bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell-Based Target Localization and Tracking with an Active Camera
Authors: You Ji’an , Hu Zhaozheng , Xiao Hanbiao , Xu Cong
Published: March 2022

This paper proposes a new method of target localization and tracking. The method consists of four parts. The first part is to divide the scene into multiple cells based on the camera’s parameters and calibrate the position and error of each vertex. The second part mainly uses the bounding box detection algorithm, YOLOv4, based on deep learning to detect and recognize the scene image sequence and obtain the type, length, width, and position of the target to be tracked. The third part is to match each vertex of the cell in the image and the cell in the scene, generate a homography matrix, and then use the PnP model to calculate the precise world coordinates of the target in the image. In this process, a cell-based accuracy positioning method is proposed for the first time. The fourth part uses the proposed PTH model to convert the obtained world coordinates into P, T, and H values for the purpose of actively tracking and observing the target in the scene with a PTZ camera. The proposed method achieved precise target positioning and tracking in a 50 cm ∗ 250 cm horizontal channel and a vertical channel. The experimental results show that the method can accurately identify the target to be tracked in the scene, can actively track the moving target in the observation scene, and can obtain a clear image and accurate trajectory of the target. It is verified that the maximum positioning error of the proposed cell-based positioning method is 2.31 cm, and the average positioning error is 1.245 cm. The maximum error of the proposed tracking method based on the PTZ camera is 1.78 degrees, and the average error is 0.656 degrees.
Arc Modeling and Kurtosis Detection of Fault with Arc in Power Distribution Networks
Authors: Hyun Seung-Yoon , Hong Ji-Song , Yun Sang-Yun , Kim Chang-Hwan , Lee Youngwoo
Published: March 2022

In power distribution networks, there are many practical fault cases such as high impedance faults, faults and so on. Especially when the faults with electric arc persist, it is dangerous for human beings and circumstances. Nevertheless, it is difficult to classify faults due to various customer load conditions or the presence of distributed energy resources. In this paper, we propose a new mathematical arc model based on experimental event data. For implementing the arc phenomenon, wet gravel was used as a contact conductor after the fault. The experimental results validate the arc transient model. Then, the simulations were performed to verify the success of arc modeling using Kizilcay’s arc model as a comparison method. Finally, we developed a fault detector using the kurtosis detection method, and power system simulations were conducted to evaluate fault detection performance using Matlab/Simulink.
On Scaled Normal Stresses in Multiaxial Fatigue and Their Exemplary Application to Ductile Cast Iron
Authors: Wächter Michael , Linn Alexander , Wuthenow Ralf , Esderts Alfons , Gaier Christian , Kraft Jan , Fällgren Carl , Vormwald Michael
Published: March 2022

The approaches used to calculate the fatigue life of components must inevitably consider multiaxial stresses. Compared to proportional loading, the calculation of nonproportional loading is particularly challenging, especially since different materials exhibit the effects of nonproportional hardening and shifts in fatigue life. In this paper, the critical plane approach of scaled normal stresses, first proposed by Gaier and Dannbauer and later published in a modified version by Riess et al., is investigated in detail. It is shown that, on the one hand, compatibilities exist or can be established with known proportional strength criteria that can account for the varying ductility of different materials. Furthermore, it is demonstrated that the scaled normal stress approach can be formulated in such a way that different strength criteria can be used therein. As an example, the generally formulated approach for scaled normal stresses is applied to test results from ductile cast iron material EN-GJS-500-14. Different correction factors accounting for nonproportional loading are investigated. Through appropriate parameterization of one of the studied corrections, proportional and nonproportional test results were observed to fall within one common scatter band.
Impact of Meteorological Uncertainties in the Methane Retrieval Ground Segment of the MERLIN Lidar Mission
Authors: Cassé Vincent , Chomette Olivier , Crevoisier Cyril , Gibert Fabien , Brožková Radmila , El Khatib Ryad , Nahan Frédéric
Published: March 2022

MERLIN (MEthane Remote sensing LIdar missioN) is a Franco-German space mission designed to provide weighted columns of atmospheric methane through an inversion of the lidar signal using a priori information on the atmospheric state. Uncertainties about the meteorological parameters of the observed scene used in the ground segment contribute to the error budget on the retrieved methane column. With the LIDSIM (LIDar SIMulator) data simulator and the PROLID (PROcessor LIDar) inversion processor developed for MERLIN, we perform an impact experiment using ECMWF (European Centre for Medium Weather Range Forecast) ensemble forecast data. In addition, we estimate the standard deviation of the error in the methane column due to the meteorological uncertainties to be about 0.6 ppb. In addition, we innovate by discussing the impact of interpolations both in time and space, focusing on vertical extrapolations under the topography by using state-of-the-art methods to determine from the scatter between these methods the range in which the actual profile should be. We conclude that, in areas where the topography variations exceed 10 m over 10 km, an additional random error of 0.1 ppb is due to our lack of knowledge of the adjustment of atmospheric profiles to terrain. Finally, we point out that further work needs to be performed on temporal interpolation. Indeed, the 3 h time interpolation of atmospheric tides can create regional biases of up to 2 ppm (which is a major problem for models trying to identify methane sinks and sources).
Review of Ground-Level Ozone Impact in Respiratory Health Deterioration for the Past Two Decades
Authors: Soares Angelo Roldão , Silva Carla
Published: March 2022

