bluuebunny/crossref_metadata_2025 huggingface dataset:
Peri, enfim, fiou-se: o caso da adaptação de O Guarani (2023), de Ailton Krenak
Authors: Salvaia Priscila
Published: December 2024

No artigo propomos uma breve reflexão a respeito da narrativa O Guarani em três temporalidades: inicialmente, enquanto romance-folhetim (1857), de José de Alencar, e, posteriormente, através das adaptações operísticas  ideadas por Carlos Gomes (1870) e Ailton Krenak (2023), respectivamente. A partir do respaldo teórico dos Estudos Pós-Coloniais, temos por fim, especialmente, a montagem contemporânea, na qual o protagonista Peri "transfigura-se" (KRENAK, 2022) entoando a própria voz e a própria ancestralidade.
O caos em literaturas de língua portuguesa: Um estudo comparado do livro-reportagem Os sertões, de Euclides da Cunha, e do romance A jangada de pedra, de José Saramago
Authors: Silva Maria Beatriz Rodrigues da , Aleixo Marcos Frederico Krüger
Published: December 2024

The article aims to identify and expose the similarities between the approach to chaos in two productions of Ibero-American literature. Therefore, it compares chapter 1 of A Jangada de Pedra, by José Saramago, with Preliminares and Antecedentes from chapter 1 of A luta, in Euclides da Cunha's Os sertões. It is mainly based on Abed's (2022) analysis. It shows that the works embrace the notion of chaos as a necessity for the subsequent creation of a new order.
Desenhando jardins de plantas sagradas nas trilhas do Jardim Botânico de Salvador-Bahia
Authors: Amorim Nayara Cristina Rosa , Araújo Mayara Mychella Sena
Published: December 2024

Este artigo é resultado de um estudo exploratório visando à construção de uma linha e um projeto de pesquisa voltados ao estudo das plantas sagradas, dos espaços livres públicos e das religiões de matriz afro-brasileira no contexto urbano de Salvador, Bahia. Para tanto, percorre as trilhas dos oitis e do pau-brasil do Jardim Botânico de Salvador (JBSSA) com o objetivo de identificar plantas consideradas sagradas, evidenciando simbologias e intenções projetuais paisagísticas. O texto introduz aspectos gerais sobre plantas sagradas e sua presença na cidade de Salvador, evidenciando o JBSSA, um espaço livre público não muito conhecido pelos soteropolitanos e ainda pouco abordado em pesquisas científicas, mas que desde a sua criação tem a intenção de abrigar plantas sagradas e preservar a Mata Atlântica. Para alcançar esse escopo, é apresentado e discutido o projeto de um jardim etnobotânico, realizado em 2019 pelo escritório Embyá, para o JBSSA e que ainda não foi implantado. Adota-se como metodologia os croquis como ferramenta de representação, projeto e reflexão.
Webcams as Windows to the Mind? A Direct Comparison Between In-Lab and Web-Based Eye-Tracking Methods
Authors: Slim Mieke Sarah , Kandel Margaret , Yacovone Anthony , Snedeker Jesse
Published: December 2024

There is a growing interest in the use of webcams to conduct eye-tracking experiments over the internet. We assessed the performance of two webcam-based eye-tracking techniques for behavioral research: manual annotation of webcam videos (manual eye-tracking) and the automated WebGazer eye-tracking algorithm. We compared these methods to a traditional infrared eye-tracker and assessed their performance in both lab and web-based settings. In both lab and web experiments, participants completed the same battery of five tasks, selected to trigger effects of various sizes: two visual fixation tasks and three visual world tasks testing real-time (psycholinguistic) processing effects. In the lab experiment, we simultaneously collected infrared eye-tracking, manual eye-tracking, and WebGazer data; in the web experiment, we simultaneously collected manual eye-tracking and WebGazer data. We found that the two webcam-based methods are suited to capture different types of eye-movement patterns. Manual eye-tracking, similar to infrared eye-tracking, detected both large and small effects. WebGazer, however, showed less accuracy in detecting short, subtle effects. There was no notable effect of setting for either method. We discuss the trade-offs researchers face when choosing eye-tracking methods and offer advice for conducting eye-tracking experiments over the internet.
The Politics of Mystical Poetics: Bahrāmshāh b. Masʿūd’s (r. 1117–1157) Patronage of Sanāʾī’s (d. 1131 or 1135) Mystical Poetry
Authors: Zahiremami Parisa
Published: December 2024

Scholarship on the intersection of Islamic mysticism and politics often focuses on the way Sufi authors preach their mystical teachings to rulers. This article draws attention to the role of court poetry composed by authors who are not considered to have been practicing Sufis in promoting and popularizing mystical teachings at royal courts by examining Sanāʾī’s court-patronized poems as early specimen of mystical works that had a political dimension. This political dimension allowed Sanāʾī to promote and legitimize his royal patron Bahrāmshāh (r. 1117–1157) as a perfect ruler. The study highlights the propaganda value of Sanāʾī’s poetry for Bahrāmshāh. Simultaneously, it investigates the ways in which Sanāʾī asserts his agency in his patron-client relationship with Bahrāmshāh. By engaging with a rhetorical feature common in adab writings – that is, Parrhesia or frank speech – Sanāʾī portrays himself as a candid, Sufi-like advisor, who is detached from the material world and can therefore criticize and counsel Bahrāmshāh without fear of punishment. This show of charisma then provides the poet with an opportunity to preach his model of kingship to the ruler and promote his mystical advice as indispensable for proper royal conduct. According to Sanāʾī, an ideal ruler is a perfect man (or a valī) who is a vessel of God. In his panegyrics, he portrays Bahrāmshāh as a valī and perfect man, thereby legitimizing his royal patron over his rival and lord, the Seljuq Sultan Sanjar (r. 1118–1157). Sanāʾī mystico-political poems therefore functioned as a form of cultural capital through which the poet navigated his complex relationship with the court of Ghazna.
Iceland’s Territorial Sea Baselines, Volcanic Eruptions and Sea Level Rise
Authors: Magnússon Bjarni Már , Árnadóttir Snjólaug
Published: December 2024

