bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating the Impact of Ultra-Radical Surgery on Survival in Advanced Ovarian Cancer Using Population-Based Data in a Multicentre UK Study
Authors: Cummins Carole , Kumar Satyam , Long Joanna , Balega Janos , Broadhead Tim , Duncan Timothy , Edmondson Richard J. , Fotopoulou Christina , Glasspool Rosalind M. , Kolomainen Desiree , Leeson Simon , Manchanda Ranjit , Morrison Jo , Naik Raj , Tidy John A. , Wood Nick , Sundar Sudha
Published: September 2022

We investigated URS and impact on survival in whole patient cohorts with AOC treated within gynaecological cancer centres that participated in the previously presented SOCQER 2 study. National cancer registry datasets were used to identify FIGO Stage 3,4 and unknown stage patients from 11 cancer centres that had previously participated in the SOCQER2 study. Patient outcomes’ association with surgical ethos were evaluated using logistic regression and Cox proportional hazards. Centres were classified into three groups based on their surgical complexity scores (SCS); those practicing mainly low complexity, (5/11 centres with >70% low SCS procedures, 759 patients), mainly intermediate (3/11, 35–50% low SCS, 356 patients), or mainly high complexity surgery (3/11, >35% high SCS, 356 patients). Surgery rates were 43.2% vs. 58.4% vs. 60.9%. across mainly low, intermediate and high SCS centres, respectively, p < 0.001. Combined surgery and chemotherapy rates were 39.2% vs. 51.8% vs. 38.3% p < 0.000 across mainly low, intermediate and high complexity groups, respectively. Median survival was 23.1 (95% CI 19.0 to 27.2) vs. 22.0 (95% CI 17.6 to 26.3) vs. 17.9 months (95% CI 15.7 to 20.1), p = 0.043 in mainly high SCS, intermediate, and low SCS centres, respectively. In an age and deprivation adjusted model, compared to patients in the high SCS centres, patients in the low SCS group had an HR of 1.21 (95% CI 1.03 to 1.40) for death. Mainly high/intermediate SCS centres have significantly higher surgery rates and better survival at a population level. Centres that practice mainly low complexity surgery should change practice. This study provides support for the utilization of URS for patients with advanced OC.
Management of Immune-Related Adverse Events from Immune-Checkpoint Inhibitors in Advanced or Metastatic Renal Cell Carcinoma
Authors: Leucht Katharina , Ali Nalyan , Foller Susan , Grimm Marc-Oliver
Published: September 2022

Immune checkpoint inhibitors (ICI) are now, among other cancers, routinely used for the treatment of advanced or metastatic renal cell carcinoma (mRCC). In mRCC various combinations of ICIs and inhibitors of the vascular epidermal growth factor receptor tyrosine kinase (VEGFR-TKIs) as well as dual checkpoint inhibition (nivolumab + ipilimumab), the latter for patients with intermediate and poor risk according to IMDC only (international metastatic renal cell carcinoma database consortium), are now standard of care in the first line setting. Therefore, a profound understanding of immune-related adverse events (irAE) and the differential diagnosis of adverse reactions caused by other therapeutic agents in combination therapies is of paramount importance. Here we describe prevention, early diagnosis and clinical management of the most relevant irAE derived from ICI treatment focusing on the new VEGFR-TKI/ICI combinations.
The Impact of KRAS Mutational Status on Long-Term Survival following Liver Resection for Hilar Cholangiocarcinoma
Authors: Ardito Francesco , Razionale Francesco , Campisi Andrea , Carlino Angela , Vellone Maria , Vani Simone , Larocca Luigi M. , Giuliante Felice
Published: September 2022

KRAS mutation is reportedly associated with poor prognosis in patients with different cancer types. However, mutational data on hilar cholangiocarcinoma are few and controversial. The aim of this study was to evaluate the rate of KRAS mutations in a single-center homogeneous population resected for hilar cholangiocarcinoma and the subsequent impact on prognosis. KRAS mutation status was evaluated in 54 patients undergoing major hepatectomy combined with resection of the main biliary confluence and regional lymphadenectomy for hilar cholangiocarcinoma between 2001 and 2019. Among these 54 patients, 12 (22.2%) had a KRAS mutation. KRAS mutation was not related with pathologic characteristics of the tumor. Five-year overall survival (OS) in patients with KRAS mutation was significantly lower than that observed in patients with KRAS wild type (0 vs. 49.2%, respectively; p = 0.003). In the multivariable analysis; independent predictors of poor OS were KRAS mutation (HR = 5.384; p = 0.003) and lymph node metastases (HR = 2.805; p = 0.023). The results of our study suggested that KRAS mutation in hilar cholangiocarcinoma was not rarely observed. KRAS mutation was an independent strong predictor of poor OS. KRAS mutation analysis should be included in the routine pathologic evaluation of resected hilar cholangiocarcinoma in order to better stratify prognosis
Effect of Modifying Carbon Materials with Metal Phthalocynines and Palladium on Their Catalytic Activity in ORR
Authors: Bulanova Andzhela Vladimirovna , Shafigulin Roman Vladimirovich , Vinogradov Kirill Yurievich , Tokranova Elena Olegovna , Martynenko Evgenia Andreevna , Vostrikov Sergey Vladimirovich , Podlipnov Vladimir Vladimirovich
Published: September 2022