Background: Ground-level ozone has been gaining notoriety with increasing evidence of its nefarious effects on health, especially respiratory diseases. Where do we stand on the solidity of this data and is there room for improvement? Objectives: Evaluate this evidence for incongruities or heterogeneity in this field of research. How is the exposure assessment conducted, where does Portugal stand in this field, and what can be improved? Health deterioration concerning asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS) are analysed. Methods: A review of 1735 studies was conducted through PubMed and Google Scholar engines for the past two decades. We identified 59 eligible studies and included an array of variables, including O3 measurements, number of air-quality monitoring stations used, relative risks, odds ratios, hazard ratios, number of hospital admissions, visits, or mortality, and size of population dataset used. Results: Approximately 83% of data in this review presents significant correlations of ozone with asthma, COPD, and ARDS. Studies that report negative or not significant associations mention a lack of data or topographic differences as the main issue with these divergent results. Studies consistently report summer as a period of particular concern. Portuguese data in this field is lacking. Conclusions: This research field is growing in interest and there is evidence that ozone plays a non-negligible role in health deterioration. The few Portuguese studies in this field seem aligned with the literature reviewed but more research is needed. Suggested improvements are more and better data through denser air-quality networks to accurately depict personal exposure to ozone. Homogenization of the exposure assessment concerning averaging times of ozone to daily maximum 8 h averages whenever possible. Risk increments based on 10 ppb instead of interquartile ranges. Lastly, contrary to some studies in this review, the topographic effect on concentrations and health deterioration should not be underestimated and seasonality should always be checked.
Does Below-Above Canopy Air Mass Decoupling Impact Temperate Floodplain Forest CO2 Exchange?
Authors: Kowalska Natalia , Jocher Georg , Šigut Ladislav , Pavelka Marian
Published: March 2022

Environmental conditions influence forest ecosystems and consequently, its productivity. Thus, the quantification of forest CO2 exchange is a critical requirement to estimate the CO2 balance of forests on a local and regional scale. Besides interpreting the annual CO2 exchange corresponding to environmental conditions over the studied years (2015–2020) at the floodplain forest in Lanžhot, Czech Republic (48.6815483 N, 16.9463317 E), the influence of below-above canopy air mass decoupling on above canopy derived CO2 exchange is the focus of this study. For this purpose, we applied the eddy covariance (EC) method above and below the forest canopy, assessing different single- and two-level flux filtering strategies. We focused on one example year (2019) of concurrent below and above canopy EC measurements. We hypothesized that conventional single-level EC flux filtering strategies such as the friction velocity (u*) filtering approach might not be sufficient to fully capture the forest CO2 exchange at the studied ecosystem. Results suggest that decoupling occurs regularly, but the implication on the above canopy derived EC CO2 fluxes appears to be negligible on an annual scale. We attribute this to the open canopy and flat EC tower surrounding terrain which inhibits horizontal removal of below-canopy respired CO2.
Magnetic Nanoparticles as a Component of Peptide-Based DNA Delivery System for Suicide Gene Therapy of Uterine Leiomyoma
Authors: Shtykalova Sofia , Egorova Anna , Maretina Marianna , Baranov Vladislav , Kiselev Anton
Published: March 2022

Suicidegene therapy is considered a promising approach for the treatment of uterine leiomyoma (UL), a benign tumor in women characterized by precise localization. In this study, we investigate the efficiency of αvβ3 integrin-targeted arginine-rich peptide carrier R6p-cRGD electrostatically bound to magnetic nanoparticles (MNPs) for targeted DNA delivery into the UL cells. The physico–chemical and cytotoxic properties, transfection efficiency, and specificity of R6p-cRGD/DNA/MNPs polyplexes were evaluated. The addition of MNPs resulted in a decrease in the time needed for successful transfection with simultaneous increase in efficiency. We revealed a therapeutic effect on primary UL cells after delivery of plasmid encoding the herpes simplex virus type 1 (HSV-1) thymidine kinase gene. Treatment with ganciclovir resulted in 20% efficiency of suicide gene therapy in UL cells transfected with the pPTK-1 plasmid. Based on these results, we conclude that the use of cationic peptide carriers with MNPs can be promising for the development of modular non-viral carriers for suicide gene delivery to UL cells.
How Do Hexokinases Inhibit Receptor-Mediated Apoptosis?
Authors: Schoeniger Axel , Wolf Philipp , Edlich Frank
Published: March 2022

The regulated cell death apoptosis enables redundant or compromised cells in ontogeny and homeostasis to remove themselves receptor-dependent after extrinsic signaling or after internal stress by BCL-2 proteins on the outer mitochondrial membrane (OMM). Mitochondrial BCL-2 proteins are also often needed for receptor-mediated signaling in apoptosis. Then, the truncated BH3-only protein BID (tBID) blocks retrotranslocation of the pro-apoptotic BCL-2 proteins BAX and BAK from the mitochondria into the cytosol. BAX and BAK in turn permeabilize the OMM. Although the BCL-2 proteins are controlled by a complex regulatory network, a specific mechanism for the inhibition of tBID remained unknown. Curiously, it was suggested that hexokinases, which channel glucose into the metabolism, have an intriguing function in the regulation of apoptosis. Recent analysis of transient hexokinase interactions with BAX revealed its participation in the inhibition of BAX and also BAK by retrotranslocation from mitochondria to the cytosol. In contrast to general apoptosis inhibition by anti-apoptotic BCL-2 proteins, hexokinase I and hexokinase 2 specifically inhibit tBID and thus the mitochondrial apoptosis pathway in response to death receptor signaling. Mitochondrial hexokinase localization and BH3 binding of cytosolic hexokinase domains are prerequisites for protection against receptor-mediated cell death, whereas glucose metabolism is not. This mechanism protects cells from apoptosis induced by cytotoxic T cells.
Adenosine-Metabolizing Enzymes, Adenosine Kinase and Adenosine Deaminase, in Cancer
Authors: Zhulai Galina , Oleinik Eugenia , Shibaev Mikhail , Ignatev Kirill
Published: March 2022

