bluuebunny/crossref_metadata_2025 huggingface dataset:
Successful management of camrelizumab-induced immune-checkpoint-inhibitors-related myocarditis
Authors: Long Hui-Dong , Du Yi-Peng , Wang Li-Yan , Liu Guan-Cheng , Liang Shi-Xiang , Zeng Zhao-Hua , Lin Yun-En
Published: December 2023

Introduction

Immune checkpoint inhibitors can cause immune-related toxicity in various systems, with myocarditis being the most severe and life-threatening manifestation. This report presents a case in which myocarditis developed following administration of programmed cell death protein-1 (PD-1) inhibitors therapy. We describe the diagnosis and treatment of this patient in detail.

Case report

We present the case of a 59-year-old female diagnosed with post-operative esophageal cancer and hepatic metastases. The patient underwent second-line treatment with domestically-made PD-1 inhibitor, camrelizumab, in combination with paclitaxel (albumin-bound) and carboplatin for two cycles. During the course of treatment, an electrocardiogram (ECG) revealed ST segment elevation in leads II, III, aVF, V2, V3, and V4, along with T wave changes in leads I and aVL. Laboratory examinations showed abnormal levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT). Despite the absence of clinical symptoms, the patient was routinely hospitalized three weeks later. Based on the findings from the ECG, cardiac biomarkers, echocardiography, echocardiogram, cardiac magnetic resonance, and angiography, she was diagnosed with immune-checkpoint-inhibitors-related myocarditis.

Management and outcome

The patient received immunoglobulin (0.5 g/kg/day) and was initially given methylprednisolone (1000 mg/day). Methylprednisolone was gradually reduced to 40 mg/day in 2 weeks. During this time, the levels of biomarkers indicative of myocardial injury also exhibited a simultaneous decline.

Discussion

This case highlights the importance of early detection and prompt intervention, including initiating appropriate steroid therapy and discontinuing of immune checkpoint inhibitors. Such measures can effectively prevent morbidity and mortality, ultimately leading to an improved prognosis.
Oblique impact on ceramic–composite armor system: A numerical study
Authors: Biswas Krishna , Datta Debasis
Published: December 2023

In this investigation, simulations are conducted to assess the ballistic resistance of an armor system composed of 95% alumina–Kevlar 29/epoxy composite subjected to normal and oblique impact. The oblique angles are varied from 0° to 70° in the step of 10-degree increments, and the projectile's impact velocities range between 220 and 1200 m/s. The present simulation results are aligned with existing numerical and experimental data available in the literature, demonstrating the consistency and reliability of the approach. Special attention is provided to obtain the critical oblique angle at which the projectile's penetration mode switches from perforation to embedment or ricochet. The simulation results also include the projectile's residual velocities, ballistic limit velocities, and the armor system's performance in terms of penetration or damage for normal and oblique impact. It is established that the oblique angle of the projectile significantly alters the effectiveness of the ceramic–composite armor against ballistic impact. When dealing with oblique angles below 30° (< 30°), the reduction in the projectile's residual velocity, as the obliquity angle increases, is limited to a maximum of 15%. This implies that the target's perforation resistance exhibits less sensitivity to the applied load of the projectile in this range. However, when incident angles exceed 45° (> 45°), the ballistic limit velocity has a significant and abrupt rise due to the augmented effective target thickness under oblique impact conditions.
The Metaverse in the Workplace: Possibilities and Implications for Human Resource Development
Authors: Lim Doo Hun , Lee Jae Young , Park Sunyoung
Published: December 2023

This study reviews the potential applications of the metaverse to various areas of human resource development (HRD) and reflects on the applications’ significance for employee and organizational development. Adopting a narrative review approach to this study, we selected and reviewed 34 cases. From our review, we found several findings that contributes to the HRD field in several ways. First, it draws the attention of HRD researchers and practitioners to a critical emerging trend that has been overlooked in the field. Second, it offers an analytical view of the metaverse in comparison to other training or learning technologies, assessing its effectiveness in employee development. Third, this study enhances the perspectives of HRD researchers and practitioners regarding this new technology by providing practical and theoretical insights into how metaverse-based interventions can reshape organizational culture and improve employee performance in the workplace. Lastly, it addresses compelling theoretical and practical questions related to HRD issues arising from the metaverse.
Establishing the New York Hippodrome as an Intrinsically ‘American’ Entertainment Venue Through Publicity & A Yankee Circus on Mars’s Performance Practice
Authors: Holmes Kate
Published: December 2023

Publicity materials heralded the New York Hippodrome as the world's largest theatre and the National Theatre. Managers Elmer Dundy and Fred Thompson based their claim for national status on the venue's size. Their ideology considered big to be better because it proclaimed success, efficiency, and the organisation and consumption of pleasurable experiences to be the responsibility of every American citizen-consumer. Using publicity, costume designs, sketches, illustrations, production stills, newspaper reports and a scrapbook, I explore their nationalistic vision. I demonstrate how the opening's entertainments performed Dundy and Thompson's populist Americanness through narrative, design aesthetics and moments that exceeded the dramatic frame. The first of the two night's productions, A Yankee Circus on Mars (1905), presented Mars as an idealised surrogate America. The production deliberately centred circus to designate their venue as ‘American’ due to circus's status as an intrinsically American entertainment. Circus provided practical benefits in filling the vast interior with spectacle and covering long stage waits. Presenting circus end-on in the New York Hippodrome designated the venue ‘American’, but created an experience that was akin to circus. Focusing on responses to aerial acts, I demonstrate the visual gains and visceral losses to experiencing aerialists within the Hippodrome space.
Constructing ambivalent masculinity and constant femininity in interracial families: Media representations of African-Chinese marriage on Xiaohongshu
Authors: Li Run
Published: December 2023