Bimetallic catalysts based on multi-walled carbon nanotubes (MWCNT), graphene oxide (GO) and ultradispersed diamonds (UDD) supports for the process of electroreduction of oxygen from alkaline electrolyte were obtained using high-temperature synthesis. The materials were characterized by low-temperature nitrogen adsorption, Raman spectroscopy, scanning electron microscopy and X-ray structure analysis. The synthesized bimetallic catalysts contain meso- and micropores. Based on the study by Raman spectroscopy, it is shown that high-temperature synthesis of MWCNT with metal phthalocyanines leads to doping of this material with nitrogen and the appearance of significant defects in the structure. Carbon nanotube-based catalysts showed enhanced activity compared to other carbon materials. Moreover, bimetallic catalysts based on cobalt phthalocyanine and palladium (MWCNT_CoPc_Pd) are characterized by higher activity on all carbon supports compared to materials contain on copper and palladium. The specific current density in the diffusion region of the MWCNT_CoPc_Pd catalyst is comparable to a commercial platinum electrode (Pt(20%)/C) and equals to 2.65 mA/cm2. The area of the electrochemically active surface of all the obtained catalysts was calculated from the CV data in a nitrogen atmosphere. The MWCNT_CoPc_Pd catalyst is characterized by high corrosivity: after 2500 revolutions, the current density in the diffusion region decreases by 7%, and, also, an increase in the values of E1/2 and Eonset is observed.
Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue!
Authors: Prat Castro Sandra , Kudrina Veronika , Jaślan Dawid , Böck Julia , Scotto Rosato Anna , Grimm Christian
Published: September 2022

Lysosomal storage diseases (LSDs) resulting from inherited gene mutations constitute a family of disorders that disturb lysosomal degradative function leading to abnormal storage of macromolecular substrates. In most LSDs, central nervous system (CNS) involvement is common and leads to the progressive appearance of neurodegeneration and early death. A growing amount of evidence suggests that ion channels in the endolysosomal system play a crucial role in the pathology of neurodegenerative LSDs. One of the main basic mechanisms through which the endolysosomal ion channels regulate the function of the endolysosomal system is Ca2+ release, which is thought to be essential for intracellular compartment fusion, fission, trafficking and lysosomal exocytosis. The intracellular TRPML (transient receptor potential mucolipin) and TPC (two-pore channel) ion channel families constitute the main essential Ca2+-permeable channels expressed on endolysosomal membranes, and they are considered potential drug targets for the prevention and treatment of LSDs. Although TRPML1 activation has shown rescue effects on LSD phenotypes, its activity is pH dependent, and it is blocked by sphingomyelin accumulation, which is characteristic of some LSDs. In contrast, TPC2 activation is pH-independent and not blocked by sphingomyelin, potentially representing an advantage over TRPML1. Here, we discuss the rescue of cellular phenotypes associated with LSDs such as cholesterol and lactosylceramide (LacCer) accumulation or ultrastructural changes seen by electron microscopy, mediated by the small molecule agonist of TPC2, TPC2-A1-P, which promotes lysosomal exocytosis and autophagy. In summary, new data suggest that TPC2 is a promising target for the treatment of different types of LSDs such as MLIV, NPC1, and Batten disease, both in vitro and in vivo.
Association between Temporal Muscle Thickness and Overall Survival in Non-Small Cell Lung Cancer Patients with Brain Metastasis
Authors: Kim Young Il , Shin Ja Young , Yang Seung Ho , Kim Hyun Ho , Shim Byoung Yong , Ahn Stephen
Published: September 2022

Temporal muscle thickness (TMT) has recently been suggested as a novel biomarker of sarcopenia in head and neck malignancies. However, few studies have evaluated TMT as a prognostic marker in patients with brain metastasis. This study investigated the association of TMT with overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastasis. The records of all NSCLC patients with brain metastasis between 2009 and 2018 at St. Vincent’s Hospital were reviewed retrospectively. A total of 221 patients met our eligibility criteria. In the group with TMT thicker than the median, OS was longer than the group with TMT thinner than the median (240 days versus 139 days, p = 0.014). In multivariate analysis, the thicker TMT group had longer survival (HR 0.73 CI 0.56–0.96, p = 0.024). Male (HR 1.58 CI 1.19–2.09, p = 0.002) and older age (≥65 years) (HR 2.05 CI 1.53–2.74, p < 0.001) also showed statistical significance. We also performed subgroup analysis in older patients (≥65 years). In this subgroup of 107 patients, the thicker TMT group also showed longer OS than the thinner TMT group (209 days versus 82 days, p = 0.009). Our findings suggest that TMT can be a useful biomarker for OS in NSCLC patients with brain metastasis.
The Ability of a Novel Trypsin-like Peptidase Activity Assay Kit to Detect Red-Complex Species
Authors: Usui Michihiko , Iwasaki Masanori , Ariyoshi Wataru , Kobayashi Kaoru , Kasai Shingo , Yamanaka Rieko , Nakashima Keisuke , Nishihara Tatsuji
Published: September 2022

The trypsin-like peptidase activity assay kit measures the trypsin-like protease produced by three red-complex species, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola, causing periodontitis, and detects the presence of these bacteria in samples. The purpose of this study was to investigate the relationship between the detection of TLPs by a novel TLP-AA, ADCHECK and the detection of red-complex pathogens by real-time PCR using tongue swabs from patients with periodontitis. The detection limit of trypsin-like protease activity by ADCHECK was validated using the culture supernatants of two different Porphyromonas gingivalis bacterial strains. Real-time PCR was performed to determine the number of red-complex species in the tongue coatings of patients with periodontal disease. Trypsin-like protease activity in tongue-swab samples was scored using ADCHECK. ADCHECK successfully detected trypsin-like protease activity in 103 Porphyromonas gingivalis bacterial strains. The specificity, positive predictive value, negative predictive value, and accuracy of ADCHECK for the presence of red-complex pathogens determined by real-time PCR were 90%, 97%, 98%, and 92%, respectively. ADCHECK is an effective tool for the detection of red-complex pathogens.
Complications and Treatments in Adult X-Linked Hypophosphatemia
Authors: Imanishi Yasuo , Shoji Tetsuo , Emoto Masanori
Published: September 2022

