have been demonstrated to be drugs able to change the disease’s natural history, as they reduce the inflammatory background to avoid irreversible organ damage and prevent systemic complications. However, several issues related to the use of biologics in patients with systemic comorbidities, remain open. All these data reflect the extraordinary potentiality of biologics, but also the unmet medical need to improve our knowledge on the long-term risk related to continuous use of these drugs, and their administration in special populations. This narrative review aims to highlight both the efficacy and safety profile of biologics in psoriasis, starting from pathophysiology and moving towards their clinical application.
Two-Phase Biocatalysis in Microfluidic Droplets
Authors: Xiang Lanting , Kaspar Felix , Schallmey Anett , Constantinou Iordania
Published: October 2021

This Perspective discusses the literature related to two-phase biocatalysis in microfluidic droplets. Enzymes used as catalysts in biocatalysis are generally less stable in organic media than in their native aqueous environments; however, chemical and pharmaceutical compounds are often insoluble in water. The use of aqueous/organic two-phase media provides a solution to this problem and has therefore become standard practice for multiple biotransformations. In batch, two-phase biocatalysis is limited by mass transport, a limitation that can be overcome with the use of microfluidic systems. Although, two-phase biocatalysis in laminar flow systems has been extensively studied, microfluidic droplets have been primarily used for enzyme screening. In this Perspective, we summarize the limited published work on two-phase biocatalysis in microfluidic droplets and discuss the limitations, challenges, and future perspectives of this technology.
An Ultra-Low Power Surface EMG Sensor for Wearable Biometric and Medical Applications
Authors: Wu Yi-Da , Ruan Shanq-Jang , Lee Yu-Hao
Published: October 2021

In recent years, the surface electromyography (EMG) signal has received a lot of attention. EMG signals are used to analyze muscle activity or to evaluate a patient’s muscle status. However, commercial surface EMG systems are expensive and have high power consumption. Therefore, the purpose of this paper is to implement a surface EMG acquisition system that supports high sampling and ultra-low power consumption measurement. This work analyzes and optimizes each part of the EMG acquisition circuit and combines an MCU with BLE. Regarding the MCU power saving method, the system uses two different frequency MCU clock sources and we proposed a ping-pong buffer as the memory architecture to achieve the best power saving effect. The measured surface EMG signal samples can be forwarded immediately to the host for further processing and additional application. The results show that the average current of the proposed architecture can be reduced by 92.72% compared with commercial devices, and the battery life is 9.057 times longer. In addition, the correlation coefficients were up to 99.5%, which represents a high relative agreement between the commercial and the proposed system.
Prevalence of Major Depressive Disorder and Correlates of Thoughts of Death, Suicidal Behaviour, and Death by Suicide in the Geriatric Population—A General Review of Literature
Authors: Obuobi-Donkor Gloria , Nkire Nnamdi , Agyapong Vincent I. O.
Published: October 2021

Background: There has been an increase in deaths by suicide in old age in the last decade. Depression and suicide in the elderly, 60 years and above, is a major global public health concern. Determining the prevalence of depression, and correlates of death by suicide in the geriatric population, is an important first step toward addressing this public health concern. This literature review aims to determine the prevalence of major depressive disorders and the correlates of death by suicide in the geriatric population. Methods: This general review of the literature was performed using relevant search terms to determine both the prevalence of depression and the correlates of death by suicide among the geriatric population. Databases such as MEDLINE, PsycINFO, CINAHL, and PubMed were searched. Relevant and current articles were extracted, reviewed, and analyzed. The elderly population was defined as individuals 60 years and above. Only full texts articles in English were reviewed. Findings: The prevalence estimates of major depressive disorder in the elderly ranged from 5.37 to 56%. Adults aged 60 years and older have a high risk of depression that exposes them to suicide. Moreover, elderly women are more likely to experience depression than elderly men, but successful suicide is more common in men. Depression and other mental health conditions (schizophrenia, anxiety disorders) and perceived stress were found to be predictors of suicide in the elderly. Other predictors included physical illnesses such as malignancies, financial constraints, cuckoldry, and sexual dysfunction, and also social factors like living alone triggers depressive symptoms and increases suicidal risk in the elderly. Hanging was found to be the most common method of death by suicide for both sexes. While elderly women preferred poisoning, elderly men in Western countries preferred firearms. Differences in gender, the aging process and social issues were also contributing factors to methods used for suicide. Conclusions: Depression and debilitating physical illnesses were identified as significant contributors to suicide risk in the elderly population, and emphasis should be placed on identifying these factors early and treating them. Recognizing and addressing factors that predict suicide in the elderly will help to improve the mental wellbeing of the elderly.
Municipal Solid Waste Incineration Ash-Incorporated Concrete: One Step towards Environmental Justice
Authors: Li Jiaqi
Published: October 2021