The immunosuppressive effect of adenosine in the microenvironment of a tumor is well established. Presently, researchers are developing approaches in immune therapy that target inhibition of adenosine or its signaling such as CD39 or CD73 inhibiting antibodies or adenosine A2A receptor antagonists. However, numerous enzymatic pathways that control ATP-adenosine balance, as well as understudied intracellular adenosine regulation, can prevent successful immunotherapy. This review contains the latest data on two adenosine-lowering enzymes: adenosine kinase (ADK) and adenosine deaminase (ADA). ADK deletes adenosine by its phosphorylation into 5′-adenosine monophosphate. Recent studies have revealed an association between a long nuclear ADK isoform and an increase in global DNA methylation, which explains epigenetic receptor-independent role of adenosine. ADA regulates the level of adenosine by converting it to inosine. The changes in the activity of ADA are detected in patients with various cancer types. The article focuses on the biological significance of these enzymes and their roles in the development of cancer. Perspectives of future studies on these enzymes in therapy for cancer are discussed.
MiRNAs in Systemic Sclerosis Patients with Pulmonary Arterial Hypertension: Markers and Effectors
Authors: Zaaroor Levy Mor , Rabinowicz Noa , Yamila Kohon Maia , Shalom Avshalom , Berl Ariel , Hornik-Lurie Tzipi , Drucker Liat , Tartakover Matalon Shelly , Levy Yair
Published: March 2022

Background: Pulmonary arterial hypertension (PAH) is a major cause of death in systemic sclerosis (SSc). Early detection may improve patient outcomes. Methods: We searched for circulating miRNAs that would constitute biomarkers in SSc patients with PAH (SSc-PAH). We compared miRNA levels and laboratory parameters while evaluating miRNA levels in white blood cells (WBCs) and myofibroblasts. Results: Our study found: 1) miR-26 and miR-let-7d levels were significantly lower in SSc-PAH (n = 12) versus SSc without PAH (SSc-noPAH) patients (n = 25); 2) a positive correlation between miR-26 and miR-let-7d and complement-C3; 3) GO-annotations of genes that are miR-26/miR-let-7d targets and that are expressed in myofibroblast cells, suggesting that these miRNAs regulate the TGF-β-pathway; 4) reduced levels of both miRNAs accompanied fibroblast differentiation to myofibroblasts, while macitentan (endothelin receptor-antagonist) increased the levels. WBCs of SSc-noPAH and SSc-PAH patients contained equal amounts of miR-26/miR-let-7d. During the study, an echocardiograph that predicted PAH development, showed increased pulmonary artery pressure in three SSc-noPAH patients. At study initiation, those patients and an additional SSc-noPAH patient, who eventually developed PAH, had miR-let-7d/miR-26 levels similar to those of SSc-PAH patients. This implies that reduced miR-let-7d/miR-26 levels might be an early indication of PAH. Conclusions: miR-26 and miR-let-7d may be serological markers for SSc-PAH. The results of our study suggest their involvement in myofibroblast differentiation and complement pathway activation, both of which are active in PAH development.
Post-Earthquake Assessment of a Historical Masonry Building after the Zagreb Earthquake—Case Study
Authors: Hafner Ivan , Lazarević Damir , Kišiček Tomislav , Stepinac Mislav
Published: March 2022

After the Zagreb earthquakes in March 2020, around 25,000 buildings were estimated damaged, most of them being in the historic city center. This fact is not that surprising since most of the city center buildings are unreinforced masonry structures that have not been assessed in quite some time and usually no retrofitting methods were ever applied. The rapid post-disaster assessment began the same day after the first earthquake occurred. Through mostly visual assessment methods, the basic idea is to identify the safety and usability of buildings in general. This type of assessment was also conducted in one of the oldest Croatian cultural institutions, Matica Hrvatska. It is a building of great historical significance and cultural value, as is most of the city center. Accordingly, this building was constructed with no consideration given to seismic events and with the use of traditional materials and building techniques. In the scope of this paper, urgent actions that were taken are shown with problems and challenges that occurred. Furthermore, the decision-making process after an earthquake is elaborated. In addition, a numerical model is developed in 3Muri software for structural modeling. A non-linear static pushover analysis is performed, and possible failure mechanisms are examined. Furthermore, real-life damage is compared to the software results, and a conclusion process of the building’s usability is explained. In the end, the results obtained are analyzed and conclusions regarding the efficiency of the used software are drawn.
The Continuum of Metastatic Prostate Cancer: Interpreting PSMA PET Findings in Recurrent Prostate Cancer
Authors: Kase Adam M. , Tan Winston , Copland John A. , Cai Hancheng , Parent Ephraim E. , Madan Ravi A.
Published: March 2022

