bluuebunny/crossref_metadata_2025 huggingface dataset:
I Can See It in Your Eyes: Gaze as an Implicit Cue of Uncanniness and Task Performance in Repeated Interactions With Robots
Authors: Perugia Giulia , Paetzel-Prüsmann Maike , Alanenpää Madelene , Castellano Ginevra
Published: April 2021

Over the past years, extensive research has been dedicated to developing robust platforms and data-driven dialog models to support long-term human-robot interactions. However, little is known about how people's perception of robots and engagement with them develop over time and how these can be accurately assessed through implicit and continuous measurement techniques. In this paper, we explore this by involving participants in three interaction sessions with multiple days of zero exposure in between. Each session consists of a joint task with a robot as well as two short social chats with it before and after the task. We measure participants' gaze patterns with a wearable eye-tracker and gauge their perception of the robot and engagement with it and the joint task using questionnaires. Results disclose that aversion of gaze in a social chat is an indicator of a robot's uncanniness and that the more people gaze at the robot in a joint task, the worse they perform. In contrast with most HRI literature, our results show that gaze toward an object of shared attention, rather than gaze toward a robotic partner, is the most meaningful predictor of engagement in a joint task. Furthermore, the analyses of gaze patterns in repeated interactions disclose that people's mutual gaze in a social chat develops congruently with their perceptions of the robot over time. These are key findings for the HRI community as they entail that gaze behavior can be used as an implicit measure of people's perception of robots in a social chat and of their engagement and task performance in a joint task.
IEEEVR2020: Exploring the First Steps Toward Standalone Virtual Conferences
Authors: Ahn Sun Joo (Grace) , Levy Laura , Eden Allison , Won Andrea Stevenson , MacIntyre Blair , Johnsen Kyle
Published: April 2021

The global COVID-19 pandemic forced all large in-person events to pivot to virtual or online platforms. IEEEVR2020 coincided with rising concerns and restrictions on travel and large gatherings, becoming one of the first academic conferences to rapidly adapt its programming to a completely virtual format. The global pandemic provided an impetus to re-examine the possibility of holding social interactions in virtual worlds. This article aims to: (1) revisit the issues of virtual conferences noted in earlier studies, focusing specifically on academic conferences, (2) introduce new survey and observational data from the recent IEEEVR2020 conference, and (3) present insights and future directions for virtual conferences during and after the COVID-19 pandemic. Findings from a field observation during the conference and a post-conference survey point to complex relationships among users, media platforms selected, and social constraints during the virtual conference.
Access to Maternal Health Services During the COVID-19 Pandemic: Experiences of Indigent Mothers and Health Care Providers in Kilifi County, Kenya
Authors: Ombere Stephen Okumu
Published: April 2021

COVID-19 has spread rapidly in Kenya and has not spared pregnant women. Evidence from Kenya shows that during the COVID-19 pandemic, health systems have been either stressed to their maximum capacity or are becoming overwhelmed. However, the population is advised not to attend hospital unless strictly necessary, and this advice seems to apply to all, including expectant mothers. There is a dearth of information on how poor expectant mothers with low bargaining power cope during COVID-19 in Kenya, which this study addresses for those in Kilifi County. This rapid qualitative study draws data from an extensive literature review and from interviews with 12 purposively selected mothers who were either expectant or had newborn babies during the pandemic in Kilifi County. Five matrons-in-charge of maternal health services and four traditional birth attendants were also interviewed via mobile phone. Data were analyzed thematically and are presented in a textual description. It emerged that expectant mothers feared attending hospitals for perinatal care due to the possibility of contracting COVID-19. Therefore, there was an increase in home deliveries with the assistance of traditional birth attendants (TBAs)/traditional midwives, who were also overwhelmed with women who sought their services. Since most causes of maternal morbidity and mortality can be prevented by prompt, suitable treatment by qualified health practitioners, the health officials interviewed recommended training and integration of TBAs in emergency healthcare responses to help during crises in MHS because they are trusted by their local communities. Notably, such integration of traditional midwives should be supported and should also include additional training and monetary incentives.
Dynamic Management of Lung Cancer Care During Surging COVID-19
Authors: Wang Annie , Chang Stephanie H. , Kim Eric J. , Bessich Jamie L. , Sabari Joshua K. , Cooper Benjamin , Geraci Travis C. , Cerfolio Robert J.
Published: April 2021

Management of patients with lung cancer continues to be challenging during the COVID-19 pandemic, due to the increased risk of complications in this subset of patients. During the COVID-19 surge in New York City, New York University Langone Health adopted triage strategies to help with care for lung cancer patients, with good surgical outcomes and no transmission of COVID-19 to patients or healthcare workers. Here, we will review current recommendations regarding screening and management of lung cancer patients during both a non-surge phase and surge phase of COVID-19.
Does Person Organization Fit and Person-Job Fit Mediate the Relationship between Public Service Motivation and Work Stress among U.S. Federal Employees?
Authors: Bright Leonard
Published: April 2021