X-linked hypophosphatemia (XLH) is a rare inherited disorder involving elevated levels of fibroblast growth factor (FGF) 23, and is caused by loss-of-function mutations in the PHEX gene. FGF23 induces renal phosphate wasting and suppresses the activation of vitamin D, resulting in defective bone mineralization and rachitic changes in the growth plate and osteomalacia. Conventional treatment with combinations of oral inorganic phosphate and active vitamin D analogs enhances bone calcification, but the efficacy of conventional treatment is insufficient for adult XLH patients to achieve an acceptable quality of life. Burosumab, a fully human monoclonal anti-FGF23 antibody, binds and inhibits FGF23, correcting hypophosphatemia and hypovitaminosis D. This review describes a typical adult with XLH and summarizes the results of clinical trials of burosumab in adults with XLH.
Analysis of Cobalamin (Vit B12) in Ripened Cheese by Ultra-High-Performance Liquid Chromatography Coupled with Mass Spectrometry
Authors: Rampazzo Giulia , Zironi Elisa , Pagliuca Giampiero , Gazzotti Teresa
Published: September 2022

The analysis of natural cobalamins in dairy products still represents an analytical challenge. The matrix’s complexity, low concentration level, light sensitivity, and binding to proteins are just some of the aspects that make their quantification a difficult goal to achieve. Vitamin B12 plays a fundamental role in human nutrition, and its intake is closely linked to a diet that includes the consumption of food of animal origin. In the current literature, few studies have been carried out on the quantitation of cobalamin in ripened cheeses. A sensitive, selective, and robust ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) method was developed, validated, and applied on ripened cheeses from different species (cow, sheep, and goat) purchased from local Italian markets, highlighting species-dependent differences in vitamin B12 concentrations. The vitamin B12 extraction procedure was performed by converting all cobalamins to the cyanocobalamin form. Furthermore, solid-phase extraction was used for matrix clean-up and analyte preconcentration. The proposed method showed good performance in terms of linearity, sensitivity, reproducibility, and repeatability. The mean vitamin B12 content ranged from <LOQ to 38.9 ng/g. Sheep cheese showed the highest concentrations of vitamin B12, with a mean content of 29.0 ng/g.
Bioactive Components in Whole Grains for the Regulation of Skeletal Muscle Function
Authors: Li Qing , Yang Haihong , Song Shuimiao , Liu Jie , Wang Ziyuan , Wang Jing
Published: September 2022

Skeletal muscle plays a primary role in metabolic health and physical performance. Conversely, skeletal muscle dysfunctions such as muscular dystrophy, atrophy and aging-related sarcopenia could lead to frailty, decreased independence and increased risk of hospitalization. Dietary intervention has become an effective approach to improving muscle health and function. Evidence shows that whole grains possess multiple health benefits compared with refined grains. Importantly, there is growing evidence demonstrating that bioactive substances derived from whole grains such as polyphenols, γ-oryzanol, β-sitosterol, betaine, octacosanol, alkylresorcinols and β-glucan could contribute to enhancing myogenesis, muscle mass and metabolic function. In this review, we discuss the potential role of whole-grain-derived bioactive components in the regulation of muscle function, emphasizing the underlying mechanisms by which these compounds regulate muscle biology. This work will contribute toward increasing awareness of nutraceutical supplementation of whole grain functional ingredients for the prevention and treatment of muscle dysfunctions.
Microbial Characterization of Retail Cocoa Powders and Chocolate Bars of Five Brands Sold in Italian Supermarkets
Authors: Iacumin Lucilla , Pellegrini Michela , Colautti Andrea , Orecchia Elisabetta , Comi Giuseppe
Published: September 2022

A microbial characterization of cocoa powder and chocolate bars of three batches of five different brands sold in Italian markets was performed. The results showed a variable microbial population consisting of mesophilic and thermophilic spore formation in both types of products. The chocolate bars were also contaminated with molds of environmental origin. Bacillus spp. and Geobacillus spp. were found in both products. The chocolate bars were also contaminated by molds belonging to the genera Penicillium and Cladosporium. The sporogenous strains mainly originate from the raw materials, i.e., cocoa beans, as the heat treatments involved (roasting of the beans and conching of the chocolate) are not sufficient to reach commercial sterility. Furthermore, the identified spore-forming species have often been isolated from cocoa beans. The molds isolated from chocolate seem to have an origin strictly linked to the final phases of production (environment and packaging). However, the level of contaminants is limited (<2 log CFU/g); the molds do not develop in both products due to their low Aw (<0.6) and do not affect the safety of the products. However, a case of mold development in chocolate bars was observed. Among the isolated molds, only Penicillium lanosocoeruleum demonstrated a high xero-tolerance and grew under some conditions on chocolate bars. Its growth could be explained by a cocoa butter bloom accompanied by the presence of humidity originating from the bloom or acquired during packaging.
Use of Grape By-Products to Enhance Meat Quality and Nutritional Value in Monogastrics
Authors: Alfaia Cristina M. , Costa Mónica M. , Lopes Paula A. , Pestana José M. , Prates José A. M.
Published: September 2022