Conventional imaging has been the standard imaging modality for assessing prostate cancer recurrence and is utilized to determine treatment response to therapy. Molecular imaging with PSMA PET–CT has proven to be more accurate, sensitive, and specific at identifying pelvic or distant metastatic disease, resulting in earlier diagnosis of advanced disease. Since advanced disease may not be seen on conventional imaging, due to its lower sensitivity, but can be identified by molecular imaging, this reveals that metastatic prostate cancer occurs on a continuum from negative PSMA PET–CT and negative conventional imaging to positive PSMA PET–CT and positive conventional imaging. Understanding this continuum, the accuracy of these modalities, and treatment related outcomes based on imaging, will allow the clinician to counsel patients on management. This review will highlight the differences in conventional and molecular imaging in prostate cancer and how PSMA PET–CT can be used for the management of prostate cancer patients in different clinical scenarios, while providing cautionary notes for overtreatment.
Targetable Pathways in the Treatment of Retroperitoneal Liposarcoma
Authors: Casadei Lucia , de Faria Fernanda Costas Casal , Lopez-Aguiar Alexandra , Pollock Raphael E. , Grignol Valerie
Published: March 2022

Liposarcoma (LPS) is the most prevalent soft tissue sarcoma histological subtype. When it occurs in the abdomen the overall survival rate is as low as 10% at 10 years and is fraught with high rates of recurrence, particularly for the more aggressive dedifferentiated subtype. Surgery remains the mainstay of treatment. Systemic therapies for the treatment of metastatic or unresectable disease have low response rates. Deep understanding of well-differentiated and de-differentiated LPS (WDLPS and DDLPS, respectively) oncologic drivers is necessary for the development of new efficacious targeted therapies for the management of this disease. This review discusses the current treatments under evaluation for retroperitoneal DDLPS and the potential targetable pathways in DDLPS.
Thymoquinone Radiosensitizes Human Colorectal Cancer Cells in 2D and 3D Culture Models
Authors: Al Bitar Samar , Ballout Farah , Monzer Alissar , Kanso Mariam , Saheb Nour , Mukherji Deborah , Faraj Walid , Tawil Ayman , Doughan Samer , Hussein Maher , Abou-Kheir Wassim , Gali-Muhtasib Hala
Published: March 2022

Resistance of cancer cells and normal tissue toxicity of ionizing radiation (IR) are known to limit the success of radiotherapy. There is growing interest in using IR with natural compounds to sensitize cancer cells and spare healthy tissues. Thymoquinone (TQ) was shown to radiosensitize several cancers, yet no studies have investigated its radiosensitizing effects on colorectal cancer (CRC). Here, we combined TQ with IR and determined its effects in two-dimensional (2D) and three-dimensional (3D) culture models derived from HCT116 and HT29 CRC cells, and in patient-derived organoids (PDOs). TQ sensitized CRC cells to IR and reduced cell viability and clonogenic survival and was non-toxic to non-tumorigenic intestinal cells. TQ sensitizing effects were associated with G2/M arrest and DNA damage as well as changes in key signaling molecules involved in this process. Combining a low dose of TQ (3 µM) with IR (2 Gy) inhibited sphere formation by 100% at generation 5 and this was associated with inhibition of stemness and DNA repair. These doses also led to ~1.4- to ~3.4-fold decrease in organoid forming ability of PDOs. Our findings show that combining TQ and IR could be a promising therapeutic strategy for eradicating CRC cells.
Cytokine-Induced Senescence in the Tumor Microenvironment and Its Effects on Anti-Tumor Immune Responses
Authors: Rentschler Maximilian , Braumüller Heidi , Briquez Priscilla S. , Wieder Thomas
Published: March 2022

In contrast to surgical excision, chemotherapy or radiation therapy, immune checkpoint blockade therapies primarily influence cells in the tumor microenvironment, especially the tumor-associated lymphocytes and antigen-presenting cells. Besides complete remission of tumor lesions, in some patients, early tumor regression is followed by a consolidation phase where residing tumors remain dormant. Whereas the cytotoxic mechanisms of the regression phase (i.e., apoptosis, necrosis, necroptosis, and immune cell-mediated cell death) have been extensively described, the mechanisms underlying the dormant state are still a matter of debate. Here, we propose immune-mediated induction of senescence in cancers as one important player. Senescence can be achieved by tumor-associated antigen-specific T helper 1 cells, cytokines or antibodies targeting immune checkpoints. This concept differs from cytotoxic treatment, which often targets the genetic makeup of cancer cells. The immune system’s ability to establish “defensive walls” around tumors also places the tumor microenvironment into the fight against cancer. Those “defensive walls” isolate the tumor cells instead of increasing the selective pressure. They also keep the tumor cells in a non-proliferating state, thereby correcting the derailed tissue homeostasis. In conclusion, strengthening the senescence surveillance of tumors by the immune cells of the microenvironment is a future goal to dampen this life-threatening disease.
Substantial Sparing of Organs at Risk with Modern Proton Therapy in Lung Cancer, but Altered Breathing Patterns Can Jeopardize Target Coverage
Authors: Boer Camilla Grindeland , Fjellanger Kristine , Sandvik Inger Marie , Ugland Maren , Engeseth Grete May , Hysing Liv Bolstad
Published: March 2022

