bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase II Trial of Guadecitabine in Children and Adults with SDH-Deficient GIST, Pheochromocytoma, Paraganglioma, and HLRCC-Associated Renal Cell Carcinoma
Authors: Ligon John A. , Sundby R. Taylor , Wedekind Mary F. , Arnaldez Fernanda I. , Del Rivero Jaydira , Wiener Lori , Srinivasan Ramaprasad , Spencer Melissa , Carbonell Amanda , Lei Haiyan , Shern John , Steinberg Seth M. , Figg William D. , Peer Cody J. , Zimmerman Sara , Moraly Josquin , Xu Xia , Fox Stephen , Chan King , Barbato Michael I. , Andresson Thorkell , Taylor Naomi , Pacak Karel , Killian J. Keith , Dombi Eva , Linehan W. Marston , Miettinen Markku , Piekarz Richard , Helman Lee J. , Meltzer Paul , Widemann Brigitte , Glod John 
Published: October 2022

Abstract

Purpose:
Succinate dehydrogenase (dSDH)-deficient tumors, including pheochromocytoma/paraganglioma, hereditary leiomyomatosis and renal cell cancer–associated renal cell carcinoma (HLRCC-RCC), and gastrointestinal stromal tumors (GIST) without KIT or platelet-derived growth factor receptor alpha mutations are often resistant to cytotoxic chemotherapy, radiotherapy, and many targeted therapies. We evaluated guadecitabine, a dinucleotide containing the DNA methyltransferase inhibitor decitabine, in these patient populations.

Patients and Methods:
Phase II study of guadecitabine (subcutaneously, 45 mg/m2/day for 5 consecutive days, planned 28-day cycle) to assess clinical activity (according to RECISTv.1.1) across three strata of patients with dSDH GIST, pheochromocytoma/paraganglioma, or HLRCC-RCC. A Simon optimal two-stage design (target response rate 30% rule out 5%) was used. Biologic correlates (methylation and metabolites) from peripheral blood mononuclear cells (PBMC), serum, and urine were analyzed.

Results:
Nine patients (7 with dSDH GIST, 1 each with paraganglioma and HLRCC-RCC, 6 females and 3 males, age range 18–57 years) were enrolled. Two patients developed treatment-limiting neutropenia. No partial or complete responses were observed (range 1–17 cycles of therapy). Biologic activity assessed as global demethylation in PBMCs was observed. No clear changes in metabolite concentrations were observed.

Conclusions:
Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. Although 4 of 9 patients had prolonged stable disease, there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, although signs of biologic activity were noted.
Cellular Senescence Is Immunogenic and Promotes Antitumor Immunity
Authors: Marin Ines , Boix Olga , Garcia-Garijo Andrea , Sirois Isabelle , Caballe Adrià , Zarzuela Eduardo , Ruano Irene , Attolini Camille Stephan-Otto , Prats Neus , López-Domínguez José A , Kovatcheva Marta , Garralda Elena , Muñoz Javier , Caron Etienne , Abad María , Gros Alena , Pietrocola Federico , Serrano Manuel 
Published: October 2022

Abstract

Cellular senescence is a stress response that activates innate immune cells, but little is known about its interplay with the adaptive immune system. Here, we show that senescent cells combine several features that render them highly efficient in activating dendritic cells (DC) and antigen-specific CD8 T cells. This includes the release of alarmins, activation of IFN signaling, enhanced MHC class I machinery, and presentation of senescence-associated self-peptides that can activate CD8 T cells. In the context of cancer, immunization with senescent cancer cells elicits strong antitumor protection mediated by DCs and CD8 T cells. Interestingly, this protection is superior to immunization with cancer cells undergoing immunogenic cell death. Finally, the induction of senescence in human primary cancer cells also augments their ability to activate autologous antigen-specific tumor-infiltrating CD8 lymphocytes. Our study indicates that senescent cancer cells can be exploited to develop efficient and protective CD8-dependent antitumor immune responses.

