Browse Articles

Transport and InsP8 gating mechanisms of the human inorganic phosphate exporter XPR1

MRD-guided zanubrutinib, venetoclax, and obinutuzumab in relapsed CLL: primary end point analysis from the CLL2-BZAG trial

Abstract The phase 2 CLL2-BZAG trial tested a measurable residual disease (MRD)–guided combination treatment of zanubrutinib, venetoclax, and obinutuzumab after an optional bendamustine debulking in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). In total, 42 patients were enrolled and 2 patients with ≤2 induction cycles were excluded from the analysis population per protocol. Patients had a median of 1 prior therapy (range, 1-5); 18 patients (45%) had already received a Bruton tyrosine kinase (BTK) inhibitor (BTKi); 7 patients (17.5%) venetoclax; and, of these, 5 (12.5%) had received both. Fifteen patients (37.5%) had a TP53 mutation/deletion, and 31 (77.5%) had unmutated immunoglobulin heavy chain variable region gene. With a median observation time of 21.5 months (range, 8.0-35.3) the most common adverse events were COVID-19 (n = 26 patients), diarrhea (n = 15), infusion-related reactions (n = 15), thrombocytopenia (n = 14), nausea (n = 12), fatigue (n = 12), and neutropenia (n = 12). Two patients had fatal adverse events (COVID-19, and fungal pneumonia secondary to COVID-19). After 6 months of the triple combination, all patients responded, and 21 (52.5%; 95% confidence interval, 36.1-68.5) showed undetectable MRD (uMRD) in the peripheral blood. In many patients, remissions deepened over time, with a best uMRD rate of 85%. The estimated progression-free and overall survival rates at 18 months were 96% and 96.8%, respectively. No patient has yet required a subsequent treatment. In summary, the MRD-guided triple combination of zanubrutinib, venetoclax, and obinutuzumab induced deep remissions in a relapsed CLL population enriched for patients previously treated with a BTKi/venetoclax. This trial was registered at www.clinicaltrials.gov as #NCT04515238.

Characterization and confirmation of the long lifetime of a-decade-aged hydroxyapatite ceramic electrets

Math models expose myeloid bias mechanisms in hematopoiesis

Regulation of WNT16 in bone may involve upstream enhancers within CPED1

How I treat patients with AML using azacitidine and venetoclax

Abstract Venetoclax (VEN) received full approval in October 2020 for use in older patients who are unfit with acute myeloid leukemia (AML) combined with either hypomethylating agents or low-dose cytarabine. This ended a semicentennial of stalled clinical progress and initiated a new treatment option with proven capacity to enhance response and prolong survival in older patients with AML. Despite widespread use of azacitidine-VEN (AZA-VEN), there is increasing appreciation that this regimen is myelosuppressive and associated with a higher risk of infectious complications than AZA alone. Key principles of initial management include prevention of tumor lysis syndrome in patients at high risk and minimizing infectious complications during induction. In the postremission phase, limiting cumulative marrow suppression by allowing sufficient time between cycles for optimal marrow recovery and truncating the duration of VEN exposure for those with delayed blood count recovery have emerged as important axioms of effective care. This article casts a clinical spotlight on important challenges and dilemmas encountered in practice. We also outline a structured framework to assist in the safe management of AZA-VEN in the clinic.

A hybrid object detection approach for visually impaired persons using pigeon-inspired optimization and deep learning models

NASA begins mass firings of scientists ahead of Trump team’s deadline

Introduction to a How I Treat series on acute myeloid leukemia

Treatment for patients with acute myeloid leukemia (AML) is being transformed for some patients, as targeted agents increase complete remission rates and survival when appropriately applied. Although the efficacy of newer regimens has been established in major clinical trials, use in routine practice is often challenging, and careful choices need to be made. Associate Editor Selina M. Luger introduces this case-based How I Treat series designed to provide guidance in those circumstances. Wei et al discuss how to maximize the benefits when the venetoclax-azacitidine regimen was indicated, while Issa and colleagues discuss differentiation therapy, highlighting how the clinical course for patients varies from what is seen with intensive chemotherapy-based induction regimens. Green and Wang tackle the challenge of managing patients with secondary AML. Finally, Roboz and Canaani outline how maintenance can benefit selected patients not undergoing allogeneic transplant, while exploring the many unanswered questions that arise in clinical practice.

