The latest medical research on Acute Lymphoblastic Leukaemia

The research magnet gathers the latest research from around the web, based on your specialty area. Below you will find a sample of some of the most recent articles from reputable medical journals about acute lymphoblastic leukaemia gathered by our medical AI research bot.

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Removal of platelets from blood plasma to improve the quality of extracellular vesicle research.

Acute Lymphoblastic Leukaemia

Blood plasma is commonly used for biomarker research of extracellular vesicles (EVs). Removing all cells prior to analysis of EVs is essential.

We therefore studied the efficacy of the most commonly used centrifugation protocol to prepare cell-free plasma.

Plasma was prepared according the double centrifugation protocol of the International Society on Thrombosis and Haemostasis (ISTH) in three independent studies. The concentration of platelets, platelet-derived EVs and erythrocyte-derived EVs were measured by calibrated flow cytometry.

The mean platelet concentration ranged from 5.1 105 /mL to 2.8 107 /mL and differed 55-fold between studies. Thus, the ISTH centrifugation protocol does not remove all platelets and results in variation between studies. As the concentration of platelet-derived EVs and platelets correlates linearly (R2 =0.56), and the volume fraction of EVs and platelets in plasma are similar, the presence of platelets affects downstream analysis. To remove platelets a 0.8-μm polycarbonate filter was used to lower the platelet concentration 146-fold (p=0.0013), without affecting the concentration of platelet-derived and erythrocyte-derived EVs (p= 0.982, p= 0.742).

To improve the quality of EV research, we recommend to (1) measure and report the platelet concentration in plasma used for EV research, or (2) remove platelets by centrifugation followed by filtration.

Posttranslational control of lipogenesis in the tumor microenvironment.

Leukaemia

Metabolic reprogramming of cancer cells within the tumor microenvironment typically occurs in response to increased nutritional, translation and pr...

Recent advances in therapeutic strategies for triple-negative breast cancer.

Leukaemia

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer (BC) with a poor prognosis. Current treatment options are limit...

CircRNA-CREIT inhibits stress granule assembly and overcomes doxorubicin resistance in TNBC by destabilizing PKR.

Leukaemia

Circular RNAs (circRNAs) represent a novel type of regulatory RNA characterized by high evolutionary conservation and stability. CircRNAs are expected to be potential diagnostic biomarkers and therapeutic targets for a variety of malignancies. However, the regulatory functions and underlying mechanisms of circRNAs in triple-negative breast cancer (TNBC) are largely unknown.

By using RNA high-throughput sequencing technology, qRT-PCR and in situ hybridization assays, we screened dysregulated circRNAs in breast cancer and TNBC tissues. Then in vitro assays, animal models and patient-derived organoids (PDOs) were utilized to explore the roles of the candidate circRNA in TNBC. To investigate the underlying mechanisms, RNA pull-down, RNA immunoprecipitation (RIP), co immunoprecipitation (co-IP) and Western blotting assays were carried out.

In this study, we demonstrated that circRNA-CREIT was aberrantly downregulated in doxorubicin resistant triple-negative breast cancer (TNBC) cells and associated with a poor prognosis. The RNA binding protein DHX9 was responsible for the reduction in circRNA-CREIT by interacting with the flanking inverted repeat Alu (IRAlu) sequences and inhibiting back-splicing. By utilizing in vitro assays, animal models and patient-derived organoids, we revealed that circRNA-CREIT overexpression significantly enhanced the doxorubicin sensitivity of TNBC cells. Mechanistically, circRNA-CREIT acted as a scaffold to facilitate the interaction between PKR and the E3 ligase HACE1 and promoted proteasomal degradation of PKR protein via K48-linked polyubiquitylation. A reduced PKR/eIF2α signaling axis was identified as a critical downstream effector of circRNA-CREIT, which attenuated the assembly of stress granules (SGs) to activate the RACK1/MTK1 apoptosis signaling pathway. Further investigations revealed that a combination of the SG inhibitor ISRIB and doxorubicin synergistically inhibited TNBC tumor growth. Besides, circRNA-CREIT could be packaged into exosomes and disseminate doxorubicin sensitivity among TNBC cells.