Municipal solid waste and cement manufacture are two sources of environmental justice issues in urban and suburban areas. Waste utilization is an attractive alternative to disposal for eliminating environmental injustice, reducing potential hazards, and improving urban sustainability. The re-use and recycling of municipal solid waste incineration (MSWI) ash in the construction industry has drawn significant attention. Incorporating MSWI ash in cement and concrete production is a potential path that mitigates the environmental justice issues in waste management and the construction industry. This paper presents a critical overview of the pretreatment methods that optimize MSWI ash utilization in cement/concrete and the influences of MSWI ash on the performance of cement/concrete. This review aims to elucidate the potential advantages and limitations associated with the use of MSWI ash for producing cement clinker, alternative binder (e.g., alkali-activated material), cement substitutes, and aggregates. A brief overview of the generation and characteristics of MSWI ash is reported, accompanied by identifying opportunities for the use of MSWI ash-incorporated products in industrial-scale applications and recognizing associated environmental justice implications.
The Effects of the Visual Environment on K-12 Student Achievement
Authors: Kuhlenengel Michael , Konstantzos Iason , Waters Clarence
Published: October 2021

The varying indoor environments among educational buildings can have an impact on students’ ability to learn. This study looks at field data from 220 classrooms in the Midwest, United States, over a two-year period, to analyze the effects of the visual environment on student achievement. The visual environmental metrics considered within this scope include the three new view metrics introduced within the EN 17037 “Daylight of Buildings” standard (Horizontal Sight Angle, Outside Distance of View, and Number of View Layers), as well as standard daylight and electric lighting metrics, focusing on light availability and glare. To capture student achievement, math and reading achievement scores were used, accompanied by auxiliary demographic variables. This allowed for a correlational analysis using multivariate regression. Among the notable results of this study, there was a positive effect of the availability of view on reading achievement. However, another view metric, Horizontal Sight Angle, showed a significant negative interaction with free and reduced lunch recipients on reading achievement, indicating that demographics can also have a significant role in the way the visual environment can affect learning.
Carbon Nanoarchitectonics for Energy and Related Applications
Authors: Shrestha Rekha Goswami , Shrestha Lok Kumar , Ariga Katsuhiko
Published: October 2021

Nanoarchitectonics has been recently proposed as a post-nanotechnology concept. It is the methodology to produce functional materials from nanoscale units. Carbon-based materials are actively used in nanoarchitectonics approaches. This review explains several recent examples of energy and related applications of carbon materials from the viewpoint of the nanoarchitectonics concept. Explanations and discussions are described according to the classification of carbon sources for nanostructured materials: (i) carbon nanoarchitectonics from molecules and supramolecular assemblies; (ii) carbon nanoarchitectonics from fullerenes; (iii) carbon nanoarchitectonics from biomass; and (iv) carbon nanoarchitectonics with composites and hybrids. Functional carbon materials can be nanoarchitected through various processes, including well-skilled organic synthesis with designed molecular sources; self-assembly of fullerenes under various conditions; practical, low-cost synthesis from biomass; and hybrid/composite formation with various carbon sources. These examples strikingly demonstrate the enormous potential of nanoarchitectonics approaches to produce functional carbon materials from various components such as small molecules, fullerene, other nanocarbons, and naturally abundant biomasses. While this review article only shows limited application aspects in energy-related usages such as supercapacitors, applications for more advanced cells and batteries, environmental monitoring and remediation, bio-medical usages, and advanced devices are also expected.
Photodynamic Priming Improves the Anti-Migratory Activity of Prostaglandin E Receptor 4 Antagonist in Cancer Cells In Vitro
Authors: Sorrin Aaron J. , Liu Cindy , Cicalo Julia , Reader Jocelyn , Najafali Daniel , Zhang Yuji , Roque Dana M. , Huang Huang-Chiao
Published: October 2021

