bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards an Integrated Healthcare System: Evolutionary Game Analysis on Competition and Cooperation Between Urban and Rural Medical Institutions in China
Authors: Xu Xinglong , Liu Jiajie , Ampon-Wireko Sabina , Asante Antwi Henry , Zhou Lulin
Published: March 2022

Background

The game of interest is the root cause of the non-cooperative competition between urban and rural medical and health institutions. The study investigates competition and cooperation among urban and rural medical institutions using the evolutionary game analysis.

Methods

With the evolutionary game model, analysis of the stable evolutionary strategies between the urban and rural medical and health facilities is carried out. A numerical simulation is performed to demonstrate the influence of various values.

Results

The result shows that the cooperation mechanism between urban and rural medical Institutions is relevant to the efficiency of rural medical institutions, government supervision, reward, and punishment mechanism.

Conclusions

Suggestions for utilizing the government's macro regulation and control capabilities, resolving conflicts of interest between urban and rural medical and health institutions is recommended. In addition, the study again advocates mobilizing the internal power of medical institutions' cooperation to promote collaboration between urban and rural medical and health institutions.
Limb Prostheses: Industry 1.0 to 4.0: Perspectives on Technological Advances in Prosthetic Care
Authors: Raschke Silvia Ursula
Published: March 2022

Technological advances from Industry 1.0 to 4.0, have exercised an increasing influence on prosthetic technology and practices. This paper explores the historical development of the sector within the greater context of industrial revolution. Over the course of the first and up the midpoint of the second industrial revolutions, Industry 1.0 and 2.0, the production and provision of prosthetic devices was an ad hoc process performed by a range of craftspeople. Historical events and technological innovation in the mid-part of Industry 2.0 created an inflection point resulting in the emergence of prosthetists who concentrated solely on hand crafting and fitting artificial limbs as a professional specialty. The third industrial revolution, Industry 3.0, began transforming prosthetic devices themselves. Static or body powered devices began to incorporate digital technology and myoelectric control options and hand carved wood sockets transitioned to laminated designs. Industry 4.0 continued digital advancements and augmenting them with data bases which to which machine learning (M/L) could be applied. This made it possible to use modeling software to better design various elements of prosthetic componentry in conjunction with new materials, additive manufacturing processes and mass customization capabilities. Digitization also began supporting clinical practices, allowing the development of clinical evaluation tools which were becoming a necessity as those paying for devices began requiring objective evidence that the prosthetic technology being paid for was clinically and functionally appropriate and cost effective. Two additional disruptive dynamics emerged. The first was the use of social media tools, allowing amputees to connect directly with engineers and tech developers and become participants in the prosthetic design process. The second was innovation in medical treatments, from diabetes treatments having the potential to reduce the number of lower limb amputations to Osseointegration techniques, which allow for the direct attachment of a prosthesis to a bone anchored implant. Both have the potential to impact prosthetic clinical and business models. Questions remains as to how current prosthetic clinical practitioners will respond and adapt as Industry 4.0 as it continues to shape the sector.
Is Precipitation Responsible for the Most Hydrological Model Uncertainty?
Authors: Bárdossy András , Kilsby Chris , Birkinshaw Stephen , Wang Ning , Anwar Faizan
Published: March 2022

Rainfall-runoff modeling is highly uncertain for a number of different reasons. Hydrological processes are quite complex, and their simplifications in the models lead to inaccuracies. Model parameters themselves are uncertain—physical parameters because of their observations and conceptual parameters due to their limited identifiability. Furthermore, the main model input—precipitation is uncertain due to the limited number of available observations and the high spatio-temporal variability. The quantification of model output uncertainty is essential for their use. Most approaches used for the quantification of uncertainty in rainfall-runoff modeling assign the uncertainty to the model parameters. In this contribution, the role of precipitation uncertainty is investigated. Instead of a standard sensitivity analysis of the model output with respect to the input variations, it is investigated to what extent realistic precipitation fields could improve model performance. Realistic precipitation fields are defined as gridded realizations of precipitation which reproduce the observed values at the observation locations, with values which reproduce the distribution of the observed values and with spatial variability the same as the spatial variability of the observations. The above conditions apply to each observation time step. Through an inverse modeling approach based on Random Mixing precipitation fields fulfilling the above conditions and reproducing the discharge output better than using traditional interpolated observations can be obtained. These realizations show how much rainfall runoff models may profit from better precipitation input and how much remains for the parameter and model concept uncertainty. The methodology is applied using two hydrological models with a contrasting basis, SHETRAN and HBV, for three different mesoscale sub-catchments of the Neckar basin in Germany. Results show that up to 50% of the model error can be attributed to precipitation uncertainty. Further, inverting precipitation using hydrological models can improve model performance even in neighboring catchments which are not considered explicitly.
The Future Is Now: Preparing Sport Management Graduates in Times of Disruption and Change
Authors: Weese W. James , El-Khoury Michael , Brown Graham , Weese W. Zachary
Published: March 2022