Significance:
Our study shows that senescent cells are endowed with a high immunogenic potential—superior to the gold standard of immunogenic cell death. We harness these properties of senescent cells to trigger efficient and protective CD8-dependent antitumor immune responses.
See related article by Chen et al., p. 432.
This article is highlighted in the In This Issue feature, p. 247
Increased CaMKK2 Expression Is an Adaptive Response That Maintains the Fitness of Tumor-Infiltrating Natural Killer Cells
Authors: Juras Patrick K. , Racioppi Luigi , Mukherjee Debarati , Artham Sandeep , Gao Xia , Akullian D'Agostino Laura , Chang Ching-Yi , McDonnell Donald P. 
Published: October 2022

Abstract

Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in several cell types. Expression of this enzyme in tumor cells promotes proliferation and migration, and expression in tumor-associated immune cells facilitates M2 macrophage polarization and the development of myeloid-derived suppressor cells. Thus, there has been interest in developing CaMKK2 inhibitors as potential anticancer therapeutics. One impediment to clinical development of these agents is that the roles of CaMKK2 in other cellular compartments within the tumor immune microenvironment remain to be established. We report herein that CaMKK2 is expressed at low basal levels in natural killer (NK) cells but is upregulated in tumor-infiltrating NK cells where it suppresses apoptosis and promotes proliferation. NK cell–intrinsic deletion of CaMKK2 increased metastatic progression in several murine models, establishing a critical role for this enzyme in NK cell–mediated antitumor immunity. Ablation of the CaMKK2 protein, but not inhibition of its kinase activity, resulted in decreased NK-cell survival. These results indicate an important scaffolding function for CaMKK2 in NK cells and suggest that competitive CaMKK2 inhibitors and ligand-directed degraders (LDD) are likely to have distinct therapeutic utilities. Finally, we determined that intracellular lactic acid is a key driver of CaMKK2 expression, suggesting that upregulated expression of this enzyme is an adaptive mechanism by which tumor-infiltrating NK cells mitigate the deleterious effects of a lactic acid–rich tumor microenvironment. The findings of this study should inform strategies to manipulate the CaMKK2-signaling axis as a therapeutic approach in cancer.
Real‐Time Magnetic Resonance Imaging to Study Orthostatic Intolerance Mechanisms in Human Beings: Proof of Concept
Authors: Gerlach Darius A. , Maier Andrea , Manuel Jorge , Bach Anja , Hoff Alex , Hönemann Jan‐Niklas , Heusser Karsten , Voit Dirk , Frahm Jens , Jordan Jens , Tank Jens 
Published: October 2022

Background
Discerning the mechanisms driving orthostatic symptoms in human beings remains challenging. Therefore, we developed a novel approach combining cardiac and cerebral real‐time magnetic resonance imaging, beat‐to‐beat physiological monitoring, and orthostatic stress testing through lower‐body negative pressure (LBNP). We conducted a proof‐of‐concept study in a patient with severe orthostatic hypotension.

Methods and Results

We included a 46‐year‐old man with pure autonomic failure. Without and during −30
mmHg LBNP
, we obtained
3T
real‐time magnetic resonance imaging of the cardiac short axis and quantitative flow measurements in the pulmonary trunk and middle cerebral artery. Blood pressure was 118/74
mmHg
during supine rest and 58/35
mmHg
with
LBNP
. With
LBNP
, left ventricular stroke volume decreased by 44.6%, absolute middle cerebral artery flow by 37.6%, and pulmonary trunk flow by 40%.

Conclusions

Combination of real‐time magnetic resonance imaging,
LBNP
, and continuous blood pressure monitoring provides a promising new approach to study orthostatic intolerance mechanisms in human beings.
Social Isolation and Implementation of Advanced Care Planning Among Hospitalized Patients With Heart Failure
Authors: Kitakata Hiroki , Kohno Takashi , Kohsaka Shun , Fujisawa Daisuke , Nakano Naomi , Sekine Otoya , Shiraishi Yasuyuki , Kishino Yoshikazu , Katsumata Yoshinori , Yuasa Shinsuke , Fukuda Keiichi 
Published: October 2022

Background
The implementation of advance care planning (ACP) in heart failure management is insufficient. Social isolation (SI) could be a barrier to ACP initiation, albeit the relationship between SI and patients' preference for ACP or end‐of‐life care remains unknown.