Interracial marriage has increasingly gained visibility on Chinese social media platforms, especially African-Chinese marriage which has been popularly represented, sparking heated discussions publically. However, although several studies have touched upon interracial marriage with analyses through political and geographical lenses, few studies investigated the media representations and mediated comments towards African-Chinese marriage in China as it has become a hot topic on Chinese social media platforms recently. To fill this niche, this study explores how African-Chinese marriage is represented on Chinese social media through mediated public comments, and what ideological implication of represented subjectivity of male and female in African-Chinese marriage. Through feminist critical discourse analysis and intersectional perspective, it found that ambivalent masculinity and constant femininity are constructed in African-Chinese marriage through comments where Chinese males are predominantly represented as positive figures, while African men are greatly dehumanised and criticised. As for women, although public attitudes are distinctive towards Chinese and African women, they, sharing the collective identity of females, are restricted in the traditional conception of gender dichotomy. Finally, the social contextualisation of such representations and potential ideological implications will be generally discussed.
Towards an economy of memory: Defining material conditions of remembrance
Authors: Palacios González Daniel
Published: December 2023

The following proposes a reframing of approaches to Memory Studies from a materialist perspective. Memory Studies emerged simultaneously with the decline of materialist theories and political economy in historical and cultural studies. Despite attempts to generate alternative genealogies and methodological updates, materialism and political economy have been omitted from the study of memory. Several possibilities to define frameworks for future work on memory will be explored here. First, working on memory as part of a mode of production; second, understanding memory as a field that organises internal hierarchies; and third, defining memory as an ideology that ensures the reproduction of the mode of production. This theoretical proposal is supported by fieldwork and experience in the study of memory practices and policies related to the Spanish Civil War and Francisco Franco’s Dictatorship.
Loose Bodies Found in the Human Intra-Articular Space Showed Characteristics Similar to Endochondral Bone Formation
Authors: Schwab Andrea , Pap Thomas , Krenn Veit , Rüther Wolfgang , Lohmann Christoph , Bertrand Jessica
Published: December 2023

Objective

Loose bodies are free-floating tissues of cartilage and bone that can cause pain, swelling, the inability to straighten the knee, or intermittent locking of the knee. Loose bodies can arise from degenerative joint disease, flake fractures, osteochondritis dissecans, or chondromatosis. We hypothesized that loose bodies can be classified in stages with tissue characteristics similar to endochondral ossification.

Design

Loose bodies were harvested from patients undergoing joint replacement. Samples were processed for histology, gene expression analysis, and micro-computed tomography (µCT). Cartilage- and bone-related genes and proteins were selected for immunofluorescence stainings (collagen type I, II, and X, SOX9 [SRY-box transcription factor 9], and MMP13 [matrix metalloproteinase 13]) and gene expression analysis ( FN [fibronectin], COL1A1, COL2A1, COL10A1, SOX9, MMP13, and aggrecan [ ACAN]).

Results

Loose bodies were grouped in 4 stages: fibrous, (mineralized) cartilaginous, cartilage and bone, and bone. Hyaline-like cartilage tissue with Benninghoff arcades was present in stages 2 and 3. A transition from cartilaginous to mineralized tissue and bone trabecula was defined by an increase in COL1A1 and COL10A1 (stage 3 vs. 4: p = 0.047) positive area. Stage 4 showed typical trabecular bone tissue. The relative volume of calcified tissue (mineralized cartilage and bone tissue) decreased with stages (stages 1-2 vs. 3: p = 0.002; stage 1-2 vs. 4: p = 0.012). COL2A1 expression and stained area decreased from stages 1-2 to 4 ( p = 0.010 and p = 0.004). ACAN expression decreased from stage 1-2 to stage 3 ( p = 0.049) and stage 4 ( p = 0.002).

Conclusion

Loose bodies show tissue characteristics similar to endochondral ossification. They are probably a relevant substrate for regenerative therapeutic interventions in joint disease.
Unleashing Potential: Overcoming Bottlenecks and Catalyzing Innovations in Intellectual Capital Intellectualization of Small and Medium-Sized Enterprises in Jiangsu During the Post-Industrial Era
Authors: Abredu Pearl , Li Cai , Essien Frank Kofi , Adegoke Isaiah Agbenu Akanbi
Published: December 2023

