bluuebunny/crossref_metadata_2025 huggingface dataset:
Dispossession by Mining and Differentiation Among Young Men by Chalaki in Eastern India
Authors: Dash Minati
Published: December 2023

Utkal Alumina started the first private bauxite mining project in India in the mid‑1990s in the Baphlimali hills of Kashipur (a town in the Rayagada district of Odisha, a state in eastern India). And it set up its refinery in the Ramibeda valley at Doraguda. Kashipur, populated mostly by Adivasis and Dalits (Scheduled Tribes and Scheduled Castes), is designated a Fifth Schedule Area under the Constitution of India to protect their interests. The villagers started a movement as soon as the project was announced. The movement stalled the project for over 18 years before collapsing in 2010. In 2012, a set of young men emerged in the refinery area, widely considered chalak, or more able than others to successfully negotiate individual gains from Utkal. This ethnographic paper, an exploration of chalaki as a strategy—and the ways it shaped the life‑chances of young men—demonstrates that chalaki drew from the skills acquired through participation in the movement and these skills were recast in the changed context in which Utkal engaged with these men closely. This creation and development of individual aspirational strategies, I argue, provide a diagnostic of emerging subaltern subjectivities among young men as they face the gap between aspirations and broken dreams; and differentiation among them in contexts where social movements opposing projects of dispossession undergo long processes of fragmentation, decline and collapse.
(Un)making labor invisible: A syllabus
Authors: Anthony Patrick , Broad Juliana , Chacko Xan , Dorner Zachary , Kaplan Judith , Yıldırım Duygu
Published: December 2023

From industrial psychology and occupational therapy to the laboratory bench and scenes of “heroic” fieldwork, there are important connections between the science of labor and the labor of science. Participants in the 2022 Gordon Cain Conference explored how greater attention to these connections might deepen historical understanding of what constitutes “science” and what counts as “labor.” Our conversations circled around themes of vulnerability (of systems, individual bodies, historical testimony), affect (pertaining to historical actors and ourselves), and interdependence (e.g. across human groups, species, political boundaries, and time). For the members of this group, which grew out of a panel discussion, these themes and motivations coalesced around a topical focus on invisibility, which helped us to articulate – in the form of a co-created syllabus – research questions about science and labor from multiple angles pertaining to practice, archival preservation, and scholarly representation. This syllabus is organized into six thematic modules that aim to challenge and historicize the concept of invisible labor by facilitating comparisons across geographic, temporal, conceptual, and disciplinary boundaries. The goals of this collaborative syllabus, in sum, are manifold: we seek to facilitate more inclusive histories of science through critical engagement with “invisibility” and thereby promote a more expansive understanding of what constitutes scientific labor; to highlight the constitutive role of gendered labor practices in the scientific enterprise; to draw attention to interdependencies that make all forms of production (knowledge or material) possible; to elucidate systems of remuneration for scientific labor over the longue durée and through pointed comparisons; and, finally, to promote self-reflexivity about the methods we use to narrate the history of science and make sense of our own labors.
Tell el-Amarna, 2022
Authors: Stevens Anna , Dabbs Gretchen R. , Balestra Fabien , Tully Gemma , Schiødt Sofie , Rose Pamela , Clapham Alan J. , Docherty Paul , Garnett Anna , Bertram Miriam
Published: December 2023

Fieldwork at Amarna in 2022 included excavation at the Great Aten Temple and the North Desert Cemetery, and the continuation of several post-excavation projects. Those post-excavation projects reported on here are the study of skeletal materials, pottery, plant and organic remains, and inscriptions from the North Desert Cemetery; pottery, plant and other organic remains from the North Cliffs Cemetery; and digital modelling of the North Desert Cemetery. A programme of community outreach in collaboration with the Amarna Visitor Centre also recommenced.

[Formula: see text]
Associations Between Physical Activity and Inactivity Levels on Physical Function and Sleep Parameters of Older Adults With Frailty Phenotype
Authors: Corral-Pérez Juan , Casals Cristina , Ávila-Cabeza-de-Vaca Laura , González-Mariscal Andrea , Mier Alba , Espinar-Toledo Milagrosa , García-Agua Soler Nuria , Vázquez-Sánchez María Á.
Published: December 2023

This study investigated the relationship between physical activity, inactivity, physical function, and sleep in older adults with a frailty phenotype. A total of 184 pre-frail/frail older adults were included. Physical activity, inactive behavior, and sleep parameters were assessed using a wrist-worn accelerometer. Participants were categorized into four groups based on their levels of inactivity and physical activity. The results showed that individuals with lower levels of inactivity had better lower body mean velocity and sleep regularity than those with higher levels of inactivity. Physically active older adults exhibited faster gait speed and performed better in lower body strength tests than physically inactive participants. Further analysis revealed that specific combinations of inactivity and physical activity were associated with varying levels of physical function. The findings highlight the importance of physical activity and the negative impact of inactivity on physical function and sleep in older adults with a frailty phenotype.
The Moral Economy of Welfare: Bulgarian Roma Migrants Reclaiming Social Citizenship through Fraud
Authors: Deneva Neda
Published: December 2023

