bluuebunny/crossref_metadata_2025 huggingface dataset:
Detecting and Processing Anomalies in a Factory of the Future
Authors: Feeken Linda , Kern Esther , Szanto Alexander , Winnicki Alexander , Kao Ching-Yu , Wudka Björn , Glawe Matthias , Mirzaei Elham , Borchers Philipp , Burghardt Christian
Published: August 2022

Production systems are changing in many aspects on the way to a Factory of the Future, including the level of automation and communication between components. Besides all benefits, this evolution raises the amount, effect and type of anomalies and unforeseen behavior to a new level of complexity. Thus, new detection and mitigation concepts are required. Based on a use-case dealing with a distributed transportation system for production environments, this paper describes the different sources of possible anomalies with the same effect, anomaly detection methods and related mitigation techniques. Depending on the identified anomaly, the FoF should react accordingly, such as fleet or AGV reconfiguration, strong authentication and access control or a deletion of adversarial noises. In this paper, different types of mitigation actions are described that support the fleet in overcoming the effect of the anomaly or preventing them in the future. A concept to select the most appreciate mitigation method is presented, where the detection of the correct source of the anomaly is key. This paper shows how various techniques can work together to gain a holistic view on anomalies in the Factory of the Future for selecting the most appropriate mitigation technique.
Characterization of Native and Human Serum Albumin-Bound Lysophosphatidic Acid Species and Their Effect on the Viability of Mesenchymal Stem Cells In Vitro
Authors: Majer Aliz , Pesthy Julianna , Besztercei Balázs , Hinsenkamp Adél , Smeller László , Lacza Zsombor , Benyó Zoltán , Ruisanchez Éva , Hornyák István
Published: August 2022

Scaffolds can provide a healthy environment for cell attachment, differentiation, proliferation, and migration in vitro and in vivo. Lysophosphatidic acid (LPA) is a naturally occurring bioactive phospholipid that is present in the serum mainly bound to albumin. The present study aims to investigate the biocompatibility of LPA. It also aims to determine the effect of different LPA species on the proliferation and migration of human bone marrow-derived mesenchymal stem cells (hBM-dMSCs) for LPA and human serum albumin (HSA) containing bone scaffold development. The HSA-LPA complex formation was assessed using Fourier-transform infrared (FTIR) spectroscopy. The effect of 18:1, 18:2, or 16:0 LPA alone, or in combination with 4% HSA, on cell viability and proliferation was determined by XTT. The cell migration was examined in a wound healing assay. The changes in the FTIR spectra of LPA-HSA compositions, compared with HSA alone, indicate the complex formation between the components. Our study showed that 18:1, 18:2, and 16:0 LPA species had no cytotoxic effects up to 10 µM concentration. The different LPA species increased the proliferation of hBM-dMSCs in a dose-dependent manner when administered in the presence of HSA, without an effect on the migration of this cell type. These findings make the in vivo application of LPA-HSA complex promising for bone regeneration.
Solving the Integrated Multi-Port Stowage Planning and Container Relocation Problems with a Genetic Algorithm and Simulation
Authors: Junqueira Catarina , de Azevedo Anibal Tavares , Ohishi Takaaki
Published: August 2022

The greater flow of containers in global supply chains requires ever-increasing productivity at port terminals. The research found in the literature has focused on optimizing specific parts of port operations but has ignored important features, such as the stack-wise organization of containers in a container ship and port yard and the effects of interconnection among the operations in both places. The objective of this paper is to show the importance of designing an integrated plan of the container relocation problem at the port yard with the stowage planning problem for loading and unloading a ship through ports. Both individual problems are NP-Complete, and exact approaches for each problem are only able to find optimal or feasible solutions for small instances. We describe a simulation-optimization methodology that combines simulation, a genetic algorithm, and a new solution representation based on rules. The test results show that the solution from the integrated plan is mutually beneficial for port yards and ship owners.
Special Issue “Nature or Synthetic Compounds for Treating Arterial Thrombosis and Ischemic Stroke”
Authors: Jayakumar Thanasekaran , Sheu Joen-Rong
Published: August 2022

Stroke is the second main cause of mortality and morbidity globally [...]
Toward a Modern Last-Mile Delivery: Consequences and Obstacles of Intelligent Technology
Authors: Sorooshian Shahryar , Khademi Sharifabad Shila , Parsaee Mehrdad , Afshari Ali Reza
Published: August 2022

Last-mile delivery (LMD) is essential in supply chains, and providers of logistics services are aware that they must adapt to changing customer and society expectations, competition challenges, and modern technologies. In light of the importance of artificial intelligence (AI) in modern technologies, this article employed a narrative literature review to recognize impacts of AI-powered technologies that aid in optimizing the LMD component. For this study, two possible classes of technologies were considered: tangible technologies, such as robots, drones, and autonomous vehicles, and intangible technologies, such as decision support tools and operating systems. Thus, this article frames potential developments in modern LMD, taking into account the fact that technological advancement brings both opportunities and challenges. According to this literature review, the modern version of LMD is capable of providing services that are both more productive and more sustainable, thus satisfying demands for better services. Last but not least, another goal of this article was to look into the challenges that limit the benefits of modern LMDs. Finally, suggestions are provided as a resource for practitioners and policymakers working in the supply chain to improve performance.
Power Consumption Forecast of Three Major Industries in China Based on Fractional Grey Model
Authors: Xie Yuhan , Yang Yunfei , Wu Lifeng
Published: August 2022