The current research attempts to determine the degree to which three primary elements (Human, Structural, and relational capital) and intellectual capital are related to profitability of SMEs technological inventions in China’s Jiangsu province of as part of the country’s intellectualization process in the post-industrial era. The research utilizes data from 1,450 SME listings on the Shenzhen stock market between 2012 and 2020. The VAICTM model was used in this inquiry. Using PLS-SEM, the study evaluated four significant hypotheses. The research indicates that human and structural capital have a substantial meaningful correlation regarding SMEs success. The research also discovered a favorable association between human and structural capital and technological innovation in Jiangsu province throughout the post-industrial period. However, a strong negative correlation occurred between relational capital and the financial performance of small and medium-sized enterprises (SMEs). The research uncovered a substantial positive relationship between the technological innovation of SMEs and their financial success. The link between intellectual capital (HC, SC, and RC) and company performance was shown to be mediated and moderated by technological innovation. According to the findings, technical innovation considerably moderates the link between Human Capital and firm performance. The research indicated that Technical Innovation (TI) moderates the association between Structural Capital (RC) and firm performance. In contrast, Technical Innovation (TI) does not alter the association between Relational Capital (RC) and firm success in a substantial way.
Situating Injustice in the Frame of Dalit Politics: A Case of Democracy in Nayattu
Authors: Vadackel Jerome , Romeo Christina
Published: December 2023

It might not be amiss to observe that, Nayattu, the Malayalam movie by filmmaker Martin Prakkat rides its last lap on the breathtaking suspense of a suspension of justice set in the backdrop of Indian electoral politics. Such suspense or suspension is hardly unanticipated in the writings of Jacques Derrida for whom the reasoning of democracy is of ‘a certain reason to come, as democracy to come’. Rather than eager anticipation ready to bear fruit, the reasoning of democracy is the contrary. It is the impossibility of ever bearing fruit which is portrayed through the executive’s insensitivity and domineeringness towards ordinary man’s justice. Several other characteristics also make the movie a worthwhile analysis in this frame. It is the story of the sheer inadequacy of traditional democratic institutions in fulfilling their role—three police officers who are wrongly accused need to run to the valley/hill outside the walls of the ‘city’ in search of a place of refuge that is never to be found. However, it is the portrayal of Dalits both as the mob and as the victimized that contributes to the tempo of the movie.
Uses of Hagia Sophia: Politics, Heritage and the Imperative for Inclusive Management
Authors: Cho Hyojung
Published: December 2023

The reconversion of Hagia Sophia into a mosque in 2020 created international controversy, and the Erdog˘an administration has been criticized for using it as a political vehicle, abandoning the state’s duties for safeguarding the World Heritage Site. This research will investigate the use of Hagia Sophia by the Republic of Turkey in their national and international politics, and it will demonstrate how both the museum and the mosque settings were oriented by the political needs of the time and affected heritage management: conservation, interpretation and visitor’s accessibility. The purpose of this study is to illustrate that the institutional uses of Hagia Sophia have always been political and to highlight the potential benefit and the continuing social, cultural and educational responsibilities as a living religious heritage site through multigovernmental and international collaboration. Recognizing the limitations of each institutional setting demands an inclusive and strategic management of Hagia Sophia that respects its complex history and diverse values to serve both local and global communities.
Explaining how and why social support groups in hospice day services benefit palliative care patients, for whom, and in what circumstances
Authors: Bradley Natasha , Dowrick Christopher , Lloyd-Williams Mari
Published: December 2023

Background:

Palliative care aims to provide holistic support for people with life-limiting illness, responding to psychological, social and spiritual needs, as well as to clinical and physical. In the United Kingdom, hospice day services (including day care, group interventions, group activities, and social events for palliative care outpatients) aim to provide opportunities for patients to gain social support, which is thought to improve their quality of life.

Objectives:

This research explored social support within hospice day services, to explain in detail how and why social support obtained within a hospice day service could be beneficial to palliative care patients.

Design:

Qualitative research using observations of hospice day services and interviews with service providers.

Methods:

Data collection involved nineteen interviews with hospice service providers ( n = 19) and researcher observations of hospice day services. The findings detail how patient and hospice context interact to produce mechanisms that lead to outcomes beyond the hospice day service.

Results:

Practical, clinical and social aspects of the hospice day service are important for patients feeling welcome and safe in the setting. The opportunity to connect with other people and work towards personal goals can boost self-confidence for patients who have lost access to meaningful activity. New friendships between patients encourages reciprocal support and feelings of belonging. It is beneficial to have permission to speak freely about topics deemed inappropriate elsewhere, because honest communication is helpful in accepting and adapting to their circumstances.

Conclusion:

Hospice day services facilitate group settings for reciprocal social support. This research proposes an initial programme theory that can be further developed and tested. It explains how and why, in some contexts, social support increases personal and practical resources to cope with illness and death, leading to changes outside of the hospice (to mood, interpersonal interactions and behaviour) that could improve quality of life.
Enduring violence and commemoration: Korea’s Cheju April 3 Incident
Authors: Kim Seong Nae , Hwang Merose
Published: December 2023

