bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Hydrogen Sulfide Concentrations and Odor Annoyance Frequency Predictions Downwind from Livestock Facilities
Authors: Akter Suraiya , Cortus Erin L.
Published: March 2020

Estimating and measuring the occurrence of a sensation, odor, around livestock facilities is challenging. This research compares the estimated frequency of odor nuisance with measured hydrogen sulfide (H2S) concentrations at various distances around a swine and a dairy operation, and discusses the results based on time of day, weather conditions, distance, and topography. The estimated odor annoyance-free and odor annoyance frequencies were based on a publically available calculator of odor impact derived from average odor emission rates, historical, and regional weather patterns, and dispersion modeling. Continuous monitoring of H2S was by single point monitors (SPM) at locations around the operations. Time-weighted average H2S concentrations were less than 10 ppb for odor annoyance-free frequencies, and less than 10 to at least 73 ppb for odor-annoyance frequencies. Verifying a proxy odor indicator can help update odor annoyance models and respond to site-specific concerns for existing facilities.
Site-Specific Fluorogenic Protein Labelling Agent for Bioconjugation
Authors: Tsao Kelvin K. , Lee Ann C. , Racine Karl É. , Keillor Jeffrey W.
Published: March 2020

Many clinically relevant therapeutic agents are formed from the conjugation of small molecules to biomolecules through conjugating linkers. In this study, two novel conjugating linkers were prepared, comprising a central coumarin core, functionalized with a dimaleimide moiety at one end and a terminal alkyne at the other. In our first design, we developed a protein labelling method that site-specifically introduces an alkyne functional group to a dicysteine target peptide tag that was genetically fused to a protein of interest. This method allows for the subsequent attachment of azide-functionalized cargo in the facile synthesis of novel protein-cargo conjugates. However, the fluorogenic aspect of the reaction between the linker and the target peptide was less than we desired. To address this shortcoming, a second linker reagent was prepared. This new design also allowed for the site-specific introduction of an alkyne functional group onto the target peptide, but in a highly fluorogenic and rapid manner. The site-specific addition of an alkyne group to a protein of interest was thus monitored in situ by fluorescence increase, prior to the attachment of azide-functionalized cargo. Finally, we also demonstrated that the cargo can also be attached first, in an azide/alkyne cycloaddition reaction, prior to fluorogenic conjugation with the target peptide-fused protein.
Hear, Hear for Notch: Control of Cell Fates in the Inner Ear by Notch Signaling
Authors: Brown Rogers , Groves Andrew K.
Published: March 2020

The vertebrate inner ear is responsible for detecting sound, gravity, and head motion. These mechanical forces are detected by mechanosensitive hair cells, arranged in a series of sensory patches in the vestibular and cochlear regions of the ear. Hair cells form synapses with neurons of the VIIIth cranial ganglion, which convey sound and balance information to the brain. They are surrounded by supporting cells, which nourish and protect the hair cells, and which can serve as a source of stem cells to regenerate hair cells after damage in non-mammalian vertebrates. The Notch signaling pathway plays many roles in the development of the inner ear, from the earliest formation of future inner ear ectoderm on the side of the embryonic head, to regulating the production of supporting cells, hair cells, and the neurons that innervate them. Notch signaling is re-deployed in non-mammalian vertebrates during hair cell regeneration, and attempts have been made to manipulate the Notch pathway to promote hair cell regeneration in mammals. In this review, we summarize the different modes of Notch signaling in inner ear development and regeneration, and describe how they interact with other signaling pathways to orchestrate the fine-grained cellular patterns of the ear.
A Comprehensive Comparison of Bovine and Porcine Decellularized Pericardia: New Insights for Surgical Applications
Authors: Zouhair Sabra , Dal Sasso Eleonora , Tuladhar Sugat R. , Fidalgo Catia , Vedovelli Luca , Filippi Andrea , Borile Giulia , Bagno Andrea , Marchesan Massimo , De Rossi Giorgio , Gregori Dario , Wolkers Willem F. , Romanato Filippo , Korossis Sotirios , Gerosa Gino , Iop Laura
Published: March 2020

Xenogeneic pericardium-based substitutes are employed for several surgical indications after chemical shielding, limiting their biocompatibility and therapeutic durability. Adverse responses to these replacements might be prevented by tissue decellularization, ideally removing cells and preserving the original extracellular matrix (ECM). The aim of this study was to compare the mostly applied pericardia in clinics, i.e., bovine and porcine tissues, after their decellularization, and obtain new insights for their possible surgical use. Bovine and porcine pericardia were submitted to TRICOL decellularization, based on osmotic shock, detergents and nuclease treatment. TRICOL procedure resulted in being effective in cell removal and preservation of ECM architecture of both species’ scaffolds. Collagen and elastin were retained but glycosaminoglycans were reduced, significantly for bovine scaffolds. Tissue hydration was varied by decellularization, with a rise for bovine pericardia and a decrease for porcine ones. TRICOL significantly increased porcine pericardial thickness, while a non-significant reduction was observed for the bovine counterpart. The protein secondary structure and thermal denaturation profile of both species’ scaffolds were unaltered. Both pericardial tissues showed augmented biomechanical compliance after decellularization. The ECM bioactivity of bovine and porcine pericardia was unaffected by decellularization, sustaining viability and proliferation of human mesenchymal stem cells and endothelial cells. In conclusion, decellularized bovine and porcine pericardia demonstrate possessing the characteristics that are suitable for the creation of novel scaffolds for reconstruction or replacement: differences in water content, thickness and glycosaminoglycans might influence some of their biomechanical properties and, hence, their indication for surgical use.
The Role of Secretory Activity Molecules of Visceral Adipocytes in Abdominal Obesity in the Development of Cardiovascular Disease: A Review
Authors: Ragino Yuliya I. , Stakhneva Ekaterina M. , Polonskaya Yana V. , Kashtanova Elena V.
Published: March 2020