COVID-19 disrupted the world, and the impacts have been experienced in many areas, including sport and higher education. Sport management academicians need to reflect on the past two years' experience, determine what worked and what did not work, and avoid the temptation of automatically returning to past practices. The authors of this manuscript applied the disruption literature and propose transformative changes in what sport management academicians teach (e.g., greater emphasis on innovation, entrepreneurship, automation, critical thinking skills to facilitate working in flexible environments and across areas), how colleagues teach (e.g., heightened integration of technology, blended learning models) and where colleagues teach (on-campus and distal delivery modes, asynchronous and synchronous delivery to students on campus and across regions/countries). Examples of start-up companies and entrepreneurial ventures are offered to help illustrate the changing sports landscape and the emerging opportunities for current and future students, graduates, and professors. Sport management professors are offered some suggestions to assist them in seizing this opportunity.
Body Pose Estimation Integrated With Notational Analysis: A New Approach to Analyze Penalty Kicks Strategy in Elite Football
Authors: Pinheiro Guilherme de Sousa , Jin Xing , Costa Varley Teoldo Da , Lames Martin
Published: March 2022

Body orientation of football players has proven to be an informative resource related to successful penalty kicks. OpenPose is one of the most popular open-source pose estimation technologies. This study aims: (i) to verify whether OpenPose can detect relevant body orientation angles from video data of penalty kicks in elite football and (ii) to investigate the relationship between these body angles and observable behaviors analyzed via an observational system for penalty kick analysis in football (OSPAF) with the penalty taker and goalkeeper strategy. A total of 34 penalty videos, with standardized viewing angle, from the main European leagues (2017–2020) were analyzed. Relevant body orientation variables were selected for penalty kicks analysis and were extracted from video data through OpenPose technique. The OSPAF, previously validated by experts, was used. The mean confidence score of OpenPose measures was 0.80 ± 0.14. OpenPose Retest reliability values was 0.976 ± 0.03. Logistic regressions were performed to investigate the relationship between OpenPose investigated variables (penalty taker: shoulder, hips, and nonkicking foot orientation; goalkeeper: right and left foot, anticipation), observable behaviors (OSPAF variables), and the strategy (penalty taker: goalkeeper dependent or independent; goalkeeper: shooter dependent or independent) in penalty kicks. The selected body orientation angle (goalkeeper anticipation) measured through OpenPose correlated significantly with the goalkeeper strategy. The prediction model of the goalkeeper's strategy had its accuracy increased to 97% when the variable goalkeeper anticipation was included [χ(35)2 = 49.648, p < 0.001]. Lower degrees of goalkeeper anticipation, the goalkeeper tactical action (awaiting), and run up speed (slow) were associated with a kicker-dependent strategy. Regarding the penalty taker, the selected body angles measured through OpenPose did not associate significantly with the shooter strategy. Body orientation analysis by using OpenPose has shown sufficient reliability and provides practical applications for analyzing the strategies adopted by goalkeepers in penalty kicks in elite football.
Use of ATP-Binding Cassette Subfamily A Member 13 (ABCA13) for Sensitive Detection of Focal Pathological Forms of Subclinical Bovine Paratuberculosis
Authors: Blanco-Vázquez Cristina , Alonso-Hearn Marta , Iglesias Natalia , Vázquez Patricia , Juste Ramón A. , Garrido Joseba M. , Balseiro Ana , Canive María , Amado Javier , Queipo Manuel A. , Iglesias Tania , Casais Rosa
Published: March 2022

Bovine paratuberculosis (PTB) is a chronic enteritis caused by Mycobacterium avium subspecies paratuberculosis (Map) that causes a heavy economic impact worldwide. Map infected animals can remain asymptomatic for years while transmitting the mycobacteria to other members of the herd. Therefore, accurate detection of subclinically infected animals is crucial for disease control. In a previous RNA-Seq study, we identified several mRNAs that were overexpressed in whole blood of cows with different PTB-associated histological lesions compared with control animals without detected lesions. The proteins encoded by two of these mRNAs, ATP binding cassette subfamily A member 13 (ABCA13) and Matrix Metallopeptidase 8 (MMP8) were significantly overexpressed in whole blood of animals with focal histological lesions, the most frequent pathological form in the subclinical stages of the disease. In the current study, the potential of sensitive early diagnostic tools of commercial ELISAs, based on the detection of these two biomarkers, was evaluated in serum samples of 704 Holstein Friesian cows (566 infected animals and 138 control animals from PTB-free farms). For this evaluation, infected animals were classified into three groups, according to the type of histological lesions present in their gut tissues: focal (n = 447), multifocal (n = 59), and diffuse (n = 60). The ELISA based on the detection of ABCA13 was successfully validated showing good discriminatory power between animals with focal lesions and control animals (sensitivity 82.99% and specificity 80.43%). Conversely, the MMP8-based ELISA showed a poor discriminatory power between the different histological groups and non-infected controls. The ABCA13-based ELISA showed a higher diagnostic value (0.822) than the IDEXX ELISA (0.517), the fecal bacterial isolation (0.523) and the real-time PCR (0.531) for the detection of animals with focal lesions. Overall, our results indicate that this ABCA13 ELISA greatly improves the identification of subclinically infected animals with focal lesions that are undetectable using current diagnostic methods.
Effects of Energy and Dietary Fiber on the Breast Development in Gilt
Authors: Xu Shengyu , Tang Lianchao , Xu Haitao , Yang Yi , Cao Meng , Chen Sirun , Jiang Xuemei , Li Jian , Lin Yan , Che Lianqiang , Fang Zhengfeng , Feng Bin , Zhuo Yong , Wang Jianping , Wu De
Published: March 2022

