Complex Patterns of Metabolic and Ca²⁺ Entrainment in Pancreatic Islets by Oscillatory Glucose

Glucose-stimulated insulin secretion is pulsatile and driven by intrinsic oscillations in metabolism, electrical activity, and Ca(2+) in pancreatic islets. Periodic variations in glucose can entrain islet Ca(2+) and insulin secretion, possibly promoting interislet synchronization. Here, we used fluorescence microscopy to demonstrate that glucose oscillations can induce distinct 1:1 and 1:2 entrainment of oscillations (one and two oscillations for each period of exogenous stimulus, respectively) in islet Ca(2+), NAD(P)H, and mitochondrial membrane potential. To our knowledge, this is the first demonstration of metabolic entrainment in islets, and we found that entrainment of metabolic oscillations requires voltage-gated Ca(2+) influx. We identified diverse patterns of 1:2 entrainment and showed that islet synchronization during entrainment involves adjustments of both oscillatory phase and period. All experimental findings could be recapitulated by our recently developed mathematical model, and simulations suggested that interislet variability in 1:2 entrainment patterns reflects differences in their glucose sensitivity. Finally, our simulations and recordings showed that a heterogeneous group of islets synchronized during 1:2 entrainment, resulting in a clear oscillatory response from the collective. In summary, we demonstrate that oscillatory glucose can induce complex modes of entrainment of metabolically driven oscillations in islets, and provide additional support for the notion that entrainment promotes interislet synchrony in the pancreas

Ideal MHD theory of low-frequency Alfven waves in the H-1 Heliac

A part analytical, part numerical ideal MHD analysis of low-frequency Alfven wave physics in the H-1 stellarator is given. The three-dimensional, compressible ideal spectrum for H-1 is presented and it is found that despite the low beta (approx. 10^-4) of H-1 plasmas, significant Alfven-acoustic interactions occur at low frequencies. Several quasi-discrete modes are found with the three-dimensional linearised ideal MHD eigenmode solver CAS3D, including beta-induced Alfven eigenmode (BAE)- type modes in beta-induced gaps. The strongly shaped, low-aspect ratio magnetic geometry of H-1 causes CAS3D convergence difficulties requiring the inclusion of many Fourier harmonics for the parallel component of the fluid displacement eigenvector even for shear wave motions. The highest beta-induced gap reproduces large parts of the observed configurational frequency dependencies in the presence of hollow temperature profiles

Complex Patterns of Metabolic and Ca²⁺ Entrainment in Pancreatic Islets by Oscillatory Glucose

Glucose-stimulated insulin secretion is pulsatile and driven by intrinsic oscillations in metabolism, electrical activity, and Ca(2+) in pancreatic islets. Periodic variations in glucose can entrain islet Ca(2+) and insulin secretion, possibly promoting interislet synchronization. Here, we used fluorescence microscopy to demonstrate that glucose oscillations can induce distinct 1:1 and 1:2 entrainment of oscillations (one and two oscillations for each period of exogenous stimulus, respectively) in islet Ca(2+), NAD(P)H, and mitochondrial membrane potential. To our knowledge, this is the first demonstration of metabolic entrainment in islets, and we found that entrainment of metabolic oscillations requires voltage-gated Ca(2+) influx. We identified diverse patterns of 1:2 entrainment and showed that islet synchronization during entrainment involves adjustments of both oscillatory phase and period. All experimental findings could be recapitulated by our recently developed mathematical model, and simulations suggested that interislet variability in 1:2 entrainment patterns reflects differences in their glucose sensitivity. Finally, our simulations and recordings showed that a heterogeneous group of islets synchronized during 1:2 entrainment, resulting in a clear oscillatory response from the collective. In summary, we demonstrate that oscillatory glucose can induce complex modes of entrainment of metabolically driven oscillations in islets, and provide additional support for the notion that entrainment promotes interislet synchrony in the pancreas

Axicabtagene Ciloleucel versus Tisagenlecleucel for Relapsed or Refractory Large B Cell Lymphoma: A Systematic Review and Meta-Analysis