This paper explores the constitution of a moral economy of welfare through acts of benefit fraud. The structural conditions of contemporary labour, citizenship, and migration regimes in Europe exclude large shares of workers from access to social citizenship and place them in a position of undeserving trespassers of the social contract. Drawing on the case of Bulgarian Roma engaged in precarious labour and short-term intensive mobility between Bulgaria and the Netherlands, I show how labour conditions in both countries and the structures of the welfare regimes effectively exclude them from access to social citizenship and confine them to the realms of informal work, thus putting them in a position of differential inclusion. The benefit fraud in this context has multiple interpretations—ranging from crime through a survival strategy to a claim to social justice. By mobilizing the idea of the moral economy of welfare, I seek to explain how migrants justify their actions not as transgression, but as a claim to social citizenship and a critique of an unjust social and economic order. In a moral economy of welfare, the migrants see themselves as deserving state support both by virtue of being citizens and of being good workers. Being excluded from proper welfare support is interpreted as a failure of both states. In this context, the fraud is framed in moral terms as an act of citizenship aiming to restore justice.
A Long March Toward Equality: Predicting the Presence of Women in Television News
Authors: Beckers Kathleen , van Dijk Rozemarijn E. , Van Aelst Peter , De Swert Knut
Published: December 2023

The (under)representation of women in the news has received much attention in scholarly research. Using a population dataset of news broadcasts in Belgium, this article describes how gender equality has changed over time (2003–2021) and investigates which factors explain the presence (or absence) of women as speaking actors in the news. The findings reveal a structural underrepresentation of women in the news, but a slow increase in their presence over time. Overall, women are more equally represented in softer news topics or in non-elite roles. Remarkable is that women journalists tend to interview more female sources than their male counterparts.
The dignitarian return
Authors: Perry Matthew Wray
Published: December 2023

Dignity underlies much philosophical debate, but the concept and its place in a broader theory of justice have received renewed analytic attention of late. In this article, I examine several recent books on dignity: Human Dignity and Political Criticism, by Colin Bird; Human Dignity and Human Rights, and Human Dignity and Social Justice, both by Pablo Gilabert; Contours of Dignity by Suzanne Killmister; and Humanity Without Dignity: Moral Equality, Respect, and Human Rights, by Andrea Sangiovanni. As I outline, each book develops and defends a position in an established disagreement between so-called ‘Naturalistic’ views, which hold that dignity inheres in natural properties, and ‘Conventionalist’ perspectives, which hold that dignity is socially defined. With these contemporary accounts in mind, I expose the contours of this disagreement and suggest that further work should focus on developing a hybrid conception of dignity consistent with Naturalism and Conventionalism.
Adverse Childhood Experiences and Autism: A Meta-Analysis
Authors: Hartley Gemma , Sirois Fuschia , Purrington Jack , Rabey Yasmin
Published: December 2023

Evidence suggests that autistic children have a higher probability of experiencing adverse childhood experiences (ACEs) compared to their non-autistic peers. This meta-analysis (PROSPERO: CRD42022262635) aimed to quantify the association of autism and ACEs. Eight databases and Google Scholar were searched for studies that reported dichotomous outcomes regarding the associations between ACEs and autistic individuals, compared to non-autistic individuals. A random-effects model was used to calculate the average Odds Ratio (OR) of the relationship between a diagnosis of autism and ACEs. A total of 40 studies with 5,619,584 participants were included, generating an overall average OR 2.11 (CI 1.61, 2.77). Significant differences in the magnitude of association were found across studies with regards to the type of ACEs studied, comparison groups, and population type. Overall, moderate certainty evidence (downgraded for bias) indicates that autistic individuals are at greater risk of experiencing ACEs, compared to non-autistic individuals. Appropriate support for autistic individuals and their families are required to prevent ACEs and treat the impact of ACEs.
Serum Protein-Based Profiles for the Diagnostic Model of Alzheimer’s Disease
Authors: Yang Li , He Liang , Bu Zhibin , Xuan Cheng , Yu Caiyan , Wu Jiong
Published: December 2023

Background

Determining a non-invasive, serum-based diagnostic panel for early diagnosis of AD will play a significant role in the prevention and treatment of the disease.

Methods

We performed standardized clinical assessments and neuroimaging measurements in 45 patients with AD and an equal number of sex - and age-matched controls. 48 target peptides of 14 identified target proteins were quantitatively analyzed by PRM.

Results

8 protein markers were screened, including SAA4, PPBP, PF4, APOA4, F10, CPB2, C1S and IGHM. An diagnosis panel including 8 proteins and demographic characteristics markers respectively was found to be the robust with a AUC of 92.3%.

Conclusions

Our study developed a new panel including protein and demographic characteristics that could be used to distinguish AD from control candidates.
Resting But Not Idle: Insights Into Epilepsy Network Suppression From Intracranial EEG
Authors: Widdess-Walsh Peter
Published: December 2023

[Box: see text]
The potential of transnational history education: Attempts at university teaching practice in East Asia
Authors: Koyama Shukuko
Published: December 2023

This essay explores transnational history education through the China–Korea–Japan CAMPUS Asia ENGAGE Program. Utilising active learning, project-based activities and joint history textbook creation, students navigate East Asia’s contested past. The approach encourages a shift from national to transnational identities, fostering a ‘global citizen’ perspective. By deconstructing conventional history narratives and constructing alternative, intersectional viewpoints, students develop a nuanced understanding that transcends divisive national boundaries. This pedagogical strategy underscores the potential of active learning in advocating global history perspectives for conflict resolution and reshaping historical memory.
Smoking and Depression Risk Reduction in a Primary Care Setting
Authors: Mahmood Naveen , Goldstein Shira , Thiele Alan , Trotchie Mark , des Bordes Jude
Published: December 2023