Grape by-products could be used in monogastric animals′ nutrition to reduce feeding costs with conventional crops (e.g., maize and soybean meal) and to improve meat quality. The main grape by-products with the largest expression worldwide, particularly in the Mediterranean region, are grape pomace, grape seed, grape seed oil and grape skins. These by-products are rich sources of bioactive polyphenols, dietary fiber and polyunsaturated fatty acids (PUFA), more specifically, the beneficial n-3 PUFA, that could be transferred to pork and poultry meat. The potential biological activities, mainly associated with antimicrobial and antioxidant properties, make them putative candidates as feed supplements and/or ingredients capable of enhancing meat quality traits, such as color, lipid oxidation and shelf life. However, grape by-products face several limitations, namely, the high level of lignified cell wall and tannin content, both antinutritional compounds that limit nutrients absorption. Therefore, it is imperative to improve grape by-products’ bioavailability, taking advantage of enzyme supplementation or pretreatment processes, to use them as feed alternatives contributing to boost a circular agricultural economy. The present review summarizes the current applications and challenges of using grape by-products from the agro-industrial sector in pig and poultry diets aiming at improving meat quality and nutritional value.
Quality Improvement of Zhayu, a Fermented Fish Product in China: Effects of Inoculated Fermentation with Three Kinds of Lactic Acid Bacteria
Authors: An Yueqi , Cai Xiaowen , Cong Lin , Hu Yang , Liu Ru , Xiong Shanbai , Hu Xiaobo
Published: September 2022

To investigate the effects of inoculation fermentation on the quality of Zhayu (a traditional fermented fish product in China), different amounts of L. plantarum, P. acidilactici, and P. pentosaceus were inoculated into samples, and the safety, nutritional, textural, and flavor properties of the samples were evaluated. Fermentation with lactic acid bacteria (LAB) decreased pH values and total volatile basic nitrogen content. The addition of 108~109 cfu/100 g LAB significantly increased the content of crude fat and water-soluble proteins in Zhayu. The addition of L. plantarum and P. acidilactici increased the content of soluble solids in Zhayu. Moreover, fermentation with LAB made the products tender and softer, and the samples prepared with 109 cfu/100 g LAB presented better overall qualities. Additionally, Zhayu fermented with L. plantarum and P. acidilactici showed the strongest sourness, while the samples prepared with P. pentosaceus showed the strongest umami taste, consistent with the highest contents of Asp (25.1 mg/100 g) and Glu (67.8 mg/100 g). The addition of LAB decreased the relative contents of aliphatic aldehydes, (Z)-3-hexen-1-ol, and 1-octen-3-ol, reducing the earthy and fishy notes. However, LAB enhanced the contents of terpenoids, acids, esters, and S-containing compounds, increasing the sour, pleasant, and unique odors of Zhayu.
Explore the Interaction between Ellagic Acid and Zein Using Multi-Spectroscopy Analysis and Molecular Docking
Authors: Zhao Shunan , Deng Yong , Yan Tianyi , Yang Xiaoling , Xu Weidong , Liu Donghong , Wang Wenjun
Published: September 2022

With the increasing interest in value-added maize products, the interaction of zein with bioactive molecules to become more nutritional and beneficial to human health has gained a lot of attention. To broaden the application of ellagic acid (EA) in maize flour products, we investigated the interaction between zein and EA. The fluorescence quenching type of zein interacting with EA was mainly static quenching through hydrophobic interaction, as demonstrated by quenching behavior modeling, and ultraviolet-visible spectroscopy confirmed the formation of zein–EA complexes. Synchronous fluorescence spectroscopy showed that EA reduced the polarity of zein around tyrosine residues, which were exposed to a more hydrophobic microenvironment. Meanwhile, circular dichroism suggested that EA noticeably changed the secondary structure of zein, which was mainly reflected in the increase of α-helix and β-sheet content and the decrease of random coil content. Finally, the molecular docking simulation found that zein could have five active sites binding to EA and there was hydrogen bond interaction besides hydrophobic interaction. The findings of this study provided a basis for a theory for the interaction mechanism between zein and EA, which could be essential for developing value-added plant-derived protein products using EA as a functional component.
Retrospective Analysis of the Safety of FOLFOX Compared to CAPOX for Adjuvant Treatment of Stage III Colorectal Cancer in Newfoundland Patients
Authors: McShane Joshua N. , Armstrong Dawn E.
Published: September 2022