A plethora of research has extolled the benefits of public service motivation (PSM) in public organizations. However, much less empirical attention has focused on its relationship to work stress. Even though it has been theorized that high levels of PSM causes individuals to be more resilient in stressful public service work environments, empirical research has failed to provide support. Only one study has been conducted which has revealed that high levels of PSM is directly associated with high levels of job stress among public employees, but that its beneficial effects are partially mediated by person-organization (PO) fit. That is, employees with high levels of PSM and high levels of fit to their organizations did not appear to suffer from high stress. This study sought to add to this limited body of research and explore the extent to which person-job (PJ) improves the field’s understanding of the relationships among PSM, PO fit, and work stress. Based on a sample of federal employees in the United States, this study challenged and confirmed the findings of existing research. For instance, PSM had no direct relationship to work stress. However, PSM maintained an indirect relationship to stress through PO fit. The respondents with high levels of PSM reported that they had high levels of fit to their organizations which was associated with significantly lower levels of work stress. Similarly, PSM was not directly related to PJ fit, but was indirectly related through its association with PO fit. PSM was associated with high levels of fit between employees and public organizations, which was subsequently associated with high levels of fit with public service jobs and lower work stress. Above all, this research clarifies the process of how PSM influences work stress among public employees, through PO fit and PJ fit.
The Impact of New Ways of Working on Organizations and Employees: A Systematic Review of Literature
Authors: Renard Karine , Cornu Frederic , Emery Yves , Giauque David
Published: April 2021

A new research stream emerged in the 2000s dedicated to flexible work arrangements in public and private organizations, called “new ways of working” (NWW). This article aims to examine NWW from both a theoretical and empirical perspective, focusing on definitional issues as well as on HR outcomes of this new concept. Current definitions of NWW are manifold and based on rather vague theoretical foundations. As NWW outcomes may be both positive and/or negative, we mobilize the “mutual gains” vs. “conflicting outcomes” theoretical debate to discuss the results of our literature review. This review is based on 21 articles (out of 90 initially selected for eligibility) dealing with NWW as a concept or as a bundle of practices. Findings demonstrate that NWW definitions are diverse and somewhat imprecise, lacking theoretical foundations and leading to fragmented research designs and findings. Findings also highlight the current lack of empirical data, which therefore does not allow any real conclusions on NWW’s effects on employees’ and organizations’ well-being and performance.
Knowledge, Perspectives, and Priorities Regarding Self-Care Activities: A Population-Based Qualitative Study among Iranian Adolescents
Authors: Mohammadzadeh Marjan , Alizadeh Tayebe , Awang Hamidin , Mohammadzadeh Zahra , Mirzaei Frahnaz , Stock Christiane
Published: April 2021

This qualitative study aimed to investigate knowledge, perspectives, and priorities related to self-care among Iranian adolescents. Through snowball sampling, the link to the questionnaire was shared in available social media apps. The results showed that 192 of 294 participants reported that they had heard about “self-care”. Parents/family and school were the most frequent sources of learning about self-care among the male and female respondents, respectively. Analyzing the participants’ statements regarding their own understanding of self-care activities, three major terms—“taking care of”, “avoid”, and “respect” were identified. When being ask about what they do for their own self-care, the results showed spending time on the Internet had the highest repetition rate among boys’ responses, followed by “going to gym”, “video games”, and “listening to music”. Regarding the desired activities, both girls’ and boys’ statements indicated that among leisure activities, “traveling” was the most frequent word, followed by being with friends. The girls showed more interest in attending night clubs or spending time outside the home late at night. Insights from this study identifying preferences in self-care activities can be used to develop intervention programs for Iranian adolescents to improve their lifestyle and, consequently, their well-being based on their needs and situation.
Four-Year Study on the Bio-Agronomic Response of Biotypes of Capparis spinosa L. on the Island of Linosa (Italy)
Authors: La Bella Salvatore , Rossini Francesco , Licata Mario , Virga Giuseppe , Ruggeri Roberto , Iacuzzi Nicolò , Leto Claudio , Tuttolomondo Teresa
Published: April 2021

The caper plant is widespread in Sicily (Italy) both wild in natural habitats and as specialized crops, showing considerable morphological variation. However, although contributing to a thriving market, innovation in caper cropping is low. The aim of the study was to evaluate agronomic and production behavior of some biotypes of Capparis spinosa L. subsp. rupestris, identified on the Island of Linosa (Italy) for growing purposes. Two years and seven biotypes of the species were tested in a randomized complete block design. The main morphological and production parameters were determined. Phenological stages were also observed. Analysis of variance showed high variability between the biotypes. Principal component analysis and cluster analysis highlighted a clear distinction between biotypes based on biometric and production characteristics. Production data collected in the two-year period 2007–2008 showed the greatest production levels in the third year following planting in 2005. In particular, biotype SCP1 had the highest average value (975.47 g) of flower bud consistency. Our results permitted the identification of biotypes of interest for the introduction into new caper fields. Further research is needed in order to characterize caper biotypes in terms of the chemical composition of the flower buds and fruits.
Can Grazing Moderate Climatic Effects on Herbage Nutritional Quality?
Authors: Dovrat Guy , Sheffer Efrat , Landau Serge Yan , Deutch Tova , Gorelik Haim , Henkin Zalmen
Published: April 2021