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-directed chimeric antigen receptor T cell (CAR -T) therapies approved for relapsed/refractory aggressive large B cell lymphoma (LBCL). Signi ficant costs and complex manufacturing underscore the importance of evidence -based counseling regarding the outcomes of these treatments. With the aim of examining the ef ficacy and safety of axi-cel versus tisa-cel in patients with relapsed/refractory aggressive LBCL, we performed a systematic literature search of comparative studies evaluating outcomes in relapsed/refractory aggressive LBCL after treatment with axi-cel or tisa-cel. We calculated odds ratios (ORs) and 95% con fidence intervals (CIs) for response, progression -free survival (PFS), overall survival (OS), cytokine release syndrome (CRS), immune effector cell -associated neurotoxicity syndrome (ICANS), and hematotoxicity. Meta -analysis and meta -regression were used to generate summary statistics. A total of 2372 participants were included in the 8 studies in our analysis. The dropout rate between apheresis and infusion was 13% for axi-cel versus 18% for tisa-cel, and the median time from apheresis to infusion was 32 days versus 45 days. Axi-cel showed higher odds for a complete response (OR, 1.65; P 3 CRS ( P = .92). Axi-cel was associated with significantly higher odds of severe ICANS grade >3 (OR, 4.03; P < .001). In terms of hematotoxicity, axi-cel was significantly associated with higher odds of severe neutropenia at 1 month after infusion (OR, 2.06; P = .003). As a result, axi-cel was associated with significantly greater resource utilization, including prolonged hospital stay, more frequent intensive care admission, and use of agents such as tocilizumab for toxicity management. We provide strong evidence of the greater efficacy of axi-cel versus tisa-cel in relapsed/refractory aggressive LBCL. The higher toxicity and NRM seen with axi-cel might not counterbalance the overall results, highlighting the need for timely intervention and careful selection of patients, balancing resource utilization and clinical benefit

an ALWP-EBMT study

Background Allogeneic stem cell transplantation is the only curative option for patients with acute myeloid leukemia (AML) experiencing relapse. Either matched sibling donor (MSD) or unrelated donor (UD) is indicated. Methods We analyzed 1554 adults with AML transplanted from MSD (n = 961) or UD (n = 593, HLA-matched 10/10, n = 481; 9/10, n = 112). Compared to MSD, UD recipients were older (49 vs 52 years, p = 0.001), transplanted more recently (2009 vs 2006, p = 0.001), and with a longer interval to transplant (10 vs 9 months, p = 0.001). Conditioning regimen was more frequently myeloablative for patients transplanted with a MSD (61 vs 46 %, p = 0.001). Median follow-up was 28 (range 3–157) months. Results Cumulative incidence (CI) of neutrophil engraftment (p = 0.07), grades II–IV acute GVHD (p = 0.11), chronic GVHD (p = 0.9), and non-relapse mortality (NRM, p = 0.24) was not different according to the type of donor. At 2 years, CI of relapse (relapse incidence (RI)) was 57 vs 49 % (p = 0.001). Leukemia-free survival (LFS) at 2 years was 21 vs 26 % (p = 0.001), and overall survival (OS) was 26 vs 33 % (p = 0.004) for MSD vs UD, respectively. Chronic GVHD as time-dependent variable was associated with lower RI (HR 0.78, p = 0.05), higher NRM (HR 1.71, p = 0.001), and higher OS (HR 0.69, p = 0.001). According to HLA match, RI was 57 vs 50 vs 45 %, (p = 0.001) NRM was 23 vs 23 vs 29 % (p = 0.26), and LFS at 2 years was 21 vs 27 vs 25 % (p = 0.003) for MSD, 10/10, and 9/10 UD, respectively. In multivariate analysis adjusted for differences between the two groups, UD was associated with lower RI (HR 0.76, p = 0.001) and higher LFS (HR 0.83, p = 0.001) compared to MSD. Interval between diagnosis and transplant was the other factor associated with better outcomes (RI (HR 0.62, p < 0.001) and LFS (HR 0.67, p < 0.001)). Conclusions Transplantation using UD was associated with better LFS and lower RI compared to MSD for high-risk patients with AML transplanted in first relapse

The addition of rituximab to chemotherapy improves overall survival in mantle cell lymphoma—a pooled trials analysis

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma and commonly used induction immunochemotherapies include the anti-CD20 antibody rituximab. However, efficacy data for rituximab regarding overall survival (OS) in first line MCL therapy remain conflicting. We report long-term outcomes of a pooled trials analysis comparing Cyclophosphamide, Doxorubicine, Vincristine, Prednisone (CHOP) to R-CHOP in MCL to confirm efficacy on failure free survival (FFS) and OS in relevant subgroups. Untreated, adult MCL patients of two prospective trials assigned to CHOP or R-CHOP were included. Primary endpoints were FFS and OS, secondary endpoints included duration of response (DOR), secondary malignancies and OS after relapse. Between 1996 and 2003, 385 MCL patients were assigned to CHOP (201) or R-CHOP (184). After a median follow-up of 13.4 years, the addition of Rituximab significantly improved FFS (1.36 vs. 2.07 years, HR 0.62 (0.50–0.77)), OS (4.84 vs. 5.81 years, HR 0.78 (0.61–0.99)) and DOR (1.48 vs. 2.08 years, HR 0.67 (0.53–0.86)). Furthermore, Rituximab improved survival across different MCL risk groups. In a post-hoc analysis of OS after relapse comparing patients receiving chemotherapy with / without rituximab, rituximab maintained efficacy with a median OS of 3.10 vs. 2.11 years (HR 0.70, 0.54–0.91). The rate of secondary malignancies was 0.5 and 3.9% for hematological and 7 and 8% for non-hematological malignancies for CHOP and R-CHOP patients, respectively. We present mature results of a pooled MCL cohort, demonstrating prolonged FFS, OS and DOR for the combined immuno-chemotherapy, confirming the standard of care in first line treatment