Methods and Results

We conducted a questionnaire survey, including assessments of SI using the 6‐item Lubben Social Network Scale as well as patients' perspectives on ACP and end‐of‐life care. Of the 160 patients approached by our multidisciplinary heart failure team during admission, 120 patients (75.0%) completed the survey (median age, 73.0 years; men, 74.2%). A Cox proportional hazard model was constructed to elucidate the short‐term (180‐day) prognostic impact of SI. Overall, 28.3% of participants were at high risk for SI (6‐item Lubben Social Network Scale score <12). High‐risk patients had more negative attitudes toward ACP than those without (61.8% versus 80.2%;
P
=0.035). The actual performance of ACP conversation in patients with and without high risk were 20.6% and 30.2%, respectively. Regarding preference in end‐of‐life care, “Saying what one wants to tell loved ones” (73.5% versus 90.6%;
P
=0.016) and “Spending enough time with family” (58.8% versus 77.9%;
P
=0.035) were less important in high‐risk patients. High risk for SI was associated with higher 180‐day risk‐adjusted all‐cause mortality (hazard ratio, 7.89 [95% CI, 1.53–40.75]).

Conclusions
In hospitalized patients with heart failure, high risk for SI was frequently observed. High‐risk patients were associated with a negative attitude toward ACP, despite higher mortality. Further research is required to establish an ideal approach to provide ACP in socially vulnerable patients.
Redefining Disability: Patient-Reported Outcome Measures After Minor Stroke and Transient Ischemic Attack
Authors: Olive-Gadea Marta , Cano David , Rodrigo-Gisbert Marc , Muchada Marian , Montiel Estefania , Baladas Maria , Sanchez-Gavilan Ester , Paredes Carolina , Garcia-Tornel Alvaro , Rubiera Marta , Requena Manuel , Ribo Marc , Molina Carlos A. 
Published: October 2022

Background:
Long-term outcome assessment patients with stroke is not fully captured by usual clinical scales such as the modified Rankin Scale (mRS). Patient-reported outcome measures (PROMs) are standardized and validated assessments that consider clinical outcomes from the patient perspective. We aim to analyze the added value of PROMs in patients with transient ischemic attack and minor stroke.

Methods:
We included consecutive patients with minor stroke or transient ischemic attack (National Institutes of Health Stroke Scale score 0–5) from April 2020 to October 2021 that participated in the PROMs-through-App program (NORA, NoraHealth Barcelona Spain). Clinician and self-evaluated outcomes were assessed at 90 days: clinician-evaluated mRS, self-reported mRS, the 10-item patient-reported outcome measures questionnaire global health survey (v1.2), Hospital Anxiety and Depression Scale, and the Fatigue Assessment Scale. We evaluated the acceptability (response rate), reliability (internal consistency), and construct validity (correlation with mRS and between scales) of each questionnaire.

Results:
We included 355 patients in the analysis, response rate was patient-reported outcome measures questionnaire 71.3% (253), Hospital Anxiety and Depression Scale 70.7% (251), Fatigue Assessment Scale 71.8% (255), and self-assessed mRS 66.8% (237). PROMS internal consistency was good or excellent, while agreement between clinician and self-reported mRS was fair (k=0.34). Rate of abnormal PROMS scores were as follows (all responders versus clinician-reported mRS score 0–2): patient-reported outcome measures questionnaire mental health (43.1% versus 36.3%), physical health (48.6% versus 43.6%); Hospital Anxiety and Depression Scale-anxiety (21.9% versus 17.7%) and depression (17.1% versus 13.3%); and Fatigue Assessment Scale (40.8% versus 36.4%). PROMs scores correlated with clinician and self-reported mRS at 90 days.

Conclusions:
Evaluation of PROMs using a mobile-app-based communication system is a reliable and valid strategy to assess the outcome of patients from their perspective after a mild stroke or transient ischemic attack.
Determinants of Job Satisfaction among Doctorate Holders: Focusing on the Relationship between Over-Education and Job Satisfaction in South Korea
Authors: Park Kihong 
Published: October 2022