To study the effects of energy and dietary fiber on breast development in gilts and its possible mechanisms, 32 gilts (Landrace × Yorkshire) were randomly allocated into a 2 × 2 factorial design to receive a diet with low or high energy [LE: 33.37 MJ/d digestible energy (DE); HE: 41.87 MJ/d DE] and low or high fiber (LF: 0.3 kg/d dietary fiber, HF: 0.6 kg/d dietary fiber). The weight of breast tissue was recorded. The mammary glands were collected for further analyses. The high energy intake increased the relative weight of breast tissue (p < 0.05) and the content of breast fat (p < 0.05). At the same time, the oil red staining of breast slices also showed an increase in breast fat content in high-energy treatment. High energy intake increased the DNA concentration in breast tissues (p < 0.05). In addition, high energy intake increased the concentration of triglycerides, free fatty acids, and total cholesterol in the blood of gilts (p < 0.05), and the supplementation of high fiber tended to reduce free fatty acids, total cholesterol, and estradiol (p < 0.1). Proteomic analysis suggested that there were notable differences in the cytoskeleton, intracellular non–membrane-bounded organelle, apoptosis, receptor activity, and endopeptidase inhibitor activity in molecular function between the energy and fiber effects (p < 0.05). High fiber intake also decreased the mRNA expression of 5-HT7, Bax, and caspase-3 in the breast tissue of gilts (p < 0.05), which further confirmed the importance of fiber in regulating breast development in gilt. Our results indicate that increasing gilt energy intake improved breast weight and fat deposition and increased breast cell apoptosis. Increased fiber intake reduced breast fat deposition and breast cell apoptosis at high energy intake in gilts. These results provide a potential strategy for dietary intervention against high energy intake in gilts and even in humans.
Exponential Fertilization Regimes Improved Growth and Nutrient Status of Quercus nuttallii Container Seedlings
Authors: Ni Ming , Gao Zhenzhou , Chen Hong , Chen Chen , Yu Fangyuan
Published: March 2022

Background: The conventional fertilization regime ignores the allometric characteristics of Quercus nuttallii seedlings, challenging them to meet the nutritional needs at each growth stage. This study was conducted to determine the impact of exponential fertilization on the growth and nutrient status of Q. nuttallii container seedlings. Methods: Two fertilization regimes (average/exponential) were performed on Q. nuttallii container seedlings, and varied gradients (0, 300, 500, 700, and 900 mg/seedling) of N supply were set for the two regimes. Result: N application promoted the seedling height, root collar diameter, total biomass, and N/P/K accumulation of Q. nuttallii, and the exponential fertilization obtained better effects in general. An appropriate amount of exponentially N application was beneficial to the growth of root system, whereas excessive dosages inhibited it. Judging from seedlings growth status and nutrient accumulation, 900 mg/seedling under exponential fertilization was adequate for Q. nuttallii seedlings. However, 500 and 700 mg/seedling under exponential fertilization may have advantages in improving seedlings’ stress resistance. Conclusions: Exponential fertilization did not only meet the nutrient requirements and promote the growth of Q. nuttallii seedlings, but also facilitated the root growth to indirectly accelerate the assimilation of N/P/K, therefore improving the afforestation quality.
Comprehensive Analysis Revealed the Specific Soil Properties and Foliar Elements Respond to the Quality Composition Levels of Tea (Camellia sinensis L.)
Authors: Tseng Wen-Yu , Lai Hung-Yu
Published: March 2022

C. sinensis cv. Sijichun is a representative Taiwanese low-altitude tea cultivar native to central Taiwan. To enrich the taste of tea in a geographically disadvantaged area, soil management became necessary but was obscure. The purpose of this study was to screen the main soil factors that influence the quality composition levels of tea to optimize the efficiency of tea tree horticulture. Soil and tea leaf samples collected from 20 tea plantations determined thirteen soil properties, nine leaf element nutrients and aluminum, and five main extractable quality compositions, including polyphenols, catechins, flavones, free amino acids, and caffeine in tea infusion. Pearson’s correlation analysis and principal component correlation analysis showed that soil available nutrients cannot respond to the concentration of corresponding essential elements in tea leaves; nevertheless, adequate leaf macronutrients and Zn could enhance polyphenol, free amino acid, and caffeine contents, but decreased flavone contents, and showed their consistent effect by soil characteristics. Of note, soil pH, EC, exchangeable calcium, exchangeable magnesium, total concentration of manganese, and total concentration of copper were shown as significant impact factors on free amino acid content. In summary, regulating the pH of soil under 3.51–5.21 in our study and managing soil effective Ca, Mg, and Zn supply could help to obtain a greater umami taste of tea.
Reduced Nitrogen Fertilizer Rates Maintained Raspberry Growth in an Established Field
Authors: Lu Qianwen , Miles Carol , Tao Haiying , DeVetter Lisa Wasko
Published: March 2022