In Mediterranean grasslands, the composition of vegetation and its nutritional quality for animals are strongly affected by the climatic conditions prevailing during winter and spring. Therefore, these seasonal ecosystems provide an opportunity to examine how variability in climatic conditions affects the regeneration and quality of pasture vegetation. The intensity of grazing in this seasonal system can moderate, or alternatively exacerbate, climatic effects on the nutritional quality of the vegetation. Herein, we analyzed the interactive effects of climate variables, grazing intensity, and grazing exclusion on herbage quality parameters using long-term vegetation and climate data collected during 2005–2018 from an extensive experiment in Galilee, Israel. We evaluated the contribution of different climate variables to the prediction of herbage quality parameters. Our results showed that climate variables have a dramatic effect on herbage quality and that this effect interacts with grazing intensity. Herbage quality improved in temperate rainy years compared to warm and dry years. High grazing intensity improved herbage quality under temperate climate conditions, but this effect was moderated or completely disappeared as winter conditions become warmer and drier. The results of the study foresee negative effects of warming and drying on the carrying capacity of natural pastures.
V-Set and Immunoglobulin Domain-Containing 1 (VSIG1), Predominantly Expressed in Testicular Germ Cells, Is Dispensable for Spermatogenesis and Male Fertility in Mice
Authors: Jung Yena , Bang Hyewon , Kim Young-Hyun , Park Na-Eun , Park Young-Ho , Park Chaeli , Lee Sang-Rae , Lee Jeong-Woong , Song Bong-Seok , Kim Ji-Su , Sim Bo-Woong , Seol Dong-Won , Wee Gabbine , Kim Sunhyung , Kim Sun-Uk , Kim Ekyune
Published: April 2021

To elucidate the functional role of V-set and immunoglobulin domain-containing 1 (VSIG1) in spermatogenesis and fertilization, we knocked out (KO) VSIG1 in a mouse embryo using CRISPR/Cas9 (Clustered regularly interspaced short palindromic repeat/CRISPR-associated protein 9) -mediated genome editing. Reverse transcription PCR was performed using cDNA synthesized from VSIG1 KO testis RNA. Although Western blot analysis using a specific antibody to VSIG1 confirmed VSIG1 protein defects in the KO mice, hematoxylin-eosin staining analysis was similar in the KO and wild-type mice. Additionally, computer-assisted sperm analysis and in vitro fertilization experiments were conducted to confirm the activity and fertilization ability of sperm derived from the KO mouse. Mice lacking VSIG1 were viable and had no serious developmental defects. As they got older, the KO mice showed slightly higher weight loss, male mice lacking VSIG1 had functional testes, including normal sperm number and motility, and both male and female mice lacking VSIG1 were fertile. Our results from VSIG1 KO mice suggest that VSIG1 may not play essential roles in spermatogenesis and normal testis development, function, and maintenance. VSIG1 in sperm is dispensable for spermatogenesis and male fertility in mice. As several genes are known to possess slightly different functions depending on the species, the importance and molecular mechanism of VSIG1 in tissues of other species needs further investigation.
The Use of Chinese Skullcap (Scutellaria baicalensis) and Its Extracts for Sustainable Animal Production
Authors: Yin Baishuang , Li Wei , Qin Hongyu , Yun Jinyan , Sun Xuezhao
Published: April 2021

Drugs have been widely adopted in animal production. However, drug residues and bacterial resistance are a worldwide issue, and thus the most important organizations (FAO, USDA, EU, and EFSA) have limited or banned the use of some drugs and the use of antibiotics as growth promoters. Natural products such as medicinal herbs are unlikely to cause bacterial resistance and have no chemical residues. With these advantages, medicinal herbs have long been used to treat animal diseases and improve animal performance. In recent years, there has been an increasing interest in the study of medicinal herbs. S. baicalensis is a herb with a high medicinal value. The main active compounds are baicalin and baicalein. They may act as antipyretic, analgesic, anti-inflammatory, antiallergenic, antimicrobial, and antitumor agents. They also possess characteristics of being safe, purely natural, and not prone to drug resistance. S. baicalensis and its extracts can effectively promote the production performance of livestock and treat many animal diseases, such as mastitis. In this review, we summarize the active compounds, biological functions, and applications of S. baicalensis in the production of livestock and provide a guideline for the application of natural medicines in the production and treatment of diseases.
Meat Demand Monitor during COVID-19
Authors: Tonsor Glynn T. , Lusk Jayson L. , Tonsor Shauna L.
Published: April 2021

Meat products represent a significant share of US consumer food expenditures. The COVID-19 pandemic directly impacted both demand and supply of US beef and pork products for a prolonged period, resulting in a myriad of economic impacts. The complex disruptions create significant challenges in isolating and inferring consumer-demand changes from lagged secondary data. Thus, we turn to novel household-level data from a continuous consumer tracking survey, the Meat Demand Monitor, launched in February 2020, just before the US pandemic. We find diverse impacts across US households related to “hoarding” behavior and financial confidence over the course of the pandemic. Combined, these insights extend our understanding of pandemic impacts on US consumers and provide a timely example of knowledge enabled by ongoing and targeted household-level data collection and analysis.
Near-Surface Atmospheric Turbulence in the Presence of a Squall Line above a Forested and Deforested Region in the Central Amazon
Authors: Bezerra Valéria L. , Dias-Júnior Cléo Q. , Vale Roseilson S. , Santana Raoni A. , Botía Santiago , Manzi Antônio O. , Cohen Julia C. P. , Martins Hardiney S. , Chamecki Marcelo , Fuentes Jose D.
Published: April 2021