Introduction:

Smoking is associated with many diseases and is a target for primary preventive efforts in numerous morbidities. Studies show that smoking and depression may be associated. Never-smokers are at significantly lower risk than current and former smokers. Despite this observation, the effect of smoking on depression risk reduction has not been adequately explored. The purpose of this study was to explore the effect of smoking on depression risk reduction in adult patients seen in a primary care clinic at an academic medical center 6 months after they were identified as being at risk for depression. Findings may influence the direction and intensity of our smoking cessation endeavors in patients at risk of depression who smoke.

Methods:

We conducted an analytic cross-sectional study using electronic medical records of patients 18 years and older seen a primary care setting between January 1, 2019 and December 31, 2020. All participants included had an initial depression risk score (assessed by the 9-item Patient Health Questionnaire (PHQ-9)) of 5 or higher, information on smoking status and a PHQ-9 score at 6 months. We determined the percentage of patients with PHQ-9 score decrease of 5 or more at 6 months and used logistic regression to determine the association depression risk reduction (of 5 units or more) at 6 months and smoking, adjusting for demographic, clinical, and behavioral characteristics.

Results:

Number of patients included were 120, mean age was 55 (16), years, 88 (74%) were female, 68 (57%) were African American, and 31 (26%) were Caucasian. Fifty (44%) had a history of smoking and 31 (25.8%) had improvement (ie, a decrease of 5 units or more) in their PHQ-9 score at 6 months. Smoking was associated with decreased odds of improvement in depressive symptoms (Odds ratio = 0.32, 95% Confidence interval: 0.12-0.87).

Conclusion:

Risk of depression was more likely to persist in smokers than non-smokers at 6 months. Addressing smoking behavior in those with risk of depression may be beneficial.
Web-Based Nutrition and Physical Activity Education Intervention to Ameliorate Cardiometabolic Risks: A Single-Arm and Non-Randomized Feasibility Study
Authors: Ab Hamid Mohd Ramadan , Buhari Siti Sabariah , Md Noor Harrinni , Azizan Nurul ‘Ain , Md Nor Norazmir
Published: December 2023

Objective:

This study aimed to evaluate the feasibility of the D-PATH website to improve dietary and physical activity management for patients with cardiometabolic risk.

Methods:

A website called D-PATH was developed, consisting of 6 learning units for managing hypertension. A 4-week program was implemented, and a pre- and post-intervention assessment was conducted to measure acceptability and changes in knowledge, attitude and practice, dietary intake, physical activity, and anthropometric status.

Results:

The D-PATH website was acceptable in terms of understandability, actionability and cognitive load. Knowledge, attitude and practice, and physical activity levels were improved, but no changes were noted for dietary intake and blood pressure level.

Conclusion:

The D-PATH website was accepted and feasible for the intervention study. This study has shed light on using the website to promote behavioral change in patients with cardiometabolic risks.
Less Form, More Meaning: A Case Study of al-Iẖtibāk in the Qur’an Through the Prism of Dependency Grammar
Authors: Hassanein Hamada
Published: December 2023

Ellipsis pervades the Qur’anic discourse. One pervasive form of it is al-iẖtibāk (“interchangeable ellipsis”). In terms of the interface between Qur’anic exegesis and Arabic rhetoric, the phenomenon of al-iẖtibāk is far more than a rhetorically heuristic technique for surface-structure analysis. It is a fruitful tool for pragmasemantic inferences of discursive implicatures defined as a fundamental mode of text construction and a logical hermeneutic of text consumption. The veracity of al-iẖtibāk has received little attention in non-Arabic research. Consequently, this article revisits the typology of al-iẖtibāk through the lens of Osborne’s dependency grammar to argue for its relevance to Qur’anic epistemology and axiology. Using a dependency grammar approach to al-iẖtibāk, the article conducts a qualitative content analysis of representative Qur’anic verses to highlight the symbiotic relationship between Qur’anic exegesis and Arabic rhetoric. Al-iẖtibāk is found to be related to givenness and newness of information structure which impact its interpretation and resolution—a finding in line with Winkler’s argument. Al-iẖtibāk proves to be a central discourse marker of interaction between the Qur’an and its recipients who take part in filling the elliptical slots co(n)textually.
Dynamic Asymmetric Causality of Bitcoin’s Price-Volume Relation
Authors: Gbadebo Adedeji Daniel
Published: December 2023

Bitcoin has attracted incessant attentions in recent times. Studies have completed models to examine the relationship between Bitcoin and other multiple attendant variables. This paper considers a simple and direct price-volume relation. The paper offers causality evidence according to the dynamic asymmetric causality test. Based on available monthly data spanning 2010:M7-2022:M10, the paper shows that Bitcoin price and volume are integrated, both been I(0)’s. Moreover, the paper discloses the short- and long-term price-volume behaviors of Bitcoin using the cointegration test and vector error correction model (VECM). Taken together, the study first confirms long run relations and presents the estimates of the parsimonious VECM. The results show short run evidence of positive price-volume relations, and in the long run, the disequilibria are as well corrective and mean reversing. The outcomes of the Hatemi-J’s causality testing suggest likely evidence of bidirectional causality between the positive and negative fragments of the shocks of Bitcoin price and volume during the periods.
Facilitators and barriers to implementation of a patient and staff reported measure for screening of palliative concerns of patients with heart failure: a qualitative analysis using the Consolidated Framework for Implementation Research
Authors: Neo Shirlyn Hui-Shan , Tan Jasmine Yun-Ting , Ng Elaine Swee-Ling , Yoon Sungwon
Published: December 2023