Adipose tissue is considered one of the endocrine organs in the body because of its ability to synthesize and release a large number of hormones, cytokines, and growth and vasoactive factors that influence a variety of physiological and pathophysiological processes, such as vascular tone, inflammation, vascular smooth muscle cell migration, endothelial function, and vascular redox state. Moreover, genetic factors substantially contribute to the risk of obesity. Research into the biochemical effects of molecules secreted by visceral adipocytes as well as their molecular genetic characteristics is actively conducted around the world mostly in relation to pathologies of the cardiovascular system, metabolic syndrome, and diabetes mellitus. Adipokines could be developed into biomarkers for diagnosis, prognosis, and therapeutic targets in different diseases. This review describes the relevance of secretory activity molecules of visceral adipocytes in cardiovascular disease associated abdominal obesity.
Reprogramming the Constant Region of Immunoglobulin G Subclasses for Enhanced Therapeutic Potency against Cancer
Authors: Kang Tae Hyun , Jung Sang Taek
Published: March 2020

The constant region of immunoglobulin (Ig) G antibodies is responsible for their effector immune mechanism and prolongs serum half-life, while the fragment variable (Fv) region is responsible for cellular or tissue targeting. Therefore, antibody engineering for cancer therapeutics focuses on both functional efficacy of the constant region and tissue- or cell-specificity of the Fv region. In the functional aspect of therapeutic purposes, antibody engineers in both academia and industry have capitalized on the constant region of different IgG subclasses and engineered the constant region to enhance therapeutic efficacy against cancer, leading to a number of successes for cancer patients in clinical settings. In this article, we review IgG subclasses for cancer therapeutics, including (i) IgG1, (ii) IgG2, 3, and 4, (iii) recent findings on Fc receptor functions, and (iv) future directions of reprogramming the constant region of IgG to maximize the efficacy of antibody drug molecules in cancer patients.
Photobiomodulation Therapy Associated with Heterologous Fibrin Biopolymer and Bovine Bone Matrix Helps to Reconstruct Long Bones
Authors: Rosso Marcelie Priscila de Oliveira , Oyadomari Aline Tiemi , Pomini Karina Torres , Della Coletta Bruna Botteon , Shindo João Vitor Tadashi Cosin , Ferreira Júnior Rui Seabra , Barraviera Benedito , Cassaro Claudia Vilalva , Buchaim Daniela Vieira , Teixeira Daniel de Bortoli , Barbalho Sandra Maria , Alcalde Murilo Priori , Duarte Marco Antonio Hungaro , Andreo Jesus Carlos , Buchaim Rogério Leone
Published: March 2020

Bone defects cause aesthetic and functional changes that affect the social, economic and especially the emotional life of human beings. This complication stimulates the scientific community to investigate strategies aimed at improving bone reconstruction processes using complementary therapies. Photobiomodulation therapy (PBMT) and the use of new biomaterials, including heterologous fibrin biopolymer (HFB), are included in this challenge. The objective of the present study was to evaluate the influence of photobiomodulation therapy on bone tibial reconstruction of rats with biomaterial consisting of lyophilized bovine bone matrix (BM) associated or not with heterologous fibrin biopolymer. Thirty male rats were randomly separated into three groups of 10 animals. In all animals, after the anesthetic procedure, a noncritical tibial defect of 2 mm was performed. The groups received the following treatments: Group 1: BM + PBMT, Group 2: BM + HFB and Group 3: BM + HFB + PBMT. The animals from Groups 1 and 3 were submitted to PBMT in the immediate postoperative period and every 48 h until the day of euthanasia that occurred at 14 and 42 days. Analyses by computed microtomography (µCT) and histomorphometry showed statistical difference in the percentage of bone formation between Groups 3 (BM + HB + PBMT) and 2 (BM + HFB) (26.4% ± 1.03% and 20.0% ± 1.87%, respectively) at 14 days and at 42 days (38.2% ± 1.59% and 31.6% ± 1.33%, respectively), and at 42 days there was presence of bone with mature characteristics and organized connective tissue. The µCT demonstrated BM particles filling the defect and the deposition of new bone in the superficial region, especially in the ruptured cortical. It was concluded that the association of PBMT with HFB and BM has the potential to assist in the process of reconstructing bone defects in the tibia of rats.
Cytotoxicity of Different Nano Composite Resins on Human Gingival and Periodontal Ligament Fibroblast Cell Lines: An In Vitro Study
Authors: Kavuncu Gamze , Yilmaz Ayse Mine , Karademir Yilmaz Betul , Yilmaz Atali Pinar , Altunok Elif Cigdem , Kuru Leyla , Agrali Omer Birkan
Published: March 2020