Background: Capecitabine and oxaliplatin (CAPOX) and infusional 5-fluouracil, folinic acid, and oxaliplatin (FOLFOX) are the two chemotherapy regimens in current clinical use for the adjuvant treatment of colorectal cancer (CRC). Many centers in Newfoundland lack the resources to support the home infusion program required for FOLFOX, leaving CAPOX as the sole treatment option. This study aimed to review if Newfoundland patients receiving CAPOX experience greater treatment-induced toxicities. Methods: A multicenter retrospective cohort study of 93 Stage III CRC patients. The frequency and severity of toxicities, healthcare resource utilization, and treatment completion rates were compared between the two treatment options. Results: Grade 3 diarrhea and grade 1 or 2 nausea/vomiting were more common in CAPOX compared to FOLFOX-treated patients (26.9% versus 2.99%, p = 0.002; 61.5% versus 31.8%; p = 0.048, respectively). Grade 1 or 2 mucositis was more common with FOLFOX (35.8% versus 3.9%, p = 0.002). CAPOX was associated with higher rates of severe toxicity (53.9% versus 25.4%, p = 0.009), while rates of grade 1 and 2 toxicities were not significantly different between groups. CAPOX-treated patients were greater than twice as likely to require emergency department treatment secondary to toxicity (mean 0.692 visits per patient versus 0.313 in FOLFOX patients, p < 0.001) and the proportion of patients that were hospitalized secondary to CAPOX toxicity was greater. Significantly more FOLFOX patients were able to finish their prescribed treatment plans compared to CAPOX patients (89.5% versus 53.8%; p < 0.001). Conclusions: Compared to FOLFOX-treated patients, CAPOX patients are more likely to experience toxicities of greater severity, require emergency services secondary to treatment-related toxicity, and to discontinue therapy. This reflects a reduced standard of care that may decrease patient safety and quality of life.
Understanding Melanoma Talk on Twitter: The Lessons Learned and Missed Opportunities
Authors: Gomaa Basma T. , Walsh-Buhi Eric R. , Funk Russell J.
Published: September 2022

Background: Melanoma is the third most common cause of cancer and the deadliest form of skin cancer among 17–39 year-olds in the United States. Melanoma is a critical public health issue with a substantial economic burden. Cases and associated burdens, however, could be prevented with a greater awareness of, and interventions related to, skin cancer and melanoma-related preventive behaviors. In fact, as social media use is close to ubiquitous, it represents a potential communication modality. However, more research is needed to understand the current state of melanoma-related information exchanged between Twitter users. This study aimed to understand the different types of users controlling the melanoma-related information diffusion and conversation themes on Twitter. Methods: Tweets (n = 692) were imported from Twitter between 1 and 31 May 2021 using the Twitter public API; and uploaded to NodeXL to conduct a social network analysis. Results: Health professionals and organizations with medical backgrounds were the main content producers, disseminators, and top influencers. However, information diffusion is slow and uneven among users. Additionally, conversations lacked a focus on preventive behaviors. Conclusion: Twitter is a potential platform for the targeted outreach of individuals in melanoma awareness campaigns. This study provides insights maximizing the effectiveness of Twitter as a communication modality. Our findings can help guide the development of customized content and interventions during melanoma awareness campaigns.
Unravelling Factors Influencing Firm Performance: Evidence from the SMEs in Tourism Industry
Authors: Samad Sarminah
Published: September 2022

The global business scenario seems to be gloomy due to the economic uncertainty caused by the COVID-19 pandemic. The COVID-19 pandemic has impacted many economic sectors and a country’s national GNP, including the tourism industry. The question is whether the influencing factors for firms involved in the tourism industry, especially in developing countries, ensure their future survival. The main aim of this paper is to examine the role of internal resources and external environmental factors on the firm performance of small–medium enterprises (SMEs) in the tourism industry, with a specific focus on SME hotels. Based on a survey carried out among hotel owners or key managerial staff in Saudi Arabia and using partial least squares (PLS), the study aimed to attain the objective of this study. Results from the statistical analysis indicate that both internal and external environmental factors have a positive impact on the performance of SME hotels. The results also revealed a more significant impact from the external environmental factors in influencing firm performance than internal resources. Implications, limitations, and recommendations for future scientific investigation are put forward.
Marine Compounds for Melanoma Treatment and Prevention
Authors: Montuori Eleonora , Capalbo Anita , Lauritano Chiara
Published: September 2022

Melanoma is considered a multifactorial disease etiologically divided into melanomas related to sun exposure and those that are not, but also based on their mutational signatures, anatomic site, and epidemiology. The incidence of melanoma skin cancer has been increasing over the past decades with 132,000 cases occurring globally each year. Marine organisms have been shown to be an excellent source of natural compounds with possible bioactivities for human health applications. In this review, we report marine compounds from micro- and macro-organisms with activities in vitro and in vivo against melanoma, including the compound Marizomib, isolated from a marine bacterium, currently in phase III clinical trials for melanoma. When available, we also report active concentrations, cellular targets and mechanisms of action of the mentioned molecules. In addition, compounds used for UV protection and melanoma prevention from marine sources are discussed. This paper gives an overview of promising marine molecules which can be studied more deeply before clinical trials in the near future.
Agrobacterium sp. ZX09 β-Glucan Attenuates Enterotoxigenic Escherichia coli-Induced Disruption of Intestinal Epithelium in Weaned Pigs
Authors: Zhou Yuankang , Luo Yuheng , Yu Bing , Zheng Ping , Yu Jie , Huang Zhiqing , Mao Xiangbing , Luo Junqiu , Yan Hui , He Jun
Published: September 2022