As one of the most significant carbon emission departments in China, the power industry will gradually become the core hub of reducing carbon emissions in the process of undertaking carbon emissions transferred from other industries. Therefore, it is of vital importance to predict the power consumption in China’s end energy consumption to achieve the carbon peak goal on time. This paper firstly uses the gray relational analysis model to study the relationship between power consumption indicators of the three major industries and some social and economic indicators and obtains the influencing factors with the greatest correlation with the power consumption of the three industries. Then, based on the analysis of socio-economic factors, considering different growth rates, the GMCN(1,N) model of electricity consumption in China’s three major industries is established. Forecast data under different scenarios have important practical significance for formulating active and effective energy policies. The data indicate that the secondary and tertiary industries consume the greatest amount of electricity. It is estimated that the power consumption of China’s three major industries will reach 10.15 trillion kWh (kilowatt hours) by 2030.
Corneal Adhesion Possesses the Characteristics of Solid and Membrane
Authors: Yang Jiajin , Ren Qiaomei , Zhao Dong , Gao Zhipeng , Li Xiaona , He Rui , Chen Weiyi
Published: August 2022

Adhesion behavior usually occurs in corneas associated with clinical treatments. Physiologically, an intact natural cornea is inflated by intraocular pressure. Due to the inflation, the physiological cornea has a mechanical property likeness to membrane. This characteristic is ignored by the classical theory used to analyze the adhesion behavior of soft solids, such as the Johnson–Kendall–Roberts (JKR) model. Performing the pull-off test, this work evidenced that the classical JKR solution was suitable for computing the corneal adhesion force corresponding to the submillimeter scale of contact. However, when the cornea was contacted at a millimeter scale, the JKR solutions were clearly smaller than the related experimental data. The reason was correlated with the membranous characteristic of the natural cornea was not considered in the JKR solid model. In this work, the modified JKR model was superimposed by the contribution from the surface tension related to the corneal inflation due to the intraocular pressure. It should be treated as a solid when the cornea is contacted at a submillimeter scale, whereas for the contact at a larger size, the characteristic of the membrane should be considered in analyzing the corneal adhesion. The modified JKR model successfully described the adhesion characteristics of the cornea from solid to membrane.
The Protective Performance of Process Operators’ Protective Clothing and Exposure Limits under Low Thermal Radiation Conditions
Authors: Heus Ronald , Kingma Boris R. M. , van Berlo Birgit M. A. , Mol Douwe , Daanen Hein A. M. , Kuklane Kalev
Published: August 2022

During the early stage of a fire, a process operator often acts as the first responder and may be exposed to high heat radiation levels. The present limit values of long- (>15 min) and short-term exposure (<5 min), 1.0 and 1.5 kW/m2, respectively, have been set using physiological models and manikin measurements. Since human validation is essentially lacking, this study investigated whether operators’ protective clothing offers sufficient protection during a short-term deployment. Twelve professional firefighters were exposed to three radiation levels (1.5, 2.0, and 2.5 kW/m2) when wearing certified protective clothing in front of a heat radiation panel in a climatic chamber (20 °C; 50% RH). The participants wore only briefs (male) or panties and a bra (female) and a T-shirt under the operators’ clothing. Skin temperatures were continuously measured at the chest, belly, forearm, thigh, and knee. The test persons had to stop if any skin temperature reached 43 °C, at their own request, or when 5 min of exposure was reached. The experiments showed that people in operators’ clothing can be safely exposed for 5 min to 1.5 kW/m2, up to 3 min to 2.0 kW/m2, and exposure to 2.5 kW/m2 or above must be avoided unless the clothing can maintain an air gap.
Acute Effects of Different Overspeed Loads with Motorized Towing System in Young Athletes: A Pilot Study
Authors: Cecília-Gallego Pau , Odriozola Adrián , Beltrán-Garrido José Vicente , Álvarez-Herms Jesús
Published: August 2022

Overspeed is a training method used to improve running speed, although its effects are not supported by consensual scientific evidence. The overspeed stimulus can be boosted by several methods, including motorized towing devices. Our objectives were to analyze the acute effects of three overspeed loads in young athletes and to select optimal loads for training periods. Eight young athletes (16.73 ± 1.69 years) performed one unassisted sprint and three assisted sprints, and kinematic and biomechanical data were compared. Significant increases (p < 0.05) in step velocity and step length were found with 2, 4, and 5.25 kg in maximum running speed, flight time and horizontal distance from the first contact to the vertical projection of the center of mass with 4 and 5.25 kg. Significant time decreases were found in 5 m flying sprint and contact time with 4 and 5.25 kg, and no significant changes were observed in step rate. The individually recommended loads would be between 3.47 ± 0.68% and 6.94 ± 1.35% body weight. Even having limitations, we can understand this work and its results as a pilot study to replicate the methodology and the use of new devices to more broadly investigate the effects of overspeed.
A Machine Learning Approach to Identify the Importance of Novel Features for CRISPR/Cas9 Activity Prediction
Authors: Vora Dhvani Sandip , Verma Yugesh , Sundar Durai
Published: August 2022