Volcanic eruptions can have various consequences, including in the field of the international law of the sea. This article addresses the impact that two volcanic eruptions had on the baselines for measuring the breadth of Iceland’s territorial sea. First, the impact of the eruption in 1918 in Katla was addressed by the Supreme Court of Iceland in 1922 which confirmed a district court decision stating that the territorial sea line was not a fixed or determined line on the sea but changed with avulsions and accretions. Second, the sudden appearance of the volcanic island Surtsey in 1963 affected the drawing of straight baselines along the southwestern coast of Iceland. This article addresses the impact of these eruptions on the territorial sea baseline and explains their relevance for current challenges in international law.
Money-Making in Antarctica and Related Challenges to the Antarctic Treaty System
Authors: Bastmeijer Kees , Jabour Julia , Leary David , Wallace Claire
Published: December 2024

This article discusses commercial activities in Antarctica and the challenges these activities pose for the Antarctic Treaty System (ATS). Attention focuses on developments in fishing, tourism and biological prospecting in Antarctica and on possible future ice harvesting. The discussions show that ‘money-making’ in Antarctica has expanded and diversified over the past decades. While all these activities are subjected to existing ATS regulations, many policy questions are waiting for an answer from the 29 countries that jointly govern the Antarctic. A common characteristic regarding all commercial activities is that decision-making to proactively prevent negative impacts and risks to the principles and values of the ATS has proven to be very limited. This can directly affect the resilience of the ATS: continued lack of decision-making is likely to water down and undermine these principles and values, which may also increase tensions between the Consultative Parties to the Antarctic Treaty. It is incumbent on Consultative Parties to work harder to try advance resolution of the outstanding policy issues, particularly in a time when the Antarctic ecosystem is also under increasing pressure from climate change.
An Examination and Analysis of the Historical Development of the Local Church Movement from an Asian Woman’s Perspective
Authors: Chan Janice
Published: December 2024

An examination of the Local Church movement reveals that the major revivalists in the early twentieth century were predominantly women. Yet, most historical sources identify and honor only men as founders and label women as helpers. This has significantly impacted how the church remembers women’s contributions. Although the Local Church often attracts criticism from mainline Protestants because of its unique contextualized theology, members of the communities vigorously defend and advocate for their standpoints. An analysis of the Local Church’s theological development shows that its ecclesiology has been dramatically influenced by the mystical tradition, the Brethren movement, and allegorized and unconventional biblical interpretations of the Local Church. This study engages in a theological dialogue with Veli-Matti Kärkkäinen to call for Christian leaders to widen, deepen, and rethink their understanding of the Local Church movement as its members continue to shape the development of ecclesiology and their practices in the Chinese diaspora.
The Self, Other and Empire
Authors: Blair Anna Ilona
Published: December 2024

For a long time, Taiwan was an island relatively unknown within the Chinese realm. The defeat of the Ming loyalist forces in 1683 would result in the island becoming an official imperial possession of the Qing empire. It was within this context that Yu Yonghe produced the Small Seas Travel Diaries, a travel account documenting his ten-month journey across Taiwan as part of an official expedition to mine for sulphur.

Moving beyond a geographical and ethnographical mode of analysis, in this article I present an alternative view through examining Yu’s literary and historical constructions of identity. The Small Seas Travel Diaries reveals an intricate narrative pertaining to themes of the self, other and empire. This not only highlights the non-linear nature of Yu Yonghe as an explorer-writer, but also can be seen to situate the Small Seas Travel Diaries within a broader context of identity in relation to the empire.
Tillandsia uiraretama (Bromeliaceae), another new species from Alcatrazes Island, southeastern Brazil
Authors: SABINO GABRIEL PAVAN , DE MELO LEODEGARIO MARCIO , MARCUSSO GABRIEL MENDES , DAVID NATHAN MIRANDA GAZINEU , KOCH INGRID , TAVARES DANILO ULBRICH , PINHEIRO FÁBIO
Published: December 2024

A new species of bromeliad, Tillandsia uiraretama, is here described and illustrated. Tillandsia uiraretama was discovered during fieldwork on an insular granitic outcrop in southeast Brazil. The proposed taxon belongs to T. subgenus Anoplophytum and is compared to the morphological related T. araujei, T. aeranthos, T. iassuensis, and T. tenuifolia. It differs from them by the unique combination of fertile portion of the inflorescence with 4–7.5 cm long, 8 to 16 flowers per inflorescence, flower length of 3–3.4 cm, floral bract length of 1.7–3.8 cm, petal lilac with 2.7–3.4 cm long and 0.8–0.9 cm wide, stamen length of 1.5–1.9 cm and style length of 1.8 cm. A preliminary conservation assessment classifies T. uiraretama as vulnerable (VU).
Intravascular lithotripsy prior to transcarotid arterial revascularization: A technical tale of two cases
Authors: Evans Alexander R , Kharbat Abdurrahman F , Gierman Joshua L , Shakir Hakeem J
Published: December 2024

