bluuebunny/crossref_metadata_2025 huggingface dataset:
Chitosan as an Adjuvant to Enhance the Control Efficacy of Low-Dosage Pyraclostrobin against Powdery Mildew of Rosa roxburghii and Improve Its Photosynthesis, Yield, and Quality
Authors: Zhang Cheng , Li Qinju , Li Jiaohong , Su Yue , Wu Xiaomao
Published: September 2022

Powdery mildew is the most serious fungal disease of Rosa roxburghii in Guizhou Province, China. In this study, the control role of chitosan-assisted pyraclostrobin against powdery mildew of R. roxburghii and its influences on the resistance, photosynthesis, yield, quality and amino acids of R. roxburghii were evaluated. The results indicate that the foliar application of 30% pyraclostrobin suspension concentrate (SC) 100 mg L−1 + chitosan 500 mg L−1 displayed a superior control potential against powdery mildew, with a control efficacy of 89.30% and 94.58% after 7 d and 14 d of spraying, respectively, which significantly (p < 0.01) exceeded those of 30% pyraclostrobin SC 150 mg L−1, 30% pyraclostrobin SC 100 mg L−1, and chitosan 500 mg L−1. Simultaneously, their co-application could effectively enhance their effect on the resistance and photosynthesis of R. roxburghii leaves compared to their application alone. Meanwhile, their co-application could also more effectively enhance the yield, quality, and amino acids of R. roxburghii fruits compared to their application alone. This work highlights that chitosan can be applied as an effective adjuvant to promote the efficacy of low-dosage pyraclostrobin against powdery mildew in R. roxburghii and improve its resistance, photosynthesis, yield, quality, and amino acids.
Functional and Structural Impact of Deleterious Missense Single Nucleotide Polymorphisms in the NR3C1, CYP3A5, and TNF-α Genes: An In Silico Analysis
Authors: Ramayanam Navakanth Raju , Manickam Ranjani , Mahalingam Vijayakumar Thangavel , Goh Khang Wen , Ardianto Chrismawan , Ganesan Poovi , Ming Long Chiau , Ganesan Rajanandh Muhasaparur
Published: September 2022

Human diseases are generally influenced by SNPs (single nucleotide polymorphisms). The mutations in amino acid residues generated by deleterious SNPs contribute to the structural and functional diversity of the encoded protein. Tumor necrosis factor-α (TNF-α), Glucocorticoid receptor gene (NR3C1), and Cytochrome P450 3A5 (CYP3A5) play a key role in glucocorticoid resistance susceptibility in humans. Possible causative mutations could be used as therapeutic targets and diagnostic markers for glucocorticoid resistance. This study evaluated the missense SNPs of TNF-α, NR3C1, and CYP3A5 to predict their impact on amino acid changes, protein interaction, and functional stability. The protein sequence of dbSNP was obtained and used online in silico method to screen deleterious mutants for the in silico analysis. In the coding regions of TNF-α, NR3C1, and CYP3A5, 14 deleterious mutations were discovered. The protein functional and stability changes in the amino acid between native and mutant energy were identified by analyzing the changes in the hydrogen bonding of these mutants from native, which were all measured using Swiss PDB and PyMOL. F446S and R439K had the highest root-mean-square deviation (RMSD) values among the 14 deleterious mutants. Additionally, the conserved region of amino acid protein interaction was analyzed. This study could aid in the discovery of new detrimental mutations in TNF-α, NR3C1, and CYP3A5, as well as the development of long-term therapy for corticosteroid resistance in several inflammatory diseases. However, more research into the deleterious mutations of the TNF-α, NR3C1, and CYP3A5 genes is needed to determine their role in corticosteroid resistance.
Effects of RIPC on the Metabolome in Patients Undergoing Vascular Surgery: A Randomized Controlled Trial
Authors: Eerik Kadri , Kasepalu Teele , Kuusik Karl , Eha Jaan , Vähi Mare , Kilk Kalle , Zilmer Mihkel , Kals Jaak
Published: September 2022

Background: remote ischemic preconditioning (RIPC) is a phenomenon in which short episodes of ischemia are applied to distant organs to prepare target organs for more prolonged ischemia and to induce protection against ischemia-reperfusion injury. This study aims to evaluate whether preoperatively performed RIPC affects the metabolome and to assess whether metabolomic changes correlate with heart and kidney injury markers after vascular surgery. Methods: a randomized sham-controlled, double-blinded trial was conducted at Tartu University Hospital. Patients undergoing elective open vascular surgery were recruited and RIPC was applied before operation. Blood was collected preoperatively and 24 h postoperatively. The metabolome was analyzed using the AbsoluteIDQ p180 Kit. Results: final analysis included 45 patients from the RIPC group and 47 from the sham group. RIPC did not significantly alter metabolites 24 h postoperatively. There was positive correlation of change in the kynurenine/tryptophan ratio with change in hs-troponin T (r = 0.570, p < 0.001), NT-proBNP (r = 0.552, p < 0.001), cystatin C (r = 0.534, p < 0.001) and beta-2-microglobulin (r = 0.504, p < 0.001) only in the RIPC group. Conclusions: preoperative RIPC did not significantly affect the metabolome 24 h after vascular surgery. The positive linear correlation of kynurenine/tryptophan ratio with heart and kidney injury markers suggests that the kynurenine–tryptophan pathway can play a role in RIPC-associated cardio- and nephroprotective effects.
Injectable Peptide Hydrogel Encapsulation of Mesenchymal Stem Cells Improved Viability, Stemness, Anti-Inflammatory Effects, and Early Stage Wound Healing
Authors: Li Quan , Qi Guangyan , Lutter Dylan , Beard Warren , Souza Camila R. S. , Highland Margaret A. , Wu Wei , Li Ping , Zhang Yuanyuan , Atala Anthony , Sun Xiuzhi
Published: September 2022