The reprogrammable CRISPR/Cas9 genome editing tool’s growing popularity is hindered by unwanted off-target effects. Efforts have been directed toward designing efficient guide RNAs as well as identifying potential off-target threats, yet factors that determine efficiency and off-target activity remain obscure. Based on sequence features, previous machine learning models performed poorly on new datasets, thus there is a need for the incorporation of novel features. The binding energy estimation of the gRNA-DNA hybrid as well as the Cas9-gRNA-DNA hybrid allowed generating better performing machine learning models for the prediction of Cas9 activity. The analysis of feature contribution towards the model output on a limited dataset indicated that energy features played a determining role along with the sequence features. The binding energy features proved essential for the prediction of on-target activity and off-target sites. The plateau, in the performance on unseen datasets, of current machine learning models could be overcome by incorporating novel features, such as binding energy, among others. The models are provided on GitHub (GitHub Inc., San Francisco, CA, USA).
Hypermetabolism and Substrate Utilization Rates in Pheochromocytoma and Functional Paraganglioma
Authors: Petrák Ondřej , Haluzíková Denisa , Klímová Judita , Zítek Matěj , Holaj Robert , Michalský David , Novák Květoslav , Petráková-Doležalová Radka , Kvasnička Jan , Nguyen Thi Minh Phuong Nikrýnová , Krátká Zuzana , Matoulek Martin , Widimský Jiří , Zelinka Tomáš
Published: August 2022

The overproduction of catecholamines in pheochromocytoma/paraganglioma (PPGL) induces a hypermetabolic state. The aim of this study was to evaluate the incidence of a hypermetabolic state and differences in substrate metabolism in consecutive PPGL patients divided by catecholamine phenotype. Resting energy expenditure (REE) and respiratory quotient (RQ) were measured in 108 consecutive PPGL patients and 70 controls by indirect calorimetry. Hypermetabolic state was defined according to the Mifflin St. Jeor Equation as a ratio above 110%. Hypermetabolic state was confirmed in 70% of PPGL patients, regardless of phenotype. Older age, prevalence of diabetes mellitus and arterial hypertension were correlated with hypermetabolic PPGL as compared to normometabolic form. Analysis according to overproduced catecholamine showed differences in VCO2 (p < 0.05) and RQ (p < 0.01) and thus different substate metabolism between phenotypes in hypermetabolic form of PPGL. Lipid utilization was higher in the adrenergic phenotype (p = 0.001) and positively associated with the percentage of REE ratio (R = 0.48, p < 0.001), whereas the noradrenergic phenotype preferentially oxidizes carbohydrates (P = 0.001) and is correlated with the percentage of REE ratio (R = 0.60, p < 0.001). Hypermetabolic state in PPGL is a common finding in both catecholamine phenotypes. Hypermetabolic PPGL patients are older and suffer more from diabetes mellitus and arterial hypertension. Under basal conditions, the noradrenergic type preferentially metabolizes carbohydrates, whereas the adrenergic phenotype preferentially metabolizes lipids.
Silencing of LLGL2 Suppresses the Estradiol-Induced BPH-1 Cell Proliferation through the Regulation of Autophagy
Authors: Kim Kyung-Hyun , Hong Geum-Lan , Kim Yae-Ji , Lee Hui-Ju , Jung Ju-Young
Published: August 2022

Lethal giant larvae (Lgl) is an apical-basal polarity gene first identified in Drosophila. LLGL2 is one of the mammalian homologs of Lgl. However, little is known about its function in the prostate. In this study, to explore the new role of LLGL2 in the prostate, we examined the proliferative activity of a BPH-1 cell line, a well-established model for the human prostate biology of benign prostatic hyperplasia (BPH). The expression of LLGL2 was dose-dependently increased in BPH-1 cells after treatment with 17β-estradiol (E2). Additionally, E2 treatment increased the proliferation of the BPH-1 cells. However, the knockdown of LLGL2 with siRNA significantly suppressed the proliferation of the E2-treated BPH-1 cells. Moreover, si-llgl2 treatment up-regulated the expression of LC-3B, ATG7, and p-beclin, which are known to play a pivotal role in autophagosome formation in E2-treated BPH-1 cells. Overexpression of LLGL2 was able to further prove these findings by showing the opposite results from the knockdown of LLGL2 in E2-treated BPH-1 cells. Collectively, our results suggest that LLGL2 is closely involved in the proliferation of prostate cells by regulating autophagosome formation. These results provide a better understanding of the mechanism involved in the effect of LLGL2 on prostate cell proliferation. LLGL2 might serve as a potential target in the diagnosis and/or treatment of human BPH.
Latency Trend Analysis as a Guide to Screening Malignancy Survivors for Second Primary Thyroid Cancer
Authors: Hussein Mohammad , Mueller Lauren , Issa Peter P. , Haidari Muhib , Trinh Lily , Toraih Eman , Kandil Emad
Published: August 2022

Primary cancer survivors have a higher risk of developing second primary thyroid cancer (SPTC). Patients with SPTC who survived primary malignancies, diagnosed from 1975 to 2016, were identified from the Surveillance, Epidemiology, and End Results (SEER) database (SEER 18 Registry). A total of 33,551 cancer cases were enrolled in the final analysis. Individuals with a primary malignancy were at a significant 90% increased risk of developing SPTC (SIR = 1.90, 95%CI = 1.86–1.93, p < 0.05) compared to the general population. More than half (54.7%) of SPTC diagnoses were made in the first three years after primary cancer diagnosis, and the most aggressive presentations of SPTC occurred within the first year following malignancy. A latency trend analysis identified persistent high risk for development of SPTC after diagnosis of lymphoma, leukemia, soft tissue tumors, kidney, breast, and uterine cancer; elevated 10-year risk for most cancers such as salivary gland, melanoma, stomach, lung, colon, ovarian, pancreas, prostate, and bladder; and high 5-year risk after cancers such as larynx, oral, orbit, bone, small intestine, and liver. Our latency period model identifying risk according to each type of primary cancer may aid clinicians in identifying at-risk patients to be screened for thyroid cancer and guide them in developing a surveillance plan according to the latency period attributed to a patient’s primary cancer.
Potential Gonado-Protective Effect of Cichorium endivia and Its Major Phenolic Acids against Methotrexate-Induced Testicular Injury in Mice
Authors: Eltamany Enas E. , Mosalam Esraa M. , Mehanna Eman T. , Awad Basma M. , Mosaad Sarah M. , Abdel-Kader Maged S. , Ibrahim Amany K. , Badr Jihan M. , Goda Marwa S.
Published: August 2022