Post-atrocity survivors construct spaces of being through various levels of visibility and stages of construction. Those with inherited memories of their ancestors from mass atrocities share the ability to exert their postmemories that mediates the past memory in its affective force to restore their sociability with their relatives, neighbors, community, and nation. A central medium of postmemory typically comes in the form of commemorative ritual practices that contain a mixture of mourning and re-creation of family and community. Ritual engages informal sociocultural processes outside the purview of the state. Commemoration rituals reflect ordinary people’s attempts to seek moral renewal and social repair to promote social reconstruction and recovery of humanity. This essay considers feminist interventions of intimate memorial scales, enabling us to envision potential alternative historical trajectories in post-massacre commemorations, memorials, reburials, and as mnemonic locations for agonistic testimonies to emerge around a mid-century massacre in South Korea called the “Cheju April 3 Incident.” We take into consideration how the postmemory of the Cheju April 3 Incident is intergenerationally transmitted and ritually re-enacted through family ancestor worship, and the reburial of remains after the exhumation of mass graves. The lessons of postmemory practices are crucial to the foundation of humanity after atrocity.
A Web-Based Mind-Body Intervention (Mindful Steps) for Promoting Walking in Chronic Cardiopulmonary Disease: Insights From a Qualitative Study
Authors: Kraemer Kristen M. , Kilgore Karen , Litrownik Daniel , Jean-Laurent Brianna , Wayne Peter M. , Richardson Caroline R. , Moy Marilyn L. , Yeh Gloria Y.
Published: December 2023

Background

Given the deleterious effects of physical inactivity in persons with chronic obstructive pulmonary disease (COPD) and/or heart failure (HF), interventions that promote long-term daily physical activity are needed. Mindful Steps, designed to promote walking behaviors in COPD and HF, is a multicomponent intervention that integrates mind-body content with other self-regulatory components. The aim of the current qualitative study was to characterize participants’ experiences with Mindful Steps and understand the perceived influence of the intervention on walking and health.

Method

In the context of a pilot randomized controlled feasibility trial comparing the year-long Mindful Steps program to usual care among individuals with COPD and HF, semi-structured qualitative interviews were administered at 6- and 12-months. Interviews were audio recorded and transcribed. The constant comparative method was used to code transcripts, identify categories, and develop interrelated themes.

Results

Nineteen participants (63% female; M age = 70.2 years, SD = 6.95) who were randomized to the intervention group completed the 6-month interview and 17 completed the 12-month interview. The pedometer with feedback, live group classes, and mind-body videos were described as the most helpful intervention components. Participants learned several strategies that helped their walking (e.g., breathing regulation and awareness, body awareness, mind-body techniques, pacing), described walking as enjoyable, and identified internal reasons for walking (e.g., to feel good). They also reported several physical and mental health benefits of the intervention. Some participants reported limited influence of the intervention on walking or health. Many participants continued to use the strategies they learned in the first half of the intervention at 12-months.

Conclusions

The mind-body content of Mindful Steps appeared to positively influence walking behaviors. Participants’ experiences with the intervention helped to identify areas for future intervention refinement. Future quantitative work is needed to corroborate these qualitative findings and assess the efficacy of the intervention on long-term physical activity engagement.

Trial Registration

This trial is registered in Clinical Trials.gov, ID number NCT01551953.
Enhancing Therapeutic Efficacy: Harnessing the Synergy of Histone Deacetylase and BCL6 Inhibition in DLBCL
Authors: Zhuang Wenzhuo , Li Qi , Zhang Yuchen , Li Bingzong
Published: December 2023

Background

Diffuse large B-cell lymphoma (DLBCL) is characterized by its aggressive nature and resistance to standard chemotherapy, necessitating the development of new therapeutic approaches. Histone acetylation, a crucial epigenetic modification, is globally decreased in DLBCL. Chidamide, a histone deacetylase (HDACs) inhibitor, has shown promise in certain lymphomas but its effectiveness in DLBCL remains under investigation.

Methods

RNA-seq and gene enrichment analysis were performed to identify chidamide's impact on the biological processes in DLBCL. The key factor influencing chidamide sensitivity was determined through correlation analysis, utilizing gene expression levels from the Cancer Cell Line Encyclopedia and IC50 values of four HDAC inhibitors across multiple cancer cell lines sourced from the Genomics of Drug Sensitivity database. Histone acetylation levels, HAT and HDAC enzyme activity analysis, and co-immunoprecipitation were performed to investigate the underlying mechanism through which BCL6 influences chidamide sensitivity. A search among small molecule drugs in clinical investigation aimed to find drugs inhibiting BCL6 to enhance DLBCL sensitivity to chidamide. Synergy between HDAC and BCL6 inhibition was explored through synergistic effects, ubiquitination, and proteasomal degradation analysis. DLBCL mouse models were utilized to evaluate the therapeutic potential of combining chidamide and lenalidomide in vivo. Additionally, chidamide's effects on macrophage polarization were investigated through RNA-seq analysis of M1, M2, and chidamide-treated M2 macrophages.

Results

Chidamide exhibited potent suppression of DLBCL both in vitro and in vivo (Figure 1A), exerting a significant impact on diverse biological processes in DLBCL. BCL6 inhibited chidamide-induced histone acetylation by recruiting HDACs, leading to drug resistance in DLBCL cells. Lenalidomide could target BCL6 degradation through the ubiquitination pathway and restored the sensitivity of drug-resistant DLBCL to chidamide (Figure 1B). Additionally, chidamide had an impact on the tumor microenvironment. Chidamide inhibited the activity of M2-like tumor-associated macrophages and redirected the polarization of macrophages toward the M1 phenotype. Moreover, we conducted a single-arm multicenter clinical trial to evaluate the safety and efficacy of chidamide in combination with lenalidomide in DLBCL.