Abstract
This study aims to analyze the determinants of job satisfaction among doctorate holders in South Korea, with a particular focus on the relationship between over-education and job satisfaction. Unlike most previous studies, this paper considers overall job satisfaction as well as six different domains of job satisfaction (promotion opportunities, intellectual challenge, level of responsibility, level of autonomy, contribution to society, and social status) using data from the Korean Survey on Careers and Mobility of Doctorate Holders of 2017. This multi-dimensional approach to job satisfaction is important since the nature of job satisfaction is a complex concept in general. The main result of an ordered probit model reveals that perceived over-education is found to be a significant negative determinant of overall job satisfaction as well as all six aspects of job satisfaction, suggesting that over-educated doctorate holders are more dissatisfied with various aspects of their job compared to their well-matched counterparts.
Influence of Rural Industrial Integration on Farmers’ Income in China
Authors: Su Guibin , Jiang Huiming 
Published: October 2022

Abstract
Rural transportation infrastructure is an important foundation for rural economic development and plays an important role in the process of rural industrial integration to increase farmers’ income. Based on China’s inter-provincial panel data from 2014 to 2019, this paper classifies rural transportation infrastructure from the perspective of external connection level, and empirically analyzes the role of the scale, type, and structure of rural transportation infrastructure in the process of rural industrial integration to increase farmers’ income. It is found that in China, rural industrial integration is conducive to increasing farmers’ income. In the process of rural industrial integration to increase farmers’ income, the overall scale of rural transportation infrastructure has played a synergistic role; Different types of rural transportation infrastructure play different roles. Township-village transportation infrastructure mainly shows synergy, while city-township transportation infrastructure mainly shows substitution. Optimizing rural transportation infrastructure structure is conducive to strengthening rural industrial integration and increasing farmers’ income. When the ratio of township-village and city-township transportation infrastructure scale is less than 1.921, rural industrial integration fails to increase farmers’ income; When the ratio of rural-village and urban-rural transportation infrastructure is between 1.921 and 7.808, the promotion of rural industrial integration on farmers’ income increase begins to be significant; When the ratio of rural-village to urban-rural transportation infrastructure is greater than 7.808, the promotion of rural industrial integration on farmers’ income will further increase.
Attraction of leaf hopper, Amrasca biguttulla biguttulla, and whitefly, Bemisia tabaci, toward natural essential oils in cotton
Authors: T N Madhu , Kumar Rishi , Naik V. Chinnababu , Prabhulinga T. , Santosh Savitha , Chandrashekar N. , Verma Pooja 
Published: October 2022

Abstract
Leaf hopper, Amrasca biguttula biguttula, and whitefly, Bemisia tabaci are the most economical sucking pests of cotton (Gossypium spp.) causing stunting, shortening of internodes and transmitting plant pathogenic viruses. The management of these pests is primarily based on application of synthetic pesticides, which not only triggers resistance to insecticide molecules but also contributes to environmental pollution. We aimed to study the attraction of A. biguttula and B. tabaci toward six natural essential oils (NEOs) viz., sandalwood, basil, grapefruit, rose, clove and mint oils using yellow sticky traps under field conditions. The results showed that traps treated with sandalwood and basil oils attract significant numbers of A. biguttula and B. tabaci as compared to the other traps during the seasons 2016-2017 and 2017-2018. Further, the Attractive Index (AI) of sandalwood and basil oils to these pests were significantly higher (i.e., >1). In addition, the traps treated with sandalwood and basil oils caught relatively lower numbers of natural enemies. The GC-MS analysis specified the presence of vital attractive volatile compounds, viz., santalene, funebrene and pentadecane in sandalwood; and linalool, β-farnesene, caryophyllene and methyl eugenol in basil oil. Based on the results obtained it can be concluded that application of sandalwood and basil oils increased the attracting efficacy of sticky traps for the management of A. biguttula and B. tabaci in cotton.
Health Care Complaints and Professional Legal Responsibility — A Cross-Country Comparative Review
Authors: Birkeland Søren Fryd 
Published: October 2022

Abstract
One approach to stimulating patient safety and health care quality is through holding health care professionals legally responsible for their performance. Law and health care variation across countries, however, makes it difficult to get an overview and make comparisons of the personal legal responsibility of health care providers. This article describes health care professional liability and complaint measures in some European countries (UK, The Netherlands, Sweden and Denmark) and US. Countries all have established a public authority to assess complaints about health professional performance and opportunities for economic compensation. The assessment of health professional legal responsibility generally relies on comparisons to supposedly “objective” standards predominantly dictated by the health profession. In line with the aim of ensuring acceptable care for all, health ethics principles on justice, respect for patients’ autonomy, and the duty to do good and prevent harm may provide an attractive supplement in the description of legal responsibility in the health professions.
The Historical, the National, and the Modern in Axel Honneth’s Recognition
Authors: Lim Shiru 
Published: October 2022