Human-adipose-derived mesenchymal stem cells (hADMSCs) are adult stem cells and are relatively easy to access compared to other sources of mesenchymal stem cells (MSCs). They have shown immunomodulation properties as well as effects in improving tissue regeneration. To better stimulate and preserve the therapeutic properties of hADMSCs, biomaterials for cell delivery have been studied extensively. To date, hyaluronic acid (HA)-based materials have been most widely adopted by researchers around the world. PGmatrix is a new peptide-based hydrogel that has shown superior functional properties in 3D cell cultures. Here, we reported the in vitro and in vivo functional effects of PGmatrix on hADMSCs in comparison with HA and HA-based Hystem hydrogels. Our results showed that PGmatrix was far superior in maintaining hADMSC viability during prolonged incubation and stimulated expression of SSEA4 (stage-specific embryonic antigen-4) in hADMSCs. hADMSCs encapsulated in PGmatrix secreted more immune-responsive proteins than those in HA or Hystem, though similar VEGF-A and TGFβ1 release levels were observed in all three hydrogels. In vivo studies revealed that hADMSCs encapsulated with PGmatrix showed improved skin wound healing in diabetic-induced mice at an early stage, suggesting possible anti-inflammatory effects, though similar re-epithelialization and collagen density were observed among PGmatrix and HA or Hystem hydrogels by day 21.
Internal Carotid Injury during Skull Base Surgery—Case Report and a Review of the Literature
Authors: Matoušek Petr , Krejčí Tomáš , Misiorzová Eva , Lipina Radim , Procházka Václav , Lubojacký Jakub , Čábalová Lenka , Komínek Pavel
Published: September 2022

Iatrogenic injury of the internal carotid artery (ICA) is a rare, and probably underreported, complication of transnasal endoscopic skull base surgery. Although treatment algorithms have been suggested, there is no definite consensus or guideline for the management of this severe complication. We describe a case of ICA injury that occurred during a transsphenoidal biopsy of a tumor in the cavernous sinus and we present a treatment algorithm for managing this complication. We reviewed the articles published from 1998 to 2021, reporting on major vascular injury during transnasal endoscopic skull base surgery and endonasal endoscopic surgery, and we compare the methods and results of ICA injury management reported in the literature with the presented case. The most promising treatment for ICA injury might be packing with a muscle graft initially, then performing an endovascular intervention.
Giant Non-Functioning Pituitary Adenomas: Treatment Considerations
Authors: Solari Domenico , Cavallo Luigi Maria , Graziadio Chiara , Corvino Sergio , Bove Ilaria , Esposito Felice , Cappabianca Paolo
Published: September 2022

Giant pituitary adenomas are a subgroup of pituitary adenomas defined by a diameter greater than 4 cm, and they account for 5–14% of adenomas in surgical series. Because of their growth patterns and locations, often involving critical neurovascular structures, they represent a true surgical challenge, and gross total resection is difficult to achieve. There is no consensus on the optimal surgical strategy for giant pituitary adenomas, and, often, integrated multi-staged treatment strategies have been considered. Transcranial or transsphenoidal approaches, alone or combined, according to tumor and patient features are the two main routes. Each of these strategies has pros and cons. The conventional transcranial approach has for a long time been considered the first choice for the removal of giant pituitary adenomas. Currently, with endoscopic techniques, it is also possible to remove lesions that involve the intradural compartment and the adjacent neurovascular structures with the use of extended approaches. Our policy for the management of these lesions is to adopt the endoscopic endonasal approach as the first choice unless the tumor presents significant intracranial extension that results in it being outside the visibility and maneuverability of the endoscopic endonasal route. In these latter cases, we agree that the transcranial approach is more appropriate. However, accurate preoperative evaluation and refined treatment plans for each patient are mandatory to define a proper strategy in order to achieve the most effective long-term result.
Emotion Recognition in Patients with Low-Grade Glioma before and after Surgery
Authors: Buunk Anne M. , Gerritsen Marleen J. J. , Jeltema Hanne-Rinck , Wagemakers Michiel , Metzemaekers Jan D. M. , Groen Rob J. M. , Spikman Jacoba M.
Published: September 2022

Research on patients with low-grade gliomas (LGGs) showed neurocognitive impairments in various domains. However, social cognition has barely been investigated. Facial emotion recognition is a vital aspect of social cognition, but whether emotion recognition is affected in LGG patients is unclear. Therefore, we aimed to investigate the effect of LGG and resection by examining emotion recognition pre- and postoperatively. Additionally, the relationships among emotion recognition and general cognition and tumor location were investigated. Thirty patients with LGG who underwent resective surgery were included and matched with 63 healthy control participants (HCs). Emotion recognition was measured with the Facial Expressions of Emotion–Stimuli and Tests (FEEST) and general cognition with neuropsychological tests. Correlations and within-group and between-group comparisons were calculated. Before surgery, patients performed significantly worse than the HCs on FEEST-Total and FEEST-Anger. Paired comparisons showed no significant differences between FEEST scores before and post-surgery. No significant correlations with general cognition and tumor location were found. To conclude, the results of this study indicate that the tumor itself contributes significantly to social cognitive dysfunction and that surgery causes no additional deficit. Impairments were not related to general cognitive deficits or tumor location. Consequently, incorporating tests for emotion recognition into the neuropsychological assessment of patients with LGG is important.
Comparing the Effects of Exoskeletal-Type Robot-Assisted Gait Training on Patients with Ataxic or Hemiplegic Stroke
Authors: Son Sungsik , Lim Kil-Byung , Kim Jiyong , Lee Changhun , Cho Sung II , Yoo Jeehyun
Published: September 2022