Optimizing nitrogen (N) fertilizer rates maintains good red raspberry (Rubus idaeus L.) production while alleviating environmental risks. Although raspberry growers in Washington are using the caneberry nutrient management guides derived from western Oregon, these guides may not be appropriate for other production regions given the differences in climate, soil type, and crop productivity. However, limited research has been conducted to observe the impact of the N fertilizer rate on floricane red raspberry growth, yield, and fruit quality in Washington. The aim of this study is to evaluate the response of “Meeker” floricane red raspberries grown in northwest Washington, USA, to different N fertilizer rates in order to provide information for future local nutrient management guides. Treatments of urea (46% nitrogen (N)) were surface-applied to raised beds of established ‘Meeker’ raspberry plots at controls, low, medium, and high rates (0, 34, 67, and 101 kg N ha−1, respectively) in 2019 and 2020. The experiment was arranged in a randomized complete block with three replications. Fruit yield and quality, plant growth and leaf tissue nutrient concentrations, and soil characteristics were evaluated. There were no N fertilizer rate treatment effects for the yield, fruit quality, plant growth, leaf tissue nutrient concentrations, and soil characteristics, except for fruit titratable acidity and soil ammonium (NH4-N) concentrations. The lack of a plant response may be due to nutrients mineralized from soil organic matter (3.81–4.0%) and the utilization of plant nutrient reserves. Based on the results, the soil organic matter level and plant nutrient reserves should be considered when making nutrient management suggestions. Fertilizer costs as well as the potential for environmental pollution from excess fertilizers could be reduced through utilizing these two potential sources of nutrients. Furthermore, longer periods of research is warranted to understand how to adjust N fertilizer rates based on plant and soil characteristics while sustaining yields.
A One Health Approach Molecular Analysis of Staphylococcus aureus Reveals Distinct Lineages in Isolates from Miranda Donkeys (Equus asinus) and Their Handlers
Authors: Silva Vanessa , Alfarela Cláudia , Caniça Manuela , Manageiro Vera , Nóvoa Miguel , Leiva Belen , Kress Maria , Capelo José Luís , Poeta Patrícia , Igrejas Gilberto
Published: March 2022

Donkeys (Equus asinus) are in decline in Europe. Occupational exposure to farm animals has been associated with increased staphylococci carriage. We aimed to isolate S. aureus and coagulase-negative staphylococci (CoNS) from donkeys and handlers and characterize the antimicrobial resistance profiles and genetic lineages of S. aureus strains. Oral and nasal swab samples were collected from 49 Miranda donkeys and 23 handlers from 15 different farms. Staphylococci species were identified by MALDI-TOF MS. The presence of antimicrobial resistance genes and virulence factors was investigated by PCR. Molecular typing was performed in S. aureus isolates. From the 49 donkey samples, 4 S. aureus (8.2%) and 21 CoNS (42.9%) were isolated. Ten handlers (43.5%) were carriers of S. aureus and 4 (17.4%) carried CoNS. The CoNS isolates showed resistance to several classes of antimicrobials encoded by the mecA, aph (3′)-IIIa, ant (4′)-Ia, tetM, tetK, lnuA, ermB, ermC, dfrA and dfrG genes. S. aureus isolates were resistant to penicillin, aminoglicosides and tetracycline harboring the blaZ, aph (3′)-IIIa, tetL, tetM and tetK genes. All S. aureus isolates from donkeys belonged to ST49 and spa-type t208 while the strains isolated from the handlers were ascribed to 3 STs and 7 spa-types. However, human isolates were from different STs than the donkey isolates. Donkeys are mainly colonized by methicillin-resistant S. sciuri. S. aureus transmission between donkeys and their handlers appears not to have occurred since the isolates belonged to different genetic lineages.
Does the COVID Pandemic Modify the Antibiotic Resistance of Uropathogens in Female Patients? A New Storm?
Authors: Mareș Cristian , Petca Răzvan-Cosmin , Petca Aida , Popescu Răzvan-Ionuț , Jinga Viorel
Published: March 2022

Urinary tract infections (UTIs) represent a common pathology among female patients, leading to overprescribing antibiotics, globally. The emergence of the COVID-19 pandemic has dramatically increased the incidence of this particular viral pneumonia with secondary bacterial superinfection, resulting in continuous therapeutic or prophylactic recommendations of antibiotic treatment; thus, an updated analysis of current antimicrobial resistance among uropathogens is mandatory. This cross-sectional retrospective study conducted in two university hospitals in Bucharest, Romania analyzed 2469 positive urine cultures, among two different periods of 6 months, before and during the COVID-19 pandemic. The most common pathogen was Escherichia coli 1505 (60.95%), followed by Klebsiella spp. 426 (17.25%). Enterococcus spp. was the leading Gram-positive pathogen 285 (11.54%). In gram negative bacteria, in almost all cases, an increased in resistance was observed, but the highest increase was represented by quinolones in Klebsiella spp., from 16.87% to 35.51% and Pseudomonas from 30.3% to 77.41%; a significant increase in resistance was also observed for carbapenems. Surprisingly, a decrease in resistance to Penicillin was observed in Enterococcus spp., but the overall tendency of increased resistance is also maintained for gram positive pathogens. The lack of data on the influence of the COVID-19 pandemic on uropathogens’ resistance promotes these findings as important for every clinician treating UTIs and for every specialist in the medical field in promoting reasonable recommendations of antibiotic therapies.
Engineering Emergence: A Survey on Control in the World of Complex Networks
Authors: Berceanu Cristian , Pătrașcu Monica
Published: March 2022

Complex networks make an enticing research topic that has been increasingly attracting researchers from control systems and various other domains over the last two decades. The aim of this paper was to survey the interest in control related to complex networks research over time since 2000 and to identify recent trends that may generate new research directions. The survey was performed for Web of Science, Scopus, and IEEEXplore publications related to complex networks. Based on our findings, we raised several questions and highlighted ongoing interests in the control of complex networks.
Disseminated Cryptococcosis Complicating Severe SARS-CoV-2 Infection
Authors: Lupia Tommaso , Gaviraghi Alberto , Concialdi Erika , Penna Maurizio , Corcione Silvia , De Rosa Francesco Giuseppe
Published: March 2022