Conclusions

These findings highlighted HDACs as a viable therapeutic strategy for DLBCL, providing valuable insights into chidamide's global impact on the disease. Furthermore, BCL6 was a pivotal determinant of chidamide sensitivity and a reliable biomarker for treatment response. Integrating HDAC and BCL6 inhibition held potential for personalized and effective DLBCL treatments.
Innovative Transformer Base Editor (tBE)-Mediated Editing at BCL11A Binding Motif Triggers High Level of γ-Globin Expression with No Observable Off-Target Mutations
Authors: Chen Jia , Han Wenyan , Qiu Hou-Yuan , Sun Shangwu , Fu Zhi-Can , Wang Guo-Quan , Yang Li , Yang Bei , Zhang Ying
Published: December 2023

Activating the silent γ-globin expression is a universal therapeutic strategy for treating β-hemoglobinopathies including β-thalassemia and sickle cell disease. Several therapeutic target sites have been identified and the editing at these sites can reactivate γ-globin expression. In this study, we used a recently developed cytosine base editor, transformer base editor (tBE), which triggers no observable off-target mutations, to edit the therapeutic target sites for triggering γ-globin expression. Through editing six therapeutic sites, we found that the editing at BCL11A binding motif in the HBG1/2 promoters induced the highest γ-globin expression level. By comparing to other approaches such as Cas9 nuclease or other base editors, tBE-meditated editing at BCL11A binding motif induced higher fetal hemoglobin (HbF) expression and meanwhile did not trigger any detected DNA or RNA off-target mutations. Of note, tBE-mediated editing at the HBG1/2 promoters induced more robust HbF expression in the erythroid progeny from β 0/β 0 thalassemia patient-derived hematopoietic stem and progenitor cells (HSPCs) than CRISPR/Cas9 approach. Moreover, persistent base editing by tBE was found in long-term repopulating hematopoietic stem cells. Taken together, this study demonstrates that tBE-mediated therapeutic base editing at BCL11A binding motif in HBG1/2 promoters is a safe and highly effective strategy for treating β-hemoglobinopathies.
The Treatment of Burkitt Lymphoma with the Berlin-Frankfurt-Münster Protocol with Rituximab and Autologous Transplantation
Authors: Broccoli Alessandro , Bagnato Gianmarco , Argnani Lisa , Casadei Beatrice , Cantelli Martina , Pellegrini Cinzia , Zoli Sabrina , Sutto Emanuele , Coppola Paolo Elia , Gentilini Marianna , Morigi Alice , Carella Matteo , Gugliotta Gabriele , Nanni Laura , Stefoni Vittorio , Zinzani Pier Luigi
Published: December 2023

Intensive treatment approaches are required for adult Burkitt lymphoma (BL), although a univocal standard of care still does not exist. The use of frontline autologous transplantation is debated.

Between 2004 and 2020, 50 HIV-negative BL patients were treated with the Berlin-Frankfurt-Münster (BFM) protocol at our institution. Treatment plan consisted of 3 blocks, A (ifosfamide, vincristine, methotrexate, etoposide, cytarabine), B (vincristine, cyclophosphamide, methotrexate, doxorubicin) and C (vindesine, methotrexate, etoposide, cytarabine), each repeated twice, every 28 days. Patients elder than 60 years did not receive block C, thus blocks A and B were repeated 3 times. Rituximab was given at day 1 each block. Intrathecal prophylaxis was given once per each block. Autologous stem cells were reinfused (ASCT) at the end of the 6-blocks after BEAM (carmustine, etoposide, cytarabine, melphalan) conditioning, when feasible.

Median age at onset was 38 years (range 16-72); 38 patients were male and 12 female. Stage III-IV disease was observed in 82% of cases; bulky disease occurred in 44% of the patients, with B-symptoms in 38%. Two patients did not receive rituximab because of adverse reaction and early death. Intrathecal prophylaxis was given in 96% of patients. Stem cell harvest was performed in 70% of patients, who all received a subsequent ASCT. The full 6-blocks treatment was completed in 70% of the patients; 8% received 5 cycles and 22% received ≤ 3 cycles. Early treatment interruption occurred because of disease progression (12%), toxicity (8%), death (4%) or other causes (4%).

The overall response rate was 74%, with a complete response rate of 60%. Three patients could not be evaluated because of early progression/death. Ten-year overall survival and progression-free survival were 83.7% and 76.0%, respectively, with both curves exhibiting a plateau (Figure). Ten-year disease-free survival was 80.3%. Eight patients had died because of disease progression (3 patients), infection or sepsis (4 patients) or cardiac arrest (1 patient). Grade 3-4 neutropenia, thrombocytopenia, anemia and mucositis were seen in 96%, 60%, 32% and 24% of patients. Infections occurred in 60% of patients; grade 4 and fatal sepsis in 14% and 8% of cases.

