CART Cell Toxicities: New Insight into Mechanisms and Management

T cells genetically engineered with chimeric antigen receptors (CART) have become a potent class of cancer immunotherapeutics. Numerous clinical trials of CART cells have revealed remarkable remission rates in patients with relapsed or refractory hematologic malignancies. Despite recent clinical success, CART cell therapy has also led to significant morbidity and occasional mortality from associated toxicities. Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) present barriers to the extensive use of CART cell therapy in the clinic. CRS can lead to fever, hypoxia, hypotension, coagulopathies, and multiorgan failure, and ICANS can result in cognitive dysfunction, seizures, and cerebral edema. The mechanisms of CRS and ICANS are becoming clearer, but many aspects remain unknown. Disease type and burden, peak serum CART cell levels, CART cell dose, CAR structure, elevated pro-inflammatory cytokines, and activated myeloid and endothelial cells all contribute to CART cell toxicity. Current guidelines for the management of toxicities associated with CART cell therapy vary between clinics, but are typically comprised of supportive care and treatment with corticosteroids or tocilizumab, depending on the severity of the symptoms. Acquiring a deeper understanding of CART cell toxicities and developing new management and prevention strategies are ongoing. In this review, we present findings in the mechanisms and management of CART cell toxicities

Cyclophosphamide-Induced Cystitis Increases Bladder CXCR4 Expression and CXCR4-Macrophage Migration Inhibitory Factor Association

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine involved in cystitis and a non-cognate ligand of the chemokine receptor CXCR4 in vitro. We studied whether CXCR4-MIF associations occur in rat bladder and the effect of experimental cystitis. METHODS AND FINDINGS: Twenty male rats received saline or cyclophosphamide (40 mg/kg; i.p.; every 3(rd) day) to induce persistent cystitis. After eight days, urine was collected and bladders excised under anesthesia. Bladder CXCR4 and CXCR4-MIF co-localization were examined with immunhistochemistry. ELISA determined MIF and stromal derived factor-1 (SDF-1; cognate ligand for CXCR4) levels. Bladder CXCR4 expression (real-time RTC-PCR) and protein levels (Western blotting) were examined. Co-immunoprecipitations studied MIF-CXCR4 associations.Urothelial basal and intermediate (but not superficial) cells in saline-treated rats contained CXCR4, co-localized with MIF. Cyclophosphamide treatment caused: 1) significant redistribution of CXCR4 immunostaining to all urothelial layers (especially apical surface of superficial cells) and increased bladder CXCR4 expression; 2) increased urine MIF with decreased bladder MIF; 3) increased bladder SDF-1; 4) increased CXCR4-MIF associations. CONCLUSIONS: These data demonstrate CXCR4-MIF associations occur in vivo in rat bladder and increase in experimental cystitis. Thus, CXCR4 represents an alternative pathway for MIF-mediated signal transduction during bladder inflammation. In the bladder, MIF may compete with SDF-1 (cognate ligand) to activate signal transduction mediated by CXCR4

Spitzer 24 micron Survey of Debris Disks in the Pleiades

We performed a 24 micron 2 Deg X 1 Deg survey of the Pleiades cluster, using the MIPS instrument on Spitzer. Fifty four members ranging in spectral type from B8 to K6 show 24 micron fluxes consistent with bare photospheres. All Be stars show excesses attributed to free-free emission in their gaseous envelopes. Five early-type stars and four solar-type stars show excesses indicative of debris disks. We find a debris disk fraction of 25 % for B-A members and 10 % for F-K3 ones. These fractions appear intermediate between those for younger clusters and for the older field stars. They indicate a decay with age of the frequency of the dust-production events inside the planetary zone, with similar time scales for solar-mass stars as have been found previously for A-stars.Comment: accepted to Ap

Smoothed Particle Hydrodynamics for Relativistic Heavy Ion Collisions

The method of smoothed particle hydrodynamics (SPH) is developped appropriately for the study of relativistic heavy ion collision processes. In order to describe the flow of a high energy but low baryon number density fluid, the entropy is taken as the SPH base. We formulate the method in terms of the variational principle. Several examples show that the method is very promising for the study of hadronic flow in RHIC physics.Comment: 14 pages, 8figure

A Constraint on brown dwarf formation via ejection: radial variation of the stellar and substellar mass function of the young open cluster IC2391