Endovascular neural stimulation with platinum and platinum black modified electrodes

Abstract Recent work has shown the ability to record neural behaviour in pre-clinical studies from an endovascular location for over a year. Previous work on stimulating neural tissue from an endovascular location has also shown motor-evoked responses in sheep. However, endovascular stimulation requires high currents and can result in electrode degradation. This study aimed to modify an endovascular electrode to increase its charge injection capacity for efficacious neural stimulation. The platinum endovascular electrode was modified with platinum black and characterised by electrochemical and microscopic techniques. The stability of the electrode coating was assessed after a 7-day continuous stimulation paradigm. Modelling of the neural activating function was performed for central and peripheral neural anatomy with both electrode materials. Platinum black coatings had a substantially larger electroactive area than uncoated platinum. This resulted in increased electrode admittance, charge storage capacity and charge injection capacity while reducing the total impedance at 10 Hz and polarisation voltage. The coated electrode was comparatively more electrochemically stable than uncoated platinum following the 7-day continuous stimulation protocol. Modelling of the neural activating function indicated a substantial increase in the electrode-neuron distance which could be safely stimulated using platinum black coated electrodes. By comparison of electrochemical response with neural modelling, we have demonstrated the feasibility of safe stimulation of neural tissue using an endovascular neural interface, opening the possibility of a new, minimally invasive neural stimulation paradigm.

How I treat acute myeloid leukemia with differentiation therapy

Abstract An increasing number of acute myeloid leukemia (AML) therapeutics have been developed, not as cytotoxic therapies but rather as targeted agents able to restore the aberrant and leukemogenic “block” in normal differentiation. All-trans retinoic acid and arsenic trioxide are classic examples of differentiating agents for treatment of acute promyelocytic leukemia (APL); newer therapies functioning through differentiation include isocitrate dehydrogenase 1 and 2 inhibitors, FMS-like tyrosine kinase 3 inhibitors, and menin inhibitors. The terminal differentiation of leukemic blasts via differentiating-agent therapy can lead to a constellation of signs and symptoms, originally referred to as “retinoic acid syndrome” and now termed “differentiation syndrome” (DS), characterized predominantly by systemic inflammatory response system–like features of dyspnea, pulmonary infiltrates, pleural and pericardial effusions, unexplained fevers, hypotension, edema, and renal insufficiency. DS in patients with newly diagnosed APL is generally straightforward to identify; however, DS in patients with multiply relapsed AML can be more challenging to diagnose, due to nonspecific signs and symptoms that can be mistakenly attributed to infectious etiologies or the underlying refractory leukemia itself. Prompt consideration of DS, rapid initiation of systemic corticosteroids, and early cytoreduction in the setting of concomitant hyperleukocytosis are essential for optimal management.

Discovery of a human parvovirus B19 analog (Erythroparvovirus) in cats

<i>Complement</i>ing CD20 antibodies’ effector functions

Influence of deficit irrigation and biochar amendment on growth, physiology, and yield of cucumber in West Texas