Intensive treatment according to BFM protocol, with rituximab and ASCT, appears feasible, safe and highly effective in adult patients with BL, as confirmed by long-term survival rates.
Earliest Possible Detection and Intervention for Synovitis in Hemophilia- Results from a Single Center Retrospective Cohort Study
Authors: Halimeh Susan , Daoud Mohamad Ayman , Siebert Manuela , Zappek Jennifer , Rosenthal Marc
Published: December 2023

Introduction

There is scientific evidence to suggest that the most serious health problems for hemophilic patients arise from joint damage, which in turn results from joint bleeding, which is overlooked and therefore not treated. The ankle joint was affected the earliest in most hemophilic patients. Strategies for detecting and treating bleeding in hemophilic patients need to be further developed and made more widely known by clinicians.

Aim of our study

The aim of our retrospective, single-center cohort study was to compare the effects of reactive versus preventive joint ultrasound as guidance for adjustments of treatment regimens for patients with severe hemophilia at our Hemophilia Comprehensive Care Center (HCCC) in Duisburg, Germany.

Methods

Before 2020, we used ultrasound according to the German hemophilia-synovitis guidelines in 2018. This meant that we sonographed the ankle joints and knees of most of our patients when they reported discomfort in the joint or when a joint bleeding had occurred. In these cases, prophylactic hemophilia treatment was immediately adjusted to a level at which the bleeding and/or discomfort stopped. If the factor treatment was not sufficient to accomplish this goal, the joints were treated with radiosynoviorthesis (RSO). In 2020, we changed our diagnostic strategy from reactive to preventive measures. Thus, we used ultrasound on every ankle and knee joint of our severely hemophilic patients at least once a year. If we found so called “silent symptoms,” which means touch-sensitive joints, the joints were sonographed once every three months. In cases of signs of joint degradation, we adjusted the prophylactic factor treatment accordingly.

Results

From 2020 to 2022, we examined a total of 1193 joints of 688 patients with hemophilia A or B, as well as with vWD disease type 2 or 3 and other severe coagulation disorders (factor VII deficiency, factor XIII deficiency, afibrinogenemia, and Glanzman disease).

Of these, 103 had severe hemophilia A or B. In this study, we examined 656 joints sonographically. Of these, we examined 281 ankle joints in 80 patients and 175 knees in 64 patients, and adjusted the therapy regimens accordingly in these patients if necessary.

Seven RSOs of the ankle joints and three RSOs of the knees were performed in the cohort up to 2020. After 2020, only two RSOs of the ankle joints were performed in the cohort.

Conclusions

At least for patients at our HCCC in Duisburg, Germany, we were able to show for the period 2020-2022 that closer ultrasound monitoring of ankle joints and knees in patients with severe hemophilia A or B and appropriate adjustment of prophylactic factor therapy was associated with less severe and less frequent joint degradation.
GATA1 and GATA2 Sense/Antisense Transcriptional Switching in Early Hematopoietic Development
Authors: Anderson Erik M , Li Hongchuan , Ruesch Michael , Eisele Caprice D , Freud Aharon G. , Anderson Stephen K
Published: December 2023

The GATA1 and GATA2 genes play essential roles in hematopoietic development. GATA1 is the master regulator of erythropoiesis and GATA2 is required for the expansion and survival of hematopoietic progenitor and stem cells, as well as the development of mast cells. A switch in GATA expression occurs during erythropoiesis, with silencing of the GATA2 gene and increased expression of GATA1. A GATA2 antisense transcript ( GATA2-AS1) has been associated with silencing of GATA2 expression. We have identified a novel GATA1 antisense promoter located in the first intron that opposes the GATA1 promoter and generates a spliced antisense transcript complementary to the SUV39H1 H3K9 methyltransferase gene. The competition between opposing sense and antisense promotersin the GATA1 and GATA2 genes may play a central role in the switching of GATA expression that occurs during hematopoiesis. To address this hypothesis, gene expression analysis of cells expressing sense versus antisense transcripts from the GATA1 or GATA2 genes was performed using 5'scRNAseq data from in vitro differentiated CD34 cells. Cells expressing only sense or only antisense GATA1 transcriptswere readily detected and comprised the majority (90%) of cells with GATA1 transcripts. Differential gene expression analysis of cells with GATA1 sense-only versus cells with GATA1 antisense-only showed association of sense transcription with erythrocyte genes, whereas antisense expression was associated with a mast cell phenotype and upregulation of GATA2 transcript levels. Conversely, GATA2 antisense expressing cells had increased GATA1 transcription and an erythrocyte phenotype, and GATA2 sense expressing cells demonstrated mast cell-specific gene expression. Single cell RNAseq analysis of HL60 cells induced to differentiate in vitro identified significant changes in GATA2 gene expression. Induction of granulocyte differentiation in HL60 cells treated with DMSO resulted in increased GATA2 antisense transcription, whereas PMA induction of monocyte differentiation was associated with increased GATA2 sense transcription. Taken together these results indicate a central role for sense/antisense promoter switching in hematopoiesis.
Phase I First-in-Human Study on the Feasibility, Safety, and Antitumor Activity of CD4-Redirected Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with CD4+ T-Cell Malignancies (TCM)
Authors: Assi Rita , Hagag Nabil , Farag Sherif , Emmons Robert V.B. , Carter Allie , Czader Magdalena , Abonour Rafat , Apetoh Lionel , Ma Yupo , Salman Huda S.
Published: December 2023

Background

TCM are aggressive diseases with poor outcomes. Translating the CAR T-cell therapy success from B-cell diseases to TCM has proven challenging. CD4 is an attractive therapeutic target, owing to its restricted expression on normal tissues. In this first-in-human phase I study, we investigate the autologous third generation CD4-redirected CAR T-cell safety, tolerability, manufacturing feasibility, trafficking and preliminary efficacy in patients with R/R CD4+ TCM who failed standard therapies.