Cichorium endivia L. (Asteraceae) is a wide edible plant that grows in the Mediterranean region. In this study, a phytochemical investigation of C. endivia L. ethanolic extract led to the isolation of stigmasterol (1), ursolic acid (2), β-amyrin (3), azelaic acid (4), vanillic acid (5), (6S, 7E)-6-hydroxy-4,7-megastigmadien-3,9-dione (S(+)-dehydrovomifoliol) (6), 4-hydroxy phenyl acetic acid (7), vomifoliol (8), ferulic acid (9), protocatechuic acid (10), kaempferol (11), p. coumaric acid (12), and luteolin (13). In addition, the total phenolic content as well as the in vitro antioxidant activity of C. endivia L. extract were estimated. Moreover, we inspected the potential gonado-protective effect of C. endivia crude extract, its phenolic fraction, and the isolated coumaric, vanillic, and ferulic acids against methotrexate (MTX)-induced testicular injury in mice. There were seven groups: normal control, MTX control, MTX + C. endivia crude extract, MTX + C. endivia phenolic fraction, MTX + isolated coumaric acid, MTX + isolated vanillic acid, and MTX + isolated ferulic acid. MTX was given by i.p. injection of a 20 mg/kg single dose. The crude extract and phenolic fraction were given with a dose of 100 mg/kg/day, whereas the compounds were given at a dose of 10 mg/kg/day. A histopathological examination was done. The testosterone level was detected in serum together with the testicular content of malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), interleukin 1β (IL-1β), IL-6, tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB), B-cell lymphoma 2 (Bcl-2), Bcl-2 associated x protein (Bax), p53, and miR-29a. C. endivia crude extract, the phenolic fraction, and the isolated compounds showed significant elevation in their levels of testosterone, CAT, SOD, Bcl-2 with a significant decrease in their levels of MDA, TNF-α, IL-1β, IL-6, NF-κB, Bax, P53, and miR-29a compared to those of the MTX control group. In conclusion, C. endivia mitigated MTX-induced germ cell toxicity via anti-inflammatory, antioxidant, and antiapoptotic effects.
CK2 and the Hallmarks of Cancer
Authors: Firnau May-Britt , Brieger Angela
Published: August 2022

Cancer is a leading cause of death worldwide. Casein kinase 2 (CK2) is commonly dysregulated in cancer, impacting diverse molecular pathways. CK2 is a highly conserved serine/threonine kinase, constitutively active and ubiquitously expressed in eukaryotes. With over 500 known substrates and being estimated to be responsible for up to 10% of the human phosphoproteome, it is of significant importance. A broad spectrum of diverse types of cancer cells has been already shown to rely on disturbed CK2 levels for their survival. The hallmarks of cancer provide a rationale for understanding cancer’s common traits. They constitute the maintenance of proliferative signaling, evasion of growth suppressors, resisting cell death, enabling of replicative immortality, induction of angiogenesis, the activation of invasion and metastasis, as well as avoidance of immune destruction and dysregulation of cellular energetics. In this work, we have compiled evidence from the literature suggesting that CK2 modulates all hallmarks of cancer, thereby promoting oncogenesis and operating as a cancer driver by creating a cellular environment favorable to neoplasia.
Therapeutic Potential of Glucagon-like Peptide-1 Agonists in Polycystic Ovary Syndrome: From Current Clinical Evidence to Future Perspectives
Authors: Jensterle Mojca , Herman Rok , Janež Andrej
Published: August 2022

Despite the continuous effort to understand the pathophysiology and determine potential therapeutic targets, PCOS treatment largely depends on lifestyle intervention and symptomatic management of individual signs and symptoms. International guidelines recognize the importance of weight reduction as a cornerstone for the achievement of better metabolic, reproductive, and cardiovascular outcomes in PCOS women who are overweight or obese. With its profound weight loss potential in patients with or without diabetes, the administration of GLP-1 receptor agonists has been investigated in overweight/obese women with PCOS in several single-center randomized control trials with considerable variation in the dosing regimen, follow-up duration, and outcome measurements over recent years. Most trials reported superior weight loss effects of GLP-1 receptor agonists compared to lifestyle changes or metformin, with additional metabolic, reproductive, and cardiovascular benefits in this population. However, their use is currently not widely accepted by the clinical community that treats this population. The major concern is how to balance the reproductive and metabolic treatment strategies since the use of GLP-1 receptor agonists requires effective contraception while on therapy and a washout period before pregnancy. Both approaches are not mutually exclusive, yet the best choice requires a careful assessment of the clinical context. Knowing a patient’s individual circumstances, precise clinical sub-phenotyping, and regular monitoring are crucial components for the safe and effective use of these new tools. In the present narrative review, we explore the current clinical evidence and provide the future perspectives and challenges for their implementation in PCOS management.
Radioimmunotherapy in HPV-Associated Head and Neck Squamous Cell Carcinoma
Authors: Zhou Xin , Wang Xiaoshen
Published: August 2022