Mrk 609: resolving the circum-nuclear structure with near-infrared integral field spectroscopy

We present first results of near infrared J and H+K ESO-SINFONI integral field spectroscopy of the composite starburst/Seyfert 1.8 galaxy Mrk 609. The data were taken during the science verification period of SINFONI. We aim to investigate the morphology and excitation conditions within the central 2 kpc. Additional Nobeyama 45 m CO(1-0) data are presented, which we used to estimate the molecular gas mass. The source was selected from a sample of adaptive optics suitable, SDSS/ROSAT based, X-ray bright AGN with redshifts of 0.03 < z < 1. This sample allows for a detailed study of the NIR properties of the nuclear and host environments with high spectral and spatial resolution. Our NIR data reveal a complex emission-line morphology, possibly associated with a nuclear bar seen in the reconstructed continuum images. The detections of [SiVI] and a broad Pa alpha component are clear indicators for the presence of an accreting super-massive black hole at the center of Mrk 609. In agreement with previous observations we find that the circum-nuclear emission is not significantly extincted. The analysis of the high angular resolution rotational-vibrational molecular hydrogen and forbidden [FeII] emission reveals a LINER character of the nucleus. The large H_2 gas mass deduced from the CO(1-0) observation provides the fuel needed to feed the starburst and Seyfert activity in Mrk 609. High angular resolution imaging spectroscopy provides an ideal tool to resolve the nuclear and starburst contribution in active galaxies. We show that Mrk 609 exhibits LINER features, that appear to be hidden in larger aperture visible/NIR spectra.Comment: published by A&A, 19 pages, 16 figures, version with high resolution figures is available via http://www.ph1.uni-koeln.de/~zuther/mrk609.pd

Organ complications after CD19 CAR T-cell therapy for large B cell lymphoma: a retrospective study from the EBMT transplant complications and lymphoma working party.

We investigated ≥ grade 3 (CTC-AE) organ toxicities for commercial CD19 chimeric antigen receptor T cell (CAR-T cell) products in 492 patients (Axi-Cel; n = 315; Tisa-Cel; n = 177) with Large B-cell Lymphoma in the European Society for Blood and Marrow Transplantation (EBMT) CAR-T registry. The incidence of ≥ grade 3 organ toxicities during the first 100 days after CAR-T was low and the most frequent were: renal (3.0%), cardiac (2.3%), gastro-intestinal (2.3%) and hepatic (1.8%). The majority occurred within three weeks after CAR-T cell therapy. Overall survival was 83.1% [79.8-86.5; 95% CI] at 3 months and 53.5% [49-58.4; 95% CI] at one year after CAR-T. The most frequent cause of death was tumour progression (85.1%). Non-relapse mortality was 3.1% [2.3-4.1; 95% CI] at 3 months and 5.2% [4.1-6.5; 95% CI] at one year after CAR-T. The most frequent causes of non-relapse mortality were cell-therapy-related toxicities including organ toxicities (6.4% of total deaths) and infections (4.4% of total deaths). Our data demonstrates good safety in the European real-world setting

Outcome of Allogeneic Transplantation for Mature T-cell Lymphomas: Impact of Donor Source and Disease Characteristics

Mature T-cell lymphomas constitute the most common indication for allogeneic hematopoietic cell transplantation (allo-HCT) of all lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) between 2008 and 2018. Hematopoietic cell transplantation (HCT) platforms compared were posttransplant cyclophosphamidebased haploidentical (haplo-)HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in vivo T-cell depletion (MUD TCD+), and matched unrelated donor HCT without in vivo T-cell depletion (MUD TCD-). Coprimary end points were overall survival (OS) and progression-free survival (PFS); secondary end points included nonrelapse mortality (NRM), and relapse/progression incidence (RI). A total of 1942 patients were eligible (237 haplo-HCT; 911 MSD; 468 MUD TCD+; 326 MUD TCD-). Cohorts were comparable for baseline characteristics with the exception of higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. Using univariate and multivariate comparisons, OS, PFS, RI, and NRM were not significantly different among the haplo-HCT, MSD, MUD TCD+, and MUD TCD- cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%, respectively, and 50%, 50%, 48%, and 52%, respectively. Significant predictors of inferior OS and PFS on multivariate analysis were active disease status at HCT and decreased PS. AITL was associated with significantly reduced relapse risk and better PFS compared with PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma (TCL). Outcomes of haplo-HCT were comparable to those of matched donor allo-HCT