Our study demonstrated that targeting circRNA-CREIT and SGs could serve as promising therapeutic strategies against TNBC chemoresistance.

Autoinhibitory module underlies species difference in shear activation of von Willebrand factor.

Acute Lymphoblastic Leukaemia

Von Willebrand factor (VWF) is a multimeric plasma protein that bridges the gap between vessel injury and platelet capture at high shear rates. Under high shear or tension, VWF can become activated upon the unfolding of its autoinhibitory module (AIM). AIM unfolding exposes the A1 domain, allowing for binding to platelet glycoprotein (GP)Ibα to initiate primary hemostasis. The characteristics of the AIM and its inhibitory properties within mouse VWF are unknown.

To determine and characterize the autoinhibitory properties of mouse VWF.

Recombinant mouse VWF A1 fragments containing or lacking the flanking regions around the A1 domain were generated. We tested the ability of these fragments to bind to human or mouse GPIbα and platelets. We compared the unfolding of mouse AIM-A1 to human AIM-A1 by single-molecule force spectroscopy.

Recombinant mouse AIM-A1 binds with higher affinity to GPIbα than its human counterpart. Recombinant mouse proteins lacking part of the AIM show increased binding to GPIbα. Activated A1 fragments lacking the AIM can effectively agglutinate platelets across the species barrier. Using single-molecule force spectroscopy, we determined that the mouse AIM unfolds under forces similar to the human AIM. Additionally, the human AIM paired with mouse A1 largely recapitulates the behavior of human AIM-A1.

Our results suggest that the regulation of VWF-GPIbα binding has been specifically tuned to work optimally in different rheological architectures. Differences in the AIM sequence may contribute to the difference in VWF shear response between human and mice.

Emerging strategies in targeting tumor-resident myeloid cells for cancer immunotherapy.

Leukaemia

Immune checkpoint inhibitors targeting programmed cell death protein 1, programmed death-ligand 1, and cytotoxic T-lymphocyte-associated protein 4 ...

Osteosarcoma with cell-cycle and fibroblast growth factor genomic alterations: case report of Molecular Tumor Board combination strategy resulting in long-term exceptional response.

Leukaemia

There is a paucity of information about molecularly driven therapy in osteosarcomas. We report a 31-year-old woman with chemotherapy-refractory met...

Connecting telomere maintenance and regulation to the developmental origin and differentiation states of neuroblastoma tumor cells.

Leukaemia

A cardinal feature that distinguishes clinically high-risk neuroblastoma from low-risk tumors is telomere maintenance. Specifically, neuroblastoma ...

Thrombotic and bleeding complications in patients with chronic lymphocytic leukemia and severe COVID-19: a study of ERIC, the European Research Initiative on CLL.

Leukaemia

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19.

This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting.

A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C-reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017-1.109 and OR = 2.438, 95%CI 1.023-5.813, respectively).

Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration.

Frequency and Predictors for Chronic Thromboembolic Pulmonary Hypertension after a first Unprovoked Pulmonary Embolism: results from PADIS studies.

Acute Lymphoblastic Leukaemia

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening pulmonary embolism's (PE) complication whose incidence and predictors are not precisely determined.

To determine the frequency and predictors for CTEPH after a first unprovoked PE.

In a randomized trial comparing an additional 18-month warfarin versus placebo in patients after a first unprovoked PE initially treated with vitamin K antagonist for 6 months, we applied recommended CTEPH screening strategies through 8-year follow-up to determine cumulative incidence of CTEPH. CTEPH predictors were estimated using Cox models. Pulmonary vascular obstruction (PVO) and systolic pulmonary arterial pressure (sPAP) at PE diagnosis and 6 months were studied by receiver operating curves analysis. All CTEPH cases and whether they were incident or prevalent were adjudicated.

During a median follow-up of 8.7 years, 9 CTEPH cases were diagnosed among 371 patients, with a cumulative incidence of 2.8% (95% confidence interval [CI], 0.95-4.64), and of 1.31% (95%CI, 0.01-2.60) after exclusion of 5 cases adjudicated as prevalent. At PE diagnosis, PVO>45% and sPAP>56mmHg were associated with CTEPH with a hazard ratio (HR) of 33.00 (95%CI 1.64-667.00, p=0.02) and 12.50 (95%CI 2.10-74.80, p<0.01) respectively. Age>65 years, lupus anticoagulant antibodies and non-O blood groups were also predictive of CTEPH. PVO>14% and sPAP>34mmHg at 6-month were associated with CTEPH (HRs 63.90 [95%CI, 3.11-1310.00, p<0.01]and 17.2 [95%CI, 2.75-108, p<0.01]).