The aim of this study is to determine the cytotoxicity of three different nano composite resins (CRs) on human gingival fibroblast (hGF) and periodontal ligament fibroblast (hPDLF) cell lines. These CRs selected were nanohybrid organic monomer-based Admira Fusion (AF), nanohybrid Bis-(acryloyloxymethyl) tricyclo [5.2.1.0.sup.2,6] decane-based Charisma Topaz (CT), and supra nano filled resin-based Estelite Quick Sigma (EQS). MTT assay was performed to assess the cytotoxicity of CRs at 24 h and one week. AF and EQS applied on hGF cells at 24 h and one week demonstrated similar cytotoxic outcomes. Cytotoxicity of CT on hGF cells at one week was higher than 24 h (p = 0.04). Cytotoxicity of CT on hGF cells was higher at 24 h (p = 0.002) and one week (p = 0.009) compared to control. All composites showed higher cytotoxicity on hPDLF cells at one week than the 24 h (AF; p = 0.02, CT; p = 0.02, EQS; p = 0.04). AF and EQS demonstrated lower cytotoxicity on hPDLF cells than the control group at 24 h (AF; p = 0.01, EQS; p = 0.001). CT was found more cytotoxic on hPDLF cells than the control (p = 0.01) and EQS group (p = 0.008) at one week. The cytotoxicity of CRs on hGF and hPDLF cells vary, according to the type of composites, cell types, and exposure time.
A Disposable Passive Microfluidic Device for Cell Culturing
Authors: Guzzi Francesco , Candeloro Patrizio , Coluccio Maria Laura , Cristiani Costanza Maria , Parrotta Elvira Immacolata , Scaramuzzino Luana , Scalise Stefania , Dattola Elisabetta , D’Attimo Maria Antonia , Cuda Giovanni , Lamanna Ernesto , Passacatini Lucia Carmela , Carbone Ennio , Krühne Ulrich , Di Fabrizio Enzo , Perozziello Gerardo
Published: March 2020

In this work, a disposable passive microfluidic device for cell culturing that does not require any additional/external pressure sources is introduced. By regulating the height of fluidic columns and the aperture and closure of the source wells, the device can provide different media and/or drug flows, thereby allowing different flow patterns with respect to time. The device is made of two Polymethylmethacrylate (PMMA) layers fabricated by micro-milling and solvent assisted bonding and allows us to ensure a flow rate of 18.6 μL/h - 7%/day, due to a decrease of the fluid height while the liquid is driven from the reservoirs into the channels. Simulations and experiments were conducted to characterize flows and diffusion in the culture chamber. Melanoma tumor cells were used to test the device and carry out cell culturing experiments for 48 h. Moreover, HeLa, Jurkat, A549 and HEK293T cell lines were cultivated successfully inside the microfluidic device for 72 h.
Association between Behavioral Ambidexterity and Brain Health
Authors: Kokubun Keisuke , Yamakawa Yoshinori , Hiraki Kazuo
Published: March 2020

Appropriately handling and switching exploration of novel knowledge and exploitation of existing knowledge is a fundamental element of genuine innovation in society. Moreover, a mounting number of studies have suggested that such “ambidexterity” is associated not only with organizational performance but also with the human brain. Among these reports, however, there have not been any definitive MRI-based parameters that objectively and easily evaluate such ambidexterity. Therefore, an MRI-based index derived from gray matter volume, called the gray-matter brain healthcare quotient (GM-BHQ), was used to measure the association between ambidexterity and the entire human brain. For this purpose, 200 healthy adults were recruited as subjects to undergo structural T1-weighted imaging and to answer multiple psychological questionnaires. Ambidexterity was evaluated using two scales: the Curiosity and Exploration Inventory II and the Short Grit Scale, as exploration–exploitation indicators of curiosity and grit, respectively. Additionally, to enrich the understanding of these associations, three additional positive thinking scales were used—the General Self-Efficacy Scale, the Rosenberg Self-Esteem Scale, and the Life Orientation Test—to evaluate self-efficacy, self-esteem, and optimism, respectively. The authors discovered the GM-BHQ was weakly associated with curiosity, grit, and self-efficacy individually after controlling for age and sex. Furthermore, the GM-BHQ was directly associated with curiosity but indirectly associated with grit in the path model. However, no significant association was found between the GM-BHQ and the other outcome indicators (i.e., self-esteem and optimism). These results suggest that brain health is weakly associated with ambidexterity evaluated using psychological tests.
Brain–Computer Interface Spellers for Communication: Why We Need to Address Their Security and Authenticity
Authors: Dutta Anirban
Published: March 2020

Brain–Computer Interfaces (BCI) have witnessed significant research and development in the last 20 years where the main aim was to improve their accuracy and increase their information transfer rates (ITRs), while still making them portable and easy to use by a broad range of users [...]
Up-regulation of MicroRNAs-21 and -223 in a Sprague-Dawley Rat Model of Traumatic Spinal Cord Injury
Authors: Chung Hyo-Jin , Chung Wook-Hun , Do Sun-Hee , Lee Jae-Hoon , Kim Hwi-yool
Published: March 2020

In this experimental animal study, we examined alterations in the degree of transcription of two microRNAs (miRs)—miR-21 and -223—in a Sprague-Dawley (SD) rat model of traumatic spinal cord injury (TSCI). Depending on the volume of the balloon catheter (V), a total of 75 male SD rats were divided into the three experimental groups: the sham group (n = 25; V = 0 μL), the mild group (n = 25; V = 20 μL), and the severe group (n = 25; V = 50 μL). Successful induction of TSCI was confirmed on both locomotor rating scale at 4 h and 1, 3 and 7 days post-lesion and histopathologic examinations. Then, RNA isolation and quantitative polymerase chain reaction (PCR) were performed. No differences in the level of miR-21 expression were found at the first time point studied (4 h post-lesion) between the three experimental groups, whereas such differences were significant at all the other time points (p < 0.05). Moreover, there were significant alterations in the level of miR-223 expression at all time points studied through all the experimental groups (p < 0.05). Furthermore, locomotor rating scale scores had a linear relationship with the level of miR-21 expression (R2 = 0.4363, Y = 1.661X + 3.096) and that of miR-223 one (R2 = 0.9104, Y = 0.8385X + 2.328). Taken together, we conclude that up-regulation of miR-21 and -223 might be closely associated with progression and the early course of TSCI, respectively.
The Role of Glass Compounds in Autoclaved Bricks
Authors: Stepien Anna , Potrzeszcz-Sut Beata , Prentice Dale P. , Oey Tandre J. , Balonis Magdalena
Published: March 2020