Background:

Screening patients with patient-reported outcome measures allows identification of palliative care concerns. The Integrated Palliative Care Outcome Scale (IPOS) was developed in the United Kingdom for this purpose. Tools developed in another setting might not be readily usable locally. We previously evaluated the validity and reliability of the IPOS in our cardiology setting. However, it remains uncertain what factors would influence the subsequent implementation of IPOS for routine screening of patients with advanced heart failure in future practice.

Objectives:

This study aimed to identify the factors that could affect the IPOS implementation for patients with advanced heart failure.

Design:

This was a qualitative study conducted at the National Heart Centre Singapore.

Methods:

Patients with advanced heart failure who participated in our previous IPOS validation study were purposively recruited for semi-structured interviews. Healthcare workers caring for these patients and involved in the testing of the IPOS tool were also invited for interviews. The interviews were analyzed thematically and mapped to the Consolidated Framework for Implementation Research (CFIR).

Results:

Our analysis identified six potential facilitators and six potential barriers to implementation across five major domains of the CFIR (intervention characteristics, inner setting, outer setting, individual characteristics, and process). Facilitators include: (i) perception of utility, (ii) perception of minimal complexity, (iii) perception of relatability, (iv) conducive culture, (v) dedicated resources, and (vi) advocates for implementation. Barriers include: (i) need for adaptation, (ii) mindsets/role strains, (iii) resource constraints, (iv) cultural concerns, (v) individual needs, and (vi) change process.

Conclusion:

Institutions could focus on cultivating appropriate perceptions and conducive cultures, providing dedicated resources for implementation and introducing facilitators to advocate for implementation. Adaptation of IPOS to suit workflows and individual needs, consideration of change processes, and systemic changes to alleviate cultural, resource, and staff role strains would improve IPOS uptake during actual implementation in clinical services.

Trial registration:

Not applicable.
Bacterial and Bacteriophage Consortia Are Associated with Protective Intestinal Immuno-Modulatory Metabolites in Allogeneic Stem Cell Transplantation Patients
Authors: Thiele Orberg Erik , Meedt Elisabeth , Hiergeist Andreas , Xue Jinling , Heinrich Paul , Ghimire Sakhila , Miltiadous Oriana , Lindner Sarah , Schwarz Alix , Janssen Klaus-Peter , Herhaus Peter , Verbeek Mareike , van den Brink Marcel R.M. , Weber Daniela , Edinger Matthias , Wolff Daniel , Kleigrewe Karin , Herr Wolfgang , Bassermann Florian , Gessner André , Deng Li , Holler Ernst , Poeck Hendrik
Published: December 2023

The human microbiome is a predictor of clinical outcome in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Besides bacteria, fungi and viruses as well as intestinal microbiota-derived metabolites are involved. However, it is still unclear how dynamic shifts in these three kingdoms contribute to the production of intestinal metabolites, how metabolites are impacted by graft-versus-host disease (GvHD) or antibiotics and whether they are associated with clinical outcome.

We report the two-year follow-up of a prospective, observational, longitudinal cohort of allo-SCT patients (n=78) at two German transplantation centers that combined three-kingdom (bacteria, fungi, viruses) analysis of intestinal microbial communities with targeted metabolomics ( Figure 1). Using Multi-omics factor analysis (MOFA), we uncovered a functional microbiome signature of bacteria from the Lachnospiraceae and Oscillospiraceae families and their associated bacteriophages, which correlated with the production of immuno-modulatory metabolites (IMMs) including short-chain fatty acids (SCFAs), branched-chain fatty acids (BCFA), metabolites associated with induction of type-I IFN signaling (IIMs) and immuno-modulatory secondary bile acids ( Figure 2). We established an Immuno-modulatory Metabolite Risk Index (IMM-RI) consisting of five index IMMs, which was associated with improved survival, less transplant-related mortality and reduced relapse rate. Onset of gastrointestinal GvHD and exposure to antibiotics significantly impacted intestinal levels of protective IMMs.

Using whole shotgun metagenomic sequencing, we observed that in IMM-RI low-risk patients, sustained production of protective IMMs was associated with a high abundance of microbial SCFA biosynthesis pathways, specifically butyric acid via butyryl-CoA:acetate CoA-transferase (BCoAT). Through genome assembly from viral metagenomic sequencing data, we detected two distinct bacteriophages which encoded BCoAT as an auxiliary metabolic gene. They were more abundant in IMM-RI low-risk patients and positively correlated with intestinal butyric acid levels, suggesting that these bacteriophages may modulate bacterial metabolite biosynthesis.