Methods

The investigational construct is engineered with a single-chain variable fragment (ScFV) and dual co-stimulators (CD28; 4-1BB), fused to CD3zeta and CD8 leader sequence, packaged in lentivirus and transducer into T-cells. Patients received conditioning therapy with fludarabine and cyclophosphamide. CD4CAR product is administered in a 3+3 dose-escalation scheme. Dose-limiting toxicities (DLT) were monitored during the initial 42-days post-treatment. Treatment-emergent adverse events (AE) were graded by CTCAE v5.0

Results

Three patients with median age of 63 years (range, 18-68) were enrolled and treated at DL1 (2.0x10^5/kg), including 2 (66%) women and 2 (66%) African-American. Median number of prior therapies was 3 (range, 2-4) (Figure). AEs included grade 3-4 hematologic toxicity in 3 (100%) patients, all present before enrollment. There was no protocol defined DLTs. All grade ≥3 lymphopenia reverted to grade 2 by day 30 and no related infections occurred between CAR infusion and hematopoietic stem cell transplantation (HSCT). Since infusion, the CAR T-cells percentage in peripheral blood had continued to expand. CD4CAR T-cells were detectable in all patients for at least 28 days post-infusion, meeting the primary endpoint, and on D111 in one patient. CD4CAR expansion was reflected on by a decrease in CD4/CD8 ratio and flow cytometry using ScFV Fab2 specific antibodies (Figure). Cytokine response analysis CD4CAR was associated with variable but significant production that seems to correlate with clinical responses (Figure; More data at meeting). No cytokine-mediated organ toxicities were observed. Bone marrow and peripheral blood flow cytometry confirmed complete remission (CR) in 2 patients at day 30 (PTCL and T-ALL). Patient 3 (mycosis fungoides) achieved hematological CR with stable skin lesions. Post-treatment day 30 skin biopsy demonstrated persistent disease with marked loss of CD4.

Conclusions

CD4CAR T-cell therapy is feasible in patients with R/R CD4+ TCM. 2/3 patients achieved CR and the third achieved hematological CR with stable skin disease. Toxicities were manageable without DLT upon completion of cohort 1. The cytokine response suggests immune activation and tumor recognition by CD4CAR T-cells. Dose escalation will proceed. NCT03829540
Clinical Analysis of 22 Cases of HIV-Associated Hodgkin Lymphoma in China
Authors: Wang Chaoyu , Liu Jun , Wu Yan , Min Haiyan , Yang Tao , Zhang Wei , Zhou Hui , Liu Yao
Published: December 2023

Introduction: Knowledge of HIV associated Hodgkin lymphoma mainly comes from case series or retrospective studies. Further,these criteria and guidelines have not been systematically evaluated. To investigate the clinical characteristics, response, and prognosis of HIV associated Hodgkin lymphoma in China.

Methods:A total of twenty-two cases of human immunodeficiency virus infection-related Hodgkin lymphoma patients from 5 Chinese hospitals were enrolled in this study, between December 2013 and June 2022. Data on the clinical features, laboratory results, response, and prognosis were collected and analyzed.

Results : The median age at diagnosis was 44(22-60) years. All patients were infected with HIV through sexual transmission, with ten cases transmitted through man sex with man and twelve cases transmitted through heterosexual transmission. Nine patients were diagnosed with lymphoma and found to be infected with HIV. Five cases were in stage III,and seventeen cases were in stage Ⅳ.After a median follow up of 30.6（4.0～112.9) months, 17 cases were alive after ABVD regimen chemotherapy combined with antiretroviral therapy. The 3-year PFS and OS rate were 80.8% and 85.9%,respectively.

Conclusion : HIV associated Hodgkin lymphoma exhibit an invasive process in clinical practice, and standardized treatment can achieve long-term survival.

【Key words】HIV; Hodgkin lymphoma; Therapeutics;Prognostic
Rational Engineering of Minimally Immunogenic Nucleases for Gene Therapy
Authors: Raghavan Rumya , Friedrich Mirco , King Indigo , Killian Michael , Platten Michael , Macrae Rhiannon , Song Yifan , Nivon Lucas , Zhang Feng
Published: December 2023