The combination of photodynamic agents and biological inhibitors is rapidly gaining attention for its promise and approval in treating advanced cancer. The activity of photodynamic treatment is mainly governed by the formation of reactive oxygen species upon light activation of photosensitizers. Exposure to reactive oxygen species above a threshold dose can induce cellular damage and cancer cell death, while the surviving cancer cells are “photodynamically primed”, or sensitized, to respond better to other drugs and biological treatments. Here, we report a new combination regimen of photodynamic priming (PDP) and prostaglandin E2 receptor 4 (EP4) inhibition that reduces the migration and invasion of two human ovarian cancer cell lines (OVCAR-5 and CAOV3) in vitro. PDP is achieved by red light activation of the FDA-approved photosensitizer, benzoporphyrin derivative (BPD), or a chemical conjugate composed of the BPD linked to cetuximab, an anti-epithelial growth factor receptor (EGFR) antibody. Immunoblotting data identify co-inhibition of EGFR, cAMP-response element binding protein (CREB), and extracellular signal-regulated kinase 1/2 (ERK1/2) as key in the signaling cascades modulated by the combination of EGFR-targeted PDP and EP4 inhibition. This study provides valuable insights into the development of a molecular-targeted photochemical strategy to improve the anti-metastatic effects of EP4 receptor antagonists.
Elevated Level of Nerve Growth Factor (NGF) in Serum-Derived Exosomes Predicts Poor Survival in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy
Authors: Jung Hae Hyun , Kim Ji-Yeon , Cho Eun Yoon , Oh Jung Min , Lee Jeong Eon , Kim Seok Won , Nam Seok Jin , Park Yeon Hee , Ahn Jin Seok , Im Young-Hyuck
Published: October 2021

Neoadjuvant chemotherapy (NAC) is a standard treatment strategy for patients with locally advanced breast cancer (LABC). However, there are no established predictors of chemosensitivity and survival in LABC patients who undergo NAC. Many studies have demonstrated that exosomes and cytokines are important players in intercellular communication between tumors and their environments, and are involved in chemotherapy resistance. Recently, it was reported that cytokines can be packaged into exosomes, but whether exosomal cytokines serve as biomarkers in breast cancer patients is still unclear. In this study, we examined the roles of cytokines in both serum and exosomes as prognostic biomarkers for long-term outcomes in patients with breast cancer who undergo NAC. We isolated exosomes from the blood of 129 patients with early breast cancer who were receiving neoadjuvant chemotherapy between 2008 and 2011 at Samsung Medical Center. The levels of cytokines and growth factors in serum and exosomes were measured with ProcartaPlex immune-related panels. We investigated correlations between clinic-pathologic variables and patient survival, and Cox proportional hazards regression analysis was performed for prognostic evaluation. We detected significant differences in expression patterns between serum cytokines and exosomal cytokines. In both serum and exosomes, many cytokines were positively correlated with age. In univariate analysis, patients with high serum IP-10, serum MMP-1, and exosomal NGF had shorter overall survival. Exosomal NGF showed significantly poorer overall survival in multivariate analysis. These findings suggest that exosomal NGF is useful for identifying patients with poor survival outcomes.
Endoscopic Ultrasound-Guided Radiofrequency Ablation as an Future Alternative to Pancreatectomy for Pancreatic Metastases from Renal Cell Carcinoma: A Prospective Study
Authors: Chanez Brice , Caillol Fabrice , Ratone Jean-Philippe , Pesenti Christian , Rochigneux Philippe , Pignot Géraldine , Thomassin Jeanne , Brunelle Serge , Walz Jochen , Salem Naji , Giovannini Marc , Gravis Gwenaelle
Published: October 2021