Our study identifies a specific microbiome signature associated with protective IMMs that could improve fecal microbiota transplantation (FMT) donor selection and provides a rationale for the development of engineered metabolite-producing consortia and defined metabolite combination drugs as novel microbiome-based therapies for cancer patients.
Elevated Heme Drives Evoked and Ongoing Pain Behaviors in WT Mice By Sensitization of Dorsal Root Ganglia Neurons
Authors: Zorn Samuel J , Ehlers Vanessa L , Brandow Amanda M. , Stucky Cheryl L
Published: December 2023

Individuals with sickle cell disease (SCD) suffer from complex stimulus-evoked and ongoing pain that is mediated in part by the hyperexcitability of their peripheral sensory neurons. However, it is unclear whether acute or chronic elevation of cell free heme, a key pathological feature of SCD, contributes to the aberrant activity of sensory neurons. Thus, determining whether heme drives pain behavior and enhanced excitability of dorsal root ganglia (DRG) primary sensory neurons involved in pain signal transduction is critical for the development of targeted pain therapies for SCD. In the current experiments, we use evoked and ongoing pain behavior assays and in vitro calcium imaging to evaluate the hypothesis that acute increases in heme causes direct sensitization of nociceptive DRG neurons in wildtype (WT) mice. Our preliminary data reveal that similar to pain behaviors in the mouse model of SCD, hind paw injection of heme into WT mice induces mechanical hypersensitivity (Figure 1). We also observed increased aversive responses to dynamic paintbrush and noxious needle stimulation as well as the onset of paw licking behavior suggesting that heme also drives ongoing, non-evoked pain. These data suggest that axon terminals in the skin become rapidly sensitized when exposed to elevated heme. We next administered heme to primary cultured DRG neurons in vitro and observed calcium flux across the neuronal cell membrane that was dependent on extracellular calcium. To determine if heme directly triggers action potentials or enhances spontaneous activity of sensory neurons, we conducted electrophysiological recordings of neuronal activity in neurons held at resting membrane potential at physiological temperature. Our preliminary data indicate that exposure to heme may directly enhance neuronal action potential firing frequency (Figure 2). Together, these data suggest that heme opens calcium channels on sensory neurons to initiate pain signal transduction and drive acute pain behaviors. We plan to conduct additional non-evoked pain behavior assays including facial grimace analysis and conditioned place aversion to determine whether heme injection is sufficient to drive ongoing pain. We will further determine whether exposure to heme enhances the intrinsic excitability of mechanical and cold sensitive neurons as heme-dependent hyperactivity of these neurons may lead to our observed acute onset mechanical and cold hypersensitivity in heme-injected mice. Completion of these experiments will shed light on the contributions of cell free heme to SCD pain and illuminate downstream effectors that may be targeted to provide analgesic relief for this historically understudied and debilitating disease.
Diagnostic Challenges in the Leukemia Phase of Blastic Plasmacytoid Dendritic Cell Neoplasm without Skin Involvement: A Clinical and Pathological Study
Authors: Zhang Qiguo , Fu Wenjing , Bao Wenqiang , Ling Chun , Jin Qichuan , Chen Bing
Published: December 2023

Objective: To improve the accurate diagnosis and treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) without skin involvement. Methods: One case of BPDCN with skin involvement progressing to the leukemia phase was used as a positive reference for bone marrow specimens, and a comparative study was conducted on one case of leukemia phase of BPDCN without skin involvement. Results: The male control was 70 years old and presented with a mass on the right forearm skin. Pathological examination indicated BPDCN. Only one cycle of decitabine + CAG was given and 5 months later, the disease progressed to the leukemia phase. Tumor cells expressed HLA-DR, CD123, CD4, CD56, CD7, CD36, TCL1 and CD304. NGS analysis of bone marrow tumor indicated ASXL1, IDH2, and TP53 mutations. The patient survived only 6 months during follow-up. Another female patient was 73 years old and was initially diagnosed with “T lymphoblastic leukemia” based on partial immunophenotyping results for 81.5% blast cells and the morphology of blast cells showing tailing phenomena. Further immunophenotyping showed that blast cells expressed CD56, HLA-DR, and CD304, partially expressed CD4, CD33, and CD117, and did not express CD34, CD13, CD3, CD5, CD7, CD8, CD10, CD11b, CD14, CD15, CD16, CD19, CD20, CD64, CD303 or MPO. Additional immunohistochemistry of bone marrow biopsy showed that CD43 was negative, TdT was mostly positive, CD4 was slightly positive, CD56 was mostly positive, CD123 was positive, CD117 was slightly positive, and lysozyme was partially weakly positive. The above results implied that after excluding BPDCN, acute myeloid leukemia subtype M5 should be considered. According to the diagnostic criteria of BPDCN in WHO 5th edition hematologic lymphoma, two scenarios can be established for diagnosing BPDCN: (1) CD4 and/or CD56 are positive and CD123 and one of pDC markers (TCL1, CD303, CD304) are expressed. (2) If any three pDC markers are expressed (CD123, TCL1, CD303, CD304), and all expected negative markers (CD3, CD14, CD19, CD34, Lysozyme, Myeloperoxidase) are negative, So the final diagnosis of BPDCN can be established according the former creteria. The latter case had ASXL1 and TET2 mutations detected by NGS analysis, achieved complete remission after receiving venetoclax + azacitidine for one cycle, followed by intermittent venoclax +demethylation agent or low-dose chemotherapy maintenance treatment and live for more than two years now. Conclusion:BPDCN without skin lesions is clinically rare, and its diagnosis is challenging. Comprehensive immunophenotyping and cautious interpretation of immunohistochemistry results such as dim lysozyme expression are crucial. Venetoclax-containing regimens have shown promising therapeutic effects.
Effect of a Crossover and Resistance Exercise Routine on IL-15 in Adults with Type B Acute Lymphoblastic Leukemia during the Induction Phase. Randomized Pilot Study
Authors: Gallardo-Rodríguez Adán Germán , Olarte Carrillo Irma , Martínez Tovar Adolfo , Cerón Maldonado Rafael , Castellanos Sinco Humberto Baldemar , Ramos Peñafiel Christian Omar
Published: December 2023