This study aimed to discover the effects of robotic rehabilitation utilizing an exoskeletal-type robot-assisted gait training (RAGT) device on patients with ataxic and hemiplegic stroke and to compare its effectiveness between the two groups. This was a retrospective study, and the electronic charts of 22 patients who underwent RAGT treatment from October 2019 to June 2021 were reviewed. Patients were divided into ataxic and hemiplegic groups based on their symptoms. The clinical outcome measures included the Berg balance scale (BBS), functional ambulation category (FAC), and mobility subcategories of the modified Barthel Index (MBI-m). Outcome measures were reviewed at two points within 48 h, before and after RAGT with EXOWALK®, a type of exoskeletal robot. After the RAGT sessions, total patients in both ataxic and hemiplegic groups demonstrated statistically significant improvements in BBS (p < 0.0001, p = 0.002, and p = 0.005, respectively) and MBI-m (p < 0.0001, p = 0.002, and p = 0.011, respectively). Additionally, FAC after RAGT was significantly improved (p = 0.0056). The regression coefficient of the number of RAGT treatments for BBS changes in the nine subjects was estimated to be 2.45; 3.50 in the ataxic group and 2.26 in the hemiplegic group. The regression coefficient of the number of RAGT treatments for MBI-m changes in the nine subjects was estimated to be 0.16; 4.00 in the ataxic group and −0.52 in the hemiplegic group. Our results suggest that RAGT using an exoskeletal-type robot, EXOWALK®, could be effective for improving walking capacity, balance, and daily activities of life in patients with ataxic and hemiplegic stroke.
Temporal Stability of Dynamic Default Mode Network Connectivity Negatively Correlates with Suicidality in Major Depressive Disorder
Authors: Ouyang Xuan , Long Yicheng , Wu Zhipeng , Liu Dayi , Liu Zhening , Huang Xiaojun
Published: September 2022

Previous studies have demonstrated that the suicidality in patients with major depressive disorder (MDD) is related to abnormal brain functional connectivity (FC) patterns. However, little is known about its relationship with dynamic functional connectivity (dFC) based on the assumption that brain FCs fluctuate over time. Temporal stabilities of dFCs within the whole brain and nine key networks were compared between 52 MDD patients and 21 age, sex-matched healthy controls (HCs) using resting-state functional magnetic resonance imaging and temporal correlation coefficients. The alterations in MDD were further correlated with the scores of suicidality item in the Hamilton Rating Scale for Depression (HAMD). Compared with HCs, the MDD patients showed a decreased temporal stability of dFC as indicated by a significantly decreased temporal correlation coefficient at the global level, as well as within the default mode network (DMN) and subcortical network. In addition, temporal correlation coefficients of the DMN were found to be significantly negatively correlated with the HAMD suicidality item scores in MDD patients. These results suggest that MDD may be characterized by excessive temporal fluctuations of dFCs within the DMN and subcortical network, and that decreased stability of DMN connectivity may be particularly associated with the suicidality in MDD.
The Impact of Stress on Innovative Work Behavior among Medical Healthcare Professionals
Authors: Anjum Amna , Zhao Yan
Published: September 2022

Background: For health systems, a fundamental challenge is adapting to changes in the patterns of health services that require technological and scientific innovations. The pace of multiple and interconnected challenges mounts extra stress on medical healthcare professionals and reduces their innovative capabilities, especially in low- and middle-income countries. To enhance the innovative capability of medical healthcare professionals under stress, the study seeks any possible correlation between stress and innovation. For that purpose, we sought to investigate the effects of stress on the innovative work behavior of employees and examine the mediating effect of health and moderating effect of supervisor support. Materials and Methods: 350 medical healthcare professionals were surveyed in different hospitals in Lahore through a survey regarding stress, health, innovative work behavior, and supervisor support with a final response rate of 89%. SPSS and AMOS were used for the analysis of the data and the investigation of the combined effects of the model. Exploratory (EFA) and Confirmatory Factor Analysis (CFA) were conducted to ensure the convergent and discriminant validity of the factors, while mediation analysis was done to check the mediating role of health. Results: It has been observed that there is partial mediation of health between eustress and innovative work behavior whereas supervisor support does not moderate between eustress and health. Furthermore, the results indicate that distress is negatively associated with innovative behavior. In addition, health fully mediates between distress and innovative work behavior. If distress increases negative effects on health, then supervisor support reduces the negative impact of distress on health. Furthermore, supervisor support also reduces the negative impact of health on innovative work behavior. Conclusion: Our study outlines a hypothetical alternative situation that explains how the two emotions of eustress and distress are brought into play in the innovative work behavior of the employees. In addition, supervisors play an important role in influencing the sustainable innovation work behavior of their staff members.
Ethical Risk Factors and Mechanisms in Artificial Intelligence Decision Making
Authors: Guan Hongjun , Dong Liye , Zhao Aiwu
Published: September 2022