Squall lines (SLs) are convective systems that cause heavy precipitation and consequently modify the atmospheric thermodynamic structure near the surface. SLs generated along the northern coast of Brazil and their effect upon atmospheric structure during their westward displacement into the Amazon are studied. Satellite imagery was employed to identify an SL above two experimental sites in the central Amazon and to characterize differences in the near-surface turbulent and ozone exchange during the passage of the SLs. The two sites, which are separated by about 100 km, feature contrasting vegetation. One site is tall canopy rainforest and the other is deforested. From our case study, it is noted that: equivalent potential temperature significantly drops, principally in the forested region; the average near-surface wind speed increases 5 fold; the skewness of vertical wind velocity becomes considerably negative; significant increases in turbulence intensity are observed. These changes suggest the presence of strong downdrafts generated by the SL. Shear production and dissipation rate of turbulent kinetic energy are considerably larger during the SL when compared to periods with absence of SL. In this study, we show that SLs are capable of modifying the vertical organization of the turbulence over forested and deforested areas, leading to changes in certain chemical processes that occur near the surface. To the best of our knowledge, this study represents a first in demonstrating that near-surface turbulent flow in the Amazon region is modified by the presence of SLs.
Soybean Meal-Dependent Intestinal Inflammation Induces Different Patterns of Bone-Loss in Adult Zebrafish Scale
Authors: Carnovali Marta , Valli Roberto , Banfi Giuseppe , Porta Giovanni , Mariotti Massimo
Published: April 2021

Inflammatory bowel disease have been linked to several health issues, including high risk of low bone mineral density. Danio rerio (zebrafish) is a good model to verify the effects of intestinal inflammation, since its gastrointestinal and immune systems are closely related to that of mammalians. Zebrafish is also a powerful model to study bone metabolism using the scale as the read-out model. Food strongly impacts zebrafish gut physiology, and it is well known that soybean meal induces intestinal inflammation. Adult zebrafish fed with defatted soybean meal (SBM) exhibited an intestinal inflammation evidenced by morphological alterations, inflammatory infiltrate, and increased mRNA expression of inflammatory cytokines (IL-1β, IL-6, IL-8, IL-10, TGFβ, TNF-α). The peak of acute intestinal inflammation, spanning between week 2 and 3, correlates with a transitory osteoporosis-like phenotype in the scale border. Later, a chronic inflammatory condition, associated with persistent IL-8 expression, correlates with the progression of resorption lacunae in the scale center. Both types of resorption lacunae were associated with intense osteoclastic tartrate-resistant acid phosphatase (TRAP) activity. After 3 weeks of SBM treatment, osteoclast activity decreased in the scale border but not in the center. At the same time, alkaline phosphatase (ALP) is activated in the border to repair the bone matrix. This model can contribute to elucidate in vivo the molecular mechanisms that links intestinal inflammation and bone metabolism in IBD.
Paper-Based Biosensors: Frontiers in Point-of-Care Detection of COVID-19 Disease
Authors: Antiochia Riccarda
Published: April 2021

This review summarizes the state of the art of paper-based biosensors (PBBs) for coronavirus disease 2019 (COVID-19) detection. Three categories of PBB are currently being been used for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostics, namely for viral gene, viral antigen and antibody detection. The characteristics, the analytical performance, the advantages and drawbacks of each type of biosensor are highlighted and compared with traditional methods. It is hoped that this review will be useful for scientists for the development of novel PBB platforms with enhanced performance for helping to contain the COVID-19 outbreak, by allowing early diagnosis at the point of care (POC).
Immunomodulatory Effect of Microglia-Released Cytokines in Gliomas
Authors: Lanza Marika , Casili Giovanna , Campolo Michela , Paterniti Irene , Colarossi Cristina , Mare Marzia , Giuffrida Raffella , Caffo Maria , Esposito Emanuela , Cuzzocrea Salvatore
Published: April 2021

Microglia, a type of differentiated tissue macrophage, are considered to be the most plastic cell population of the central nervous system (CNS). Microglia substantially contribute to the growth and invasion of tumor mass in brain tumors including glioblastoma (GB). In response to pathological conditions, resting microglia undergo a stereotypic activation process and become capable of phagocytosis, antigen presentation, and lymphocyte activation. Considering their immune effector function, it is not surprising to see microglia accumulation in almost every CNS disease process, including malignant brain tumors. Large numbers of glioma associated microglia and macrophages (GAMs) can accumulate within the tumor where they appear to have an important role in prognosis. GAMs constitute the largest portion of tumor infiltrating cells, contributing up to 30% of the entire glioma mass and upon interaction with neoplastic cells. GAMs acquire a unique phenotype of activation, including both M1 and M2 specific markers. It has been demonstrated that microglia possess a dual role: on one hand, microglia may represent a CNS anti-tumor response, which is inactivated by local secretion of immunosuppressive factors by glioma cells. On the other hand, taking into account that microglia are capable of secreting a variety of immunomodulatory cytokines, it is possible that they are attracted by gliomas to promote tumor growth. A better understanding of microglia-glioma interaction will be helpful in designing novel immune-based therapies against these fatal tumors. Concluding, as microglia significantly may contribute to glioma biology, favoring tumor growth and invasiveness, these cells represent a valuable alternative/additional target for the development of more effective treatments for gliomas.
Calibrated Numerical Approach for the Dynamic Analysis of Glass Curtain Walls under Spheroconical Bag Impact
Authors: Bez Alessia , Bedon Chiara , Manara Giampiero , Amadio Claudio , Lori Guido
Published: April 2021