HPV-associated head and neck squamous cell carcinoma (HNSCC) is a cancer entity with unique biological and clinical characteristics that requires more personalized treatment strategies. As the backbone of conventional therapeutics, radiation is now harnessed to synergize with immunotherapy in multiple malignancies. Accumulating preclinical and clinical data have suggested the potential of radioimmunotherapy in eliciting local and systemic anti-tumor response via direct killing of tumor cells and immunogenic cell death. However, this effect remains uncertain in HPV-associated HNSCC. Owing to its intrinsic radiosensitivity and distinct tumor microenvironment, HPV-associated HNSCC may represent a good candidate for radioimmunotherapy. In this review, we provide a detailed illustration of the biology, the genomic features, and immune landscapes of HPV-associated HNSCC that support the synergism between radiation and immune agents. The interaction between radiotherapy and immunotherapy is described. We also highlight the present evidence as well as ongoing trials using different combination strategies in the recurrent/metastatic or definitive settings. In addition, we have summarized the challenges and outlook for future trial design, with special emphasis on radiotherapy optimization and novel therapeutic options to incorporate.
Application of a Brain–Computer Interface System with Visual and Motor Feedback in Limb and Brain Functional Rehabilitation after Stroke: Case Report
Authors: Gao Wen , Cui Zhengzhe , Yu Yang , Mao Jing , Xu Jun , Ji Leilei , Kan Xiuli , Shen Xianshan , Li Xueming , Zhu Shiqiang , Hong Yongfeng
Published: August 2022

(1) Objective: To investigate the feasibility, safety, and effectiveness of a brain–computer interface (BCI) system with visual and motor feedback in limb and brain function rehabilitation after stroke. (2) Methods: First, we recruited three hemiplegic stroke patients to perform rehabilitation training using a BCI system with visual and motor feedback for two consecutive days (four sessions) to verify the feasibility and safety of the system. Then, we recruited five other hemiplegic stroke patients for rehabilitation training (6 days a week, lasting for 12–14 days) using the same BCI system to verify the effectiveness. The mean and Cohen’s w were used to compare the changes in limb motor and brain functions before and after training. (3) Results: In the feasibility verification, the continuous motor state switching time (CMSST) of the three patients was 17.8 ± 21.0s, and the motor state percentages (MSPs) in the upper and lower limb training were 52.6 ± 25.7% and 72.4 ± 24.0%, respectively. The effective training revolutions (ETRs) per minute were 25.8 ± 13.0 for upper limb and 24.8 ± 6.4 for lower limb. There were no adverse events during the training process. Compared with the baseline, the motor function indices of the five patients were improved, including sitting balance ability, upper limb Fugel–Meyer assessment (FMA), lower limb FMA, 6 min walking distance, modified Barthel index, and root mean square (RMS) value of triceps surae, which increased by 0.4, 8.0, 5.4, 11.4, 7.0, and 0.9, respectively, and all had large effect sizes (Cohen’s w ≥ 0.5). The brain function indices of the five patients, including the amplitudes of the motor evoked potentials (MEP) on the non-lesion side and lesion side, increased by 3.6 and 3.7, respectively; the latency of MEP on the non-lesion side was shortened by 2.6 ms, and all had large effect sizes (Cohen’s w ≥ 0.5). (4) Conclusions: The BCI system with visual and motor feedback is applicable in active rehabilitation training of stroke patients with hemiplegia, and the pilot results show potential multidimensional benefits after a short course of treatment.
Objective Detection of Tinnitus Based on Electrophysiology
Authors: Fan Shuwen , Li Shufeng
Published: August 2022

Tinnitus, a common disease in the clinic, is associated with persistent pain and high costs to society. Several aspects of tinnitus, such as the pathophysiology mechanism, effective treatment, objective detection, etc., have not been elucidated. Any change in the auditory pathway can lead to tinnitus. At present, there is no clear and unified mechanism to explain tinnitus, and the hypotheses regarding its mechanism include auditory plasticity theory, cortical reorganization theory, dorsal cochlear nucleus hypothesis, etc. Current theories on the mechanism of tinnitus mainly focus on the abnormal activity of the central nervous system. Unfortunately, there is currently a lack of objective diagnostic methods for tinnitus. Developing a method that can detect tinnitus objectively is crucial, only in this way can we identify whether the patient really suffers from tinnitus in the case of cognitive impairment or medical disputes and the therapeutic effect of tinnitus. Electrophysiological investigations have prompted the development of an objective detection of tinnitus by potentials recorded in the auditory pathway. However, there is no objective indicator with sufficient sensitivity and specificity to diagnose tinnitus at present. Based on recent findings of studies with various methods, possible electrophysiological approaches to detect the presence of tinnitus have been summarized. We analyze the change of neural activity throughout the auditory pathway in tinnitus subjects and in patients with tinnitus of varying severity to find available parameters in these methods, which is helpful to further explore the feasibility of using electrophysiological methods for the objective detection of tinnitus.
Clinical Outcomes of Adults with Systemic Mastocytosis: A 15-Year Multidisciplinary Experience
Authors: Ungerstedt Johanna , Ljung Christopher , Klimkowska Monika , Gülen Theo
Published: August 2022