calcific carotid stenosis is becoming more common as the advanced-age population grows, requiring new therapeutic approaches. As such, transcarotid arterial revascularization is gaining significant popularity in the management of carotid stenosis due to low rates of perioperative complications and optimal clinical outcomes. In addition, intravascular lithotripsy has shown promise in safely facilitating the success of endovascular procedures in the context of calcified lesions. The combination of neuroprotective technology offered by transcarotid arterial revascularization and circumferential plaque remodeling by intravascular lithotripsy has been utilized for complex lesions. We present two cases of symptomatic calcific carotid stenosis treated with intravascular lithotripsy before transcarotid arterial revascularization. A 4 × 40 mm lithotripsy balloon delivered shockwaves at two and four atmospheres over a 0.014 wire. Transcarotid arterial revascularization was successfully completed without complications, and luminal patency was observed in both patients. C﻿alcific carotid stenosis was effectively treated with intravascular lithotripsy before transcarotid arterial revascularization, resulting in optimal safety and clinical recovery. Thus, when combined with novel shockwave technology, the neuroprotective effect of flow reversal in transcarotid arterial revascularization procedures demonstrates promise in maintaining safety while providing a novel treatment technique for high-risk patients with calcific cervical internal carotid artery stenosis.
Novel Method to Evaluate the Quantitative Immune Functionality of CAR T-Cells to Analyze the Localization Change of CAR Molecules
Authors: Yasui Hiroshi , Hirano Keiji , Kobayashi Asako , Li Lihua , Takahashi Takuya , Artemenko Margarita , Noda Naotaka , Sadato Daichi , Haraguchi Kyoko , Arai Ayako , Imai Kohzoh , Doki Noriko , Yanagida Masatoshi , Ishigaki Tomohiro
Published: December 2024

Background: Chimeric antigen receptor (CAR) T cells, genetically synthesized to reprogram T cells to recognize tumor antigen inducing intracellular signaling to destruct tumor cells, is a ground approach to hematological malignancies. As either loss of immune function or exhaustion in CAR T cells is a recurrence mechanism in patients with hematological malignancies who receive CAR T-cell therapy, evaluating CAR T-cell immune functions is a crucial clinical need. In this study, we used molecular imaging flow cytometry (MI-FCM) to develop a new evaluation method to quantitatively determine the immune functionality of CAR T-cells to analyze the change in CAR molecule localization.

Methods: Eight CAR T-cell clones were constructed via genetically modifying peripheral blood mononuclear cells from eight healthy donors (21-69 years old) using lentivirus to express an anti-CD19 CAR (FMC63-41BBz), as previously described by Kochenderfer et al. (J Immunol, 2009). The cytotoxic activity of these clones was then evaluated in vitro. Each clone was co-cultured with K562-CD19 cells that stably expressed the reporter gene encoding firefly luciferase (FLuc) for 15 h to assess the killing activity using a luciferase-mediated bioluminescence imaging assay. These clones were then stimulated with a fluorescently labeled CD19 protein for an hour. The change in CAR localization was determined via analyzing the intensity, area, and distribution (spot counts) of CAR expression in detail using a MI-FCM. The antitumor activity of some clones of CAR T-cells in vivo using a xenotransplantation model. NOG mice were injected intravenously with the CD19 positive human B-cell precursor leukemia cell line (NALM6) transfected with the FLuc reporter gene was also determined. Each CAR T-cell clone (5×106) cells was injected intravenously seven days after NALM6 injection. To assess antitumor activity, tumor volume was quantified using the IVIS imaging system to detect luminescent intensity.

Results: We found CAR molecules on cell surface aggregates in the immune response and detected the concentration as a decrease in CAR expression area. The percentage of CAR T-cells with single-spot CAR concentration was significantly correlated with cytotoxic activity (Pearson R = 0.83). We also confirmed that the clone with a higher percentage could demonstrate antitumor response and prolong the survival in xenotransplantation mouse models compared with non-treated mice, whereas the clone with the lowest percentage did not show these effects. We also confirmed that this method could be applied to CAR T-cell therapy products.

Conclusions: Quantifying the superficial CAR T-cell concentration using MI-FCM could be useful for evaluating their immune function.
The Efficacy and Safety of Obinutuzumab with Zanubrutinib As First-Line Treatment in Older Patients with Mantle Cell Lymphoma
Authors: Zhu Yanan , Lv Yunfei , Ye Xingnong , Wei Juying , Sheng Lixia , Lin Ying , Zhang Xiang , Zhang Xuewu , Tong Hongyan , Jin Jie , Yu Wen-Juan
Published: December 2024

Backgroud: Mantle cell lymphoma (MCL) is a heterogeneous malignancy and its incidence increases with age. Elder patients have poor performance status and low tolerance to chemotherapy, so many investigators look for chemo-free therapeutic approaches for newly diagnosed elderly MCL patients.

Aims: This study aims to investigate the efficacy and safety of a combination of obinutuzumab plus zanubrutinib (GZ) in previously untreated elderly patients with MCL.

Methods: Elderly patients (age ≥ 65 years) with newly diagnosed MCL were enrolled in this open-label, multicenter, single-arm, phase II clinical trial (ChiCTR2300071433), blastoid or pleomorphic histology were excluded. Patients received obinutuzumab (1000mg, intravenously, on days 1, 8, and 15 of cycle 1 and day 1 of cycle 2-4, 4 weeks per cycle), and zanubrutinib (160 mg twice daily, orally, from cycle 2) as induction therapy. Patients achieved complete remission (CR) were followed by zanubrutinib maintenance. Patients achieved partial remission (PR) received obinutuzumab for another 2 cycles and then zanubrutinib maintenance. Zanubrutinib was administered until disease progression or unacceptable toxicity or any other reasons of discontinuation. The primary endpoint was complete response rate (CRR). The secondary endpoints were overall response rate (ORR), overall survival (OS), progression free survival (PFS) and safety profiles.