Background: Pancreatic metastases (PM) from renal cell carcinoma (RCC) are rare, are associated with favorable outcomes and are usually handled by surgery or VEGFR inhibitors, which both have side effects. Endoscopic Ultrasound (EUS)-guided radiofrequency ablation (RFA) is an innovative approach to treat focally deep metastases and could be a relevant technique to control PM from RCC. Methods: This monocentric, prospective study aimed to evaluate the safety and efficacy of EUS-RFA to treat PM. We included patients with confirmed and progressive PM from RCC. PM was ablated under general anesthesia with a linear EUS scope and a EUS-RFA 19-gauge needle electrode placed into the tumor. Results: Twelve patients from Paoli-Calmettes Institute were recruited between May 2017 and December 2019. Median age was 70.5 years (range 61–75), 50% were female, 100% were ECOG 0–1. At inclusion, mean PM size was 17 mm (range 3–35 mm); and all were progressive before EUS-RFA. Seven patients had EUS-RFA as the only treatment for RCC. We performed 26 EUS-RFA procedures and 21 PM was ablated. Median follow up was 27.7 months (range 6.4–57.1). For evaluable PM, the 6- and 12-month focal control rates were 84% and 73% respectively. One patient treated with TKI developed a paraduodenal abscess 2 months after EUS-RFA and another patient with biliary stent developed hepatic abscesses few days after EUS-RFA. No other severe side effects were experienced. Conclusions: in this series, which is the largest ever reported, we showed that EUS-RFA is feasible and yields an excellent local control rate for PM from mRCC. With manageable complications, it could be a valuable alternative to pancreatic surgery in well-selected patients.
Patterns and Predictors of Healthcare Use among Adolescent and Young Adult Cancer Survivors versus a Community Comparison Group
Authors: Sansom-Daly Ursula M. , Wakefield Claire E. , Signorelli Christina , Donoghoe Mark W. , Anazodo Antoinette , Sawyer Susan M. , Osborn Michael , Viney Rosalie , Daniell Nicholas , Faasse Kate , Cohn Richard J.
Published: October 2021

Healthcare use (HCU) during survivorship can mitigate adolescent and young adult (AYA) cancer survivors’ (aged 15–39 years) risk of medical and psychosocial late effects, but this is understudied. We surveyed 93 Australian AYA post-treatment cancer survivors (Mage = 22.0 years, SD = 3.5; 55.9% female) and a comparison sample of 183 non-matched AYAs (Mage = 19.7, SD = 3.2; 70.5% female) on their HCU, medication use, depression/anxiety, and general functioning. Relative to our comparison AYAs, a higher proportion of our survivor group reported medical HCU (community-delivered: 65.6% versus 47.0%, p = 0.003; hospital-delivered: 31.2% versus 20.3%, p = 0.044) and mental HCU (53.8% vs. 23.5%; p < 0.0001) in the past six months. A higher proportion of our survivors reported taking medications within the past six months than our comparison AYAs (61.3% vs. 42.1%, p = 0.003) and taking more types (p < 0.001). Vitamin/supplement use was most common followed by psychotropic medications. Our survivor group reported lower depression (p = 0.001) and anxiety symptoms (p = 0.003), but similar work/study participation (p = 0.767) to our comparison AYAs. Across groups, psychological distress was associated with higher mental HCU (p = 0.001). Among survivors, those who were female, diagnosed with brain/solid tumors and who had finished treatment more recently reported greater HCU. Future research should establish whether this level of HCU meets AYAs’ survivorship needs.
Healthcare Use during the Last Six Months of Life in Patients with Advanced Breast Cancer
Authors: Schmitz Renée. S. J. M. , Geurts Sandra. M. E. , Ibragimova Khava. I. E. , Tilli Dominique. J. P. , Tjan-Heijnen Vivianne. C. G. , de Boer Maaike
Published: October 2021

New treatment options in cancer have resulted in increased use of health care resources near the end of life. We assessed health care use near the end of life of patients with advanced breast cancer (ABC). From the Southeast Netherlands Breast cancer (SONABRE) registry, we selected all deceased patients diagnosed with ABC in Maastricht University Medical Center between January 2007 and October 2017. Frequency of health care use in the last six months of life was described and predictors for health care use were assessed. Of 203 patients, 76% were admitted during the last six months, 6% to the intensive care unit (ICU) and 2% underwent cardiopulmonary resuscitation (CPR). Death in hospital occurred in 25%. Nine percent of patients received a new line of chemotherapy ≤30 days before death, which was associated with age <65 years and <1 year survival since diagnosis of metastases. In these patients, the hospital admission rate was 95%, of which 79% died in the hospital, mostly due to progressive disease (80%). In conclusion, the frequency of ICU-admission, CPR or a new line of chemotherapy ≤30 days before death was low. Most patients receiving a new line of chemotherapy ≤30 days before death, died in the hospital.
Circulating Tumor Cell Clusters Are Cloaked with Platelets and Correlate with Poor Prognosis in Unresectable Pancreatic Cancer
Authors: Lim Minji , Park Suhyun , Jeong Hyoung-Oh , Park Sung Hee , Kumar Sumit , Jang Aelee , Lee Semin , Kim Dong Uk , Cho Yoon-Kyoung
Published: October 2021