The structural design of glass curtain walls and facades is a challenging issue, considering that building envelopes can be subjected extreme design loads. Among others, the soft body impact (SBI) test protocol represents a key design step to protect the occupants. While in Europe the standardized protocol based on the pneumatic twin-tire (TT) impactor can be nowadays supported by Finite Element (FE) numerical simulations, cost-time consuming experimental procedures with the spheroconical bag (SB) impactor are still required for facade producers and manufacturers by several technical committees, for the impact assessment of novel systems. At the same time, validated numerical calibrations for SB are still missing in support of designers and manufacturers. In this paper, an enhanced numerical approach is proposed for curtain walls under SB, based on a coupled methodology inclusive of a computationally efficient two Degree of Freedom (2-DOF) and a more geometrically accurate Finite Element (FE) model. As shown, the SB impactor is characterized by stiffness and dissipation properties that hardly match with ideal rigid elastic assumptions, nor with the TT features. Based on a reliable set of experimental investigations and records, the proposed methodology acts on the time history of the imposed load, which is implicitly calibrated to account for the SB impactor features, once the facade features (flexibility and damping parameters) are known. The resulting calibration of the 2-DOF modelling parameters for the derivation of time histories of impact force is achieved with the support of experimental measurements and FE model of the examined facade. The potential and accuracy of the method is emphasized by the collected experimental and numerical comparisons. Successively, the same numerical approach is used to derive a series of iso-damage curves that could support practical design calculations.
Combined Assessment of Immune Checkpoint Regulator VISTA on Tumor-Associated Immune Cells and Platelet-to-Lymphocyte Ratio Identifies Advanced Germ Cell Tumors with Higher Risk of Unfavorable Outcomes
Authors: Pęksa Rafał , Kunc Michał , Popęda Marta , Piątek Michał , Bieńkowski Michał , Żok Jolanta , Starzyńska Anna , Perdyan Adrian , Sowa Marek , Duchnowska Renata , Biernat Wojciech
Published: April 2021

In the current study, we aimed to investigate whether expression of immune checkpoint proteins (V-domain Ig suppressor of T cell activation (VISTA) and programmed death-ligand 1 (PD-L1)) and markers of systemic inflammation could predict progression/relapse and death in the cohort of 180 patients with testicular germ-cell tumors (GCTs). Expression of PD-L1 and VISTA was assessed by immunohistochemistry utilizing tissue microarrays. To estimate systemic inflammation neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) were calculated. We found high PD-L1 and VISTA expression on tumor-associated immune cells (TAICs) in 89 (49.44%) and 63 (37.22%) of GCTs, respectively, whereas tumor cells besides trophoblastic elements were almost uniformly negative. High PD-L1 was associated with seminomatous histology and lower stage. Relapses in stage I patients occurred predominantly in cases with low numbers of PD-L1 and VISTA-expressing TAICs. In stage II/III disease, the combination of low VISTA-expressing TAICs and high PLR was identified as predictor of shorter event-free survival (HR 4.10; 1.48–11.36, p = 0.006) and overall survival (HR 15.56, 95% CI 1.78–135.51, p = 0.001) independently of tumor histology and location of metastases. We demonstrated that the assessment of immune checkpoint proteins on TAICs may serve as a valuable prognostic factor in patients with high-risk testicular GCTs. Further study is warranted to explore the predictive utility of these biomarkers in GCTs.
Psychotherapy with Music Intervention Improves Anxiety, Depression and the Redox Status in Breast Cancer Patients Undergoing Radiotherapy: A Randomized Controlled Clinical Trial
Authors: Zeppegno Patrizia , Krengli Marco , Ferrante Daniela , Bagnati Marco , Burgio Vincenzo , Farruggio Serena , Rolla Roberta , Gramaglia Carla , Grossini Elena
Published: April 2021