This study describes the relationship between the physio-mechanical and chemical properties of sand-lime materials which have undergone hydrothermal treatment, and which were modified through the introduction of glass components (90% glass sand, GS). Process parameters such as temperature, pressure and saturation vapor pressure were found to have a significant impact on the series of chemical reactions as well as on the formation and transformation of solid hydrates. During the stirring process of sand-lime mass, the temperature of the reaction between lime and water in the presence of quartz sand (QS) was determined to be 83 °C. In the presence of glass sand, measured temperature was only 42 °C. Thermodynamic equilibrium-based modelling was applied to predict stable phase assemblages in the studied systems. It was found that compositional modification along with the application of the autoclaving process resulted in the formation of two crystalline phases: natrolite and gyrolite. Compressive strength and density were also assessed. The strength of fresh laboratory samples was found to be greater than their traditional analogues by 15 MPa. In addition to experimental characterization, sand-lime materials were also modeled using neural networks (backpropagation neural network, BPNN) which serve as a universal approximation method capable of modelling complex functions.
Association of Cholecystectomy with the Risk of Prostate Cancer in Patients with Gallstones
Authors: Chen Chien-Hua , Lin Cheng-Li , Kao Chia-Hung
Published: March 2020

Objectives: To assess the association of cholecystectomy with the risk of prostate cancer in patients with gallstones. Methods: This nationwide population-based cohort study was conducted by retrieving the Longitudinal Health Insurance Research Database (LHID2000) for inpatient claims in the Taiwan National Health Insurance (NHI) program. The study cohort consisted of 72,606 men aged ≥ 20 years with gallstones undergoing cholecystectomy between 2000 and 2010. The control cohort consisted of the men with gallstones, but without cholecystectomy, by 1:1 propensity score matching with the study cohort based on age, sex, urbanization, occupation, comorbidities, and the index date. We compared the hazard ratio of prostate cancer between both of the cohorts. Results: The incidence of prostate cancer was 0.76/1000 person-years for the non-cholecystectomy cohort and 1.28/1000 person-years for the cholecystectomy cohort [aHR (adjusted hazard ratio) = 1.67, 95% confidence interval (CI = 1.45–1.92), respectively (p < 0.001). When compared with the non-cholecystectomy cohort, the hazard ratio of prostate cancer for the cholecystectomy cohort was 1.49-fold greater (95% CI = 1.04–2.11) for follow-up ≤ 1 year, 1.52-fold greater (95% CI = 1.24–1.86) for follow-up 1–5 years, and 1.99-fold greater (95% CI = 1.56–2.53) for follow-up > 5 years, respectively. Conclusions: Cholecystectomy is associated with an increased hazard ratio of prostate cancer in gallstones patients, and the risk increases with an incremental period of follow-up. This observational study cannot ascertain the detrimental mechanisms of cholecystectomy for the development of prostate cancer, and cholecystectomy is not recommended for the prevention of prostate cancer based on our study.
Association of Steroids Use with Survival in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis
Authors: Petrelli Fausto , Signorelli Diego , Ghidini Michele , Ghidini Antonio , Pizzutilo Elio Gregory , Ruggieri Lorenzo , Cabiddu Mary , Borgonovo Karen , Dognini Giuseppina , Brighenti Matteo , De Toma Alessandro , Rijavec Erika , Garassino Marina Chiara , Grossi Francesco , Tomasello Gianluca
Published: March 2020

Immune checkpoint inhibitors (ICIs) can elicit toxicities by inhibiting negative regulators of adaptive immunity. Sometimes, management of toxicities may require systemic glucocorticoids. We performed a systematic review and meta-analysis of published studies to evaluate the correlation between steroids use, overall survival (OS), and progression-free survival (PFS) in cancer patients treated with ICIs. Publications that compared steroids with non-steroid users in cancer patients treated with ICIs from inception to June 2019 were identified by searching the EMBASE, PubMed, SCOPUS, Web of Science, and Cochrane Library databases. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Patients (studies, n = 16; patients, n = 4045) taking steroids were at increased risk of death and progression compared to those not taking steroids (HR = 1.54, 95% CI: 1.24–1.91; p = 0.01 and HR = 1.34, 95% CI: 1.02–1.76; p = 0.03, respectively). The main negative effect on OS was associated with patients taking steroids for supportive care (HR = 2.5, 95% CI 1.41–4.43; p < 0.01) or brain metastases (HR = 1.51, 95% CI 1.22–1.87; p < 0.01). In contrast, steroids used to mitigate adverse events did not negatively affect OS. In conclusion, caution is needed when steroids are used for symptom control. In these patients, a negative impact of steroid use was observed for both OS and PFS.
Non-Surgical Cancer Risk Reduction in BRCA1 Mutation Carriers: Disabling the Remote Control
Authors: Widschwendter Martin , Dubeau Louis
Published: March 2020