While artificial intelligence (AI) technology can enhance social wellbeing and progress, it also generates ethical decision-making dilemmas such as algorithmic discrimination, data bias, and unclear accountability. In this paper, we identify the ethical risk factors of AI decision making from the perspective of qualitative research, construct a risk-factor model of AI decision making ethical risks using rooting theory, and explore the mechanisms of interaction between risks through system dynamics, based on which risk management strategies are proposed. We find that technological uncertainty, incomplete data, and management errors are the main sources of ethical risks in AI decision making and that the intervention of risk governance elements can effectively block the social risks arising from algorithmic, technological, and data risks. Accordingly, we propose strategies for the governance of ethical risks in AI decision making from the perspectives of management, research, and development.
Constrained Mode–Damping Solvent Extraction Combined Method for the Soil Incorporation into a Real-Time Hybrid Test of the Soil–Structure System
Authors: Luo Lanfang , Jiang Nan
Published: September 2022

The real-time hybrid test is an effective testing method for soil–structure interaction research. Due to the data interaction time requirement and formula derivation method, the traditional real-time hybrid test of soil–structure interaction mostly employs a simple numerical substructure model. This study investigated the model construction and numerical simulation of a finite element soil substructure with high simulation accuracy and calculation efficiency. The soil was subdivided into near-field and far-field zones. A constrained mode–damping solvent extraction combined method was applied to the latter zone, reducing the soil’s computational scale and simulating the far-field energy dissipation effect. Then, the basic formula of the near-field zone–structure system was derived using the branch mode method, and the motion equation of the soil–structure system applied to real-time hybrid test was obtained. The soil’s numerical model was realized by the joint application of ANSYS and MATLAB software packages and verified through the real-time hybrid test of the soil–structure system. The results show that the proposed constrained mode–damping solvent extraction combined method had high calculation efficiency and good accuracy. It satisfied the requirements of the soil numerical substructure in real-time hybrid tests.
Development of a New Uplift Pile with Prestressed Semi-Bonded Composite Anchor
Authors: Mao Zongyuan , Guo Hao , Wu Yongkang , Wang Enzhi , Li Xu
Published: September 2022

This paper introduces a new type of prestressed uplift pile that adopts the semi-bonded composite anchor as the main reinforcement. An in-situ experimental study was carried out to investigate the new pile’s deformation, stress, bearing capacity, and cracking characteristics, which were then compared with the conventional piles. Results show that although the reinforcement ratio of the new pile is only 0.75%, much less than that of the conventional pile (i.e., 3.84%), it achieves similar or even better mechanical properties under uplift loads. The cost of the pile’s anchorage system is reduced by 43.8%, and the total cost of a single pile is reduced by 33.6%. Compared with the conventional pile, the new pile makes better use of the lateral friction resistance of the lower pile body, and the uplift bearing capacity and the uplift resistance of the pile are improved correspondingly. In addition, the cracking resistance of the new pile is significantly improved, with the cracking load increased by 88.2% and the cracking area reduced by 48.3%. In addition, the multi-layer structure of the composite main bar provides better protection for the load-bearing steel strands against corrosion. As such, the new type of pile is expected to gain much better durability than the conventional ones.
Investigations on the Dynamic Response of Adjacent Buildings Connected by Viscous Dampers
Authors: Chen Peng , Wu Xiaobin
Published: September 2022

This paper investigates the seismic performance of two adjacent buildings connected by viscous dampers. Three types of damper placement are discussed, including installing dampers within a single building, connecting two buildings at the same floor level, and connecting two buildings at the inter-story level. Analytical models are established to consider various dynamic properties of the adjacent buildings, and the theoretical solutions are obtained, including the transmissibility curves, additional modal damping, and input energy under the seismic design spectrum. Time history analyses of an engineering project are performed with different damper placements. Different numerical models are compared for frequently and rarely occurred earthquakes. The seismic mitigation effect is discussed with regard to the story drift reduction rate and dynamic energy. Theoretical and numerical results demonstrate that the connecting dampers provide added modal damping while causing the coupled response. As a result, it is less efficient than traditional ways of placement within a building. Furthermore, the connecting dampers significantly increase the reaction of the floors without installed dampers. When designing dampers to connect the adjacent buildings, careful engineering calculations should be made.
Study on Shear Mechanical Properties and Microscopic Failure Mechanism of Dentate Joints Based on DEM and Laboratory Tests
Authors: Guo Jiaqi , Cheng Lipan , Lai Yongbiao , Tian Yongchao , Li Lu
Published: September 2022

The stability control of the surrounding rock is greatly influenced by the rock joint’s shear mechanical characteristics and deformation failure mechanism. A numerical model of the dentate joints was created using a particle flow discrete element method (DEM). To study the shear mechanical behavior and damage evolution characteristics of the joints, a numerical simulation of the joints shear test under the same normal stress was conducted. Additionally, the joints’ shear failure mechanism and failure mode were investigated from a microscopic perspective in conjunction with laboratory tests. The results show that the shear strength steadily increases as the roughness of the rock joints increases and that it rapidly decreases after reaching its peak shear strength, indicating an obvious brittle failure. Varied rock joints exhibit significantly different micro-crack evolution, with rougher rock joints (r = 0.30, r = 0.37) exhibiting greater micro-crack production and crack extension into the model’s interior. Rock joint specimens with lower roughness (r = 0.17) had less concentration and fewer areas of contact force concentration. The shear failure mode of the rock joints gradually shifts from abrasion failure mode to snip failure mode as the roughness rises, which is largely compatible with the failure characteristics shown in the laboratory testing. The pattern of micro-crack development within the model specimen and the failure characteristics of the laboratory tests are in good agreement with the distribution characteristics of contact force on the rock joints.
Racial Disparity in Quadruple Negative Breast Cancer: Aggressive Biology and Potential Therapeutic Targeting and Prevention
Authors: Jinna Nikita , Jovanovic-Talisman Tijana , LaBarge Mark , Natarajan Rama , Kittles Rick , Sistrunk Christopher , Rida Padmashree , Seewaldt Victoria L.
Published: September 2022