The aim of this study was to assess the effects of psychotherapy with music intervention (PMI) on anxiety, depression, redox status, and inflammation in breast cancer patients undergoing radiotherapy (RT). This monocentric randomized clinical trial recruited 60 patients who had a breast cancer operation and were undergoing postoperative RT. Eligible patients were randomized (1:1) in two groups: the control group (CG) received treatment as usual (n = 30), i.e., RT alone; the intervention group (PMI) received RT and psychotherapy with music intervention (n = 30), which was delivered in a group setting. Five patients were excluded after randomization. Assessments were performed at baseline (T0), at the end of RT (T1), and three months after the end of RT (T2). The main objectives of the study were the assessment of anxiety/depression, plasma glutathione (GSH), and thiobarbituric acid reactive substances (TBARS) in the two arms of the study. Our findings revealed a positive effect of PMI on anxiety, depression, resilience, and quality of life. Furthermore, a positive effect of PMI on redox status was found for the first time. Thus, in the PMI group, we found a significant increase of GSH (mean change 2.2 95%, CI 0.7 to 3.7) and a significant reduction of TBARS (mean change −1.1 95%, CI −1.8 to −0.3) at T2 vs. T0.
Incidence and Survival Outcomes in Patients with Lung Neuroendocrine Neoplasms in the United States
Authors: Shah Shrunjal , Gosain Rohit , Groman Adrienne , Gosain Rahul , Dasari Arvind , Halfdanarson Thorvardur R. , Mukherjee Sarbajit
Published: April 2021

Background: The incidence and prevalence of neuroendocrine neoplasms (NENs) are rapidly rising. Epidemiologic trends have been reported for common NENs, but specific data for lung NENs are lacking. Methods: We conducted a retrospective analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Associated population data were utilized to report the annual age-adjusted incidence and overall survival (OS) trends. Trends for large-cell neuroendocrine carcinoma (LCNEC) and atypical carcinoid (AC) were reported from 2000–2015, while those for typical carcinoid (TC) and small cell lung cancer (SCLC) were reported from 1988–2015. Results: We examined a total of 124,969 lung NENs [103,890—SCLC; 3303—LCNEC; 8146—TC; 656—AC; 8974—Other]. The age-adjusted incidence rate revealed a decline in SCLC from 8.6 in 1988 to 5.3 in 2015 per 100,000; while other NENs showed an increase: TC increased from 0.57 in 1988 to 0.77 in 2015, AC increased from 0.17 in 2001 to 0.22 in 2015, and LCNEC increased from 0.16 in 2000 to 0.41 in 2015. The 5-year OS rate among SCLC, LCNEC, AC, and TC patients was 5%, 17%, 64%, and 84%, respectively. On multivariable analyses, OS and disease-specific survival (DSS) varied significantly by stage, sex, histological type, insurance type, marital status, and race, with a better survival noted in earlier stages, females, married, insured, Hispanic and other races, and urban population. Similarly, TC and AC had better survival compared to SCLC and LCNEC. Conclusion: The incidence of lung NENs is rising, possibly in part because of advanced radiological techniques. However, the incidence of SCLCs is waning, likely because of declining smoking habits. Such population-based studies are essential for resource allocation and to prioritize future research directions.
Systematic Review of Recurrent Osteosarcoma Systemic Therapy
Authors: Gazouli Ioanna , Kyriazoglou Anastasios , Kotsantis Ioannis , Anastasiou Maria , Pantazopoulos Anastasios , Prevezanou Maria , Chatzidakis Ioannis , Kavourakis Georgios , Economopoulou Panagiota , Kontogeorgakos Vasileios , Papagelopoulos Panayiotis , Psyrri Amanda
Published: April 2021

Osteosarcoma is the most frequent primary bone cancer, mainly affecting those of young ages. Although surgery combined with cytotoxic chemotherapy has significantly increased the chances of cure, recurrent and refractory disease still impose a tough therapeutic challenge. We performed a systematic literature review of the available clinical evidence, regarding treatment of recurrent and/or refractory osteosarcoma over the last two decades. Among the 72 eligible studies, there were 56 prospective clinical trials, primarily multicentric, single arm, phase I or II and non-randomized. Evaluated treatment strategies included cytotoxic chemotherapy, tyrosine kinase and mTOR inhibitors and other targeted agents, as well as immunotherapy and combinatorial approaches. Unfortunately, most treatments have failed to induce objective responses, albeit some of them may sustain disease control. No driver mutations have been recognized, to serve as effective treatment targets, and predictive biomarkers of potential treatment effectiveness are lacking. Hopefully, ongoing and future clinical and preclinical research will unlock the underlying biologic mechanisms of recurrent and refractory osteosarcoma, expanding the therapeutic choices available to pre-treated osteosarcoma patients.
Rituximab-Containing Risk-Adapted Treatment Strategy in Nodular Lymphocyte Predominant Hodgkin Lymphoma: 7-Years Follow-Up
Authors: Pugliese Novella , Picardi Marco , Della Pepa Roberta , Giordano Claudia , Muriano Francesco , Leone Aldo , Delle Cave Giuseppe , D’Ambrosio Alessandro , Marafioti Violetta , Rascato Maria Gabriella , Russo Daniela , Mascolo Massimo , Pane Fabrizio
Published: April 2021