Women-specific cancers are a major health issue, particularly those associated with the BRCA1 germline mutation carrier state, which include triple-negative basal breast carcinomas and high-grade serous ovarian carcinomas (referred to as extra-uterine Müllerian carcinomas). Whereas many chronic diseases can currently be prevented (e.g., cardiovascular diseases), no recent tangible progress was made in cancer prevention of BRCA1 mutation carriers apart from surgical resections of at-risk organs. This lack of progress is largely due to (1) poor understanding of the initiating events triggered by known risk factors in the development of these cancers, (2) the fact that current preventive measures rely on evidence obtained from adjuvant breast cancer treatment that fail to protect against poor prognostic cancers, and (3) problems with using cancer incidence in high-risk women as an ethically justifiable endpoint in cancer prevention trials. Here, we propose that cancer predisposition in BRCA1 mutation carriers is driven, at least in part, by cell-nonautonomous mechanisms (i.e., driven by consequences of this carrier state on hormonal and other systemic factors controlled in organs other than those that are cancer-prone) and that biomarkers of epigenomic reprogramming, hypothesized to be a direct consequence of such cell-nonautonomous mechanisms, are attractive as intermediate surrogate endpoints to assess the efficacy of cancer risk-reducing strategies targeting these mechanisms.
Sphere-Forming Culture for Expanding Genetically Distinct Patient-Derived Glioma Stem Cells by Cellular Growth Rate Screening
Authors: Shin Kayoung , Shin Hyemi , Cho Hee Jin , Kang Hyunju , Lee Jin-Ku , Seo Yun Jee , Shin Yong Jae , Kim Donggeon , Koo Harim , Kong Doo-Sik , Seol Ho Jun , Lee Jung-Il , Lee Hye Won , Nam Do-Hyun
Published: March 2020

Diffusely infiltrating gliomas (DIGs) are difficult to completely resect and are associated with a high rate of tumor relapse and progression from low- to high-grade glioma. In particular, optimized short-term culture-enriching patient-derived glioma stem cells (GSCs) are essential for customizing the therapeutic strategy based on clinically feasible in vitro drug screening for a wide range of DIGs, owing to the high inter-tumoral heterogeneity. Herein, we constructed a novel high-throughput culture condition screening platform called ‘GFSCAN’, which evaluated the cellular growth rates of GSCs for each DIG sample in 132 serum-free combinations, using 13 previously reported growth factors closely associated with glioma aggressiveness. In total, 72 patient-derived GSCs with available genomic profiles were tested in GFSCAN to explore the association between cellular growth rates in specific growth factor combinations and genomic/molecular backgrounds, including isocitrate dehydrogenase 1 (IDH1) mutation, chromosome arm 1p and 19q co-deletion, ATRX chromatin remodeler alteration, and transcriptional subtype. GSCs were clustered according to the dependency on epidermal growth factor and basic fibroblast growth factor (E&F), and isocitrate dehydrogenase 1 (IDH1) wild-type GSCs showed higher E&F dependencies than IDH1 mutant GSCs. More importantly, we elucidated optimal combinations for IDH1 mutant glioblastoma and lower grade glioma GSCs with low dependencies on E&F, which could be an aid in clinical decision-making for these DIGs. Thus, we demonstrated the utility of GFSCAN in personalizing in vitro cultivation to nominate personalized therapeutic options, in a clinically relevant time frame, for individual DIG patients, where standard clinical options have been exhausted.
The Effect of Cholecystectomy on the Risk of Colorectal Cancer in Patients with Gallbladder Stones
Authors: Chen Chien-Hua , Lin Cheng-Li , Kao Chia-Hung
Published: March 2020

To evaluate the risk of colorectal cancer (CRC) after cholecystectomy for gallbladder stones (GBS). Methods: This nationwide population-based cohort study analyzed the inpatient data from the Taiwan National Health Insurance Research Database. The study cohort comprised of 83,963 patients aged ≥ 20 years undergoing cholecystectomy for GBS between 2000 and 2010. The control cohort comprised the GBS patients without cholecystectomy, who were propensity matched with the study cohort at a 1:1 ratio based on age, sex, comorbidities, and the index date for cholecystectomy. Results: The cumulative incidence of CRC within 6 months of follow-up was higher in the cholecystectomy cohort than that in the non-cholecystectomy cohort (aHR (adjusted hazard ratio) = 7.90, 95% confidence interval (CI) = 6.27–9.94; log-rank test, p < 0.001). The cumulative incidence of CRC after 6 months of follow-up was lower in the cholecystectomy cohort than that in the non-cholecystectomy cohort (aHR = 0.66, 95% CI = 0.60–0.73; log-rank test, p < 0.001), but the reduced risk of CRC for the cholecystectomy cohort was statistically significant only in rectal cancer after separately considering females (aHR = 0.64, 95% CI = 0.46–0.88) and males (aHR = 0.59, 95% CI = 0.44–0.79). Conclusions: The positive association between cholecystectomy and the CRC risk within the first 6 months after cholecystectomy might be due to a detection bias or pre-existing CRC. However, cholecystectomy is associated with a decreased risk of rectal cancer, rather than proximal or distal colon cancer, after more than 6 months of follow-up.
Evaluation of the 8th Edition TNM Classification for Anaplastic Thyroid Carcinoma
Authors: Onoda Naoyoshi , Sugitani Iwao , Ito Ken-ichi , Suzuki Akifumi , Higashiyama Takuya , Fukumori Tatsuya , Suganuma Nobuyasu , Masudo Katsuhiko , Nakayama Hirotaka , Uno Atsuhiko , Yane Katsunari , Yoshimoto Seiichi , Ebina Aya , Kawasaki Yukari , Maeda Shigeto , Iwadate Manabu , Suzuki Shinichi
Published: March 2020