Black/African-American (AA) women, relative to their White/European-American (EA) counterparts, experience disproportionately high breast cancer mortality. Central to this survival disparity, Black/AA women have an unequal burden of aggressive breast cancer subtypes, such as triple-negative breast cancer (ER/PR-, HER2-wild type; TNBC). While TNBC has been well characterized, recent studies have identified a highly aggressive androgen receptor (AR)-negative subtype of TNBC, quadruple-negative breast cancer (ER/PR-, HER2-wildtype, AR-; QNBC). Similar to TNBC, QNBC disproportionately impacts Black/AA women and likely plays an important role in the breast cancer survival disparities experienced by Black/AA women. Here, we discuss the racial disparities of QNBC and molecular signaling pathways that may contribute to the aggressive biology of QNBC in Black/AA women. Our immediate goal is to spotlight potential prevention and therapeutic targets for Black/AA QNBC; ultimately our goal is to provide greater insight into reducing the breast cancer survival burden experienced by Black/AA women.
Clinical Features, Gene Alterations, and Outcomes in Prefibrotic and Overt Primary and Secondary Myelofibrotic Patients
Authors: Kim Tong-Yoon , Kwag Daehun , Lee Jong-Hyuk , Lee Joonyeop , Min Gi-June , Park Sung-Soo , Park Silvia , Jeon Young-Woo , Yoon Jae-Ho , Shin Seung-Hawn , Yahng Seung-Ah , Cho Byung-Sik , Eom Ki-Seong , Kim Yoo-Jin , Lee Seok , Kim Hee-Je , Min Chang-Ki , Cho Seok-Goo , Lee Jong-Wook , Lee Jong-Mi , Kim Myungshin , Lee Sung-Eun
Published: September 2022

The Philadelphia-negative myeloproliferative neoplasms (MPNs) are divided in three major groups: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 WHO classification incorporates also prefibrotic PMF (pre-PMF) and overt PMF. This study aimed to discriminate the clinical features, genetic alterations, and outcomes in patients with prefibrotic, overt PMF, and secondary MF (SMF). This study included 229 patients with diagnosed myelofibrosis (MF). Among 229 patients, 67 (29%), 122 (53%), and 40 (18%) were confirmed as SMF, overt PMF, and pre-PMF, respectively. The JAK2 V617F mutation was differentially distributed in SMF and PMF, contradictory to CALR and MPL mutations. Regarding nondriver mutations, the occurrence of ASXL1 mutations differed between PMF and SMF or pre-PMF. The three-year overall survival was 91.5%, 85.3%, and 94.8% in SMF, overt PMF, and pre-PMF groups. Various scoring systems could discriminate the overall survival in PMF but not in SMF and pre-PMF. Still, clinical features including anemia and thrombocytopenia were poor prognostic factors throughout the myelofibrosis, whereas mutations contributed differently. Molecular grouping by wild-type SF3B1 and SRSF2/RUNX1/U2AF1/ASXL1/TP53 mutations showed inferior progression-free survival (PFS) in PMF, SMF, and pre-PMF. We determined the clinical and genetic features related to poor prognosis in myelofibrosis.
Optimization of the Management of Category III Thyroid Nodules Using Repeat FNA and TIRADS
Authors: Słowińska-Klencka Dorota , Klencki Mariusz , Duda-Szymańska Joanna , Popowicz Bożena
Published: September 2022

The aim of the study was to examine the benefits of the joint use of repeat FNA (rFNA) and EU-TIRADS in category III nodules in relation to the kind of atypia: nuclear vs. architectural (denoted by AUS and FLUS respectively). The study included 127 AUS and 1739 FLUS nodules with a known category of EU-TIRADS. Repeat FNA was performed in 82 AUS and 934 FLUS nodules of which 57 and 515 were excised, respectively. AUS nodules had higher malignancy risk than FLUS nodules. EU-TIRADS showed higher accuracy for AUS nodules, the opposite to rFNA, that had higher accuracy for FLUS nodules. The combined criterion for AUS nodules (at least rFNA-V or EU-TIRADS-4) maximized sensitivity (92.3%) with acceptable specificity (70.0%); OR: 28.0. In the case of FLUS nodules, the combined criterion (rFNA-V or EU-TIRADS-5) maximized specificity (95.2%) with 57.7% sensitivity and a low percentage (13.9%) of positive nodules, OR: 27.0. In both types of nodules, the low risk category in EU-TIRADS and benign result of rFNA excluded cancer. Concluding, category III nodules with and without nuclear atypia differ in their risk of malignancy and, consequently, diagnostic criteria adopted for the evaluation of these nodules with rFNA and EU-TIRADS should be specific to AUS and FLUS nodules.
Concomitant Inhibition of FASN and SREBP Provides a Promising Therapy for CTCL
Authors: Chi Cheng , Harth Lisa , Galera Marina Ramírez , Torrealba Marina Passos , Vadivel Chella Krishna , Geisler Carsten , Bonefeld Charlotte Menné , Nielsen Pia Rude , Bzorek Michael , Becker Jürgen C. , Gjerdrum Lise Mette Rahbek , Ødum Niels , Woetmann Anders
Published: September 2022