Circulating tumor cells (CTCs) are known to be heterogeneous and clustered with tumor-associated cells, such as macrophages, neutrophils, fibroblasts, and platelets. However, their molecular profile and clinical significance remain largely unknown. Thus, we aimed to perform a comprehensive gene expression analysis of single CTCs and CTC clusters in patients with pancreatic cancer and to identify their potential clinical relevance to provide personalized medicine. Epitope-independent, rapid (>3 mL of whole blood/min) isolation of single CTCs and CTC clusters was achieved from a prospective cohort of 16 patients with unresectable pancreatic cancer using a centrifugal microfluidic device. Forty-eight mRNA expressions of individual CTCs and CTC clusters were analyzed to identify pancreatic CTC phenotype. CTC clusters had a larger proportion of mesenchymal expression than single CTCs (p = 0.0004). The presence of CTC clusters positively correlated with poor prognosis (progression-free survival, p = 0.0159; overall survival, p = 0.0186). Furthermore, we found that most CTCs in these patients (90.7%) were cloaked with platelets and found the presence of a positive correlation between the increase in CTC clusters and rapid disease progression during follow-ups. Efficient CTC cluster isolation and analysis techniques will enhance the understanding of complex tumor metastasis processes and can facilitate personalized disease management.
Dual Targeting with Cell Surface Electrical Charge and Folic Acid via Superparamagnetic Fe3O4@Cu2–xS for Photothermal Cancer Cell Killing
Authors: Deng Zicheng , Lin Jou , Bud’ko Sergey L. , Webster Brent , Kalin Tanya V. , Kalinichenko Vladimir V. , Shi Donglu
Published: October 2021

A major challenge in cancer therapy is to achieve high cell targeting specificity for the highest therapeutic efficacy. Two major approaches have been shown to be quite effective, namely, (1) bio-marker mediated cell targeting, and (2) electrical charge driven cell binding. The former utilizes the tumor-specific moieties on nano carrier surfaces for active targeting, while the latter relies on nanoparticles binding onto the cancer cell surfaces due to differences in electrical charge. Cancer cells are known for their hallmark metabolic pattern: high rates of glycolysis that lead to negatively charged cell surfaces. In this study, the nanoparticles of Fe3O4@Cu2–xS were rendered positively charged by conjugating their surfaces with different functional groups for strong electrostatic binding onto the negatively-charged cancer cells. In addition to the positively charged surfaces, the Fe3O4@Cu2–xS nanoparticles were also modified with folic acid (FA) for biomarker-based cell targeting. The dual-targeting approach synergistically utilizes the effectiveness of both charge- and biomarker-based cell binding for enhanced cell targeting. Further, these superparamagnetic Fe3O4@Cu2–xS nanoparticles exhibit much stronger IR absorptions compared to Fe3O4, therefore much more effective in photothermal therapy.
The Impact of SARS-CoV-2 Pandemic on Time to Primary, Secondary Resection and Adjuvant Intravesical Therapy in Patients with High-Risk Non-Muscle Invasive Bladder Cancer: A Retrospective Multi-Institutional Cohort Analysis
Authors: Ferro Matteo , Del Giudice Francesco , Carrieri Giuseppe , Busetto Gian Maria , Cormio Luigi , Hurle Rodolfo , Contieri Roberto , Arcaniolo Davide , Sciarra Alessandro , Maggi Martina , Porpiglia Francesco , Manfredi Matteo , Fiori Cristian , Antonelli Alessandro , Tafuri Alessandro , Bove Pierluigi , Terrone Carlo , Borghesi Marco , Costantini Elisabetta , Iliano Ester , Montanari Emanuele , Boeri Luca , Russo Giorgio Ivan , Madonia Massimo , Tedde Alessandro , Veccia Alessandro , Simeone Claudio , Liguori Giovanni , Trombetta Carlo , Brunocilla Eugenio , Schiavina Riccardo , Dal Moro Fabrizio , Racioppi Marco , Vartolomei Mihai Dorin , Longo Nicola , Spirito Lorenzo , Crocetto Felice , Cantiello Francesco , Damiano Rocco , Di Stasi Savino M. , Marchioni Michele , Schips Luigi , Parma Paolo , Carmignani Luca , Conti Andrea , Soria Francesco , Gontero Paolo , Barone Biagio , Deho Federico , Zaffuto Emanuele , Papalia Rocco , Scarpa Roberto M. , Pagliarulo Vincenzo , Lucarelli Giuseppe , Ditonno Pasquale , Botticelli Francesco Maria Gerardo , Musi Gennaro , Catellani Michele , de Cobelli Ottavio
Published: October 2021