Opportunistic invasive fungal infections (IFI) have been described in severe SARS-CoV-2 infection. COVID-19-related cytokine storm, immune dysregulation and lymphopenia may increase IFI susceptibility in comorbid patients. We described the case of a 64-year-old man with respiratory failure due to SARS-CoV-2 infection complicated with disseminated cryptococosis. We analyzed the role played by the SARS-CoV-2-associated lymphopenia and the cumulative risk factors that lead to secondary infection by Cryptococcus neoformans, and its part in the dysregulation of the immunity response.
High-Throughput Drug Library Screening in Primary KMT2A-Rearranged Infant ALL Cells Favors the Identification of Drug Candidates That Activate P53 Signaling
Authors: Wander Priscilla , Arentsen-Peters Susan T. C. J. M. , Vrenken Kirsten S. , Pinhanҫos Sandra Mimoso , Koopmans Bianca , Dolman M. Emmy M. , Jones Luke , Garrido Castro Patricia , Schneider Pauline , Kerstjens Mark , Molenaar Jan J. , Pieters Rob , Zwaan Christian Michel , Stam Ronald W.
Published: March 2022

KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year of age) represents an aggressive type of childhood leukemia characterized by a poor clinical outcome with a survival chance of <50%. Implementing novel therapeutic approaches for these patients is a slow-paced and costly process. Here, we utilized a drug-repurposing strategy to identify potent drugs that could expeditiously be translated into clinical applications. We performed high-throughput screens of various drug libraries, comprising 4191 different (mostly FDA-approved) compounds in primary KMT2A-rearranged infant ALL patient samples (n = 2). The most effective drugs were then tested on non-leukemic whole bone marrow samples (n = 2) to select drugs with a favorable therapeutic index for bone marrow toxicity. The identified agents frequently belonged to several recurrent drug classes, including BCL-2, histone deacetylase, topoisomerase, microtubule, and MDM2/p53 inhibitors, as well as cardiac glycosides and corticosteroids. The in vitro efficacy of these drug classes was successfully validated in additional primary KMT2A-rearranged infant ALL samples (n = 7) and KMT2A-rearranged ALL cell line models (n = 5). Based on literature studies, most of the identified drugs remarkably appeared to lead to activation of p53 signaling. In line with this notion, subsequent experiments showed that forced expression of wild-type p53 in KMT2A-rearranged ALL cells rapidly led to apoptosis induction. We conclude that KMT2A-rearranged infant ALL cells are vulnerable to p53 activation, and that drug-induced p53 activation may represent an essential condition for successful treatment results. Moreover, the present study provides an attractive collection of approved drugs that are highly effective against KMT2A-rearranged infant ALL cells while showing far less toxicity towards non-leukemic bone marrow, urging further (pre)clinical testing.
Strategies for Sudden Cardiac Death Prevention
Authors: Corianò Mattia , Tona Francesco
Published: March 2022

Sudden cardiac death (SCD) represents a major challenge in modern medicine. The prevention of SCD orbits on two levels, the general population level and individual level. Much research has been done with the aim to improve risk stratification of SCD, although no radical changes in evidence and in therapeutic strategy have been achieved. Artificial intelligence (AI), and in particular machine learning (ML) models, represent novel technologic tools that promise to improve predictive ability of fatal arrhythmic events. In this review, firstly, we analyzed the electrophysiological basis and the major clues of SCD prevention at population and individual level; secondly, we reviewed the main research where ML models were used for risk stratification in other field of cardiology, suggesting its potentiality in the field of SCD prevention.
The Induced Membrane Technique—The Filling Matters: Evaluation of Different Forms of Membrane Filling with and without Bone Marrow Mononuclear Cells (BMC) in Large Femoral Bone Defects in Rats
Authors: Verboket René D. , Söhling Nicolas , Heilani Myriam , Fremdling Charlotte , Schaible Alexander , Schröder Katrin , Brune Jan C. , Marzi Ingo , Henrich Dirk
Published: March 2022

The Masquelet technique is used to treat large bone defects; it is a two-stage procedure based on an induced membrane. To improve the induced membrane process, demineralized bone matrix in granular (GDBM) and fibrous form (f-DBM) was tested with and without bone marrow mononuclear cells (BMC) as filling of the membrane against the gold standard filling with syngeneic cancellous bone (SCB). A total of 65 male Sprague–Dawley rats obtained a 5 mm femoral defect. These defects were treated with the induced membrane technique and filled with SCB, GDBM, or f-DBM, with or without BMC. After a healing period of eight weeks, the femurs were harvested and submitted for histological, radiological, and biomechanical analyses. The fracture load in the defect zone was lower compared to SCB in all groups. However, histological analysis showed comparable new bone formation, bone mineral density, and cartilage proportions and vascularization. The results suggest that f-DBM in combination with BMC and the induced membrane technique cannot reproduce the very good results of this material in large, non-membrane coated bone defects, nevertheless it supports the maturation of new bone tissue locally. It can be concluded that BMC should be applied in lower doses and inflammatory cells should be removed from the cell preparation before implantation.
Chemorefractory Gastric Cancer: The Evolving Terrain of Third-Line Therapy and Beyond
Authors: Alsina Maria , Tabernero Josep , Diez Marc
Published: March 2022