Results: 19 patients were enrolled with a median age of 72 years. 14 patients had bone marrow involvement. High mantle cell lymphoma international prognostic index (MIPI) risk score was observed in 7 patients, and 10 patients had ki-67≥30%. 1 patient had a history of atrial fibrillation. Next-generation sequencing results were available in 15 patients, and detected 4 (26.7%) TP53 mutation. 9 patients had finished induction therapy, with 8 (88.9%) achieved CR, 1 achieved PR, and the ORR was 100%. With a median follow-up of 7 months, no patients had disease progression.

Most adverse events (AEs) were grade 1-2. 2 patients had grade 2 infusion-related response during the first obinutuzumab dose, each developed grade 3 or grade 4 thrombocytopenia, and both recovered in a week. 1 patient had grade 3 anemia, 1 patient had Covid-19 infection along with paroxysmal atrial fibrillation. No bleeding was observed. No patient discontinued therapy.

Conclusion: Obinutuzumab plus zanubrutinib demonstrated a favorable efficacy and a manageable safety profile in elderly patients with untreated MCL.
The Use of ATP-Release Identifies Platelet Function Disorders in Patients with Bleeding Disorder of Unknown Cause (BDUC) and Normal LTA Results
Authors: Monard Amaury , Van Dellen Floris , Hellenbrand Dave , Verhezen Paul , Beckers Erik AM , Henskens Yvonne , Moenen Floor CJI
Published: December 2024

Background:

About 60-70% of patients that are referred to a medical specialist with an increased bleeding tendency remain undiagnosed after extensive laboratory testing. These patients are classified as having a Bleeding Disorder of Unknown Cause (BDUC). The golden standard for the assessment of platelet function is light transmission aggregometry (LTA), but this technique is not able to detect all platelet granule defects. Therefore, the aim of this study was to investigate the additional diagnostic value of lumi-aggregomtery/ATP-release on top of LTA in patients with an increased bleeding tendency, to test for dense granule secretion disorders.

Methods:

Data from 336 patients in the ProBe-AHP study, including patients referred for analysis of an increased bleeding tendency, were used. The CHRONO-LOG® 490 4+4 light transmission aggregometer was used to perform LTA and the CHRONO-LOG® model 700 lumi- aggregometer was used to measure ATP-release by luminometry. LTA was performed according to the consensus SSC ISTH document by Cattaneo et al. For ATP-release, collagen, epinephrine and an thromboxane A2 analogue (U46619) were used as agonists. An abnormal LTA outcome was defined as more than one abnormal agonists and an abnormal ATP-release outcome was defined as one or more abnormal agonists. Other clinical and laboratory pre-existing data, including medical history, ISTH-BAT score and routine coagulation tests, were available.

Results:

In 274/336 patients LTA was performed and in 74/274 patients, additional ATP-release was done. LTA showed abnormal results in 41/274 (15%) of the patients and ATP-release showed abnormal results in 13/74 (18%) of the patients. Within the group of 74 patients in whom LTA and ATP-release was performed, initially 41 patients were diagnosed with BDUC, 15 patients with no bleeding disorder (NBD), 13 patients with a PFD (based on LTA), 1 patient with hyperfibrinolysis, 3 patients with von Willebrands disease type 1 and 1 patient with a mild FVII deficiency. After the performance of ATP-release, 10 additional diagnoses of PFD were made within the group of patients that were diagnosed with BDUC (n=10/41). This implicates a diagnostic yield of 24% with the use of additional ATP-release on top of LTA in this relatively small group of BDUC-patients.

Conclusion:

Our study showed that the addition of ATP-release testing to the diagnostic algorithm for patients with an increased bleeding tendency leads to more diagnoses of platelet function disorders, reducing the number of patients that are classified as having BDUC. Therefore, and in line with recommendations from previous studies, it is advised to perform platelet dense granule tests on top of LTA, if available, in patients with in an increased bleeding tendency.
LY4152199, a First-in-Class BAFF-RxCD3 Bispecific Antibody for the Treatment of B Cell Malignancies
Authors: Yang Wei , Burns Colleen , Lindquist Kevin , Dobkin Julie , Shin Hee Rae , Nguyen Cindy , Huang Xiaodong , Helms Whitney , Arce Nicholas , Mak Yvonne , Au Audrey , Abouzeid Abraham , Witek Marta , Leow Ching Ching , Gong Xueqian , Srinivasan Mohan , Park Joshua I. , Driscoll Kyla , Hass Andrew , Holmgaard Rikke , Duramad Omar , Bedard Kristin
Published: December 2024

The treatment paradigm for B-cell malignancies has been evolving with the availability of newer therapies such as CD19 CAR-Ts, as well as CD19×CD3 and CD20×CD3 bispecific antibodies. However, CD19/20 antigen loss can affect the long-term response to these treatments, which occurs frequently in patients who relapse following CD19/CD20-targeted therapy. BAFF-R (also known as TNFRSF13C or BR3) is a TNF-receptor super-family member that is essential to B-cell development and survival. Less broadly expressed than CD19 and similar with CD20, BAFF-R is expressed as a surface protein by most of B cells, including both healthy and malignant B cells, starting from late pre-B lymphocytes and ending before terminally differentiated plasmablasts and plasma cells. Importantly, BAFF-R expression appears unaffected after CD19/20 antigen loss. We have developed a fully human BAFF-R×CD3 bispecific antibody using a common light chain on an effector-less IgG1 backbone, LY4152199, that engages BAFF-R on the surface of B cells and CD3 on the surface of T cells, which leads to effective T cell-mediated elimination of BAFF-R-expressing malignant B cells. LY4152199 binds BAFF-R with high affinity. In co-culture assays with T cells and BAFF-R-expressing malignant B cells, LY4152199 engaged both CD3 and BAFF-R to induce concentration-dependent T-cell activation and T-cell mediated cytotoxicity, which was more potent than mosunetuzumab, a comparator CD20xCD3 bispecific antibody and a clinical benchmark for a TCE with lower cytokine release syndrome in B cell malignancies. Furthermore, LY4152199-induced in vitro cytokine production was lower than that observed for mosunetuzumab. In human PBMC transplanted mouse models implanted with human B cell lymphomas expressing physiologically relevant levels of BAFF-R, weekly treatment with LY4152199 demonstrated robust anti-tumor activities, including tumor clearance in 2 models. In addition, LY4152199 resulted in comparable or lower levels of human cytokines in the serum from these animals compared to animals treated with mosunetuzumab. Lastly, LY4152199 showed IgG-like pharmacokinetics and low immunogenicity. Taken together, LY4152199 exhibits specificity, desirable functional activity and good developability. It has demonstrated the potential as a first-in-class BAFF-RxCD3 bispecific antibody to treat BAFF-R-positive B cell malignancies, including relapsed or refractory cases with CD19/CD20 expression loss.
Hetrombopag, an Emerging Iron-Chelating Agent, Alleviates Systemic Iron Overload
Authors: Yufei Zhao , Zhao Xin , Yang Wenrui , Zhang Fengkui
Published: December 2024