Background: To investigate the impact of COVID-19 outbreak on the diagnosis and treatment of non-muscle invasive bladder cancer (NMIBC). Methods: A retrospective analysis was performed using an Italian multi-institutional database of TURBT patients with high-risk urothelial NMIBC between January 2019 and February 2021, followed by Re-TURBT and/or adjuvant intravesical BCG. Results: A total of 2591 patients from 27 institutions with primary TURBT were included. Of these, 1534 (59.2%) and 1056 (40.8%) underwent TURBT before and during the COVID-19 outbreak, respectively. Time between diagnosis and TURBT was significantly longer during the COVID-19 period (65 vs. 52 days, p = 0.002). One thousand and sixty-six patients (41.1%) received Re-TURBT, 604 (56.7%) during the pre-COVID-19. The median time to secondary resection was significantly longer during the COVID-19 period (55 vs. 48 days, p < 0.0001). A total of 977 patients underwent adjuvant intravesical therapy after primary or secondary resection, with a similar distribution across the two groups (n = 453, 86% vs. n = 388, 86.2%). However, the proportion of the patients who underwent maintenance significantly differed (79.5% vs. 60.4%, p < 0.0001). Conclusions: The COVID-19 pandemic represented an unprecedented challenge to our health system. Our study did not show significant differences in TURBT quality. However, a delay in treatment schedule and disease management was observed. Investigation of the oncological impacts of those differences should be advocated.
Vascular Resection in Perihilar Cholangiocarcinoma
Authors: Serrablo Alejandro , Serrablo Leyre , Alikhanov Ruslan , Tejedor Luis
Published: October 2021

Among the cholangiocarcinomas, the most common type is perihilar (phCC), accounting for approximately 60% of cases, after which are the distal and then intrahepatic forms. There is no staging system that allows for a comparison of all series and extraction of conclusions that increase the long-term survival rate of this dismal disease. The extension of the resection, which theoretically depends on the type of phCC, is not a closed subject. As surgery is the only known way to achieve a cure, many aggressive approaches have been adopted. Despite extended liver resections and even vascular resections, margins are positive in around one third of patients. In the past two decades, with advances in diagnostic and surgical techniques, surgical outcomes and survival rates have gradually improved, although variability is the rule, with morbidity and mortality rates ranging from 14% to 76% and from 0% to 19%, respectively. Extended hepatectomies and portal vein resection, or even right hepatic artery reconstruction for the left side tumors are frequently needed. Salvage procedures when arterial reconstruction is not feasible, as well as hepatopancreatoduodenectomy, are still under evaluation too. In this article, we discuss the aggressive surgical approach to phCC focused on vascular resection. Disparate results on the surgical treatment of phCC made it impossible to reach clear-cut conclusions.
Magnetic Particle Imaging: An Emerging Modality with Prospects in Diagnosis, Targeting and Therapy of Cancer
Authors: Tay Zhi Wei , Chandrasekharan Prashant , Fellows Benjamin D. , Arrizabalaga Irati Rodrigo , Yu Elaine , Olivo Malini , Conolly Steven M.
Published: October 2021