Background: IL-15 is a proinflammatory myokine essential for activating NK cells and CD8+ T lymphocytes, and its overexpression has been associated with decreased survival in patients with Acute Lymphoblastic Leukemia (ALL). Physical exercise has been shown to be safe, feasible, and beneficial in hematological cancers. This requires the activation of muscles that secrete cytokines such as IL-15, causing immune mobilization and accumulating CD8 T cells. The objective was to compare the effect of two exercise strategies on IL-15 and survival prognosis in adult patients diagnosed with de novo ALL. Material and Methods: A blind randomized clinical study was carried out where twenty-three peripheral blood samples were obtained pre- and post-exercise from patients classified into three types of intervention: resistance exercise (GER), crossover exercise (GEC), and control group (GC). Ethical disclosure: All patients gave written informed consent for the study and data collection. This three-arm, prospective, randomized, blinded, open-label pilot study (ratio 1:1:1) was conducted in accordance with the Declaration of Helsinki. Results: The results showed that the changes in IL-15 levels during the intervention were not significant in any of the groups (GC p= 0.237, GER p= 0.866, and GEC p= 0.678). However, 78.26% of patients achieved remission at the end of induction, while only 21.73% experienced a relapse. There were no deaths during the study. Conclusions: Although IL-15 compliance levels in GER and GC were similar, GER patients had a better prognosis. It is suggested that resistance exercises may help improve survival prognosis and reduce early relapses in patients with ALL.

Keywords

Interleukin-15; exercise; Acute lymphoblastic leukemia; chemotherapy; body composition
Efficacy of Bortezomib Combined with Hyper-CVAD in Adults with Relapsed Acute Lymphoblastic Leukemia or Positive Measurable Residual Disease
Authors: Ramos Peñafiel Christian Omar , Pérez Sámano Daniela , Gallardo-Rodríguez Adán Germán , Olarte Carrillo Irma , Terreros Palacios Camila , Martínez Murillo Carlos , Barranco Lampón Gilberto Israel , Cabrera García Álvaro , Castellanos Sinco Humberto Baldemar , Martínez Tovar Adolfo
Published: December 2023

Background: Despite the advances in treating adult Acute Lymphoblastic Leukemia (ALL), relapses are among the most significant challenges to improving the prognosis. One of the tools that can predict bone marrow relapse, according to its positivity, is Measurable Residual Disease (MRD). Unfortunately, due to the high cost, access to innovative therapies is limited, so chemotherapy remains the most common treatment option. The combination of Bortezomib with Hyper-CVAD has already shown efficacy in patients with Multiple Myeloma. However, in patients with ALL, it is not yet proven. Material and Methods: A prospective cohort was carried out in patients with ALL who presented an +MRD or relapse and received treatment based on the combination of Bortezomib and Hyper-CVAD in two reference centers in Mexico City. Results: 20 cases with positive MRD were analyzed; 60% (n=12) became negative after the combination, 30% (n=6) persisted with a positive result, and 10% (n=2) passed away. Of the 43 individuals with bone marrow relapse, 43.5% (n=10) achieved a second complete remission (2CR), 34.8% (n=6) were refractory, and 21.7% (n=5) passed away. To integrate a second complete remission, 20% (n=2) achieved it in < 4 cycles, while 50% (n=5) required four cycles of treatment (2 cycles A and two cycles B), and 30% (n=3) required six cycles. Conclusion: The combination of Bortezomib with the increased Hyper-CVAD scheme showed better results in making MRD negative, suggesting that this combination can be incorporated into first-line strategies.

Keywords: Bortezomib; Chemotherapy; Acute Lymphoblastic Leukemia; Relapse; Measurable Residual Disease.
Risk of Cancer in Relatives of Patients with Myelodysplastic Neoplasia and Acute Leukemias
Authors: Nitschke Nikolaj Juul , Rostgaard Klaus , Hjalgrim Henrik , Andersen Mette Klarskov , Grønbæk Kirsten
Published: December 2023

Background:

The risk of cancer among relatives of patients with either myelodysplastic neoplasia (MDS), acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) has not been thoroughly examined.

Methods:

We linked the Danish Civil Registration System with the Danish Cancer Registry, the Danish National Acute Leukemia Registry, and the Danish Myelodysplastic Syndrome Database to estimate the relative risk of cancer among relatives of patients with MDS/AML/ALL. We used standardized incidence ratios (SIRs), i.e., the ratio of observed to expected number of cancers among the relatives as a measure of relative risk.