Background: Iron overload is a syndrome in which excessive iron accumulates in the body, leading to tissue damage and functional disorders. This condition is common in patients with refractory anaemia who receive long-term red blood cell transfusions. Hetrombopag (HPAG) is a new generation, oral, small molecule, nonpeptide thrombopoietin receptor agonist that can chelate iron and alleviate iron overload while promoting haematopoiesis. Nevertheless, there is currently a lack of research on the iron-chelating function of HPAG, and its mechanism of regulating iron metabolism in the body is not clear.

Aims: The aim of this study was to clarify the iron-chelating function of HPAG, its effects on haematopoiesis, immune abnormalities, and tissue damage caused by iron overload and explore its potential mechanism of systemic iron metabolism, providing a new theoretical basis for the treatment of haematological diseases with HPAG.

Methods: Iron overload was induced in mice by intraperitoneal injection of iron dextran, and treatment was performed with HPAG, deferasirox (DFX, an iron chelator), or ferrostatin-1 (Fer-1, a ferroptosis inhibitor). The iron-chelating function of HPAG and its effects on haematopoiesis, immune abnormalities, and tissue damage caused by iron overload were clarified in vivo, and the underlying mechanism was explored via transcriptomics and lipidomics.

Results: Iron-overloaded mice treated with HPAG or DFX showed recovery in terms the of weight loss, hepatomegaly, histopathological iron deposition, reduced glutathione/oxidized glutathione (GSH/GSSG) balance and superoxide dismutase (SOD) activity, and increased non-transferrin-bound iron (NTBI) and malondialdehyde (MDA) levels caused by iron overload. Importantly, compared with untreated mice, iron-overloaded mice treated with HPAG, DFX, or Fer-1 presented restored tissue fibrosis and increased numbers of long-term haematopoietic stem cells (LT-HSCs), short-term haematopoietic stem cells (ST-HSCs), and Treg cells and an increased CD4/CD8 ratio. Lipidomic and transcriptomic data from the liver and c-kit+ cells in bone marrow revealed that HPAG induces molecular changes consistent with intracellular iron reduction and lipid peroxidation inhibition, with decreased expression of the HAMP, FTH1, BMP6, and HMOX1 genes. Furthermore, compared with those in DFX-treated mice, immune response-related signalling pathways, especially those related to the inhibition of the response to type I interferon, were significantly enriched in HPAG-treated mice.

Conclusion: HPAG is an emerging iron-chelating agent and a potential inhibitor of ferroptosis that alleviates tissue damage, haematopoietic stem cell injury, and immune abnormalities caused by systemic iron overload and provides an immunoregulatory function.
Venetoclax Plus D-CAG (decitabine, cytarabine, aclarubicin, G-CSF) for Elderly or Unfit Patients with Newly Diagnosed Acute Myeloid Leukemia: A Multicenter, Prospective Study
Authors: Ma Hongbing , Du Yiwen , Li Jianjun , Rao Jin , Guo Yong , Yang Yunfan , Zhang Duanzhong , Wang Jia , Liao Yi , Gong Yuping
Published: December 2024

Background:

Induction regimens with satisfactory remission rates are limited for patients with acute myeloid leukemia (AML) who are elderly or ineligible for intensive chemotherapy.

Objectives:

This study aims to evaluate the efficacy and safety of venetoclax plus decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (VD-CAG) for newly diagnosed AML patients who are elderly or ineligible for intensive chemotherapy.

Design:

This is a single-arm, multicenter, prospective phase I/II study.

Methods:

The patients(n=40) received 1 cycle of the VD-CAG regimen for induction chemotherapy. The primary endpoint was composite complete remission (CRc) after 1 cycle of induction chemotherapy. The secondary endpoints were measurable residual disease (MRD) by flow cytometry and adverse events.

Results:

The median age of the patients was 64 (55-81) years, and 10 patients (25%) had secondary AML. Our results showed that 1 cycle of VD-CAG had a high overall response rate of 97.5% and CRc of 95%, and all 10 patients with secondary AML achieved CRc. Moreover, the patients who achieved CRc had deep remission, with MRD-negativity of 71.1% and 54.2% by flow cytometry and molecular assessment, respectively. In addition, blood cell recovery was quick, with a median time to absolute neutrophil count ≥ 1.0×109/L and platelet count ≥ 100×109/L at 19 days and 15.5 days, respectively.