To explore the protective effect of dietary β-glucan (BGL) supplementation on intestinal epithelium exposure to enterotoxigenic Escherichia coli (ETEC), thirty-two weaned pigs were assigned to four groups. Pigs were fed with a basal diet or basal diet containing 500 mg/kg BGL, and were orally infused with ETEC or culture medium. Results showed BGL supplementation had no influence on growth performance in weaned pigs. However, BGL supplementation increased the absorption of D-xylose, and significantly decreased the serum concentrations of D-lactate and diamine oxidase (DAO) in the ETEC-challenged pigs (p < 0.05). Interestingly, BGL significantly increased the abundance of the zonula occludens-1-(ZO-1) in the jejunal epithelium upon ETEC challenge (p < 0.05). BGL supplementation also increased the number of S-phase cells and the number of sIgA-positive cells, but significantly decreased the number of total apoptotic cells in the jejunal epithelium upon ETEC challenge (p < 0.05). Moreover, BGL significantly increased the duodenal catalase (CAT) activity and the ileal total superoxide dismutase (T-SOD) activity in the ETEC-challenged pigs (p < 0.05). Importantly, BGL significantly decreased the expression levels of critical inflammation related proteins such as the tumor necrosis factor-α (TNF-α), interlukin-6 (IL-6), myeloid differentiation factor 88 (MyD88), and nuclear factor-κB (NF-κB) in the jejunal and ileal mucosa upon ETEC challenge (p < 0.05). BGL also elevated the propanoic acid content and the abundance of Lactobacillus and Bacillus in the colon upon ETEC challenge (p < 0.05). These results suggested BGL could alleviate the ETEC-induced intestinal epithelium injury, which may be associated with suppressed inflammation and improved intestinal immunity and antioxidant capacity, as well as the improved intestinal macrobiotic.
Idiopathic Plasmacytic Lymphadenopathy Forms an Independent Subtype of Idiopathic Multicentric Castleman Disease
Authors: Nishikori Asami , Nishimura Midori Filiz , Nishimura Yoshito , Otsuka Fumio , Maehama Kanna , Ohsawa Kumiko , Momose Shuji , Nakamura Naoya , Sato Yasuharu
Published: September 2022

Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease that is not related to KSHV/HHV8 infection. Currently, iMCD is classified into iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) and iMCD-NOS (not otherwise specified). The former has been established as a relatively homogeneous disease unit that has been recently re-defined, while the latter is considered to be a heterogeneous disease that could be further divided into several subtypes. In 1980, Mori et al. proposed the concept of idiopathic plasmacytic lymphadenopathy (IPL), a disease presenting with polyclonal hypergammaglobulinemia and a sheet-like proliferation of mature plasma cells in the lymph nodes. Some researchers consider IPL to be a part of iMCD-NOS, although it has not been clearly defined to date. This is the first paper to analyze iMCD-NOS clinicopathologically, to examine whether IPL forms a uniform disease unit in iMCD. Histologically, the IPL group showed prominent plasmacytosis and the hyperplasia of germinal centers, while the non-IPL group showed prominent vascularity. Clinically, the IPL group showed significant thrombocytosis and elevated serum IgG levels compared to the non-IPL group (p = 0.007, p < 0.001, respectively). Pleural effusion and ascites were less common in the IPL group (p < 0.001). The IPL group was more likely to have an indolent clinical course and a good response to the anti-IL-6 receptor antibody, while the non-IPL counterpart frequently required more aggressive medical interventions. Thus, the IPL group is a clinicopathologically uniform entity that forms an independent subtype of iMCD.
The Magnetosome Protein, Mms6 from Magnetospirillum magneticum Strain AMB-1, Is a Lipid-Activated Ferric Reductase
Authors: Singappuli-Arachchige Dilini , Feng Shuren , Wang Lijun , Palo Pierre E. , Shobade Samuel O. , Thomas Michelle , Nilsen-Hamilton Marit
Published: September 2022

Magnetosomes of magnetotactic bacteria consist of magnetic nanocrystals with defined morphologies enclosed in vesicles originated from cytoplasmic membrane invaginations. Although many proteins are involved in creating magnetosomes, a single magnetosome protein, Mms6 from Magnetospirillum magneticum strain AMB-1, can direct the crystallization of magnetite nanoparticles in vitro. The in vivo role of Mms6 in magnetosome formation is debated, and the observation that Mms6 binds Fe3+ more tightly than Fe2+ raises the question of how, in a magnetosome environment dominated by Fe3+, Mms6 promotes the crystallization of magnetite, which contains both Fe3+ and Fe2+. Here we show that Mms6 is a ferric reductase that reduces Fe3+ to Fe2+ using NADH and FAD as electron donor and cofactor, respectively. Reductase activity is elevated when Mms6 is integrated into either liposomes or bicelles. Analysis of Mms6 mutants suggests that the C-terminal domain binds iron and the N-terminal domain contains the catalytic site. Although Mms6 forms multimers that involve C-terminal and N-terminal domain interactions, a fusion protein with ubiquitin remains a monomer and displays reductase activity, which suggests that the catalytic site is fully in the monomer. However, the quaternary structure of Mms6 appears to alter the iron binding characteristics of the C-terminal domain. These results are consistent with a hypothesis that Mms6, a membrane protein, promotes the formation of magnetite in vivo by a mechanism that involves reducing iron.
Changes in the Mechanical Properties of Alginate-Gelatin Hydrogels with the Addition of Pygeum africanum with Potential Application in Urology
Authors: Kurowiak Jagoda , Kaczmarek-Pawelska Agnieszka , Mackiewicz Agnieszka , Baldy-Chudzik Katarzyna , Mazurek-Popczyk Justyna , Zaręba Łukasz , Klekiel Tomasz , Będziński Romuald
Published: September 2022