Enhancing treatment of locally advanced non-small cell lung cancer (LA-NSCLC) by using pencil beam scanning proton therapy (PBS-PT) is attractive, but little knowledge exists on the effects of uncertainties occurring between the planning (Plan) and the start of treatment (Start). In this prospective simulation study, we investigated the clinical potential for PBS-PT under the influence of such uncertainties. Imaging with 4DCT at Plan and Start was carried out for 15 patients that received state-of-the-art intensity-modulated radiotherapy (IMRT). Three PBS-PT plans were created per patient: 3D robust single-field uniform dose (SFUD), 3D robust intensity-modulated proton therapy (IMPT), and 4D robust IMPT (4DIMPT). These were exposed to setup and range uncertainties and breathing motion at Plan, and changes in breathing motion and anatomy at Start. Target coverage and dose-volume parameters relevant for toxicity were compared. The organ at risk sparing at Plan was greatest with IMPT, followed by 4DIMPT, SFUD and IMRT, and persisted at Start. All plans met the preset criteria for target robustness at Plan. At Start, three patients had a lack of CTV coverage with PBS-PT. In conclusion, the clinical potential for heart and lung toxicity reduction with PBS-PT was substantial and persistent. Altered breathing patterns between Plan and Start jeopardized target coverage for all PBS-PT techniques.
Health-Related Quality of Life in Adrenocortical Carcinoma: Development of the Disease-Specific Questionnaire ACC-QOL and Results from the PROFILES Registry
Authors: Steenaard Rebecca V. , Kerkhofs Thomas M. A. , Zijlstra Myrte , Mols Floortje , Kerstens Michiel N. , Timmers Henry J. L. M. , van Leeuwaarde Rachel S. , Dreijerink Koen M. A. , Eekhoff Elisabeth M. W. , Nieveen van Dijkum Els J. M. , Corssmit Eleonora P. M. , Kapiteijn Ellen , Kremers Marjolein N. T. , Feelders Richard A. , Haak Harm R.
Published: March 2022

We aimed to develop a disease-specific adrenocortical carcinoma (ACC) health-related quality of life (HRQoL) questionnaire (ACC-QOL) and assess HRQoL in a population-based cohort of patients with ACC. Development was in line with European Organization for Research and Treatment of Cancer (EORTC) guidelines, though not an EORTC product. In phase I and II, we identified 90 potential HRQoL issues using literature and focus groups, which were reduced to 39 by healthcare professionals. Pilot testing resulted in 28 questions, to be used alongside the EORTC QLQ-C30. In Phase III, 100 patients with ACC were asked to complete the questionnaires twice in the PROFILES registry (3-month interval, respondents: first 67, second 51). Confirmatory factor analysis demonstrated the structural validity of 26 questions with their scale structure (mitotane side-effects, hypercortisolism/hydrocortisone effects, emotional effects). Internal consistency and reliability were good (Cronbach’s alpha 0.897, Interclass correlation coefficient 0.860). Responsiveness analysis showed good discriminative ability (AUC 0.788). Patients diagnosed more than 5 years ago reported a good HRQoL compared with the Dutch reference population, but experienced residual fatigue and emotional problems. Patients who underwent recent treatment reported a lower HRQoL and problems in several domains. In conclusion, we developed an ACC-specific HRQoL questionnaire with good psychometric properties.
Circulating Tumor DNA Profiling of a Diffuse Large B Cell Lymphoma Patient with Secondary Acute Myeloid Leukemia
Authors: Kerle Irina A. , Jägerhuber Ludwig , Secci Ramona , Pfarr Nicole , Blüm Philipp , Roesch Romina , Götze Katharina S. , Weichert Wilko , Bassermann Florian , Ruland Jürgen , Winter Christof
Published: March 2022

Diffuse large B cell lymphomas (DLBCL) are the most common neoplasia of the lymphatic system. Circulating cell-free DNA released from tumor cells (ctDNA) has been studied in many tumor entities and successfully used to monitor treatment and follow up. Studies of ctDNA in DLBCL so far have mainly focused on tracking mutations in peripheral blood initially detected by next-generation sequencing (NGS) of tumor tissue from one lymphoma manifestation site. This approach, however, cannot capture the mutational heterogeneity of different tumor sites in its entirety. In this case report, we present repetitive targeted next-generation sequencing combined with digital PCR out of peripheral blood of a patient with DLBCL relapse. By combining both detection methods, we were able to detect a new dominant clone of ctDNA correlating with the development of secondary therapy-related acute myeloid leukemia (t-AML) during the course of observation. Conclusively, our case report reinforces the diagnostic importance of ctDNA in DLBCL as well as the importance of repeated ctDNA sequencing combined with focused digital PCR assays to display the dynamic mutational landscape during the clinical course.
The Role of Endoscopic Ultrasonography in the Diagnosis and Staging of Pancreatic Cancer
Authors: Zakaria Ali , Al-Share Bayan , Klapman Jason B. , Dam Aamir
Published: March 2022

Pancreatic cancer is the fourth leading cause of cancer-related death and the second gastrointestinal cancer-related death in the United States. Early detection and accurate diagnosis and staging of pancreatic cancer are paramount in guiding treatment plans, as surgical resection can provide the only potential cure for this disease. The overall prognosis of pancreatic cancer is poor even in patients with resectable disease. The 5-year survival after surgical resection is ~10% in node-positive disease compared to ~30% in node-negative disease. The advancement of imaging studies and the multidisciplinary approach involving radiologists, gastroenterologists, advanced endoscopists, medical, radiation, and surgical oncologists have a major impact on the management of pancreatic cancer. Endoscopic ultrasonography is essential in the diagnosis by obtaining tissue (FNA or FNB) and in the loco-regional staging of the disease. The advancement in EUS techniques has made this modality a critical adjunct in the management process of pancreatic cancer. In this review article, we provide an overall description of the role of endoscopic ultrasonography in the diagnosis and staging of pancreatic cancer.
Potential Metabolite Markers for Pancreatic Cancer Identified by Metabolomic Analysis of Induced Cancer-Associated Fibroblasts
Authors: Miyazaki Yoshihiro , Mori Nobuhito , Akagi Yuka , Oda Tatsuya , Kida Yasuyuki S.
Published: March 2022