Conclusions:

VD-CAG demonstrates high efficacy as an induction treatment for elderly or unfit patients with newly diagnosed AML, and it could be an alternative upfront therapy for this subpopulation, Trials with large-scale subjects are needed for further validation, especially for secondary AML.
All-Trans Retinoic Acid Enhances CS1-BCMA Dual-Target CAR-T Cells in Multiple Myeloma
Authors: Zhang Yinqiang , Zhuolin Wu , Luo Wenjing , Li Chenggong , Mei Heng
Published: December 2024

Background:CS1-BCMA dual-target chimeric antigen receptor T cell (CAR-T) has exhibited superior efficacy in multiple myeloma (MM). However, there are still obstacles such as target down-regulation and barriers to immune infiltration, which results in refractory or relapse in certain patients. All-trans retinoic acid (ATRA) has been reported to upregulate the expression of CD38 and modulate the tumor microenvironment (TME), but its synergistic effect on CS1-BCMA CAR-T and potential mechanism remains unexplored.

Methods:CS1-BCMA dual-target CAR-T cells were generated by lentiviral transduction of healthy donor T cells. BCMA/CS1 expression was measured by flow cytometry and quantitative real-time PCR after 24 hours coculture of MM cells and ATRA. Tumor lysis of ATRA combined with CS1-BCMA dual-target CAR-T cells was assessed in vitro and in NXG xenograft models. Cancer related fibroblast (CAF) was induced by bone marrow mesenchymal stem cell coculturing with MM cell lines in transwell inserts (0.4um) for 48 hours. Transcriptome sequencing was conducted to reveal the mechanism of ATRA sensibilizing MM cells to CAR-T therapy.

Results: Experiments in vitro demonstrated thatcoculturing MM cell lines with ATRA at concentrations of 10nM-1000nM upregulated BCMA expression (MM.1S: 1.5-fold, P<0.01 at 1000nM by flow cytometry), which was verified in the NXG xenograft model. ARTA synergized CS1-BCMA dual-target CAR-T cells against MM cells both in vitro (MM.1S: P<0.01 at 1000nM for 6-hour coculturing) and in the NXG xenograft model. The addition of CAF to MM cells impaired the cytotoxicity of CAR-T by 27% (P<0.05) but its immunosuppression was reversed by ATRA (P<0.05). Transcriptome sequencing analysis of MM cells showed that ATRA upregulated the arachidonic acid metabolism pathway and down-regulated of the TGF-β pathway..

Conclusion: Our study expands on the hypothesized mechanism that ATRA promotes the cytotoxicity of CS1-BCMA dual-target CAR-T cells by upregulating the expression of BCMA and reversing the immunosuppressive effect of CAF. Sequencing demonstrates that tumor sensitivity is associated with metabolism and TGF-β pathway. Further underlying mechanisms and clinical translation need to be explored.
Split CAR-T Cells Targeting CD312 and TIM-3 for AML to Reduce the Risk of Antigen Escape
Authors: Chai Xiao , Zhang Xiaomei , Zhao Mingfeng , Zhang Rui
Published: December 2024

Background: Acute myeloid leukemia (AML) is a malignant disorder characterized by the presence of a limited number of leukemia-initiating cells or leukemic stem cells (LSCs), which form a clonal population. Traditional therapies often fail to achieve durable responses due to the disease's intrinsic resistance mechanisms and the presence of leukemic stem cells. CD312 Chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising treatment modality. However, its efficacy is limited when targeting a single antigen, leading to antigen escape and subsequent relapse. TIM-3 CAR-T cell therapy may improve the clinical outcomes of patients with AML by eradication of the LSCs present in the minimal residual disease (MRD).

Objective: In this study, we aim to evaluate the efficacy of modified split CD312/TIM-3 CAR-T cell against AML tumor cells with varying levels of antigen expression through in vitro experiments and immunodeficient mouse models, particularly focusing on their ability to eradicate LSCs and reduce the risk of relapse following CAR-T cell infusion.

Methods: The expression levels of CD312 and TIM-3 were assessed in AML cell lines and primary blasts by flow cytometry. Subsequently, split CD312/TIM-3 CAR-T cell were developed. The cytotoxicity of CD312 CAR-T cell and split CD312/TIM-3 CAR-T cell were evaluated in vitro against AML cell lines, primary blasts. Additionally, the activation rates and cytotoxicity of split CD312/TIM-3 CAR-T cell against CD34+CD38- LSCs and normal monocyte were assessed in a coexisting milieu consisting of CAR-T cells, primary blasts, and CD64-positive monocyte. Then, the cellular characteristics and functionality were compared through in vitro experiments. Ultimately, the efficacy and safety of CD312 CAR-T cell and split CD312/TIM-3 CAR-T cell were evaluated in vivo.

Results: Split CD312/TIM-3 CAR-T cell demonstrated significantly enhanced cytotoxicity against AML cell lines, primary blasts and CD34+CD38- LSCs compared to CD312 CAR-T cell. Meanwhile, split CD312/TIM-3 CAR-T cell revealed a remarkable cytotoxicity against CD34+CD38- LSCs and remained unaffected by monocyte influence derived from healthy donors PBMCs in a coexisting milieu consisting of CAR-T cells, LSCs and CD64-positive monocyte. In a relapsed AML animal transplantation model, split CD312/TIM-3 CAR-T exhibited remarkable anti-AML activity, leading to prolonged survival of the treated animals. Importantly, the split CAR-T cells could be safely eliminated in emergency situations through a natural safety switch mechanism, ensuring that hematopoietic stem cells remained unaffected.