Gastric and gastro-oesophageal junction cancer (GC) represent a global healthcare problem being the fifth most common tumour type and the fourth cause of cancer mortality. Extremely poor median survival of approximately 10 months is normally reported within advanced GC patients, mainly secondary to two factors, i.e., the fragility of these patients and the aggressiveness of this disease. In this context, the correct treatment of GC patients requires not only a multidisciplinary team with special attention to palliative and nutritional care but also a close follow-up with regular monitoring of disease symptoms and tumour evaluation. Sequential treatment lines with few toxic adverse events have emerged as the best therapeutic approach, and a third line of therapy could further improve survival and quality of life of GC patients. Chemotherapy, immunotherapy, and targeted agents -when indicated- constitute the treatment armamentarium of these patients. In this review, we discuss treatment options in the refractory setting as well as novel approaches to overcome the poor prognosis of GC.
Impact of Delaying the Addition of Anti-EGFR in First Line of RAS Wild-Type Metastatic Colorectal Cancer: A Propensity-Weighted Pooled Data Analysis
Authors: Palmieri Lola-Jade , Buchler Tomas , Meyer Antoine , Veskrnova Veronika , Fiala Ondrej , Brabec Petr , Baranova Jana , Coriat Romain
Published: March 2022

The first-line therapy of patients with RAS wild-type (WT) non-resectable metastatic colorectal cancer (mCRC) is usually 5-fluorouracil-based chemotherapy with either bevacizumab or an anti-epidermal growth factor receptor (EGFR). The addition of anti-EGFR antibodies is commonly delayed in clinical practice because of late RAS testing results. Our objective was to evaluate the impact on overall survival (OS) of a delayed anti-EGFR introduction strategy. This study pooled the data of two large retrospective studies. Patients with RAS WT non-resectable mCRC, treated in first line by a doublet chemotherapy with an anti-EGFR introduced with a delay of 2 to 4 cycles, were compared to an anti-EGFR and to an anti-VEGF that was introduced immediately. Patients numbering 305 in the delayed anti-EGFR group, 401 in the immediate anti-EGFR group, and 129 in the immediate anti-VEGF group were analyzed. After propensity scoring, there was no difference between the characteristics of the three groups. Median OS was 28.6 months (95% CI: 23.5–34.1) in the immediate anti-EGFR group, 35.1 (95% CI: 29.9–43.5) in the delayed anti-EGFR group, and 32.4 (95% CI: 25.4–44.8) in the immediate anti-VEGF group. There was no significant difference concerning median OS (p = 0.24) or progression-free survival (p = 0.56). This study suggests that delaying the introduction of an anti-EGFR has no deleterious impact on survival compared to the immediate introduction of an anti-VEGF or of an anti-EGFR.
Treatment of Resectable Gallbladder Cancer
Authors: Vega Eduardo A. , Mellado Sebastian , Salehi Omid , Freeman Richard , Conrad Claudius
Published: March 2022

Gallbladder cancer (GBC) is the most common biliary tract cancer worldwide and its incidence has significant geographic variation. A unique combination of predisposing factors includes genetic predisposition, geographic distribution, female gender, chronic inflammation, and congenital developmental abnormalities. Today, incidental GBC is the most common presentation of resectable gallbladder cancer, and surgery (minimally invasive or open) remains the only curative treatment available. Encouragingly, there is an important emerging role for systemic treatment for patients who have R1 resection or present with stage III–IV. In this article, we describe the pathogenesis, surgical and systemic treatment, and prognosis.
Spreading of Alpha Synuclein from Glioblastoma Cells towards Astrocytes Correlates with Stem-like Properties
Authors: Ryskalin Larisa , Biagioni Francesca , Morucci Gabriele , Busceti Carla L. , Frati Alessandro , Puglisi-Allegra Stefano , Ferrucci Michela , Fornai Francesco
Published: March 2022

Evidence has been recently provided showing that, in baseline conditions, GBM cells feature high levels of α-syn which are way in excess compared with α-syn levels measured within control astrocytes. These findings are consistent along various techniques. In fact, they are replicated by using antibody-based protein detection, such as immuno-fluorescence, immuno-peroxidase, immunoblotting and ultrastructural stoichiometry as well as by measuring α-syn transcript levels at RT-PCR. The present manuscript further questions whether such a high amount of α-syn may be induced within astrocytes, which are co-cultured with GBM cells in a trans-well system. In astrocytes co-cultured with GBM cells, α-syn overexpression is documented. Such an increase is concomitant with increased expression of the stem cell marker nestin, along with GBM-like shifting in cell morphology. This concerns general cell morphology, subcellular compartments and profuse convolutions at the plasma membrane. Transmission electron microscopy (TEM) allows us to assess the authentic amount and sub-cellular compartmentalization of α-syn and nestin within baseline GBM cells and the amount, which is induced within co-cultured astrocytes, as well as the shifting of ultrastructure, which is reminiscent of GBM cells. These phenomena are mitigated by rapamycin administration, which reverts nestin- and α-syn-related overexpression and phenotypic shifting within co-cultured astrocytes towards baseline conditions of naïve astrocytes. The present study indicates that: (i) α-syn increases in astrocyte co-cultured with GBM cells; (ii) α-syn increases in astrocytes along with the stem cell marker nestin; (iii) α-syn increases along with a GBM-like shift of cell morphology; (iv) all these changes are replicated in different GBM cell lines and are reverted by the mTOR inhibitor rapamycin. The present findings indicate that α-syn does occur in high amount within GBM cells and may transmit to neighboring astrocytes as much as a stem cell phenotype. This suggests a mode of tumor progression for GBM cells, which may transform, rather than merely substitute, surrounding tissue; such a phenomenon is sensitive to mTOR inhibition.
Hyperspectral Imaging for Tissue Classification after Advanced Stage Ovarian Cancer Surgery—A Pilot Study
Authors: van Vliet-Pérez Sharline M. , van de Berg Nick J. , Manni Francesca , Lai Marco , Rijstenberg Lucia , Hendriks Benno H. W. , Dankelman Jenny , Ewing-Graham Patricia C. , Nieuwenhuyzen-de Boer Gatske M. , van Beekhuizen Heleen J.
Published: March 2022