Cutaneous T cell lymphoma (CTCL) is a group of non-Hodgkin’s primary cutaneous T cell lymphomas, with Mycosis Fungoides and Sézary syndrome (SS) being the two most common subtypes. Fatty acid synthase (FASN) is a crucial enzyme that catalyses the biosynthesis of fatty acids, which has been reported to play an oncogenic role in various malignancies but not in CTCL so far. Herein, we show that FASN is highly expressed in CTCL cell lines and in peripheral blood mononuclear cells (PBMCs) from CTCL patients, while it is not in PBMCs from healthy individuals. The inhibition of FASN in CTCL cell lines impairs cell viability, survival, and proliferation, but, interestingly, it also increases FASN expression. However, inhibiting sterol regulatory element binding protein (SREBP), a transcription factor that promotes the expression of FASN, partially reversed the upregulation of FASN induced by FASN inhibitors. Thus, the combination of FASN and SREBP inhibitors enhanced the effects on both CTCL cell lines and PBMCs from SS patients, where a valid inhibition on cell proliferation could be verified. Importantly, compared to non-malignant cells, primary malignant cells are more sensitive to the inhibition of FASN and SREBP, making the combination of FASN and SREBP inhibitors a promising novel therapeutic strategy in CTCL.
CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma
Authors: Barankiewicz Joanna , Salomon-Perzyński Aleksander , Misiewicz-Krzemińska Irena , Lech-Marańda Ewa
Published: September 2022

Multiple myeloma (MM) is the second most common hematological malignancy with a recurrent clinical course. The introduction of immunomodulatory drugs (IMiDs) was one of the milestones in MM therapy leading to a significant improvement in patients’ prognosis. Currently, IMiDs are the backbone of MM therapy in newly diagnosed and relapsed/refractory settings. It is now known that IMiDs exert their anti-myeloma activity mainly by binding cereblon (CRBN), the substrate receptor protein of the CRL4 E3 ubiquitin ligase (CRL4CRBN) complex. By binding CRBN, IMiDs alter its substrate specificity, leading to ubiquitination and proteasomal degradation of proteins essential for MM cell survival. Following the success of IMiDs, it is not surprising that the possibility of using the CRL4CRBN complex’s activity to treat MM is being further explored. In this review, we summarize the current state of knowledge about novel players in the MM therapeutic landscape, namely the CRBN E3 ligase modulators (CELMoDs), the next generation of IMiDs with broader biological activity. In addition, we discuss a new strategy of tailored proteolysis called proteolysis targeting chimeras (PROTACs) using the CRL4CRBN to degrade typically undruggable proteins, which may have relevance for the treatment of MM and other malignancies in the future.
Clinical Utility of Rapid On-Site Evaluation of Touch Imprint Cytology during Cryobiopsy for Peripheral Pulmonary Lesions
Authors: Muto Yutaka , Uchimura Keigo , Imabayashi Tatsuya , Matsumoto Yuji , Furuse Hideaki , Tsuchida Takaaki
Published: September 2022

Cryobiopsy enables us to obtain larger specimens than conventional forceps biopsy despite the caution regarding complications. This study aimed to evaluate the clinical utility of rapid on-site evaluation of touch imprint cytology (ROSE-TIC) during cryobiopsy of peripheral pulmonary lesions (PPLs). We retrospectively reviewed the data of consecutive patients who underwent cryobiopsy for solid PPLs between June 2020 and December 2021. ROSE-TIC was performed on the first specimen obtained via cryobiopsy and assessed using Diff-Quik staining. The results of ROSE-TIC for each patient were compared with the histological findings of the first cryobiopsy specimen. Sixty-three patients were enrolled in this study. Overall, 57 (90.5%) lesions were ≤30 mm in size and 37 (58.7%) had positive bronchus signs. The radial endobronchial ultrasound findings were located within and adjacent to the lesion in 46.0% and 54.0% of the cases, respectively. The sensitivity, specificity, and positive and negative predictive values of the ROSE results for histological findings of the corresponding specimens were 69.8%, 90.0%, 93.8%, and 58.1%, respectively. The concordance rate was 76.2%. In conclusion, ROSE-TIC, due to its high specificity and positive predictive value, may be a potential tool in deciding whether cryobiopsy sampling could be finished during bronchoscopy.
Pathophysiology of Immune Checkpoint Inhibitor-Induced Myocarditis
Authors: Jiménez-Alejandre Rosa , Ruiz-Fernández Ignacio , Martín Pilar
Published: September 2022

Immune checkpoint inhibitors (ICIs) have recently emerged as strong therapies for a broad spectrum of cancers being the first-line treatment for many of them, even improving the prognosis of malignancies that were considered untreatable. This therapy is based on the administration of monoclonal antibodies targeting inhibitory T-cell receptors, which boost the immune system and prevent immune evasion. However, non-specific T-cell de-repression can result in a wide variety of immune-related adverse events (irAEs), including gastrointestinal, endocrine, and dermatologic, with a smaller proportion of these having the potential for fatal outcomes such as neurotoxicity, pulmonary toxicity, and cardiotoxicity. In recent years, alarm has been raised about cardiotoxicity as it has the highest mortality rate when myocarditis develops. However, due to the difficulty in diagnosing this cardiac condition and the lack of clinical guidelines for the management of cardiovascular disease in patients on therapy with ICIs, early detection of myocarditis has become a challenge in these patients. In this review we outline the mechanisms of tolerance by which this fatal cardiomyopathy may develop in selected cancer patients treated with ICIs, summarize preclinical models of the disease that will allow the development of more accurate strategies for its detection and treatment, and discuss the challenges in the future to decrease the risks of its development with better decision making in susceptible patients.
Tumor Microenvironment CD14+ Cells Correlate with Poor Overall Survival in Patients with Early-Stage Lung Adenocarcinoma
Authors: Schenk Erin L. , Boland Jennifer M. , Withers Sarah G. , Bulur Peggy A. , Dietz Allan B.
Published: September 2022