Results:

We identified 13010 first-degree (FDR) and 22051 second-degree (SDR) relatives of 8386 patients with MDS/ALL/AML. Disregarding basal cell carcinoma (BCC), the relative risk for cancer overall was increased in both FDR (SIR=1.3; 95% confidence interval (CI) 1.1-1.4) and SDR (SIR=1.5; 95% CI 1.2-1.8). SIRs among FDRs were statistically significantly increased for malignant melanoma, BCC and for the combined groups of cancers of the male genital organs, urinary tract, and MDS/AML/ALL. Among SDRs, SIRs were statistically significantly increased for malignant melanoma, BCC, and the combined group of cancers in the digestive organs and peritoneum.

Conclusions:

We observed an increased risk of cancer among FDR and SDR of patients with MDS/AML/ALL.
Evaluation of Artificial Intelligence (AI) for Acute Graft-Versus-Host Disease(GVHD) Classification
Authors: Choi Yoonhee
Published: December 2023

Introduction

Graft-Versus-Host Disease(GVHD) following hematopoietic stem cell transplant is a significant complication, causing a 10-30% mortality rate. Staging and grading are often performed by physicians in training, such as residents and fellows, and the assessments can be inconsistent between different physicians and clinical centers. This inconsistency may lead to confusion for both the medical team and the patients. This study evaluates the performance of an artificial intelligence (AI) tool in determining the grade of acute GVHD, exploring its potential role in the classification of GVHD.

Method

We conducted a performance assessment of Chat-GPT-3.5 and Chat-GPT-4 in grading acute GVHD. We constructed a dataset comprising simulated patients with acute GVHD grades 1-4. We then posed a question to both Chat-GPT-3.5 and Chat-GPT-4.0, asking for the severity of GVHD in each patient. The physicians' assessment was based on the modified Glucksberg criteria.

Result

Both Chat-GPT tools use the Glucksberg criteria as a reference source. Overall, Chat-GPT-4.0 demonstrated 75% concordance with physician assessment, whereas Chat-GPT-3.5 showed 62.5% concordance. When provided with numerical data, both tools successfully graded acute GVHD with 100% accuracy. However, when given subjective data, Chat-GPT-4.0 exhibited 50% concordance with physician assessment, whereas Chat-GPT-3.5 showed 25%. Although Chat-GPT was able to provide staging for each organ involvement, it struggled to estimate the volume of diarrhea based on the number of episodes. For instance, when asked about the grading of a patient experiencing more than 20 episodes of diarrhea per day, the system concluded that the patient had acute GVHD grade 4. This suggests that Chat-GPT-4.0 has difficulty accurately assessing the amount of diarrhea unless it's exceeding significant amount.

Chat-GPT-3.5 exhibited challenges in accurately quantifying the Body Surface Area (BSA). It was unable to assess the BSA if it was less than 25%. Moreover, if the rash involved more than two areas of the body, even when described with alternative language (e.g., ‘torso’, ‘entire torso‘), it would disproportionately inflated the BSA.

Conclusion

The above results demonstrate that both tools are insufficient for accurately determining the grading of acute GVHD when only subjective data is provided, primarily due to the incapacity of Chat-GPT-3.5 to assess the Body Surface Area (BSA) and Chat-GPT-4.0 to evaluate the volume of diarrhea. However, both tools displayed 100% accuracy when objective data was provided, with Chat-GPT-4.0 notably capable of accurately indicating the stages of organ involvement. Healthcare professionals should not solely rely on Chat-GPT for assessment, and it is advisable to instruct patients against utilizing Chat-GPT to evaluate their own acute GVHD.
MPO and Trh within Leukemia Stem Cells Increased Chemosensitivity in Acute Myeloid Leukemia: A Single-Cell RNA Sequencing Approach
Authors: Teng Chieh-Lin Jerry , Chen Chung-Hsing , Hsiao Tzu-Hung , Wu Ting-Shuan , Liao Yu-Min
Published: December 2023

Introduction

The “7+3” regimen is widely recognized as the established standard induction therapy for newly diagnosed acute myeloid leukemia (AML), exhibiting a complete remission (CR) rate of 70%. However, the prognosis for patients who do not achieve CR following induction remains discouraging. Leukemia stem cells (LSCs) are recognized as major contributors to chemoresistance in AML. Hence, it is crucial to identify potential targets within LSCs that can overcome chemoresistance.

Patients and methods

This prospective study involved 20 consecutive de novo AML patients who underwent “7+3” induction therapy. These patients were divided into CR (n=15) and non-CR (n=5) groups. By employing single-cell RNA sequencing (scRNA-seq), we meticulously examined the cellular states of bone marrow mononuclear cells from AML patients at the time of diagnosis and identified LSCs among these cells. The genetic profiles of the LSCs were subsequently compared between the CR and non-CR groups and further validated using independent cohorts.

Results

The non-CR AML patients exhibited a significant increase in the proportion of immature cells during hematopoiesis within the AML cell populations. Moreover, we found that expressions of MPO and TRH within LSCs were significantly higher in the CR than non-CR groups, which were further validated by independent cohorts. Furthermore, patients with higher expression of TRH and MPO demonstrated substantially improved relapse-free survival (p = 0.009 for TRH; p = 0.002 for MPO) and overall survival (p < 0.001 for TRH; p = 0.002 for MPO). The dysregulation of the OXPHOS pathway, along with altered interferon alpha and gamma responses, disrupted cholesterol homeostasis, and aberrant MYC activity, may contribute as underlying mechanisms for the observed association between MPO or TRH and chemotherapy response.