Background: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare variant of HL that accounts for 5% of all HL cases. The expression of CD20 on neoplastic lymphocytes provides a suitable target for novel treatments based on Rituximab. Due to its rarity, consolidated and widely accepted treatment guidelines are still lacking for this disease. Methods: Between 1 December 2007 and 28 February 2018, sixteen consecutive newly diagnosed adult patients with NLPHL received Rituximab (induction ± maintenance)-based therapy, according to the baseline risk of German Hodgkin Study Group prognostic score system. The treatment efficacy and safety of the Rituximab-group were compared to those of a historical cohort of 12 patients with NLPHL who received Doxorubicin, Bleomycin, Vinblastine, Dacarbazine (ABVD) chemotherapy followed by radiotherapy (RT), if needed, according to a similar baseline risk. The primary outcome was progression-free survival (PFS) and secondary outcomes were overall survival (OS) and side-effects (according to the Common Terminology Criteria for Adverse Events, v4.03). Results: After a 7-year follow-up (range, 1–11 years), PFS was 100% for patients treated with the Rituximab-containing regimen versus 66% for patients of the historical cohort (p = 0.036). Four patients in the latter group showed insufficient response to therapy. The PFS for early favorable and early unfavorable NLPHLs was similar between treatment groups, while a better PFS was recorded for advanced-stages treated with the Rituximab-containing regimen. The OS was similar for the two treatment groups. Short- and long-term side-effects were more frequently observed in the historical cohort. Grade ≥3 neutropenia was more frequent in the historical cohort compared with the Rituximab-group (58.3% vs. 18.7%, respectively; p = 0.03). Long-term non-hematological toxicities were observed more frequently in the historical cohort. Conclusion: Our results confirm the value of Rituximab in NLPHL therapy and show that Rituximab (single-agent) induction and maintenance in a limited-stage, or Rituximab with ABVD only in the presence of risk factors, give excellent results while sparing cytotoxic agent- and/or RT-related damage. Furthermore, Rituximab inclusion in advanced-stage therapeutic strategy seems to improve PFS compared to conventional chemo-radiotherapy.
Digital Gene Expression Analysis of Epithelioid and Sarcomatoid Mesothelioma Reveals Differences in Immunogenicity
Authors: Brcic Luka , Mathilakathu Alexander , Walter Robert F. H. , Wessolly Michael , Mairinger Elena , Beckert Hendrik , Kreidt Daniel , Steinborn Julia , Hager Thomas , Christoph Daniel C. , Kollmeier Jens , Mairinger Thomas , Wohlschlaeger Jeremias , Schmid Kurt Werner , Borchert Sabrina , Mairinger Fabian D.
Published: April 2021

Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with asbestos exposure. Median survival ranges from 14 to 20 months after initial diagnosis. As of November 2020, the FDA approved a combination of immune checkpoint inhibitors after promising intermediate results. Nonetheless, responses remain unsatisfying. Adequate patient stratification to improve response rates is still lacking. This retrospective study analyzed formalin fixed paraffin embedded specimens from a cohort of 22 MPM. Twelve of those samples showed sarcomatoid, ten epithelioid differentiation. Complete follow-up, including radiological assessment of response by modRECIST and time to death, was available with reported deaths of all patients. RNA of all samples was isolated and subjected to digital gene expression pattern analysis. Our study revealed a notable difference between epithelioid and sarcomatoid mesothelioma, showing differential gene expression for 304/698 expressed genes. Whereas antigen processing and presentation to resident cytotoxic T cells as well as phagocytosis is highly affected in sarcomatoid mesothelioma, cell–cell interaction via cytokines seems to be of greater importance in epithelioid cases. Our work reveals the specific role of the immune system within the different histologic subtypes of MPM, providing a more detailed background of their immunogenic potential. This is of great interest regarding therapeutic strategies including immunotherapy in mesothelioma.
Tumor Signature Analysis Implicates Hereditary Cancer Genes in Endometrial Cancer Development
Authors: Kondrashova Olga , Shamsani Jannah , O’Mara Tracy A. , Newell Felicity , Reed Amy E. McCart , Lakhani Sunil R. , Kirk Judy , Pearson John V. , Waddell Nicola , Spurdle Amanda B.
Published: April 2021

Risk of endometrial cancer (EC) is increased ~2-fold for women with a family history of cancer, partly due to inherited pathogenic variants in mismatch repair (MMR) genes. We explored the role of additional genes as explanation for familial EC presentation by investigating germline and EC tumor sequence data from The Cancer Genome Atlas (n = 539; 308 European ancestry), and germline data from 33 suspected familial European ancestry EC patients demonstrating immunohistochemistry-detected tumor MMR proficiency. Germline variants in MMR and 26 other known/candidate EC risk genes were annotated for pathogenicity in the two EC datasets, and also for European ancestry individuals from gnomAD as a population reference set (n = 59,095). Ancestry-matched case–control comparisons of germline variant frequency and/or sequence data from suspected familial EC cases highlighted ATM, PALB2, RAD51C, MUTYH and NBN as candidates for large-scale risk association studies. Tumor mutational signature analysis identified a microsatellite-high signature for all cases with a germline pathogenic MMR gene variant. Signature analysis also indicated that germline loss-of-function variants in homologous recombination (BRCA1, PALB2, RAD51C) or base excision (NTHL1, MUTYH) repair genes can contribute to EC development in some individuals with germline variants in these genes. These findings have implications for expanded therapeutic options for EC cases.
RGL2 Drives the Metastatic Progression of Colorectal Cancer via Preventing the Protein Degradation of β-Catenin and KRAS
Authors: Sun Meng-Shun , Yuan Lan-Ting , Kuei Chia-Hao , Lin Hui-Yu , Chen Yen-Lin , Chiu Hui-Wen , Lin Yuan-Feng
Published: April 2021