Patients with early-stage lung adenocarcinoma have a high risk of recurrent or metastatic disease despite undergoing curative intent therapy. We hypothesized that increased CD14+ cells within the tumor microenvironment (TME) could stratify patient outcomes. Immunohistochemistry for CD14 was performed on 189 specimens from patients with lung adenocarcinoma who underwent curative intent surgery. Outcomes and associations with clinical and pathologic variables were determined. In vitro studies utilized a coculture system to model the lung cancer TME containing CD14+ cells. Patients with high levels of TME CD14+ cells experienced a median overall survival of 5.5 years compared with 8.3 and 10.7 years for those with moderate or low CD14 levels, respectively (p < 0.001). Increased CD14+ cell tumor infiltration was associated with a higher stage at diagnosis and more positive lymph nodes at the time of surgery. This prognostic capacity remained even for patients with early-stage disease. Using an in vitro model system, we found that CD14+ cells reduced chemotherapy-induced cancer cell death. These data suggest that CD14+ cells are a biomarker for poor prognosis in early-stage lung adenocarcinoma and may promote tumor survival. CD14+ cell integration into the lung cancer TME can occur early in the disease and may be a promising new therapeutic avenue.
The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma
Authors: Stewart Connor E. , Guerra-García María E. , Luo Lixia , Williams Nerissa T. , Ma Yan , Regal Joshua A. , Ghosh Debosir , Sansone Patrick , Oldham Mark , Deland Katherine , Becher Oren J. , Kirsch David G. , Reitman Zachary J.
Published: September 2022

Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase, ataxia–telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if ATM inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by ATM deletion, which may guide the design of future clinical trials.
Role of Fe, Transferrin and Transferrin Receptor in Anti-Tumor Effect of Vitamin C
Authors: Qiu Jia , Wu Renbo , Long Yali , Peng Lei , Yang Tianhong , Zhang Bing , Shi Xinchong , Liu Jianbo , Zhang Xiangsong
Published: September 2022

High-dose vitamin C (VC) exhibits anti-tumor effects, and the cytotoxicity of VC is correlated with oxidative stress. However, iron, as a redox metal, plays an important effect in redox cycling and free radical formation in cells. This study addresses the role of iron ion in the cytotoxicity of VC. We found that iron supplementation increases the anti-tumor effect of VC, which was influenced by the cellular iron uptake pathway–transferrin (TF)/transferrin receptor (TFR) system. The TFR expression of tumors can be assessed by 68Ga-citrate PET imaging, and it would be helpful to screen out the tumor type which is more sensitive to VC combined with an iron supplementation treatment.
Targeting the Tumor Microenvironment through mTOR Inhibition and Chemotherapy as Induction Therapy for Locally Advanced Head and Neck Squamous Cell Carcinoma: The CAPRA Study
Authors: Evrard Diane , Dumont Clément , Gatineau Michel , Delord Jean-Pierre , Fayette Jérôme , Dreyer Chantal , Tijeras-Raballand Annemilaï , de Gramont Armand , Delattre Jean-François , Granier Muriel , Aissat Nasredine , Garcia-Larnicol Marie-Line , Slimane Khemaies , Chibaudel Benoist , Raymond Eric , Le Tourneau Christophe , Faivre Sandrine
Published: September 2022

Mammalian target of rapamycin (mTOR) regulates cellular functions by integrating intracellular signals and signals from the tumor microenvironment (TME). The PI3K-AKT-mTOR pathway is activated in 70% of head and neck squamous cell carcinoma (HNSCC) and associated with poor prognosis. This phase I-II study investigated the effect of mTOR inhibition using weekly everolimus (30 mg for dose level 1, 50 mg for dose level 2) combined with weekly induction chemotherapy (AUC2 carboplatin and 60 mg/m2 paclitaxel) in treatment-naïve patients with locally advanced T3-4/N0-3 HNSCC. Patients received 9 weekly cycles before chemoradiotherapy. Objectives were safety and antitumor activity along with tissue and blood molecular biomarkers. A total of 50 patients were enrolled. Among 41 evaluable patients treated at the recommended dose of 50 mg everolimus weekly, tolerance was good and overall response rate was 75.6%, including 20 major responses (≥50% reduction in tumor size). A significant decrease in expression of p-S6K (p-value: 0.007) and Ki67 (p-value: 0.01) was observed in post-treatment tumor tissue. Pro-immunogenic cytokine release (Th1 cytokines IFN-γ, IL-2, and TNF-β) was observed in the peripheral blood. The combination of everolimus and chemotherapy in HNSCC was safe and achieved major tumor responses. This strategy favorably impacts the TME and might be combined with immunotherapeutic agents.
Therapeutic Adenovirus Vaccine Combined Immunization with IL-12 Induces Potent CD8+ T Cell Anti-Tumor Immunity in Hepatocellular Carcinoma
Authors: Zheng Yanyan , Lu Zheng , Ding Jiage , Jiang Nan , Wang Jiawei , Yang Jie , Song Jingyuan , Chen Hongliang , Fang Lin , Li Huizhong , Tian Hui , Wang Gang , Zheng Junnian , Chai Dafei
Published: September 2022