New hydrogel materials developed to improve soft tissue healing are an alternative for medical applications, such as tissue regeneration or enhancing the biotolerance effect in the tissue-implant–body fluid system. The biggest advantages of hydrogel materials are the presence of a large amount of water and a polymeric structure that corresponds to the extracellular matrix, which allows to create healing conditions similar to physiological ones. The present work deals with the change in mechanical properties of sodium alginate mixed with gelatin containing Pygeum africanum. The work primarily concentrates on the evaluation of the mechanical properties of the hydrogel materials produced by the sol–gel method. The antimicrobial activity of the hydrogels was investigated based on the population growth dynamics of Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923, as well as the degree of degradation after contact with urine using an innovative method with a urine flow simulation stand. On the basis of mechanical tests, it was found that sodium alginate-based hydrogels with gelatin showed weaker mechanical properties than without the additive. In addition, gelatin accelerates the degradation process of the produced hydrogel materials. Antimicrobial studies have shown that the presence of African plum bark extract in the hydrogel enhances the inhibitory effect on Gram-positive and Gram-negative bacteria. The research topic was considered due to the increased demand from patients for medical devices to promote healing of urethral epithelial injuries in order to prevent the formation of urethral strictures.
Salt Tolerance of Rice Is Enhanced by the SS3 Gene, Which Regulates Ascorbic Acid Synthesis and ROS Scavenging
Authors: Chen Guang , Han Huimin , Yang Xiuli , Du Ruiying , Wang Xu
Published: September 2022

Mining the key genes involved in the balance of rice salt tolerance is extremely important for developing salt-tolerant rice varieties. A library of japonica mutants was screened under salinity conditions to identify putative salt stress-responsive genes. We identified a highly salt-sensitive mutant ss3 and used a map-based cloning approach to isolate the gene SS3, which encodes mannose-1-phosphate guanylyltransferase. Under salt treatment, ss3 mutants have decreased ascorbic acid (AsA) content and increased reactive oxygen species (ROS) levels compared with the wild type (WT). Exogenous AsA restored the salt tolerance of ss3 plants, indicating that inhibition of AsA synthesis was an important factor in the salt sensitivity of the mutant. Functional complementation using the WT allele rescued the mutation, and transcription of SS3 was induced by salt stress. Vector SS3p:SS3 was constructed containing the 1086 bp coding sequence of SS3. Under salinity conditions, transgenic seedlings expressing SS3p:SS3 had improved salt tolerance relative to WT, as demonstrated by better growth status, higher chlorophyll content, a lower level of Na+, and a reduced Na+/K+ ratio. Further investigation revealed that several senescence- and autophagy-related genes were expressed at lower levels in salt-stressed transgenic lines compared to WT. These results demonstrate the positive impact of SS3 on salt tolerance in rice through the regulation of AsA synthesis and ROS accumulation, and indicate that SS3 is a valuable target for genetic manipulation.
The Impact of the Anticoagulant Type in Blood Collection Tubes on Circulating Extracellular Plasma MicroRNA Profiles Revealed by Small RNA Sequencing
Authors: Zhelankin Andrey V. , Iulmetova Liliia N. , Sharova Elena I.
Published: September 2022

Pre-analytical factors have a significant influence on circulating microRNA (miRNA) profiling. The aim of this study was a comprehensive assessment of the impact of the anticoagulant type in blood collection tubes on circulating plasma miRNA profiles using small RNA sequencing. Blood from ten healthy participants (five males and five females from 25 to 40 years old) was taken in collection tubes with four different anticoagulants: acid citrate dextrose (ACD-B), sodium citrate, citrate-theophylline-adenosine-dipyridamole (CTAD) and dipotassium-ethylenediaminetetraacetic acid (K2 EDTA). Platelet-free plasma samples were obtained by double centrifugation. EDTA plasma samples had elevated levels of hemolysis compared to samples obtained using other anticoagulants. Small RNA was extracted from plasma samples and small RNA sequencing was performed on the Illumina NextSeq 500 system. A total of 30 samples had been successfully sequenced starting from ~1 M reads mapped to miRNAs, allowing us to analyze their diversity and isoform content. The principal component analysis showed that the EDTA samples have distinct circulating plasma miRNA profiles compared to samples obtained using other anticoagulants. We selected 50 miRNA species that were differentially expressed between the sample groups based on the type of anticoagulant. We found that the EDTA samples had elevated levels of miRNAs which are abundant in red blood cells (RBC) and associated with hemolysis, while the levels of some platelet-specific miRNAs in these samples were lowered. The ratio between RBC-derived and platelet-derived miRNAs differed between the EDTA samples and other sample groups, which was validated by quantitative PCR. This study provides full plasma miRNA profiles of 10 healthy adults, compares them with previous studies and shows that the profile of circulating miRNAs in the EDTA plasma samples is altered primarily due to an increased level of hemolysis.
Targeted Next-Generation Sequencing-Based Multiple Gene Mutation Profiling of Patients with Rectal Adenocarcinoma Receiving or Not Receiving Neoadjuvant Chemoradiotherapy
Authors: Chang You-Kang , Tseng Hui-Hwa , Leung Chung-Man , Lu Kuo-Cheng , Tsai Kuo-Wang
Published: September 2022

This study investigated whether oncogenic and tumor-suppressive gene mutations are involved in the differential outcomes of patients with rectal carcinoma receiving neoadjuvant chemoradiotherapy (nCRT). Genomic DNA was obtained from formalin-fixed paraffin-embedded (FFPE) specimens of patients with rectal carcinoma who received a complete nCRT course. Gene mutation status was examined in specimens from patients before and after nCRT by using the AmpliSeq platform. Our data revealed that the nonsynonymous p53, APC, KRAS, CDKN2A, and EGFR mutations were observed in 93.1%, 65.5%, 48.6%, and 31% of the patients with rectal adenocarcinoma, respectively. BRAF, FBXW7, PTEN, and SMAD4 mutations were observed in 20.7% of patients with rectal carcinoma. The following 12 gene mutations were observed more frequently in the patients exhibiting a complete response than in those demonstrating a poor response before nCRT: ATM, BRAF, CDKN2A, EGFR, FLT3, GNA11, KDR, KIT, PIK3CA, PTEN, PTPN11, SMAD4, and TP53. In addition, APC, BRAF, FBXW7, KRAS, SMAD4, and TP53 mutations were retained after nCRT. Our results indicate a complex mutational profile in rectal carcinoma, suggesting the involvement of BRAF, SMAD4, and TP53 genetic variants in the outcomes of patients with nCRT.
The Role of PEDF in Reproductive Aging of the Ovary
Authors: Nemerovsky Luba , Bar-Joseph Hadas , Eldar-Boock Anat , Tarabeih Rana , Elmechaly Cindy , Ben-Ami Ido , Shalgi Ruth
Published: September 2022