Background: Magnetic Particle Imaging (MPI) is an emerging imaging modality for quantitative direct imaging of superparamagnetic iron oxide nanoparticles (SPION or SPIO). With different physics from MRI, MPI benefits from ideal image contrast with zero background tissue signal. This enables clear visualization of cancer with image characteristics similar to PET or SPECT, but using radiation-free magnetic nanoparticles instead, with infinite-duration reporter persistence in vivo. MPI for cancer imaging: demonstrated months of quantitative imaging of the cancer-related immune response with in situ SPION-labelling of immune cells (e.g., neutrophils, CAR T-cells). Because MPI suffers absolutely no susceptibility artifacts in the lung, immuno-MPI could soon provide completely noninvasive early-stage diagnosis and treatment monitoring of lung cancers. MPI for magnetic steering: MPI gradients are ~150 × stronger than MRI, enabling remote magnetic steering of magneto-aerosol, nanoparticles, and catheter tips, enhancing therapeutic delivery by magnetic means. MPI for precision therapy: gradients enable focusing of magnetic hyperthermia and magnetic-actuated drug release with up to 2 mm precision. The extent of drug release from the magnetic nanocarrier can be quantitatively monitored by MPI of SPION’s MPS spectral changes within the nanocarrier. Conclusion: MPI is a promising new magnetic modality spanning cancer imaging to guided-therapy.
Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436
Authors: Uckun Fatih M. , Watts Justin , Mims Alice S. , Patel Prapti , Wang Eunice , Shami Paul J. , Cull Elizabeth , Lee Cynthia , Cogle Christopher R. , Lin Tara L.
Published: October 2021

We evaluate the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome (CRS) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received APVO436 during the dose-escalation phase of a Phase 1B study (ClinicalTrials.gov, identifier: NCT03647800). Of four patients who developed Grade ≥ 3 CRS, two received steroid prophylaxis. The dose level, gender, race, obesity, or baseline hematologic parameters in peripheral blood did not predict the risk of CRS. Patients with a higher leukemia burden as determined by a higher total WBC, higher percentage of blasts in bone marrow, or higher percentage of blasts in peripheral blood (by hematopathology or immunophenotyping) did not have a higher incidence of CRS. There was an age difference between patients who did versus patients who did not develop CRS (72.9 ± 1.6 years (Median 73.5 years) vs. 63.3 ± 2.3 years (Median: 65.0 years), which was borderline significant (p = 0.04). Premedication with steroids did not eliminate the risk of CRS. Cytokine profiling in patients who developed CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response was IL-6. APVO436-associated CRS was generally manageable with tocilizumab with or without dexamethasone. Notably, the development of CRS after APVO436 therapy did not appear to be associated with a response. The prolonged stabilization of disease, partial remissions and complete remissions were achieved in both patients who experienced CRS, as well as patients who did not experience CRS after APVO436 infusions.
CSF1R Inhibition Combined with GM-CSF Reprograms Macrophages and Disrupts Protumoral Interplays with AML Cells
Authors: Smirnova Tatiana , Spertini Caroline , Spertini Olivier
Published: October 2021

Relapse is a major issue in acute myeloid leukemia (AML) and while the contribution of gene mutations in developing drug resistance is well established, little is known on the role of macrophages (MΦs) in an AML cell microenvironment. We examined whether myeloblasts could educate MΦs to adopt a protumoral orientation supporting myeloblast survival and resistance to therapy. Flow cytometry analyses demonstrated that M2-like CD163+ MΦs are abundantly present, at diagnosis, in the bone marrow of AML patients. We showed that myeloblasts, or their conditioned medium, polarize monocytes to M2-like CD163+ MΦs, induce the secretion of many protumoral factors, and promote myeloblast survival and proliferation as long as close intercellular contacts are maintained. Importantly, pharmacologic inhibition of the CSF1 receptor (CSF1R), in the presence of GM-CSF, reprogrammed MΦ polarization to an M1-like orientation, induced the secretion of soluble factors with antitumoral activities, reduced protumoral agonists, and promoted the apoptosis of myeloblasts interacting with MΦs. Furthermore, myeloblasts, which became resistant to venetoclax or midostaurin during their interplay with protumoral CD163+ MΦs, regained sensitivity to these targeted therapies following CSF1R inhibition in the presence of GM-CSF. These data reveal a crucial role of CD163+ MΦ interactions with myeloblasts that promote myeloblast survival and identify CSF1R inhibition as a novel target for AML therapy.
Rac GTPase Signaling in Immune-Mediated Mechanisms of Atherosclerosis
Authors: Lee Cadence F. , Carley Rachel E. , Butler Celia A. , Morrison Alan R.
Published: October 2021