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment perform glycolysis to produce energy, i.e., ATP. Since the origin of CAFs is unidentified, it is not determined whether the intracellular metabolism transitions from oxidative phosphorylation (OXPHOS) to glycolysis when normal tissue fibroblasts differentiate into CAFs. In this study, we established an experimental system and induced the in vitro differentiation of mesenchymal stem cells (MSCs) to CAFs. Additionally, we performed metabolomic and RNA-sequencing analyses before and after differentiation to investigate changes in the intracellular metabolism. Consequently, we discovered that OXPHOS, which was the primary intracellular metabolism in MSCs, was reprogrammed to glycolysis. Furthermore, we analyzed the metabolites in pancreatic tumor tissues in a mice model. The metabolites extracted as candidates in the in vitro experiments were also detected in the in vivo experiments. Thus, we conclude that normal tissue fibroblasts that differentiate into CAFs undergo a metabolic reprogramming from OXPHOS to glycolysis. Moreover, we identified the CAF-specific metabolites expressed during metabolic reprogramming as potential future biomarkers for pancreatic cancer.
Association of Low-Grade Glioma Diagnosis and Management Approach with Mental Health Disorders: A MarketScan Analysis 2005–2014
Authors: Bhanja Debarati , Ba Djibril , Tuohy Kyle , Wilding Hannah , Trifoi Mara , Padmanaban Varun , Liu Guodong , Sughrue Michael , Zacharia Brad , Leslie Douglas , Mansouri Alireza
Published: March 2022

Low-grade gliomas (LGGs) comprise 13–16% of glial tumors. As survival for LGG patients has been gradually improving, it is essential that the effects of diagnosis and disease progression on mental health be considered. This retrospective cohort study queried the IBM Watson Health MarketScan® Database to describe the incidence and prevalence of mental health disorders (MHDs) among LGG patients and identify associated risk factors. Among the 20,432 LGG patients identified, 12,436 (60.9%) had at least one MHD. Of those who never had a prior MHD, as documented in the claims record, 1915 (16.7%) had their first, newly diagnosed MHD within 12 months after LGG diagnosis. Patients who were female (odds ratio (OR), 1.14, 95% confidence intervals (CI), 1.03–1.26), aged 35–44 (OR, 1.20, 95% CI, 1.03–1.39), and experienced glioma-related seizures (OR, 2.19, 95% CI, 1.95–2.47) were significantly associated with MHD incidence. Patients who underwent resection (OR, 2.58, 95% CI, 2.19–3.04) or biopsy (OR, 2.17, 95% CI, 1.68–2.79) were also more likely to develop a MHD compared to patients who did not undergo a first-line surgical treatment. These data support the need for active surveillance, proactive counseling, and management of MHDs in patients with LGG. Impact of surgery on brain networks affecting mood should also be considered.
MET Exon 14 Splice-Site Mutations Preferentially Activate KRAS Signaling to Drive Tumourigenesis
Authors: Lu Daniel , Nagelberg Amy , Chow Justine LM , Chen Yankuan T , Michalchuk Quentin , Somwar Romel , Lockwood William W.
Published: March 2022

Targeted therapies for MET exon 14-skipping (METΔex14)-driven lung cancers have generated some promising results but response rates remain below that seen for other kinase-driven cancers. One strategy for improving treatment outcomes is to employ rational combination therapies to enhance the suppression of tumour growth and delay or prevent the emergence of resistance. To this end, we profiled the transcriptomes of MET-addicted lung tumours and cell lines and identified the RAS-mitogen-activated protein kinase (MAPK) pathway as a critical effector required for METΔex14-dependent growth. Ectopic expression of MET in an isogenic cell line model showed that overexpression of the mutant MET receptor led to higher levels of MAPK phosphorylation and nuclear import, resulting in increased expression and phosphorylation of nuclear MAPK targets. In comparison, other known MET effectors were unaffected. Inhibition of this pathway by KRAS knockdown in MET-addicted cells in vitro led to decreased viability in only the METΔex14-mutant cells. Conversely, decoupling RAS-MAPK axis, but not other effector pathways, from MET activity via the introduction of constitutively active mutants conferred resistance to MET inhibitors in vitro. Our results suggest that aberrant hyperactivity of the MET receptor caused by the exon 14-skipping mutation does not uniformly upregulate all known downstream effectors, rather gaining a predilection for aberrantly activating and subsequently relying on the RAS-MAPK pathway. These findings provide a rationale for the co-targeting of the RAS-MAPK pathway alongside MET to prolong therapeutic response and circumvent resistance to improve patient survival.
Study: International Multicentric Minimally Invasive Liver Resection for Colorectal Liver Metastases (SIMMILR-CRLM)
Authors: Gumbs Andrew A. , Lorenz Eric , Tsai Tzu-Jung , Starker Lee , Flanagan Joe , Benedetti Cacciaguerra Andrea , Yu Ng Jing , Bajul Melinda , Chouillard Elie , Croner Roland , Abu Hilal Mohammad
Published: March 2022