Colorectal cancer (CRC) is one of the most common cancers and results in high mortality worldwide, owing to cancer progression, i.e., metastasis. However, the molecular mechanism underlying the metastatic evolution of CRC remains largely unknown. Here, we find that the upregulation of Ral Guanine Nucleotide Dissociation Stimulator Like 2 (RGL2) is commonly detected in primary tumors compared normal tissues and is significantly associated with a poorer prognosis in CRC patients. Moreover, RGL2 expression appeared to positively correlate with the metastatic potentials of CRC cells. Whereas RGL2 knockdown dramatically suppresses the metastatic potentials of CRC cells in vitro and in vivo, RGL2 overexpression in the poorly metastatic CRC cells and reconstitution in the RGL2-silenced CRC cells enhanced and rescued the cellular metastatic ability, respectively. Computational simulation using Gene Set Enrichment Analysis program and cell-based assays demonstrated that RGL2 expression causally associated with the activity of Wnt/β-catenin signaling axis and Kirsten ras (KRAS)S, as well as the progression of epithelial-mesenchymal transition (EMT) in the detected CRC cells. Importantly, RGL2 upregulation was capable of preventing the protein degradation of β-catenin and KRAS in CRC cells. These findings suggest that RGL2 acts as a driver to promote the metastatic progression of CRC and also serves as a poor prognostic biomarker in CRC patients.
Towards an Image-Informed Mathematical Model of In Vivo Response to Fractionated Radiation Therapy
Authors: Hormuth David A. , Jarrett Angela M. , Davis Tessa , Yankeelov Thomas E.
Published: April 2021

Fractionated radiation therapy is central to the treatment of numerous malignancies, including high-grade gliomas where complete surgical resection is often impractical due to its highly invasive nature. Development of approaches to forecast response to fractionated radiation therapy may provide the ability to optimize or adapt treatment plans for radiotherapy. Towards this end, we have developed a family of 18 biologically-based mathematical models describing the response of both tumor and vasculature to fractionated radiation therapy. Importantly, these models can be personalized for individual tumors via quantitative imaging measurements. To evaluate this family of models, rats (n = 7) with U-87 glioblastomas were imaged with magnetic resonance imaging (MRI) before, during, and after treatment with fractionated radiotherapy (with doses of either 2 Gy/day or 4 Gy/day for up to 10 days). Estimates of tumor and blood volume fractions, provided by diffusion-weighted MRI and dynamic contrast-enhanced MRI, respectively, were used to calibrate tumor-specific model parameters. The Akaike Information Criterion was employed to select the most parsimonious model and determine an ensemble averaged model, and the resulting forecasts were evaluated at the global and local level. At the global level, the selected model’s forecast resulted in less than 16.2% error in tumor volume estimates. At the local (voxel) level, the median Pearson correlation coefficient across all prediction time points ranged from 0.57 to 0.87 for all animals. While the ensemble average forecast resulted in increased error (ranging from 4.0% to 1063%) in tumor volume predictions over the selected model, it increased the voxel wise correlation (by greater than 12.3%) for three of the animals. This study demonstrates the feasibility of calibrating a model of response by serial quantitative MRI data collected during fractionated radiotherapy to predict response at the conclusion of treatment.
BTLA/HVEM Axis Induces NK Cell Immunosuppression and Poor Outcome in Chronic Lymphocytic Leukemia
Authors: Sordo-Bahamonde Christian , Lorenzo-Herrero Seila , Gonzalez-Rodriguez Ana P , R. Payer Ángel , González-García Esther , López-Soto Alejandro , Gonzalez Segundo
Published: April 2021

Chronic lymphocytic leukemia (CLL) is characterized by progressive immunosuppression and diminished cancer immunosurveillance. Immune checkpoint blockade (ICB)-based therapies, a major breakthrough against cancer, have emerged as a powerful tool to reinvigorate antitumor responses. Herein, we analyzed the role of the novel inhibitory checkpoint BTLA and its ligand, HVEM, in the regulation of leukemic and natural killer (NK) cells in CLL. Flow cytometry analyses showed that BTLA expression is upregulated on leukemic cells and NK cells from patients with CLL, whereas HVEM is downregulated only in leukemic cells, especially in patients with advanced Rai-Binet stage. In silico analysis revealed that increased HVEM, but not BTLA, mRNA expression in leukemic cells correlated with diminished overall survival. Further, soluble BTLA (sBTLA) was found to be increased in the sera of patients with CLL and highly correlated with poor prognostic markers and shorter time to treatment. BTLA blockade with an anti-BTLA monoclonal antibody depleted leukemic cells and boosted NK cell-mediated responses ex vivo by increasing their IFN-γ production, cytotoxic capability, and antibody-dependent cytotoxicity (ADCC). In agreement with an inhibitory role of BTLA in NK cells, surface BTLA expression on NK cells was associated with poor outcome in patients with CLL. Overall, this study is the first to bring to light a role of BTLA/HVEM in the suppression of NK cell-mediated immune responses in CLL and its impact on patient’s prognosis, suggesting that BTLA/HVEM axis may be a potential therapeutic target in this disease.