Coronary artery disease caused by atherosclerosis is a major cause of morbidity and mortality around the world. Data from preclinical and clinical studies support the belief that atherosclerosis is an inflammatory disease that is mediated by innate and adaptive immune signaling mechanisms. This review sought to highlight the role of Rac-mediated inflammatory signaling in the mechanisms driving atherosclerotic calcification. In addition, current clinical treatment strategies that are related to targeting hypercholesterolemia as a critical risk factor for atherosclerotic vascular disease are addressed in relation to the effects on Rac immune signaling and the implications for the future of targeting immune responses in the treatment of calcific atherosclerosis.
Neonatal Porcine Germ Cells Dedifferentiate and Display Osteogenic and Pluripotency Properties
Authors: Fayaz Mohammad Amin , Rosa Gustavo dos Santos , Honaramooz Ali
Published: October 2021

Gonocytes are progenitors of spermatogonial stem cells in the neonatal testis. We have previously shown that upon culturing, neonatal porcine gonocytes and their colonies express germ cell and pluripotency markers. The objectives of present study were to investigate in vitro trans-differentiation potential of porcine gonocytes and their colonies into cells from three germinal layers, and to assess pluripotency of cultured gonocytes/colonies in vivo. For osteogenic and tri-lineage differentiation, cells were incubated in regular culture media for 14 and 28 days, respectively. Cells were cultured for an additional 14 days for osteogenic differentiation or 7 days for differentiation into derivates of the three germinal layers. Osteogenic differentiation of cells and colonies was verified by Alizarin Red S staining and tri-lineage differentiation was confirmed using immunofluorescence and gene expression analyses. Furthermore, upon implantation into recipient mice, the cultured cells/colonies developed teratomas expressing markers of all three germinal layers. Successful osteogenic differentiation from porcine germ cells has important implications for bone regeneration and matrix formation studies. Hence, gonocytes emerge as a promising source of adult pluripotent stem cells due to the ability to differentiate into all germinal layers without typical biosafety risks associated with viral vectors or ethical implications.
Progesterone Induced Blocking Factor Reduces Hypertension and Placental Mitochondrial Dysfunction in Response to sFlt-1 during Pregnancy
Authors: Deer Evangeline , Jones Jalisa , Cornelius Denise C. , Comley Kyleigh , Herrock Owen , Campbell Nathan , Fitzgerald Sarah , Ibrahim Tarek , LaMarca Babbette , Amaral Lorena M.
Published: October 2021

Preeclampsia (PE) is characterized by new onset hypertension in association with placental ischemia, reduced fetal weight, elevated soluble fms-like tyrosine kinase-1 (sFlt-1), and placental mitochondrial (mt) dysfunction and oxidative stress (ROS). Progesterone induced blocking factor (PIBF) is a product of progesterone signaling that blocks inflammatory processes and we have previously shown PIBF to lower mean arterial blood pressure (MAP) and sFlt-1 in a rat model of PE. Infusion of sFlt-1 causes hypertension and many characteristics of PE in pregnant rodents, however, its role in causing mt dysfunction is unknown. Therefore, we hypothesize that PIBF will improve mt function and MAP in response to elevated sFlt-1 during pregnancy. We tested our hypothesis by infusing sFlt-1 via miniosmotic pumps in normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg−1·day−1) on gestation days (GD) 13–19 in the presence or absence of PIBF (2.0 µg/mL) injected intraperitoneally on GD 15 and examined mean arterial blood pressure (MAP) and placental mt ROS on GD 19. sFlt-1 increased MAP to 112 + 2 (n = 11) compared to NP rats (98 + 2 mmHg, n = 15, p < 0.05), which was lowered in the presence of sFlt-1 (100 + 1 mmHg, n = 5, p < 0.05). Placental mtATP was reduced in sFlt-1 infused rats versus NP controls, but was improved with PIBF. Placental mtROS was elevated with sFlt-1 compared to NP controls, but was reduced with PIBF. Sera from NP + sFlt-1 increased endothelial cell mtROS, which was attenuated with PIBF. These data demonstrate sFlt-1 induced HTN during pregnancy reduces placental mt function. Importantly, PIBF improved placental mt function and HTN, indicating the efficacy of improved progesterone signaling as potential therapeutics for PE.