Background: The tumor–node–metastasis (TNM) classification system to categorized anaplastic thyroid cancer (ATC) was revised. Methods: The revised system was evaluated using a large database of ATC patients. Results: A total of 757 patients were analyzed. The proportion and median overall survival values (OS: months) for each T category were T1 (n = 8, 1.1%, 12.5), T2 (n = 43, 5.7%, 10.9), T3a (n = 117, 15.5%, 5.7), T3b (n = 438, 57.9%, 3.9), and T4 (n = 151, 19.9%, 5.0). The OS of the N0 and N1 patients were 5.9 and 4.3, respectively (log-rank p < 0.01). Sixty-three (58.3%) patients migrated from stage IV A to IV B by revision based on the existence of nodal involvement and 422 patients (55.7%) were stratified into stage IV B, without a worsening of their OS (6.1), leaving 45 patients (5.9%) in stage IV A with fair OS (15.8). The hazard ratios for the survival of the patients of stage IV B compared to stage IV A increased from 1.1 to 2.1 by the revision. No change was made for stage IV C (n = 290, 38.8%, 2.8). Conclusion: The revised TNM system clearly indicated the prognoses of ATC patients by extracting rare patients with fair prognoses as having stage IV A disease and categorized many heterogeneous patients in stage IV B.
Personalized Indicator Thrombocytosis Shows Connection to Staging and Indicates Shorter Survival in Colorectal Cancer Patients with or without Type 2 Diabetes
Authors: Herold Zoltan , Herold Magdolna , Lohinszky Julia , Dank Magdolna , Somogyi Aniko
Published: March 2020

Background: Pre- and postoperative thrombocytosis was reported to have significant effect on patient survival. However, the definition of thrombocytosis throughout the literature is not unified. Methods: A retrospective longitudinal observational study has been conducted with the inclusion of 150 colorectal cancer (CRC) patients and 100 control subjects. A new measure of platelet changes at an individual level, named personalized indicator thrombocytosis (PIT) was defined, including 4 anemia adjusted variants. Results: In concordance with the literature, PIT values of control subjects showed a slow decrease in platelet counts, while PIT values of CRC patients were significantly higher (p < 0.0001). More advanced staging (p < 0.0001) and both local (p ≤ 0.0094) and distant (p ≤ 0.0440) metastasis are associated with higher PIT values. Higher PIT values suggested shorter survival times (p < 0.0001). Compared to conventional, a PIT-based definition resulted in approximately 3-times more patients with thrombocytosis. 28% and 77% of the deceased patients had conventional- and PIT-based thrombocytosis, respectively. Conclusions: Compared to conventional thrombocytosis, as an individual metric, PIT values may indicate the condition of patients more precisely. Possible future applications of PIT may include its usage in therapy decision and early cancer detection; therefore, further investigations are recommended.
Can Bioelectrical Impedance Analysis and BMI Be a Prognostic Tool in Head and Neck Cancer Patients? A Review of the Evidence
Authors: Mantzorou Maria , Tolia Maria , Poultsidi Antigoni , Pavlidou Eleni , Papadopoulou Sousana K. , Papandreou Dimitrios , Giaginis Constantinos
Published: March 2020

Background: Malnutrition can significantly affect disease progression and patient survival. The efficiency of weight loss and bioimpedance analysis (BIA)-derived measures in the evaluation of malnutrition, and disease progression and prognosis in patients with head and neck cancer (HNC) are an important area of research. Method: The PubMed database was thoroughly searched, using relative keywords in order to identify clinical trials that investigated the role of BIA-derived measures and weight loss on the disease progression and prognosis of patients with HNC. Twenty-seven studies met the criteria. More specifically, six studies examined the prognostic role of the tissue electrical properties in HNC patients; five examined the role of the tissue electrical properties on identifying malnutrition; four studies looked at the changes in the tissue electrical properties of HNC patients; and 12 examined the prognostic role of weight loss on survival and/or treatment outcomes. Results: Several studies have investigated the role of nutritional status tools on prognosis in HNC patients. Current studies investigating the potential of BIA-derived raw data have shown that phase angle (PA) and capacitance of the cell membrane may be considered prognostic factors of survival. Weight loss may be a prognostic factor for treatment toxicity and survival, despite some conflicting evidence. Conclusions: Further studies are recommended to clarify the role of BIA-derived measures on patients’ nutritional status and the impact of PA on clinical outcomes as well as the prognostic role of weight loss.
Telomeres and Telomere Length: A General Overview
Authors: Srinivas Nalini , Rachakonda Sivaramakrishna , Kumar Rajiv
Published: March 2020

Telomeres are highly conserved tandem nucleotide repeats that include proximal double-stranded and distal single-stranded regions that in complex with shelterin proteins afford protection at chromosomal ends to maintain genomic integrity. Due to the inherent limitations of DNA replication and telomerase suppression in most somatic cells, telomeres undergo age-dependent incremental attrition. Short or dysfunctional telomeres are recognized as DNA double-stranded breaks, triggering cells to undergo replicative senescence. Telomere shortening, therefore, acts as a counting mechanism that drives replicative senescence by limiting the mitotic potential of cells. Telomere length, a complex hereditary trait, is associated with aging and age-related diseases. Epidemiological data, in general, support an association with varying magnitudes between constitutive telomere length and several disorders, including cancers. Telomere attrition is also influenced by oxidative damage and replicative stress caused by genetic, epigenetic, and environmental factors. Several single nucleotide polymorphisms at different loci, identified through genome-wide association studies, influence inter-individual variation in telomere length. In addition to genetic factors, environmental factors also influence telomere length during growth and development. Telomeres hold potential as biomarkers that reflect the genetic predisposition together with the impact of environmental conditions and as targets for anti-cancer therapies.
PLAG Exerts Anti-Metastatic Effects by Interfering with Neutrophil Elastase/PAR2/EGFR Signaling in A549 Lung Cancer Orthotopic Model
Authors: Kim Guen Tae , Hahn Kyu Woong , Yoon Sun Young , Sohn Ki-Young , Kim Jae Wha
Published: March 2020