The most important prognostic factor for the survival of advanced-stage epithelial ovarian cancer (EOC) is the completeness of cytoreductive surgery (CRS). Therefore, an intraoperative technique to detect microscopic tumors would be of great value. The aim of this pilot study is to assess the feasibility of near-infrared hyperspectral imaging (HSI) for EOC detection in ex vivo tissue samples. Images were collected during CRS in 11 patients in the wavelength range of 665–975 nm, and processed by calibration, normalization, and noise filtering. A linear support vector machine (SVM) was employed to classify healthy and tumorous tissue (defined as >50% tumor cells). Classifier performance was evaluated using leave-one-out cross-validation. Images of 26 tissue samples from 10 patients were included, containing 26,446 data points that were matched to histopathology. Tumorous tissue could be classified with an area under the curve of 0.83, a sensitivity of 0.81, a specificity of 0.70, and Matthew’s correlation coefficient of 0.41. This study paves the way to in vivo and intraoperative use of HSI during CRS. Hyperspectral imaging can scan a whole tissue surface in a fast and non-contact way. Our pilot study demonstrates that HSI and SVM learning can be used to discriminate EOC from surrounding tissue.
Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives
Authors: Ullah Asad , Khan Jaffar , Waheed Abdul , Sharma Nitasha , Pryor Elizabeth , Stumpe Tanner , Velasquez Zarate Luis , Cason Frederick , Kumar Suresh , Misra Subhasis , Kavuri Sravan , Mesa Hector , Roper Nitin , Foroutan Shahin , Karki Nabin , Del Rivero Jaydira , Simonds William , Karim Nagla
Published: March 2022

Introduction: Parathyroid carcinoma (PC) is an extremely rare entity, with a frequency of 0.005% of all malignancies. Most data related to this rare disease are limited to case series and a few database studies. We present a large database study that aims to investigate the demographic, clinical, and pathological factors, prognosis, and survival of PC. Methods: Data of parathyroid carcinoma were extracted from the Surveillance, Epidemiology, and End Results (SEER) diagnosed between 1975 and 2016. Results: PC had a slightly higher incidence in men (52.2%, p < 0.005), the majority of cases affected Caucasians (75.4%, p < 0.005), and the mean age at diagnosis was 62 years. Histologically, 99.7% were adenocarcinomas not otherwise specified (p < 0.005), well-differentiated (p < 0.005), and 2–4 cm (p < 0.001) in size among the patients with available data. In cases with staging provided, most PC were organ-confined (36.8%, p < 0.001). Lymph nodes were positive in 25.2% of cases where lymph node status was reported. The main treatment modality was surgery (97.2%), followed by radiation alone (2%), and very few received chemotherapy alone (0.8%), p < 0.005. Five-year follow-up was available for 82.7% of the cases. Those who underwent surgery only or radiation alone had 5-year survivals of 83.8% and 72.2%, respectively (p < 0.037). Multivariable analysis identified tumor size >4 cm, age > 40 years, male sex, Caucasian race, distant spread, and poorly differentiated grade as independent risk factors for mortality (p < 0.001). Conclusion: PC is a very rare tumor mostly affecting Caucasian individuals in the fifth decade. Older age, poor histologic differentiation, and distant metastasis are associated with a worse prognosis. Surgical resection offers the best survival outcome. To better understand the pathogenesis and factors affecting survival, all PC patients should be enrolled in national and international registries.
Health-Related Quality of Life (HRQoL) in Neuroendocrine Tumors: A Systematic Review
Authors: Gosain Rohit , Gupta Medhavi , Roy Arya Mariam , Strosberg Jonathan , Glaser Kathryn M. , Iyer Renuka
Published: March 2022