Abstract
On what basis might we consider European thinkers to have bequeathed to us a theory of recognition? How relatable were their ideas across national lines—and coherent within them? And to what use can such a theory be put? This piece explores how Axel Honneth’s Recognition: A Chapter in the History of European Ideas (2021) tackles these questions. It examines its premises and uses of history, and tries to understand it both as part of a wider political-philosophical project, as well as an intervention in the history of political thought.
Recognition, Transformation, and Critical Intellectual History: A Reply to Honneth’s Recognition: A Chapter in the History of Ideas
Authors: Levine William 
Published: October 2022

Abstract
This article critically responds to Axel Honneth’s Recognition: A Chapter in the History of Ideas. It argues that, although Recognition provides a compelling historical investigation into the history of the concept of recognition as it emerged in modern France, Great Britain, and Germany, Honneth’s text retains some questionable methodological commitments that undermine its more provocative and potentially wide-ranging contributions. This article interrogates these commitments in addition to some of Honneth’s more specific arguments to speculate about other lessons that Honneth’s history of recognition can provide.
Forced Migration and the Plight of the Chakma Refugees in Arunachal Pradesh: ‘Citizenship’ as a Bone of Contention
Authors: Choden Nawang 
Published: October 2022

Abstract
The present paper explores the persistent and contentious issue of citizenship of the Chakma community in Arunachal Pradesh. The Chakmas were originally uprooted from the Chittagong Hill Tracts of former East Pakistan and were resettled in Arunachal Pradesh, formerly known as the North East Frontier Agency (nefa). The forced migration of the Chakma community has implications at different levels and raises critical questions about exclusion, belongingness, citizenship and the various rights which comes with it. The article explores the relationship between refugee identity and citizenship rights to see how this relationship is mediated through denial or extension of state entitlements. Examining the nature of citizenship within this context may help to further uncover how the concept of citizenship is both understood and used today.
Bad Becoming Normal is Detrimental to Beef Cattle Welfare
Authors: Grandin Temple 
Published: October 2022

Abstract
The author has worked in the cattle industry for fifty years. In the 1970’s, cattle handling was terrible and today it has greatly improved. During the last fifteen years, there have been increasing problems with lameness, heat stress, and heart failure in fed beef cattle. These problems slowly increased and people did not notice them until they became really serious. I called this bad becoming normal. The increase is these welfare issues is partially related to increased genetic selection for more muscle and weight gain. Other factors may be muddy pens, a lack of roughage in the ration, heavier cattle at a younger age, or overuse of growth promotants. These practices may overload the animal’s biology and make it dysfunctional. There is a significant minority of producers who push cattle for maximum production, which is detrimental to animal welfare.
Action-Based Embodied Design for Proportions: From the Laboratory to the Classroom
Authors: Alberto Rosa , van Helden Gitte , Bakker Arthur 
Published: October 2022

Abstract
Embodied learning technologies have shown efficacy in laboratories with ideal supportive conditions, but their effectiveness in classroom with “real-world” constraints is yet understudied. Inspired by the innovation implementation framework, we compare the classroom-situated engagements of two student pairs and their teachers with the action-based embodied design for proportions with earlier laboratory and classroom study findings and conjecture on influential factors. Much of these classroom students’ sensorimotor learning resembled laboratory findings, but they had more opportunities to be overtly engaged with their hands and self-directed in including artifacts, likely influenced by (unintended) technological changes and setting-specific environmental affordances. Their teachers’ engagements resembled laboratory findings to some extent, but showed less perceptiveness to students’ qualitative multimodal expressions and more directedness in introducing new quantitative forms of engagements, likely influenced by setting-specific fragmented access and novelty of the embodied pedagogy. We discuss the importance of focusing on teachers and conducting semi-natural efficacy research.
The impact sheet to this article can be accessed at 10.6084/m9.figshare.21205298.