Using the Wide Field Imager (WFI) at the ESO 2.2m telescope at La Silla and the CPAPIR camera at the CTIO 1.5m telescope at Cerro Tololo, we have performed an extensive, multiband photometric survey of the open cluster IC2391 (D~146pc, age~50Myr, solar metallicity). Here we present the results from our photometric survey and from a spectroscopic follow-up of the central part of the survey.Comment: 4 pages, 3 figures, to appear in the proceedings of the Cool Stars 15 conferenc

The Efficacy of a Holding Community Program—Promoting Social Reflection at School

Received 17 December 2020. Accepted 8 September 2021. Published online 11 October 2021.The authors developed a Holding Community Program to achieve the following objectives: (a) to increase the perspective-taking capacity of adolescents; (b) to promote interpersonal and intergroup harmony; (c) to empower school students to be more (pro)active in their communities and in public life. Apart from the intervention itself, the study comprised a pre-test and a post-test and involved a total of 240 Hungarian high school students (159 female, 66.3%). The students were aged 14–18 (Mage = 15.33; S Dage = 0.88). They were recruited from four high schools. Control groups (N = 122) were chosen from the same institution and graded as experimental classes (N = 118, 7 classes). Both immediate and long-term effects of the intervention (4–6 months after the intervention) were explored. Quantitative analysis of the data indicated that the two-day intervention program had significantly increased the students’ perspective-taking capacity (short-term: F(1, 238) = 6.03, p < 0.05, long-term: n.s.) and efficacy beliefs (short-term: F(1, 238) = 3.83, p = 0.052, long-term: F(1, 238) = 3.38, p < 0.05). After the training, students were more willing to participate in collective actions (short-term: F(1, 238) = 7.32, p < 0.01, long-term: F(1, 238) = 3.83, p < 0.05). These results seem quite promising but the outcome was not significant regarding its effect on prejudice.This work was supported by the [Hungarian National Research, Development and Innovation Office—NKFIH] under Grant [K 119793—The influence of social identity on intergroup prejudice and collective action]

Discovery of Two Very Low-Mass Binaries: Final Results of an Adaptive Optics Survey of Nearby M6.0-M7.5 Stars

We present updated results of a high-resolution, magnitude limited (Ks<12 mag) imaging survey of nearby low-mass M6.0-M7.5 field stars. The observations were carried out using adaptive optics at the Gemini North, VLT, Keck II, and Subaru telescopes. Our sample of 36 stars consists predominantly of nearby (<30 pc) field stars, 5 of which we have resolved as binaries. Two of the binary systems, 2MASSI J0429184-312356 and 2MASSI J1847034+552243, are presented here for the first time. All 5 discovered binary systems have separations between 0.08"-0.53" (2-9 AU) with similar mass ratios (q>0.8, delta Ks < 1 mag). This result supports the hypothesis that wide (a>20 AU) very low-mass (M_tot<0.19 M_sun) binary systems are rare. The projected semimajor axis distribution of these systems peak at ~ 5 AU and we report a sensitivity-corrected binary fraction of 9% (-3%, +4%) for stars with primaries of spectral type M6.0-M7.5 with separations >3 AU and mass ratios q>0.6. Within these instrumental sensitivities, these results support the overall trend that both the semimajor axis distribution and binary fraction are a function of the mass of the primary star and decrease with decreasing primary mass. These observations provide important constraints for low-mass binary star formation theories.Comment: 20 pages, 8 figures, accepted to Ap

Challenging the Science Curriculum Paradigm: TeachingPrimary Children Atomic-Molecular Theory

Solutions to global issues demand the involvement of scientists, yet concern exists about retention rates in science as students pass through school into University. Young children are curious about science, yet are considered incapable of grappling with abstract and microscopic concepts such as atoms, sub-atomic particles, molecules and DNA. School curricula for primary (elementary) aged children reflect this by their limitation to examining only what phenomena are without providing any explanatory frameworks for how or why they occur. This research challenges the assumption that atomic-molecular theory is too difficult for young children, examining new ways of introducing atomic theory to 9 year olds and seeks to verify their efficacy in producing genuine learning in the participants. Early results in three cases in different schools indicate these novel methods fostered further interest in science, allowed diverse children to engage and learn aspects of atomic theory, and satisfied the children’s desire for intellectual challenge. Learning exceeded expectations as demonstrated in the post-interview findings. Learning was also remarkably robust, as demonstrated in two schools eight weeks after the intervention, and in one school, one year after their first exposure to ideas about atoms, elements and molecules

Controlling with light the interaction between trans-tetrapyridyl ruthenium complexes and an oligonucleotide

Metals in Catalysis, Biomimetics & Inorganic Material