Genome editing using CRISPR-Cas systems is a promising avenue for the treatment of genetic diseases. On the horizon for FDA approval next year are several of the first treatment tools involving CRISPR based gene editing for sickle cell anemia and beta thalassemia (Frangoul et al. 2021). However, cellular and humoral immunogenicity of genome editing tools, which originate from bacteria, complicates their clinical use(Charlesworth et al. 2019; Chew 2018; Mehta and Merkel 2020). Here we report reduced immunogenicity (Red)(i)-variants of two clinically-relevant nucleases, SaCas9 and AsCas12a. Through MHC-associated peptide proteomics (MAPPs) analysis, we identified putative immunogenic epitopes on each nuclease(Sekiguchi et al. 2018). Then, we used computational modeling to rationally design these proteins to evade the immune response(King et al. 2014). SaCas9 and AsCas12a Redi variants were substantially less recognized by adaptive immune components, including reduced binding affinity to MHC molecules and attenuated generation of cytotoxic T cell responses, while maintaining wild-type levels of activity and specificity. In vivo editing of PCSK9 with SaCas9.Redi variant was comparable in efficiency to wild-type SaCas9, but significantly reduced undesired immune responses. This demonstrates the utility of this approach in engineering proteins to evade immune detection and expand in vivo clinical use for a wide assortment of hematological disorders.
The Role of Red Blood Cell Lifespan Testing in the Evaluation of Patients with Paroxysmal Nocturnal Hemoglobinuria
Authors: Ye Lei , Zhao Xin , Jing Liping , Zhang Fengkui , Zhang Li
Published: December 2023

Objective To explore the role of red blood cell(RBC) lifespan testing in the evaluation of patients with paroxysmal nocturnal hemoglobinuria (PNH). Methods The endogenous breath carbon monoxide (CO) test was used to detect the RBC lifespan of PNH patient with the treatment of crovalimab（ Roche） or iptacopan（ Novartis.），for comparison of different hemolysis indices in the assessment of patients' condition. Results Nine patients have been enrolled in the study at our centre from June to December 2021, 4 with the treatment of crovalimab and 5 with iptacopan. The median lifespan in the untreated patients was 17 (range 12-38) days, median hemoglobin(Hb) 83(69-94) g/l, median lactic dehydrogenase（LDH）590.8(446.1-935.5)U/L, median PNH clones 96.0(33.2-99.9)%. By 6 months post-treatment, 8 patients achieved hematologic improvement without breakthrough hemolysis. In all patients, LDH levels decreased rapidly and stabilized at lower levels after starting treatment. But the degree of Hb recovery varied，median 60(20-85)g/L. Analyzing the correlation between different hemolytic indices (LDH, RBC lifespan, total bilirubin, indirect bilirubin, etc.) and Hb changes, RBC lifespan showed good correlation（P=0.002，R=0.867）. In the crovalimab group, three patients presented with a positive Coombs test and the negative patient didn't obtain hematologic improvement. No patients with a positive Coombs test were seen in the iptacopan group. Conclusion Different (upstream/downstream) complement inhibitors have different effects on the condition of PNH patients, and different indicators can reflect different results; LDH responds to intravascular hemolysis, and red blood cell lifespan also quantifies extravascular hemolysis, and is applied to monitor hemolysis. The application of RBC lifespan testing can provide an accurate scientific basis for the assessment of PNH conditions.

Keywords: red blood cell lifespa, paroxysmal nocturnal hemoglobinuria ,red blood cell lifespan,lactic dehydrogenase
Vaccination Recommendations and Clinical Characteristics of Children after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Cai Jiaoyang , Chen Wenjuan , Zhang Hua , Chen Jing , FEI YI , Cao Qing
Published: December 2023

To investigate the clinical characteristics, the risk factors related to antibody-negative conversion, and the effectiveness and safety of revaccination in children who underwent allogeneic hematopoietic stem cell transplantation (Allo-HSCT). The clinical characteristics of 516 children after Allo-HSCT who were eligible for revaccination in the Vaccination Evaluation Clinic of Shanghai Children's Medical Center from March 2017 to March 2023 were analyzed. Of the 516 patients enrolled, 464 (89.9%) had started revaccination, with a median time of 2.1 (IQR, 1.8-2.6) years after transplantation and 1.1 (IQR, 0.7-1.5) years after cessation of immunosuppressive therapy. There were 418 cases of hepatitis B surface antibody (HBsAb) seropositive before transplantation, and 339 cases (81.1%) became negative at the time of evaluation after transplantation. The visit time for children with persistently HBsAb seropositive was 1.9 (IQR, 1.3-2.3) years after transplantation, which was shorter than the time for children with HBsAb seronegative (2.2 [IQR, 1.9-2.8] years, P<0.001). HBsAb negative conversion was related to the HBsAb titers pre-transplantation, with a lower proportion of high titers in the negative conversion group (4.7% vs. 17.7%, P<0.001). Both univariate and multivariate analyses suggested that HBsAb seroconversion was statistically related to uncompleted three doses of the hepatitis B vaccine before transplantation, low pre-transplantation antibody titers, and ≥2 years after transplantation. Among 40 patients with HBsAb seronegative who received hepatitis B vaccination, 39 (97.5%) had HBsAb titers converted to seropositive. The immune response rates of measles, mumps, and rubella (MMR) were 96.6% (28/29), 69.0% (20/29,) and 88.5% (23/26), respectively. There were no serious adverse side effects after revaccination.After Allo-HSCT, standard evaluation procedures for revaccination are highly recommended. The immune response rates after hepatitis B and MMR revaccination were highly recommended. No severe adverse side effects were observed.