After a first unprovoked PE, CTEPH cumulative incidence was 2.8% during 8-year follow-up. PVO and sPAP at PE diagnosis and at 6 months were the main predictors for CTEPH diagnosis.

A gain-of-function filamin A mutation in mouse platelets induces thrombus instability.

Acute Lymphoblastic Leukaemia

Filaminopathies A are rare disorders affecting brain, intestine or skeleton, characterized by dominant X-linked filamin A (FLNA) gene mutations. Macrothrombocytopenia with functionally defective platelets is frequent. We have described a filaminopathy A male patient, exhibiting a C-terminal frame-shift FLNa mutation (Berrou et al., Arterioscler Thromb Vasc Biol. 2017;37:1087-1097). Contrasting with female patients, this male patient exhibited gain of platelet functions, including increased platelet aggregation, integrin αIIbβ3 activation, and secretion at low agonist concentration, raising the issue of thrombosis risk.

Our goal is to assess the thrombotic potential of the patient FLNa mutation in an in vivo model.

We have established a mutant FlnA knock-in mouse model.

The mutant FlnA mouse platelets phenocopied patient platelets, showing normal platelet count, lower expression level of mutant FlnA, and gain of platelet functions: increased platelet aggregation, secretion and αIIbβ3 activation, as well as increased spreading and clot retraction. Surprisingly, mutant FlnA mice exhibited a normal bleeding time, but with increased re-bleeding (77%) compared with WT FlnA mice (27%), reflecting hemostatic plug instability. Again, in an in vivo thrombosis model, the occlusion time was not altered by the FlnA mutation, but arteriolar embolies were increased (7 fold more frequent in mutant FlnA mice versus WT mice), confirming thrombus instability.

This study shows that the FlnA mutation found in the male patient induced gain of platelet functions in vitro, but thrombus instability in vivo. Implications for the role of FLNa in physiology of thrombus formation are discussed.

Quantitative Interpretation of PF4/Heparin-EIA Optical Densities in Predicting for Platelet-Activating VITT Antibodies.

Acute Lymphoblastic Leukaemia

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a prothrombotic, heparin-induced thrombocytopenia(HIsT)-mimicking, adverse reaction caused by platelet-activating anti-platelet factor 4 (PF4) antibodies that occurs rarely after adenovirus vector-based Covid-19 vaccination. Strength of PF4-dependent enzyme-immunoassay (EIA) reactivity - judged by optical density (OD) measurements - strongly predicts for platelet-activating properties of HIT antibodies in a functional test. Whether a similar relationship holds for VITT antibodies is unknown.

To evaluate probability for positive platelet activation testing for VITT antibodies based upon EIA OD reactivity; and to investigate simple approaches to minimize false-negative platelet activation testing for VITT.

All samples referred for VITT testing were systematically evaluated by semiquantitative in-house PF4/heparin-EIA (OD readings) and PF4-induced platelet activation (PIPA) testing within a cohort study. EIA-positive sera testing PIPA-negative were retested following 1/4 to 1/10 dilution. Logistic regression was performed to predict the probability of a positive PIPA per magnitude of EIA reactivity.

Greater EIA ODs in sera from patients with suspected VITT correlated strongly with greater likelihood of PIPA reactivity. Of 61 sera (with OD values >1.0) testing negative in the PIPA, a high proportion (27/61, 44.3%) became PIPA-positive when tested at 1/4 to 1/10 dilution.

VITT serology resembles HIT in that greater EIA OD reactivity predicts for higher probability of positive testing for platelet-activating antibodies. Unlike the situation with HIT antibodies, however, diluting putative VITT serum increases probability of a positive platelet activation assay, suggesting that optimal complex formation depends on the stoichiometric ratio of PF4 and anti-PF4 VITT antibodies.