Systemic mastocytosis (SM) is a rare, clonal, clinically heterogeneous disorder of the mast cells (MCs), and mainly affects adults. The present study aims to describe the clinical and laboratory features as well as the outcomes of SM. A 15-year retrospective study was conducted on 195 consecutive SM patients (aged ≥ 18 years) diagnosed in 2006–2020 at the Multidisciplinary Mastocytosis Center at Karolinska University Hospital. Patients with indolent SM (ISM) represented the most common SM variant (88.2%). Furthermore, the frequencies of aggressive SM and SM with associated non-mast-cell hematological neoplasm were 4.1% and 7.7%, respectively. The prevalence of SM in the adult population of the Stockholm region was estimated to be 10.6/100,000 inhabitants, and the mean incidence of SM cases in the Stockholm region was 0.77/100,000 people per year. In this series, tryptase levels were below 20 ng/mL in 51 patients (26%). Osteoporosis was present in 21.9% of all cases. Interestingly, there was no progression from ISM to advanced SM variants in our study. Furthermore, overall survival was significantly better in ISM patients compared to advanced SM patients (p < 0.0001). Our data suggest that the early recognition and correct diagnosis of SM has prognostic significance.
A Simultaneous Multiparametric 18F-FDG PET/MRI Radiomics Model for the Diagnosis of Triple Negative Breast Cancer
Authors: Romeo Valeria , Kapetas Panagiotis , Clauser Paola , Baltzer Pascal A. T. , Rasul Sazan , Gibbs Peter , Hacker Marcus , Woitek Ramona , Pinker Katja , Helbich Thomas H.
Published: August 2022

Purpose: To investigate whether a machine learning (ML)-based radiomics model applied to 18F-FDG PET/MRI is effective in molecular subtyping of breast cancer (BC) and specifically in discriminating triple negative (TN) from other molecular subtypes of BC. Methods: Eighty-six patients with 98 BC lesions (Luminal A = 10, Luminal B = 51, HER2+ = 12, TN = 25) were included and underwent simultaneous 18F-FDG PET/MRI of the breast. A 3D segmentation of BC lesion was performed on T2w, DCE, DWI and PET images. Quantitative diffusion and metabolic parameters were calculated and radiomics features extracted. Data were selected using the LASSO regression and used by a fine gaussian support vector machine (SVM) classifier with a 5-fold cross validation for identification of TNBC lesions. Results: Eight radiomics models were built based on different combinations of quantitative parameters and/or radiomic features. The best performance (AUROC 0.887, accuracy 82.8%, sensitivity 79.7%, specificity 86%, PPV 85.3%, NPV 80.8%) was found for the model combining first order, neighborhood gray level dependence matrix and size zone matrix-based radiomics features extracted from ADC and PET images. Conclusion: A ML-based radiomics model applied to 18F-FDG PET/MRI is able to non-invasively discriminate TNBC lesions from other BC molecular subtypes with high accuracy. In a future perspective, a “virtual biopsy” might be performed with radiomics signatures.
Clinical Outcome and Prognostic Factors of Pancreatic Adenosquamous Carcinoma Compared to Ductal Adenocarcinoma—Results from the German Cancer Registry Group
Authors: Braun Rüdiger , Klinkhammer-Schalke Monika , Zeissig Sylke Ruth , Kleihus van Tol Kees , Bolm Louisa , Honselmann Kim C. , Petrova Ekaterina , Lapshyn Hryhoriy , Deichmann Steffen , Abdalla Thaer S. A. , Heckelmann Benjamin , Bronsert Peter , Zemskov Sergii , Hummel Richard , Keck Tobias , Wellner Ulrich F.
Published: August 2022

Background: Adenosquamous carcinoma of the pancreas (ASCP) is a rare malignancy and its pathophysiology is poorly understood. Sparse clinical data suggest that clinical outcome and overall survival is worse in comparison to common pancreatic ductal adenocarcinoma (PDAC). Methods: We evaluated clinical outcome and prognostic factors for overall survival of patients with ASCP in comparison to patients with PDAC recorded between 2000 and 2019 in 17 population-based clinical cancer registries at certified cancer centers within the Association of German Tumor Centers (ADT). Results: We identified 278 (0.5%) patients with ASCP in the entire cohort of 52,518 patients with pancreatic cancer. Significantly, more patients underwent surgical resection in the cohort of ASCP patients in comparison to patients with PDAC (p < 0.001). In the cohort of 142 surgically resected patients with ASCP, the majority of patients was treated by pancreatoduodenectomy (44.4%). However, compared to the cohort of PDAC patients, significantly more patients underwent distal pancreatectomy (p < 0.001), suggesting that a significantly higher proportion of ASCP tumors was located in the pancreatic body/tail. ASCPs were significantly more often poorly differentiated (G3) (p < 0.001) and blood vessel invasion (V1) was detected more frequently (p = 0.01) in comparison with PDAC. Median overall survival was 6.13 months (95% CI 5.20–7.06) for ASCP and 8.10 months (95% CI 7.93–8.22) for PDAC patients, respectively (p = 0.094). However, when comparing only those patients who underwent surgical resection, overall survival of ASCP patients was significantly shorter (11.80; 95% CI 8.20–15.40 months) compared to PDAC patients (16.17; 95% CI 15.78–16.55 months) (p = 0.007). ASCP was a highly significant prognostic factor for overall survival in univariable regression analysis (p = 0.007) as well as in multivariable Cox regression analysis (HR 1.303; 95% CI 1.013–1.677; p = 0.039). Conclusions: In conclusion, ASCP showed poorer differentiation and higher frequency of blood vessel invasion indicative of a more aggressive tumor biology. ASCP was a significant prognostic factor for overall survival in a multivariable analysis. Overall survival of resected ASCP patients was significantly shorter compared to resected PDAC patients. However, surgical resection still improved survival significantly.
Multidisciplinary Tumor Board in the Management of Patients with Colorectal Liver Metastases: A Single-Center Review of 847 Patients
Authors: Milana Flavio , Famularo Simone , Luberto Antonio , Rimassa Lorenza , Scorsetti Marta , Comito Tiziana , Pressiani Tiziana , Franzese Ciro , Poretti Dario , Di Tommaso Luca , Personeni Nicola , Rodari Marcello , Pedicini Vittorio , Donadon Matteo , Torzilli Guido
Published: August 2022