Reproductive aging is characterized by a decline in ovarian function and in oocytes’ quantity and quality. Pigment epithelium-derived factor (PEDF), a pivotal player in ovarian angiogenic and oxidative balance, was evaluated for its involvement in reproductive aging. Our work examines the initial stage of reproductive aging in women and mice, and the involvement of PEDF in the process. Granulosa cells from reproductively-aged (RA) women and mice (36–44 years old and 9–10 months old, respectively) indicated an increase in the level of PEDF mRNA (qPCR), with yet unchanged levels of AMH and FSHR mRNAs. However, the PEDF protein level in individual women showed an intra-cellular decrease (ELISA), along with a decrease in the corresponding follicular fluid, which reflects the secreted fraction of the protein. The in vitro maturation (IVM) rate in the oocytes of RA mice was lower compared with the oocytes of young mice, demonstrated by a reduced polar body extrusion (PBE) rate. The supplementation of PEDF improved the hampered PBE rate, manifested by a higher number of energetically-competent oocytes (ATP concentration and mtDNA copy number of individual oocytes). Our findings propose PEDF as an early marker of reproductive aging, and a possible therapeutic in vitro agent that could enhance the number of good-quality oocytes in older IVF patients.
Examination of Longitudinal Alterations in Alzheimer’s Disease-Related Neurogenesis in an APP/PS1 Transgenic Mouse Model, and the Effects of P33, a Putative Neuroprotective Agent Thereon
Authors: Szögi Titanilla , Borbély Emőke , Schuster Ildikó , Bozsó Zsolt , Sántha Miklós , Tóth Melinda E. , Penke Botond , Fülöp Lívia
Published: September 2022

Neurogenesis plays a crucial role in cognitive processes. During aging and in Alzheimer’s disease (AD), altered neurogenesis and neuroinflammation are evident both in C57BL/6J, APPSwe/PS1dE9 (Tg) mice and humans. AD pathology may slow down upon drug treatment, for example, in a previous study of our group P33, a putative neuroprotective agent was found to exert advantageous effects on the elevated levels of APP, Aβ, and neuroinflammation. In the present study, we aimed to examine longitudinal alterations in neurogenesis, neuroinflammation and AD pathology in a transgenic (Tg) mouse model, and assessed the putative beneficial effects of long-term P33 treatment on AD-specific neurological alterations. Hippocampal cell proliferation and differentiation were significantly reduced between 8 and 12 months of age. Regarding neuroinflammation, significantly elevated astrogliosis and microglial activation were observed in 6- to 7-month-old Tg animals. The amounts of the molecules involved in the amyloidogenic pathway were altered from 4 months of age in Tg animals. P33-treatment led to significantly increased neurogenesis in 9-month-old animals. Our data support the hypothesis that altered neurogenesis may be a consequence of AD pathology. Based on our findings in the transgenic animal model, early pharmacological treatment before the manifestation of AD symptoms might ameliorate neurological decline.
Evaluation of the Complex p.[Leu467Phe;Phe508del] CFTR Allele in the Intestinal Organoids Model: Implications for Therapy
Authors: Kondratyeva Elena , Efremova Anna , Melyanovskaya Yuliya , Voronkova Anna , Polyakov Alexander , Bulatenko Nataliya , Adyan Tagui , Sherman Viktoriya , Kovalskaia Valeriia , Petrova Nika , Starinova Marina , Bukharova Tatiana , Kutsev Sergei , Goldshtein Dmitry
Published: September 2022

In the cohort of Russian patients with cystic fibrosis, the p.[Leu467Phe;Phe508del] complex allele (legacy name [L467F;F508del]) of the CFTR gene is understudied. In this research, we present the results of frequency evaluation of the [L467F;F508del] complex allele in the Russian Federation among patients with a F508del/F508del genotype, its effect on the clinical course of cystic fibrosis, the intestinal epithelium ionic channel function, and the effectiveness of target therapy. The frequency of the [L467F;F508del] complex allele among patients with homozygous F508del was determined with multiplex ligase-dependent probe amplification followed by polymerase chain reaction and fragment analysis. The function of ionic channels, including the residual CFTR function, and the effectiveness of CFTR modulators was analyzed using intestinal current measurements on rectal biopsy samples and the forskolin-induced swelling assay on organoids. The results showed that the F508del/[L467F;F508del] genotype is present in 8.2% of all Russian patients with F508del in a homozygous state. The clinical course of the disease in patients with the F508del/[L467F;F508del] genotype is severe and does not vary from the course in the cohort with homozygous F508del, although the CFTR channel function is significantly lower. For patients with the F508del/[L467F;F508del] genotype, we can recommend targeted therapy using a combined ivacaftor + tezacaftor + elexacaftor medication.