The effectiveness of chemotherapy and radiotherapy to treat lung cancer is limited because of highly metastatic nature. Novel strategies and drugs to attenuate metastatic activity are urgently required. In this study, red fluorescence proteins (RFP)-labeled A549 human lung cancer cells were orthotopically implantation, where they developed primary tumors. Metastasis in brain and intestines were reduced by up to 80% by treatment with 100 mpk 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) compared with that in control mice. PLAG treatment also reduced the migration of the primary tumors. Interestingly, substantial neutrophil infiltration was observed in the tumors in control mice. The neutrophil contribution to A549 cell metastatic activity was examined in in vitro co-culture system. Metastatic activity could be achieved in the A549 cells through epidermal growth factor receptor (EGFR) transactivation mediated by protease activating receptor 2 (PAR2) receptor. Neutrophil elastase secreted from tumor-infiltrating neutrophils stimulated PAR2 and induced EGFR transactivation. However, this transactivation was inhibited by inducing PAR2 degradation following PLAG treatment and metastatic activity was effectively inhibited. PLAG attenuated cancer metastatic activity via modulated PAR2/EGFR transactivation by accelerating PAR2 degradation. These results suggest PLAG as potential therapeutic agent to combat tumor metastasis via regulating the activation signal pathway of PAR2 by tumor infiltrate-neutrophils.
Autophagy: A Potential Therapeutic Target of Polyphenols in Hepatocellular Carcinoma
Authors: Kiruthiga Chandramohan , Devi Kasi Pandima , Nabavi Seyed M. , Bishayee Anupam
Published: March 2020

Autophagy is a conserved biological phenomenon that maintains cellular homeostasis through the clearing of damaged cellular components under cellular stress and offers the cell building blocks for cellular survival. Aberrations in autophagy subsidize to various human pathologies, such as dementia, cardiovascular diseases, leishmaniosis, influenza, hepatic diseases, and cancer, including hepatocellular carcinoma (HCC). HCC is the fifth common mortal type of liver cancer globally, with an inhomogeneous topographical distribution and highest incidence tripled in men than women. Existing treatment procedures with liver cancer patients result in variable success rates and poor prognosis due to their drug resistance and toxicity. One of the pathophysiological mechanisms that are targeted during the development of anti-liver cancer drugs is autophagy. Generally, overactivated autophagy may lead to a non-apoptotic form of programmed cell death (PCD) or autophagic cell death or type II PCD. Emerging evidence suggests that manipulation of autophagy could induce type II PCD in cancer cells, acting as a potential tumor suppressor. Hence, altering autophagic signaling offers new hope for the development of novel drugs for the therapy of resistant cancer cells. Natural polyphenolic compounds, including flavonoids and non-flavonoids, execute their anticarcinogenic mechanism through upregulating tumor suppressors and autophagy by modulating canonical (Beclin-1-dependent) and non-canonical (Beclin-1-independent) signaling pathways. Additionally, there is evidence signifying that plant polyphenols target angiogenesis and metastasis in HCC via interference with multiple intracellular signals and decrease the risk against HCC. The current review offers a comprehensive understanding of how natural polyphenolic compounds exhibit their anti-HCC effects through regulation of autophagy, the non-apoptotic mode of cell death.
The Determination of Immunomodulation and Its Impact on Survival of Rectal Cancer Patients Depends on the Area Comprising a Tissue Microarray
Authors: Gruber Elisabeth S. , Oberhuber Georg , Pils Dietmar , Stork Theresa , Sinn Katharina , Gruber Sylvia , Nica Robert , Kolmer Dan , Turner Suzanne D. , Schlederer Michaela , Widder Joachim , Doerr Wolfgang , Teleky Béla , Kenner Lukas
Published: March 2020

Background: T cell density in colorectal cancer (CRC) has proven to be of high prognostic importance. Here, we evaluated the influence of a hyperfractionated preoperative short-term radiation protocol (25 Gy) on immune cell density in tumor samples of rectal cancer (RC) patients and on patient survival. In addition, we assessed spatial tumor heterogeneity by comparison of analogue T cell quantification on full tissue sections with digital T cell quantification on a virtually established tissue microarray (TMA). Methods: A total of 75 RC patients (60 irradiated, 15 treatment-naïve) were defined for retrospective analysis. RC samples were processed for immunohistochemistry (CD3, CD8, PD-1, PD-L1). Analogue (score 0–3) as well as digital quantification (TMA: 2 cores vs. 6 cores, mean T cell count) of marker expression in 2 areas (central tumor, CT; invasive margin, IM) was performed. Survival was estimated on the basis of analogue as well as digital marker densities calculated from 2 cores (Immunoscore: CD3/CD8 ratio) and 6 cores per tumor area. Results: Irradiated RC samples showed a significant decrease in CD3 and CD8 positive T cells, independent of quantification mode. T cell densities of 6 virtual cores approximated to T cell densities of full tissue sections, independent of individual core density or location. Survival analysis based on full tissue section quantification demonstrated that CD3 and CD8 positive T cells as well as PD-1 positive tumor infiltrating leucocytes (TILs) in the CT and the IM had a significant impact on disease-free survival (DFS) as well as overall survival (OS). In addition, CD3 and CD8 positive T cells as well as PD-1 positive TILs in the IM proved as independent prognostic factors for DFS and OS; in the CT, PD-1 positive TILs predicted DFS and CD3 and CD8 positive T cells as well as PD-1 positive TILs predicted OS. Survival analysis based on virtual TMA showed no impact on DFS or OS. Conclusion: Spatial tumor heterogeneity might result in inadequate quantification of immune marker expression; however, if using a TMA, 6 cores per tumor area and patient sample represent comparable amounts of T cell densities to those quantified on full tissue sections. Consistently, the tissue area used for immune marker quantification represents a crucial factor for the evaluation of prognostic and predictive biomarker potential.
The Development of Rucaparib/Rubraca®: A Story of the Synergy Between Science and Serendipity
Authors: Curtin Nicola J
Published: March 2020