There is still debate over how reviewing oncological histories and addressing appropriate therapies in multidisciplinary team (MDT) discussions may affect patients’ overall survival (OS). The aim of this study was to describe MDT outcomes for a single cancer center’s patients affected by colorectal liver metastases (CRLMs). From 2010 to 2020, a total of 847 patients with CRLMs were discussed at our weekly MDT meeting. Patients’ characteristics and MDT decisions were analyzed in two groups: patients receiving systemic therapy (ST) versus patients receiving locoregional treatment (LRT). Propensity-score matching (PSM) was run to reduce the risk of selection bias. The median time from MDT indication to treatment was 27 (IQR 13–51) days. The median OS was 30 (95%CI = 27–34) months. After PSM, OS for patients undergoing LRT was 51 (95%CI = 36–64) months compared with 15 (95%CI = 13–20) months for ST patients (p < 0.0001). In this large retrospective study, the MDT discussions were useful in providing the patients with all available locoregional options.
Efficacy and Safety of Amrubicin in Small Cell Carcinoma Previously Treated with Immune Checkpoint Inhibitors and Chemotherapy
Authors: Nishimura Tadashi , Fujimoto Hajime , Fujiwara Takumi , Ito Kentaro , Fujiwara Atsushi , Yuda Hisamichi , Itani Hidetoshi , Naito Masahiro , Kodama Shuji , Yagi Akihiko , D’Alessandro Valeria Fridman , Yasuma Taro , Furuhashi Kazuki , Saiki Haruko , Okano Tomohito , Tomaru Atsushi , Tanigawa Motoaki , D’Alessandro-Gabazza Corina N. , Gabazza Esteban C. , Yoshida Masamichi , Hataji Osamu , Ibata Hidenori , Kobayashi Tetsu
Published: August 2022

Adding an immune checkpoint inhibitor to chemotherapy to treat extensive-stage small cell lung cancer is effective. However, there are no reports of an effective second-line treatment in patients previously treated with chemotherapy and immune checkpoint inhibitors as a first-line treatment. Here, we assessed the efficacy and safety of amrubicin as a second-line treatment for extensive-stage small cell lung cancer after chemotherapy and immune checkpoint inhibitor combination therapy. The study enrolled 150 patients with extensive-stage small cell lung cancer. The efficacy and the incidence of adverse events were compared between patients previously treated with immune checkpoint inhibitors and patients without previous immune checkpoint inhibitor treatment. One hundred and twenty-three patients were eligible. There was no difference in objective response rate, time-to-treatment failure, progression-free survival, and overall survival between both groups. The incidence of adverse events was similar in both treatment groups. Pretreatment with immune checkpoint inhibitors was not associated with an increase in amrubicin-related adverse events. This study shows that the efficacy of amrubicin in extensive-stage small cell lung cancer remains unchanged irrespective of previous treatment with immune checkpoint inhibitors. Amrubicin-related adverse events did not increase in patients previously treated with immune checkpoint inhibitors.
Combined Liquid Biopsy Methylation Analysis of CADM1 and MAL in Cervical Cancer Patients
Authors: Leffers Markus , Herbst Johanna , Kropidlowski Jolanthe , Prieske Katharina , Bohnen Anna Lena , Peine Sven , Jaeger Anna , Oliveira-Ferrer Leticia , Goy Yvonne , Schmalfeldt Barbara , Pantel Klaus , Wölber Linn , Effenberger Katharina , Wikman Harriet
Published: August 2022

Cervical cancer is the fourth most common cancer in women, which is associated in >95% with a high-risk human papillomavirus (HPV) infection. Methylation of specific genes has been closely associated with the progress of cervical high-grade dysplastic lesions to invasive carcinomas. Therefore, DNA methylation has been proposed as a triage for women infected with high-risk HPV. Methylation analyses of cervical cancer tissue have shown that cell adhesion molecule 1 (CADM1) and myelin and lymphocyte protein (MAL) methylation are present in over 90% of all cervical high-grade neoplasias and invasive cervical cancers. Here, we established a liquid biopsy-based assay to detect MAL and CADM1 methylation in cell free (cf)DNA of cervical cancer. Methylation of the target gene was validated on bisulfite converted smear-DNA from cervical dysplasia patients and afterward applied to cfDNA using quantitative real-time PCR. In 52 smears, a combined analysis of CADM1 and/or MAL (CADM1/MAL) showed methylation in 86.5% of the cases. In cfDNA samples of 24 cervical cancer patients, CADM1/MAL methylation was detected in 83.3% of the cases. CADM1/MAL methylation was detected already in 81.8% of stage I-II patients showing the high sensitivity of this liquid biopsy assay. In combination with a specificity of 95.5% towards healthy donors (HD) and an area under the curve (AUC) of 0.872 in the receiver operating characteristic (ROC) analysis, CADM1/MAL cfDNA methylation detection might represent a novel and promising liquid biopsy marker in cervical cancer.
Survival after Multimodal Treatment Including Surgery for Metastatic Esophageal Cancer: A Systematic Review
Authors: Bardol Thomas , Ferre Lorenzo , Aouinti Safa , Dupuy Marie , Assenat Eric , Fabre Jean-Michel , Picot Marie-Christine , Souche Regis
Published: August 2022