(1) Background: Here we report on a retrospective study of an international multicentric cohort after minimally invasive liver resection (SIMMILR) of colorectal liver metastases (CRLM) from six centers. (2) Methods: Resections were divided by the approach used: open liver resection (OLR), laparoscopic liver resection (LLR) and robotic liver resection (RLR). Patients with macrovascular invasion, more than three metastases measuring more than 3 cm or a solitary metastasis more than 5 cm were excluded, and any remaining heterogeneity found was further analyzed after propensity score matching (PSM) to decrease any potential bias. (3) Results: Prior to matching, 566 patients underwent OLR, 462 LLR and 36 RLR for CRLM. After PSM, 142 patients were in each group of the OLR vs. LLR group and 22 in the OLR vs. RLR and 21 in the LLR vs. RLR groups. Blood loss, hospital stay, and morbidity rates were all highly statistically significantly increased in the OLR compared to the LLR group, 636 mL vs. 353 mL, 9 vs. 5 days and 25% vs. 6%, respectively (p < 0.001). Only blood loss was significantly decreased when RLR was compared to OLR and LLR, 250 mL vs. 597 mL, and 224 mL vs. 778 mL, p < 0.008 and p < 0.04, respectively. (4) Conclusions: SIMMILR indicates that minimally invasive approaches for CRLM that follow the Milan criteria may have short term advantages. Notably, larger studies with long-term follow-up comparing robotic resections to both OLR and LLR are still needed.
Assessing the Acceptability of Home-Based HPV Self-Sampling: A Qualitative Study on Cervical Cancer Screening Conducted in Reunion Island Prior to the RESISTE Trial
Authors: Pourette Dolorès , Cripps Amber , Guerrien Margaux , Desprès Caroline , Opigez Eric , Bardou Marc , Dumont Alexandre
Published: March 2022

Cervical cancer incidence and mortality rates are 2 to 3 times higher in the overseas department of Reunion compared with mainland France. RESISTE’s cluster-randomized controlled trial aims to test the effectiveness of home-based self-sampling (HBSS) through a high-risk oncogenic papillomavirus test sent out by post to women who have not been screened in the past 3 years, despite having been invited to do so through a reminder letter. Prior to the trial, qualitative research was carried out to understand screening barriers and assess anticipated acceptability. Semi-structured interviews were conducted with 35 women and 20 healthcare providers. Providers consider HBSS a viable method in reaching women who tend not to visit a doctor regularly, or who are reluctant to undergo a smear pap, as well as those who are geographically isolated. They considered, however, that women would require support, and that outreach was necessary to ensure more socially isolated women participate. The majority of the women surveyed were in favour of HBSS. However, two-thirds voiced concerns regarding the test’s efficiency and their ability to perform the test correctly, without harming themselves. Based on these findings, recommendations were formulated to reassure women on usage and quality, and to help reach socially isolated women.
A Cell Double-Barcoding System for Quantitative Evaluation of Primary Tumors and Metastasis in Animals That Uncovers Clonal-Specific Anti-Cancer Drug Effects
Authors: Hesin Arkadi , Kumar Santosh , Gahramanov Valid , Becker Maria , Vilenchik Maria , Alexandrov Ilya , Yaglom Julia , Sherman Michael Y.
Published: March 2022

Imaging in monitoring metastasis in mouse models has low sensitivity and is not quantitative. Cell DNA barcoding, demonstrating high sensitivity and resolution, allows monitoring effects of drugs on the number of tumor and metastatic clones. However, this technology is not suitable for comparison of sizes of metastatic clones in different animals, for example, drug treated and untreated, due to high biological and technical variability upon tumor and metastatic growth and isolation of barcodes from tissue DNA. However, both numbers of clones and their sizes are critical parameters for analysis of drug effects. Here we developed a modification of the barcoding approach for monitoring drug effects on tumors and metastasis that is quantitative, highly sensitive and highly reproducible. This novel cell double-barcoding system allows simultaneously following the fate of two or more cell variants or cell lines in xenograft models in vivo, and also following the fates of individual clones within each of these populations. This system allows comparing effects of drugs on different cell populations and thus normalizing drug effects by drug-resistant lines, which corrects for both biological and technical variabilities and significantly increases the reproducibility of results. Using this barcoding system, we uncovered that effects of a novel DYRK1B kinase inhibitor FX9847 on primary tumors and metastasis is clone-dependent, while a distinct drug osimertinib demonstrated clone-independent effects on cancer cell populations. Overall, a cell double-barcoding approach can significantly enrich our understanding of drug effects in basic research and preclinical studies.
Occurrence of Total and Proteinase K-Resistant Alpha-Synuclein in Glioblastoma Cells Depends on mTOR Activity
Authors: Ryskalin Larisa , Ferese Rosangela , Morucci Gabriele , Biagioni Francesca , Busceti Carla L. , Michetti Fabrizio , Lenzi Paola , Frati Alessandro , Fornai Francesco
Published: March 2022

Alpha-synuclein (α-syn) is a protein considered to be detrimental in a number of degenerative disorders (synucleinopathies) of which α-syn aggregates are considered a pathological hallmark. The clearance of α-syn strongly depends on autophagy, which can be stimulated by inhibiting the mechanistic target of rapamycin (mTOR). Thus, the overexpression of mTOR and severe autophagy suppression may produce α-syn accumulation, including the proteinase K-resistant protein isoform. Glioblastoma multiforme (GBM) is a lethal brain tumor that features mTOR overexpression and severe autophagy inhibition. Cell pathology in GBM is reminiscent of a fast, progressive degenerative disorder. Therefore, the present work questions whether, as is analogous to neurons during degenerative disorders, an overexpression of α-syn occurs within GBM cells. A high amount of α-syn was documented in GBM cells via real-time PCR (RT-PCR), Western blotting, immunohistochemistry, immuno-fluorescence, and ultrastructural stoichiometry, compared with the amount of β- and γ-synucleins and compared with the amount of α-syn counted within astrocytes. The present study indicates that (i) α-syn is overexpressed in GBM cells, (ii) α-syn expression includes a proteinase-K resistant isoform, (iii) α-syn is dispersed from autophagy-like vacuoles to the cytosol, (iv) α-syn overexpression and cytosol dispersion are mitigated by rapamycin, and (v) the α-syn-related GBM-like phenotype is mitigated by silencing the SNCA gene.
Patterns of Tumor Infiltrating Lymphocytes in Adenoid Cystic Carcinoma of the Head and Neck
Authors: Doescher Johannes , Meyer Moritz , Arolt Christoph , Quaas Alexander , Klußmann Jens Peter , Wolber Philipp , Bankfalvi Agnes , Schildhaus Hans-Ulrich , Bastian Tobias , Lang Stephan , Laban Simon , Schuler Patrick J. , Brunner Cornelia , Hoffmann Thomas K. , Weissinger Stephanie E.
Published: March 2022