Therapeutic advancements in neuroendocrine tumors (NETs) have improved survival outcomes. This study aims to review the impact of the current therapeutics on health-related quality of life (HRQoL) in NET patients. A literature review was performed utilizing PubMed, The Cochrane Library, and EMBASE, using the keywords “Carcinoid”, “Neuroendocrine tumor”, “NET”, “Quality of life”, “Chemotherapy”, “Chemoembolization”, “Radiofrequency ablation”, “Peptide receptor radionucleotide therapy”, “PRRT”, “Surgery”, “Everolimus”, “Octreotide”, “Lanreotide”, “Sunitinib”, and “Somatostatin analog”. Letters, editorials, narrative reviews, case reports, and studies not in English were excluded. Out of 2375 publications, 61 studies met our inclusion criteria. The commonly used instruments were EORTC QLQ-C30, FACT G, and EORTC- QLQ GI.NET-21. HRQoL was assessed in all pivotal trials that led to approvals of systemic therapies. All systemic therapies showed no worsening in HRQoL. The NETTER-1 study was the only study to show a statistically significant improvement in HRQoL in several domains. The trial examining sunitinib versus placebo in pancreatic NETs showed no change in QoL, except for worsening of diarrhea. In addition to clinical outcomes, patient-reported outcomes are a key element in making appropriate treatment decisions. HRQoL data should be readily provided to patients to assist in shared decision-making.
The Interplay between Cell-Extracellular Matrix Interaction and Mitochondria Dynamics in Cancer
Authors: Yanes Bian , Rainero Elena
Published: March 2022

The tumor microenvironment, in particular the extracellular matrix (ECM), plays a pivotal role in controlling tumor initiation and progression. In particular, the interaction between cancer cells and the ECM promotes cancer cell growth and invasion, leading to the formation of distant metastasis. Alterations in cancer cell metabolism is a key hallmark of cancer, which is often associated with alterations in mitochondrial dynamics. Recent research highlighted that, changes in mitochondrial dynamics are associated with cancer migration and metastasis—these has been extensively reviewed elsewhere. However, less is known about the interplay between the extracellular matrix and mitochondria functions. In this review, we will highlight how ECM remodeling associated with tumorigenesis contribute to the regulation of mitochondrial function, ultimately promoting cancer cell metabolic plasticity, able to fuel cancer invasion and metastasis.
Exosomes as Emerging Drug Delivery and Diagnostic Modality for Breast Cancer: Recent Advances in Isolation and Application
Authors: Kumar Dulla Naveen , Chaudhuri Aiswarya , Aqil Farrukh , Dehari Deepa , Munagala Radha , Singh Sanjay , Gupta Ramesh C. , Agrawal Ashish Kumar
Published: March 2022

Breast cancer (BC) is the most common type of malignancy which covers almost one-fourth of all the cancers diagnosed in women. Conventionally, chemo-, hormonal-, immune-, surgery, and radiotherapy are the clinically available therapies for BC. However, toxicity and other related adverse effects are still the major challenges. A variety of nano platforms have been reported to overcome these limitations, among them, exosomes provide a versatile platform not only for the diagnosis but also as a delivery vehicle for drugs. Exosomes are biological nanovesicles made up of a lipidic bilayer and known for cell-to-cell communication. Exosomes have been reported to be present in almost all bodily fluids, viz., blood, milk, urine, saliva, pancreatic juice, bile, peritoneal, and cerebrospinal fluid. Such characteristics of exosomes have attracted immense interest in cancer diagnosis and therapy. They can deliver bioactive moieties such as protein, lipids, hydrophilic as well as hydrophobic drugs, various RNAs to both distant and nearby recipient cells as well as have specific biological markers. By considering the growing interest of the scientific community in this field, we comprehensively compiled the information about the biogenesis of exosomes, various isolation methods, the drug loading techniques, and their diverse applications in breast cancer diagnosis and therapy along with ongoing clinical trials which will assist future scientific endeavors in a more organized direction.
Emerging Canonical and Non-Canonical Roles of Granzyme B in Health and Disease
Authors: Tibbs Ellis , Cao Xuefang
Published: March 2022

The Granzyme (Gzm) family has classically been recognized as a cytotoxic tool utilized by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells to illicit cell death to infected and cancerous cells. Their importance is established based on evidence showing that deficiencies in these cell death executors result in defective immune responses. Recent findings have shown the importance of Granzyme B (GzmB) in regulatory immune cells, which may contribute to tumor growth and immune evasion during cancer development. Other studies have shown that members of the Gzm family are important for biological processes such as extracellular matrix remodeling, angiogenesis and organized vascular degradation. With this growing body of evidence, it is becoming more important to understand the broader function of Gzm’s rather than a specific executor of cell death, and we should be aware of the many alternative roles that Gzm’s play in physiological and pathological conditions. Therefore, we review the classical as well as novel non-canonical functions of GzmB and discuss approaches to utilize these new findings to address current gaps in our understanding of the immune system and tissue development.
The Matrisome Is Associated with Metabolic Reprograming in Stem-like Phenotypes of Gastric Cancer
Authors: Sung Ji-Yong , Cheong Jae-Ho
Published: March 2022

The extracellular matrix (ECM) is an important regulator of all cellular functions, and the matrisome represents a major component of the tumor microenvironment. The matrisome is an essential component comprising genes encoding ECM glycoproteins, collagens, and proteoglycans; however, its role in cancer progression and the development of stem-like molecular subtypes in gastric cancer is unknown. We analyzed gastric cancer data from five molecular subtypes (n = 497) and found that metabolic reprograming differs based on the state of the matrisome. Approximately 95% of stem-like cancer type samples of gastric cancer were in the high-matrisome category, and energy metabolism was considerably increased in the high-matrisome group. Particularly, high glycosaminoglycan biosynthesis-chondroitin sulfate metabolic reprograming was associated with an unfavorable prognosis. Glycosaminoglycan biosynthesis-chondroitin sulfate metabolic reprograming may occur according to the matrisome status and contribute to the development of stem-like phenotypes. Our analysis suggests the possibility of precision medicine for anticancer therapies.