(1) Background: The management of metastatic esophageal cancer is more often limited to palliative chemotherapy. Limited data are available regarding the role of surgery that remains controversial. The aim of this systematic review is to assess the survival outcome of surgically treated metastatic esophageal cancer patients. (2) Methods: The present systematic review is designed using the PRISMA guidelines and has been registered with PROSPERO (CRD42019140306). Two reviewers independently searched and identified studies dealing with surgery for stage IV esophageal cancer in the Medline and Google Scholar databases between January 2008 and December 2019. (3) Results: Seven retrospective nonrandomized studies, totaling 1756 patients with stage IV esophageal cancer who underwent curative surgery, were included. Our analysis demonstrates a three-year overall survival rate of 23% (CI 95% 17–31) among patients undergoing surgery. Because only two comparative studies were identified, data compilation and relative risk evaluation through meta-analysis were not possible. (4) Conclusions: Multimodality treatment, including surgery in curative intent, seems associated with a significant chance of three-year overall survival. A prospective evaluation of this approach and validation of adequate selection criteria are needed.
Glycine Substitution of Residues with Unfavored Dihedral Angles Improves Protein Thermostability
Authors: Lu Zhili , Zhong Qiaoxian , Li Jingxian , Zhou Bingjie , Xing Yan-Ni , Liu Kaien , Cao Kexin , Lan Dongming , Zhou Teng , Wang Yonghua , Wang Jiaqi
Published: August 2022

Single mutations that can substantially enhance stability are highly desirable for protein engineering. However, it is generally rare for this kind of mutant to emerge from directed evolution experiments. This study used computational approaches to identify hotspots in a diacylglycerol-specific lipase for mutagenesis with functional hotspot and sequence consensus strategies, followed by ∆∆G calculations for all possible mutations using the Rosetta ddg_monomer protocol. Single mutants with significant ∆∆G changes (≤−2.5 kcal/mol) were selected for expression and characterization. Three out of seven tested mutants showed a significantly enhanced thermostability, with Q282W and A292G in the catalytic pocket and D245G located on the opposite surface of the protein. Remarkably, A292G increased the T5015 (the temperature at which 50% of the enzyme activity was lost after a 15 min of incubation) by ~7 °C, concomitant with a twofold increase in enzymatic activity at the optimal reaction temperature. Structural analysis showed that both A292 and D245 adopted unfavored dihedral angles in the wild-type (WT) enzyme. Substitution of them by glycine might release a steric strain to increase the stability. In sum, substitution by glycine might be a promising strategy to improve protein thermostability.
An Efficient Zr-ZSM-5-st Solid Acid Catalyst for the Polyol Esterification Reaction
Authors: Su Huaigang , Zong Ze , Lou Wenjing , Zhao Qin , Wang Xiaobo , Feng Xiang , Qi Yanxing , Song Zhaoning
Published: August 2022

In this study, Zr active species were implanted into a ZSM-5 zeolite framework to form a solid acid catalyst through steam treatment and the liquid-solid isomorphous substitution process. The as-synthesized Zr-ZSM-5-st catalyst ensured excellent esterification of trimethylolpropane and fatty acids (FAs) to achieve a polyol ester production yield of 94.41%. Combined with N2 physisorption, X-ray diffraction, Fourier transform infrared spectroscopy, ultraviolet-visible spectroscopy, transmission electron microscopy mapping, X-ray photoelectron spectroscopy, NH3 temperature-programmed desorption, and inductively coupled mass plasma spectroscopy were conducted. The results revealed that the excellent performance of Zr-ZSM-5-st catalyst could be attributed to the enhanced acidity and the developed surface area and pore structure.
Site and Structural Requirements for the Dehydra-Decyclization of Cyclic Ethers on ZrO2
Authors: Fan Mengjie , Ji Yichen , Lawal Ajibola , Abdelrahman Omar A. , Gorte Raymond J. , Vohs John M.
Published: August 2022

In this study, we examined the site and structural requirements for the dehydra-decyclization of cyclic ethers, tetrahydrofuran, and tetrahydropyran to produce conjugated dienes over ZrO2-based catalysts, a reaction that could be an important step in the use of biomass-derived sugars as a starting material to produce monomers for the plastics industry. To help identify the active sites for this reaction, studies were conducted in which ZrO2 surfaces were decorated with Na. These studies showed that Na was effective at poisoning the activity for the ring opening of cyclic ethers, but much less so for the dehydration of the resulting adsorbed alkoxides. The studies of the activity of different types of ZrO2 for the dehydra-decyclization reaction, including single crystals and ultra-thin films supported on MgAl2O4 and silica, also showed that the reaction was dependent on the local structure of the ZrO2 surface. The insights these results provide for identifying the active sites on the ZrO2 surface are discussed.