Conclusions

MPO and TRH in LSCs may increase chemosensitivity in AML and serve as chemoresponse biomarkers, offering potential benefits in guiding induction strategies for newly diagnosed AML patients
Blastic Plasmacytoid Dendritic Cell Neoplasm Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database
Authors: Haddad Philip A , Gaddam Shiva Jashwanth
Published: December 2023

Background:

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with a propensity for cutaneous involvement. This disorder has gone through many reiterations over the years, being classified initially as a blastic NK-cell lymphoma, then a subset of AML, and finally recognized as a unique myeloid neoplasm. However, due to the poor understanding and the rarity of the disease, varied treatment approaches have historically been implemented, and no optimal data or guidelines for managing BPDCN are available. Therefore, we conducted this pooled database analysis to identify the prognostic factors, clinicopathological characteristics, and therapeutic strategies that influence survival in this disease.

Methods:

To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 273 cases that fit the diagnostic criteria for BPDCN. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS).

Results:

A total of 273 patients with confirmed BPDCN were identified. The median age was 61.5. There was a male preponderance with M:F of 2.4. The median duration of symptoms before diagnosis was 5 months. Eighty-one percent of patients presented with skin lesions, 65% of which were disseminated. Involvement of Lymph nodes (LN), bone marrow (BM), spleen, peripheral blood, and CNS occurred in 62%, 73%, 55%, 71%, and 57%. Constitutional symptoms were reported in 13%. The median OS and DFS of the whole group were 16 and 13 months, respectively. Patients younger than 60 had better median OS (30 vs. 10 months, p < 0.0001). The involvement of LN (p = 0.03), BM (p = 0.007), spleen (p = 0.02), and peripheral blood (p = 0.01) was associated with worse OS. Furthermore, disseminated skin involvement had worse OS than focal (p = 0.001). Though CNS involvement, presence of constitutional symptoms, elevated LDH, and TdT negative status had numerically worse OS, it did not reach statistical significance. Sex did not impact OS. Compared to no treatment, non-dose-intense chemotherapy, dose-intense chemotherapy, and stem cell transplant had incrementally superior OS (3 vs. 10 vs. 22 vs. 66 months, p < 0.0001). Patients who attained CR as their best response also had a superior median OS (26 vs. 5 months, p < 0.0001).

Conclusions:

This study presents updated clinicopathologic data from a large, pooled cohort of patients with BPDCN. It identifies age, organ involvement, type of therapy, and quality of response to treatment as critical determinants of OS.
Establishing an AML Ex Vivo Platform to Generate Physiologically Relevant Models
Authors: Tavana Omid , Willis Brandon , Liu Siyu , Christie Amanda , Andersen Courtney L , Roderick-Richardson Justine , Robichaud Amanda , Prickett Laura , Reimer Corinne , Drew Lisa
Published: December 2023

Acute myelogenous leukemia (AML) comprises a highly polyclonal and heterogeneous disease containing leukemic stem cells, progenitors, and differentiated blasts. Despite advances in treatment, the long-term relapse-free survival for AML remains poor. Due to complex mutational profiles and highly divergent subtypes in AML, the use of physiologically relevant, patient-derived models is needed. Traditional cell line models of AML almost exclusively represent differentiated blasts, are homogenous in clonality, and often do not encompass major genetic subtypes. To address these gaps, we have established a culture system that supports the growth of higher-order AML samples ex vivo.

By optimizing culture conditions, we successfully cultivated 70% (10/14) of AML disseminated PDX models ex vivo and demonstrated they continue to proliferate after long term cultures. We established a 16-color flow panel to characterize their cell maturity state and show they maintain cell surface heterogeneity. Importantly, these models have not ‘drifted’ transcriptomically after multiple passages. Our platform includes 2 NPM1c mutant and 3 IDH1/2 mutant ex vivo lines, in addition to other subtypes underrepresented in traditional culture methods.

Furthermore, we treated AML PDXs in vivo with a clinically-relevant dose of venetoclax + azacytidine (Ven/AZA) for 2 cycles (14 days) and then evaluated post-VEN/AZA cells in our ex vivo assay. Growing these models ex vivo, we show using our flow panel that Ven/AZA treatment shifts the differentiation status from a stem-like state to a more mature-like cell state which is consistent with literature evidence of treatment resistance. Additionally, a second PDX model treated with three cycles of Ven/AZA in vivo and harvested in ex vivo culture conditions maintained both Ven and AZA resistance. Interestingly, compared with the vehicle treatment, Ven/AZA treatment caused resistance to other cell death agents including selective MCL1 and dual Bcl2/xL inhibitors. Lastly, we performed a 7-day cell compound panel screen using common standard of care agents for the treatment of AML. Many of the targeted agent activity correlated with expected genetic subtypes, such as FLT3 inhibitors in FLT3-ITD mutants and venetoclax in WT TP53 models. This established ex vivo platform provides physiologically relevant models to explore novel target biology, better understand compound mechanism of action (MoA), and generate drug resistant models through in vivo driven clinically relevant dose scheduling using standard of care agents.