Hepatocellular carcinoma (HCC) is one of the cancers with the highest morbidity and mortality in the world. However, clinical progress in the treatment of HCC has not shown a satisfactory therapeutic effect. Here, we have developed a novel strategy to treat HCC with an adenovirus (Ad)-based vaccine, which contains a specific antigen glypican-3 (GPC3) and an immunostimulatory cytokine IL-12. In the subcutaneous tumor model, Ad-IL-12/GPC3 vaccine was injected into muscles three times to evaluate its therapeutic effect. Compared with the control immunization group, the Ad-IL-12/GPC3 immunization group showed a significant tumor growth inhibition effect, which was confirmed by the reduced tumor volume and the increased tumor inhibition. Ad-IL-12/GPC3 co-immunization promoted the induction and maturation of CD11c+ or CD8+CD11c+ DCs and increased the number of tumor-infiltrating CD8+ T cells. Furthermore, in the Ad-IL-12/GPC3 group, the proliferation of CD8+ T cells, the induction of multifunctional CD8+ T cells, and CTL activity were significantly increased. Interestingly, the deletion of CD8+ T cells abolished tumor growth inhibition by Ad-IL-12/GPC3 treatment, suggesting that CD8+ T cell immune responses were required to eliminate the tumor. Likewise, Ad-IL-12/GPC3 vaccine also effectively inhibited lung tumor growth or metastasis by enhancing CD8+ DCs-mediated multifunctional CD8+ T cell immune responses in the lung metastasis model. Therefore, these results indicate that IL-12 combined with Ad-GPC3 vaccine co-immunization might provide a promising therapeutic strategy for HCC patients.
Adjuvant Radiotherapy in Surgically Treated HPV-Positive Oropharyngeal Carcinoma with Adverse Pathological Features
Authors: Soliman Shady I. , Faraji Farhoud , Pang John , Mell Loren K. , Califano Joseph A. , Orosco Ryan K.
Published: September 2022

Purpose: HPV-positive oropharyngeal carcinoma (HPV-OPC) is increasingly treated with primary surgery. The National Comprehensive Cancer Network (NCCN) recommends adjuvant therapy for surgically treated HPV-OPC displaying adverse pathological features (AF). We evaluated adjuvant radiotherapy patterns and outcomes in surgically treated AF-positive HPV-OPC (AF-HPV-OPC). Methods: The National Cancer Database was interrogated for patients ≥ 18 years with early-stage HPV-OPC from 2010 to 2017 who underwent definitive resection. Patients that had an NCCN-defined AF indication for adjuvant radiotherapy were assessed, including positive surgical margins (PSM), extranodal extension (ENE), lymphovascular invasion, and level 4/5 cervical lymph nodes. Overall survival (OS) was evaluated using Cox proportional hazards models and Kaplan–Meier analysis in whole and propensity score matched (PM) cohorts. Results: Of 15,036 patients meeting inclusion criteria, 55.7% were positive for at least one AF. Presence of any AF was associated with worse OS (hazard ratio (HR) = 1.56, p < 0.001). In isolation, each AF was associated with worse OS. On PM analysis, insurance status, T2 category, Charlson-Deyo comorbidity score, ENE (HR = 1.81, p < 0.001), and PSM (HR = 1.58, p = 0.002) were associated with worse OS. Median 3-year OS was 92.0% among AF-HPV-OPC patients undergoing adjuvant radiotherapy and 84.2% for those who did not receive adjuvant radiotherapy (p < 0.001, n = 1678). The overall rate of patients with AF-HPV-OPC who did not receive adjuvant radiotherapy was 13% and increased from 10% in 2010 to 17% in 2017 (ptrend = 0.007). Conclusions: In patients with AF-HPV-OPC, adjuvant radiotherapy is associated with improved survival. In the era of de-escalation therapy for HPV-OPC, our findings demonstrate the persistent prognostic benefit of post-operative radiotherapy in the setting of commonly identified adverse features. Ongoing clinical trials will better elucidate optimized patient selection for de-escalated therapy.
Therapeutic Benefit of Systematic Lymphadenectomy in Node-Negative Uterine-Confined Endometrioid Endometrial Carcinoma: Omission of Adjuvant Therapy
Authors: Otsuka Isao
Published: September 2022

Endometrial cancer is the most common gynecological tract malignancy in developed countries, and its incidence has been increasing globally with rising obesity rates and longer life expectancy. In endometrial cancer, extrauterine disease, in particular lymph node metastasis, is an important prognostic factor. Nevertheless, pelvic lymphadenectomy is not considered to have a therapeutic benefit, as it did not improve survival in randomized studies. However, lymphadenectomy may have a therapeutic benefit if adjuvant therapy can be omitted without decreasing oncological outcomes, as the long-term quality of life is maintained by avoiding morbidities associated with adjuvant therapy. In intermediate- and high-risk endometrioid endometrial carcinomas, adjuvant therapy may be safely omitted without decreasing long-term survival by open surgery including systematic pelvic and para-aortic lymphadenectomy when patients are node-negative. Systematic lymphadenectomy may remove undetectable low-volume lymph node metastasis in both pelvic and para-aortic regions, and open surgery may reduce vaginal recurrence even without vaginal brachytherapy. However, lymphadenectomy may not improve survival in elderly patients and patients with p53-mutant tumors. In this review, I discuss the characteristics of lymph node metastasis, the methods of lymph node assessment, and the therapeutic benefits of systematic lymphadenectomy in patients with intermediate- and high-risk endometrioid endometrial carcinoma.