Conclusion

The split CAR-T cells targeting CD312 and TIM-3 exhibit potential as a promising and secure therapeutic approach for patients with refractory and relapsed AML, particularly focusing on their ability to eradicate LSCs and reduce the risk of relapse following CAR-T cell infusion.
Ribosome Profiling Sequencing Reveals LPIN1 As a Potential Therapeutic Target for Acute Myeloid Leukemia with FLT3 -ITD Mutation
Authors: Yuang Gao , Zhang Qianyu , Lv Zhichun , Liu Shuhong , Sun Yide , Gao Huiying , Zhao Xiongwei , Li Xin , Xue Yang , Li Hao , Li Changyan , Ning Hongmei
Published: December 2024

Internal tandem duplication mutations of FLT3 (FLT3-ITD) are the most frequent genetic alteration in adult acute myeloid leukemia (AML) and confer poor prognosis. The use of FLT3 inhibitors has improved outcome among FLT3-ITD mutant patients, but clinical efficacy is transient and limited, largely due to the emergence of drug resistance which can occur through activation of alternative signaling pathways or metabolic degradation of the inhibitors within the tumor microenvironment. Therefore, it is urgent to explore new intervention targets and develop novel therapeutic strategies for FLT3-ITD mutant AML.

In this study, we use ribosome profiling sequencing from 13 healthy donors and 35 AML patients (including 17 FLT3-ITD mutant AML cases and 18 non-FLT3-ITD mutant AML cases) to identify differentially expressed genes.In FLT3-ITD mutant AML patients, 143 up-regulated genes were obtained, which are mainly involved in cell adhesion, embryonic skeletal cell formation, coping with hypoxia, and T-cell activation etc. 538 down-regulated genes are mainly associated with signal transduction, cell differentiation etc. Among these up-regulated genes, we validated the abnormally elevated expression of LPIN1 in FLT3-ITD mutant AML patients using RT-PCR. LPIN1 has been previously reported to be a divalent magnesium ion-dependent phosphatidic acid phosphatase and play a key role in lipid metabolism. Analysis of clinical data from public databases indicated that high LPIN1 expression is positively correlated with poor prognosis in FLT3-ITD mutant AML patients.

In FLT3-ITD mutant AML cell lines, both shRNA-mediated knockdown of LPIN1 expression and pharmacological inhibition of LPIN1 activity suppressed cell proliferation and increased apoptosis, indicating that LPIN1 plays an important role in the growth and survival of FLT3-ITD mutant AML cells. The combination of the LPIN1 inhibitor Propranolol with the FLT3 inhibitor Quizartinib significantly reduced the cell proliferation of both FLT3-ITD AML cell lines and primary FLT3-ITD mutant AML patient samples. Furthermore, the combination of Propranolol with Quizartinib eradicated leukemic cells and prolonged survival in a xenograft FLT3-ITD mutant AML model.

In summary, our study demonstrates that LPIN1 plays a pivotal role in FLT3-ITD mutant AML pathogenesis and chemotherapy resistance. LPIN1 inhibition synergizes with FLT3 inhibitor to eliminate FLT3-ITD AML cells in vitro and in vivo, providing a new therapeutic target for FLT3-ITD mutant AML.
Impact of Ultra Rapid Molecular Profiling on Treatment Delays and Healthcare Utilization of Patients Hospitalized for Acute Leukemia
Authors: Dhawale Tejaswini , Nardi Valentina , Wang Charlotte , Bard Adam , Essigmann Natalia , Leonard Daniel , Graubert Timothy Aaron , Fathi Amir T.
Published: December 2024

Background

Molecular testing is fundamental to treatment decisions in patients with acute leukemia. The impact of rapid molecular profiling on the timing of treatment initiation and healthcare utilization in patients hospitalized for suspected acute leukemia has not been described.

Methods

We conducted a retrospective chart review of patients hospitalized and treated for suspected acute leukemia at Massachusetts General Hospital between September 2023 and April 2024. We conducted a detailed workflow analysis comparing the time to obtaining molecular profiling results from admission [“time to results” or TTR] between routine (legacy) methods (i.e., RT-PCT, karyotype, FISH, targeted DNA and RNA sequencing) and an ultra-rapid genomic profiling test (Thermo Fisher Genexus Oncomine Myeloid Panel, or “Genexus”) which was run in parallel. We used linear regression models to evaluate the impact of TTR on time to treatment initiation from admission [TTTI] and hospital length of stay [LOS].

Results

Of the 111 patients who had ultra-rapid genomic profiling conducted during the study period, 57 (51.4%) were adult patients who were hospitalized for diagnostic workup and treatment of suspected acute leukemia. The most common leukemia subtypes were acute myeloid leukemia (n=39/57, 68.4%), B-lymphoblastic leukemia (n=9/57, 15.8%), and acute promyelocytic leukemia (n=4/57, 7.0%). The mean TTTI was 5.2 days (range 1-17) and mean LOS was 30.9 days (range 3-86). Genexus had a mean TTR of 3.1 days (range 1-8), whereas legacy methods had a mean TTR of 5.4 days (range 3-10). Longer TTR was associated with longer TTTI (b=0.95; SE=0.20; P=<0.001) and longer LOS (b=4.08; SE=1.30; P=<0.003).

Conclusions

Ultra-rapid molecular profiling reduces the time to obtaining actionable genetic sequencing results for patients hospitalized for suspected acute leukemia by 2 days compared to legacy methods. Delays in obtaining molecular profiling of these patients is associated with treatment initiation delays and longer hospital length of stay, underscoring the importance of expanded access to ultra-rapid molecular profiling for acute leukemia. Further work is needed to elucidate the full economic impact of ultra-rapid molecular profiling on overall healthcare utilization.
The “Walk through the Clinic Door” Effect: Differences in Survival and Toxicity Based on Site of CAR T Administration in a Default Outpatient CAR T Program
Authors: Hunter Bradley D. , Hoda Daanish , Asch Julie , Sharma Prashant
Published: December 2024

Introduction:

Due to the potential of long-term PFS, CAR T-cell therapy is frequently given to patients with suboptimal performance status (PS). Differences in outcomes regarding PS of 2 or greater have been demonstrated in real world analyses of CAR T outcomes. However, it is unknown if patients who require hospitalization at the time of CAR T-cell infusion due to non-CAR T comorbidities have differential outcomes compared to patients who would otherwise be able to “walk into clinic.” To date, many patients are infused with CAR T as inpatients due to monitoring needs, not necessarily due to medical status. The Intermountain Health CAR T-cell program's default infusion setting is outpatient for all commercial CAR T-cell products, thus allowing for a more accurate evaluation of the association between true inpatient status and CAR T-cell therapy related outcomes.