The poly(ADP-ribose) polymerase (PARP) inhibitor, Rubraca®, was given its first accelerated approval for BRCA-mutated ovarian cancer by the FDA at the end of 2016, and further approval by the FDA, EMA and NICE followed. Scientists at Newcastle University initiated the early stages, and several collaborations with scientists in academia and the pharmaceutical industry enabled its final development to the approval stage. Although originally considered as a chemo- or radiosensitiser, its current application is as a single agent exploiting tumour-specific defects in DNA repair. As well as involving intellectual and physical effort, there have been a series of fortuitous occurrences and coincidences of timing that ensured its success. This review describes the history of the relationship between science and serendipity that brought us to the current position.
A Preclinical Embryonic Zebrafish Xenograft Model to Investigate CAR T Cells in Vivo
Authors: Pascoal Susana , Salzer Benjamin , Scheuringer Eva , Wenninger-Weinzierl Andrea , Sturtzel Caterina , Holter Wolfgang , Taschner-Mandl Sabine , Lehner Manfred , Distel Martin
Published: March 2020

Chimeric antigen receptor (CAR) T cells have proven to be a powerful cellular therapy for B cell malignancies. Massive efforts are now being undertaken to reproduce the high efficacy of CAR T cells in the treatment of other malignancies. Here, predictive preclinical model systems are important, and the current gold standard for preclinical evaluation of CAR T cells are mouse xenografts. However, mouse xenograft assays are expensive and slow. Therefore, an additional vertebrate in vivo assay would be beneficial to bridge the gap from in vitro to mouse xenografts. Here, we present a novel assay based on embryonic zebrafish xenografts to investigate CAR T cell-mediated killing of human cancer cells. Using a CD19-specific CAR and Nalm-6 leukemia cells, we show that live observation of killing of Nalm-6 cells by CAR T cells is possible in zebrafish embryos. Furthermore, we applied Fiji macros enabling automated quantification of Nalm-6 cells and CAR T cells over time. In conclusion, we provide a proof-of-principle study that embryonic zebrafish xenografts can be used to investigate CAR T cell-mediated killing of tumor cells. This assay is cost-effective, fast, and offers live imaging possibilities to directly investigate CAR T cell migration, engagement, and killing of effector cells.
ATF4-Dependent NRF2 Transcriptional Regulation Promotes Antioxidant Protection during Endoplasmic Reticulum Stress
Authors: Sarcinelli Carmen , Dragic Helena , Piecyk Marie , Barbet Virginie , Duret Cédric , Barthelaix Audrey , Ferraro-Peyret Carole , Fauvre Joelle , Renno Toufic , Chaveroux Cédric , Manié Serge N.
Published: March 2020

Endoplasmic reticulum (ER) stress generates reactive oxygen species (ROS) that induce apoptosis if left unabated. To limit oxidative insults, the ER stress PKR-like endoplasmic reticulum Kinase (PERK) has been reported to phosphorylate and activate nuclear factor erythroid 2-related factor 2 (NRF2). Here, we uncover an alternative mechanism for PERK-mediated NRF2 regulation in human cells that does not require direct phosphorylation. We show that the activation of the PERK pathway rapidly stimulates the expression of NRF2 through activating transcription factor 4 (ATF4). In addition, NRF2 activation is late and largely driven by reactive oxygen species (ROS) generated during late protein synthesis recovery, contributing to protecting against cell death. Thus, PERK-mediated NRF2 activation encompasses a PERK-ATF4-dependent control of NRF2 expression that contributes to the NRF2 protective response engaged during ER stress-induced ROS production.
Ocular Manifestations in Patients with Philadelphia-Negative Myeloproliferative Neoplasms
Authors: Liisborg Charlotte , Hasselbalch Hans Carl , Sørensen Torben Lykke
Published: March 2020

The major complications of Philadelphia-negative (Ph-Negative) myeloproliferative neoplasms (MPNs) are thrombosis, haemorrhage and leukemic transformation. As systemic and haematological diseases, MPNs have the potential to affect many tissues and organs. Some complications lead to the diagnosis of MPNs, but other signs and symptoms are often misdiagnosed or neglected as a sign of MPN disease. Therefore, we reviewed the current literature to investigate and delineate the clinical manifestations seen in the eyes of Ph-negative MPN patients. We found that ocular manifestations are common among patients with MPNs. The most frequently described manifestations are due to the consequences of haematological abnormalities causing microvascular disturbances and hyperviscosity. More serious and vision-threatening complications as thrombotic events in the eyes have been repeatedly reported as well. These ocular symptoms may precede more serious extraocular complications. Accordingly, combined ophthalmological and haematological management have the potential to discover these diseases earlier and prevent morbidity and mortality in these patients. Furthermore, routine ophthalmological screening of all newly diagnosed MPN patients may be a preventive approach for early diagnosis and timely treatment of the ocular manifestations.