Adenoid cystic carcinoma (ACC) is a rare malignancy in the head and neck. The prognosis remains poor and late recurrences often occur after 5 years and later. To date, there are no reliable prognostic markers for ACC. In several solid tumors, tertiary lymphoid structures (TLS) are associated with improved survival. This study aims to investigate the role of distribution patterns of tumor infiltrating immune cells (TIL) in ACC. A cohort of 50 patients from three different cancer centers was available for analysis. Sections were stained for CD3, CD4, CD8 and CD20 and evaluated with regard to their distribution of TIL. Patterns were determined as infiltrated-excluded, infiltrated-inflamed and presence of tertiary lymphoid structures. About half of the cases showed an infiltrated-excluded TIL pattern and only a minority of six cases had TLS present within the tumor. Within the inflamed phenotype CD3+ cells were by far the most abundant lymphocyte subtype, and within this compartment, CD8+ T cells were predominant. There was no influence on overall or disease-free survival by any of the TIL patterns. This indicates that ACC is a tumor with very low immunogenicity and even abundance of lymphocytes does not seem to improve prognosis for this disease. Therefore, the observed lack of response towards immunotherapy is not surprising and other methods to induce recognition of ACC by the immune system must be found.
Deciphering Tumour Heterogeneity: From Tissue to Liquid Biopsy
Authors: Gilson Pauline , Merlin Jean-Louis , Harlé Alexandre
Published: March 2022

Human solid malignancies harbour a heterogeneous set of cells with distinct genotypes and phenotypes. This heterogeneity is installed at multiple levels. A biological diversity is commonly observed between tumours from different patients (inter-tumour heterogeneity) and cannot be fully captured by the current consensus molecular classifications for specific cancers. To extend the complexity in cancer, there are substantial differences from cell to cell within an individual tumour (intra-tumour heterogeneity, ITH) and the features of cancer cells evolve in space and time. Currently, treatment-decision making usually relies on the molecular characteristics of a limited tumour tissue sample at the time of diagnosis or disease progression but does not take into account the complexity of the bulk tumours and their constant evolution over time. In this review, we explore the extent of tumour heterogeneity with an emphasis on ITH and report the mechanisms that promote and sustain this diversity in cancers. We summarise the clinical strikes of ITH in the management of patients with cancer. Finally, we discuss the current material and technological approaches that are relevant to adequately appreciate ITH.
Current Methods to Unravel the Functional Properties of Lysosomal Ion Channels and Transporters
Authors: Festa Margherita , Minicozzi Velia , Boccaccio Anna , Lagostena Laura , Gradogna Antonella , Qi Tianwen , Costa Alex , Larisch Nina , Hamamoto Shin , Pedrazzini Emanuela , Milenkovic Stefan , Scholz-Starke Joachim , Ceccarelli Matteo , Vitale Alessandro , Dietrich Petra , Uozumi Nobuyuki , Gambale Franco , Carpaneto Armando
Published: March 2022

A distinct set of channels and transporters regulates the ion fluxes across the lysosomal membrane. Malfunctioning of these transport proteins and the resulting ionic imbalance is involved in various human diseases, such as lysosomal storage disorders, cancer, as well as metabolic and neurodegenerative diseases. As a consequence, these proteins have stimulated strong interest for their suitability as possible drug targets. A detailed functional characterization of many lysosomal channels and transporters is lacking, mainly due to technical difficulties in applying the standard patch-clamp technique to these small intracellular compartments. In this review, we focus on current methods used to unravel the functional properties of lysosomal ion channels and transporters, stressing their advantages and disadvantages and evaluating their fields of applicability.
Loss of Human Beta Cell Identity in a Reconstructed Omental Stromal Cell Environment
Authors: Secco Blandine , Saitoski Kevin , Drareni Karima , Soprani Antoine , Pechberty Severine , Rachdi Latif , Venteclef Nicolas , Scharfmann Raphaël
Published: March 2022

In human type 2 diabetes, adipose tissue plays an important role in disturbing glucose homeostasis by secreting factors that affect the function of cells and tissues throughout the body, including insulin-producing pancreatic beta cells. We aimed here at studying the paracrine effect of stromal cells isolated from subcutaneous and omental adipose tissue on human beta cells. We developed an in vitro model wherein the functional human beta cell line EndoC-βH1 was treated with conditioned media from human adipose tissues. By using RNA-sequencing and western blotting, we determined that a conditioned medium derived from omental stromal cells stimulates several pathways, such as STAT, SMAD and RELA, in EndoC-βH1 cells. We also observed that upon treatment, the expression of beta cell markers decreased while dedifferentiation markers increased. Loss-of-function experiments that efficiently blocked specific signaling pathways did not reverse dedifferentiation, suggesting the implication of more than one pathway in this regulatory process. Taken together, we demonstrate that soluble factors derived from stromal cells isolated from human omental adipose tissue signal human beta cells and modulate their identity.