Methods:

Patients were identified from scheduling and billing records. Patient's oncology notes for CAR-T 30-day, 100-day and 1 year follow up visits were reviewed to evaluate setting of CAR-T infusion, treatment response and toxicity. Survival was determined by any death record within the IH EMR and the patient's last known visit date. Two proportion pooled z-tests were calculated to compare OS rates between inpatient and outpatient groups.

Results:

There were 125 patients included in this analysis. 5 patients received CAR T for ALL, 98 patients received CAR T for B-cell lymphoma, and 22 patients received CAR T for multiple myeloma. 27/125 patients (22%) received CAR T-cell therapy in the inpatient setting, and 98/125 (78%) were infused at as outpatients. Overall survival (OS) was significantly inferior for patients who received CAR T-cell therapy as inpatients vs outpatients, with 30 -day OS of 81% vs 97% (p=0.02), 90- day OS of 56% vs 92% (p<0.01), and 1 year OS of 30% vs 77% (p<0.01). 1 year CR rates were 19% in inpatients vs 48% in outpatients. Among lymphoma patients, 7/21 (33%) of those who received inpatient CAR T were alive at 1 year, vs 59/77 (77%) of outpatients (p<0.01). For multiple myeloma patients, 1 year OS for those who received inpatient infusion was 25% (1/4 patients), vs 72% (13/18) for outpatients (p=0.02). Grade 3+ CRS in inpatients was 30% for inpatients vs 2% in outpatients (p,0.01). Grade 3+ ICANS was 26% in inpatients vs 10% in outpatients (p=0.04).

Conclusion:

Patients who require inpatient CAR T-cell administration due to performance status experienced significantly inferior OS and rates of CR at 1 year compared to patients who received CAR T-cell therapy in the outpatient setting. Rates of high-grade CRS and ICANS were significantly increased in patients who required inpatient CAR T administration. There appears to be a “walk through the clinic door” effect that may better capture CAR T-cell treatment risk for both outcomes and toxicity.
Combination of Mitoxantrone Hydrochloride Liposome with Gemcitabine, Cisplatin and Dexamethasone in Patients with Relapsed or Refractory Peripheral T Cell Lymphoma: A Phase I Study
Authors: Wei Chong , Zhou Shengyu , Xu Shuangnian , Jing Hongmei , Liu Hui , Zhang Wei , Zhou Daobin
Published: December 2024

Background : Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature aggressive T-cell non-Hodgkin's lymphomas characterized by poor prognosis, highlighting the urgent need for novel therapeutic strategies. The combination of gemcitabine, cisplatin and dexamethasone (GDP) is recommended as the second-line treatment regimen according to lymphoma guidelines. Mitoxantrone hydrochloride liposome (Lipo-MIT) is a nano-drug that has been approved as the first treatment option for relapsed/refractory (r/r) PTCL, and has shown certain efficacy and safety in a pivotal phase Ⅱ study. This study aims to investigate the safety and efficacy of combining Lipo-MIT with GDP regimen (MGDP) in patients (pts) with r/r PTCL (NCT05441761).

Methods: Pts with r/r PTCL were recruited in this prospective, multicenter, open-label phase I study with a 3+3 dose-escalation design. Lipo-MIT was administered at three dose levels (DL1: 12 mg/m2, DL2: 16 mg/m2, DL3: 20 mg/m2, d1). Gemcitabine was given at 1000 mg/m2, cisplatin at 75 mg/m2, and dexamethasone at 40 mg on day 1 of each cycle (Q3W), and up to 6 cycles of therapy were planned. The primary endpoint is to explore the recommended phase II dose (RP2D) of Lipo-MIT. Secondary endpoints were to assess the tolerability (i.e. dose-limiting toxicity (DLT)), complete response (CR) rate, objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety.

Results: At data cut-off on 17 July 2024, 9 eligible pts (DL1: n=3, DL2: n=3, DL3: n=3) were enrolled including 3 with angioimmunoblastic T-cell lymphoma (AITL), 5 with PTCL-NOS and 1 with ALK positive anaplastic large cell lymphoma (ALCL). Among them, 6 cases (66.7%) were refractory pts. The median age of all pts is 46 (range, 31-70) years, and 4 pts (44.4%) were IPI score 3-5. 8 pts (88.9%) had advanced stage III or IV (Ann Arbor stage). No DLT occurred in this phase I study. And the RP2D was 20 mg/m2 for Lipo-MIT. The CR rate and ORR were 33.3% (3/9, 95% CI 7.5%-70.1%) and 55.6% (5/9, 95% CI 21.2%-86.3%), respectively. Besides, in refractory pts, the CR rate was 33.3% (2/6) and ORR rate was 66.7% (4/6). With a median follow-up of 5.1 (range, 0.03-20.2) months currently, the median PFS and OS will be reported after long-term follow-up. The common grade 3/4 Treatment-related adverse events (TRAEs) were mainly hematological toxicity, including neutropenia (66.7%), leucopenia (44.4%), anaemia (33.3%) and thrombocytopenia (11.1%). Overall, safety in all pts was tolerable during this study.

Conclusions: Lipo-MIT plus GDP (MGDP) regimen proves an promising efficacy in r/r PTCL pts with manageable safety profiles. A phase II, multi-center, single-arm study is ongoing to confirm and validate the findings from this study.