How I treat secondary acute myeloid leukemia

Abstract Secondary acute myeloid leukemia (sAML) has traditionally been used to designate any AML disease arising from an antecedent hematologic disorder or after prior cytotoxic or radiation therapy. We now know sAML comprises multiple disease entities with distinct clinical and biological features: AML, myelodysplastic related; myeloproliferative neoplasm-blast phase; and AML post–cytotoxic therapy. These entities largely represent adverse-risk phenotypes with the majority of patients experiencing suboptimal outcomes with standard therapeutic options. Given the aging general population and the increased life span of individuals receiving DNA-damaging agents for other medical conditions, the incidence of these diseases is steadily rising and now comprise ∼25% to 30% of all new AML diagnoses. Despite the plethora of novel agents approved for AML since 2017, many either are not applicable to sAML (ie, lacking a targetable mutation), have limited efficacy, or have not been studied in these specific entities. Furthermore, these patients are underrepresented in clinical trials, and novel therapeutic options are critically needed. Here, we present multiple patient cases exemplifying the new nomenclature and classification of the diseases comprising sAML and highlighting their diverse presentations. We provide our therapeutic approach for each clinical scenario and discuss the challenges of treatment with the currently available armamentarium.

Spatio-temporal epidemic forecasting using mobility data with LSTM networks and attention mechanism

LSS-Skin Sclerosis: key addition to cGVHD assessments

Current situation and related factors of fatigue among doctors and nurses in tertiary general hospitals in Northeast China

SPO11 dimers are sufficient to catalyse DNA double-strand breaks in vitro

Abstract SPO11 initiates meiotic recombination through the induction of programmed DNA double-strand breaks (DSBs)1,2, but this catalytic activity has never been reconstituted in vitro3,4. Here, using Mus musculus SPO11, we report a biochemical system that recapitulates all the hallmarks of meiotic DSB formation. We show that SPO11 catalyses break formation in the absence of any partners and remains covalently attached to the 5′ broken strands. We find that target site selection by SPO11 is influenced by the sequence, bendability and topology of the DNA substrate, and provide evidence that SPO11 can reseal single-strand DNA breaks. In addition, we show that SPO11 is monomeric in solution and that cleavage requires dimerization for the reconstitution of two hybrid active sites. SPO11 and its partner TOP6BL form a 1:1 complex that catalyses DNA cleavage with an activity similar to that of SPO11 alone. However, this complex binds DNA ends with higher affinity, suggesting a potential role after cleavage. We propose a model in which additional partners of SPO11 required for DSB formation in vivo assemble biomolecular condensates that recruit SPO11–TOP6BL, enabling dimerization and cleavage. Our work establishes SPO11 dimerization as the fundamental mechanism that controls the induction of meiotic DSBs.

Potentiating CD20 monoclonal antibody therapy by targeting complement C3 fragments covalently deposited on lymphoma cells

Abstract Monoclonal antibodies (mAbs) improve survival of patients with mature B-cell malignancies. Fcγ receptor–dependent effector mechanisms kill tumor cells but can promote antigen loss through trogocytosis, contributing to treatment failures. Cell-bound mAbs trigger the complement cascade to deposit C3 activation fragments and lyse cells. Within 24 hours after ofatumumab administration to patients with chronic lymphocytic leukemia (CLL), circulating tumor cells had lost CD20 and were opsonized with C3d, the terminal covalently bound form of complement protein C3. We hypothesized that C3d provides a target to eliminate residual CD20− tumor cells. To test this hypothesis, we generated C8xi, a mouse/human chimeric immunoglobulin G1 (IgG1) that reacts with human but not mouse C3d. C8xi was effective in a patient-derived xenograft model against CD20−, C3d opsonized CLL cells from patients treated with ofatumumab. We also generated rabbit mAbs, 2 of which were chosen because they bound mouse and human C3d with low nanomolar affinity but were minimally cross-reactive with full-length C3. Anti-C3d rabbit/human chimeric IgG1 in combination with ofatumumab or rituximab prolonged survival of xenografted mice that model 3 different types of non-Hodgkin lymphoma (NHL). For example, in a diffuse large B-cell lymphoma model (SU-DHL-6), median survival with single-agent CD20 mAb was 114 days but was not reached for mAb combination treatment (P = .008). In another NHL model (SU-DHL-4), single-agent and combination mAb therapy eradicated lymphoma in most mice. In long-term survivors from both cohorts, there was no evidence of adverse effects. We propose that C3d mAbs combined with complement-fixing CD20 mAbs can overcome antigen-loss escape and increase efficacy of mAb-based therapy.