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BackgroundAnti-GD2 monoclonal antibodies (mAbs) have shown to improve the overall survival of patients with high-risk neuroblastoma (HR-NB). Serious adverse events (AEs), including pain, within hours of antibody infusion, have limited the development of these therapies. In this study, we provide evidence of Autonomic Nervous System (ANS) activation as the mechanism to explain the main side effects of anti-GD2 mAbs.MethodsThrough confocal microscopy and computational super-resolution microscopy experiments we explored GD2 expression in postnatal nerves of infants. In patients we assessed the ANS using the Sympathetic Skin Response (SSR) test. To exploit tachyphylaxis, a novel infusion protocol (the Step-Up) was mathematically modelled and tested.ResultsThrough confocal microscopy, GD2 expression is clearly visible in the perineurium surrounding the nuclei of nerve cells. By computational super-resolution microscopy experiments we showed the selective expression of GD2 on the cell membranes of human Schwann cells in peripheral nerves (PNs) significantly lower than on NB. In patients, changes in the SSR were observed 4 minutes into the anti-GD2 mAb naxitamab infusion. SSR latency quickly shortened followed by gradual decrease in the amplitude before disappearance. SSR response did not recover for 24 hours consistent with tachyphylaxis and absence of side effects in the clinic. The Step-Up protocol dissociated on-target off-tumor side effects while maintaining serum drug exposure.ConclusionWe provide first evidence of the ANS as the principal non-tumor target of anti-GD2 mAbs in humans. We describe the development and modeling of the Step-Up protocol exploiting the tachyphylaxis phenomenon we demonstrate in patients using the SSR test.

To cultivate a learning environment promoting meaningful engagement with research, Huron University College—a small, primarily undergraduate liberal arts institution—launched the Centre for Undergraduate Research Learning (CURL). One major initiative of CURL's pilot phase was to fund extracurricular research opportunities (Student Fellowships) for undergraduate students. These projects enable students to conduct independent research projects with the guidance of a faculty mentor. The current paper presents the findings from a case study of the first four CURL Student Research Fellowship award recipients and their faculty mentors, using the concept of transformative experience (Heddy and Pugh, 2015) as the lens to conduct a content analysis of participant interviews. Our findings show evidence of substantive dialogue and active collaboration between students and their faculty mentors, providing a safe space for students to experiment, explore and develop their research skills. The students articulated development of specific skills related to research process, connection between theory and practice, as well as personal intellectual and interpersonal gains, which are suggestive of a transformative experience in progress. Although this paper reports on a limited sample, the findings may provide insight into the potential transformative impact of mentored undergraduate research experiences in the liberal arts.

Background Acute myeloid leukemia (AML) remains one of the most challenging hematological malignancies. Despite progress in therapeutics, majority of patients succumb to this neoplasm. CD33 is a proven therapeutic target, given its expression on most AML cells. Almost all anti-CD33 antibodies target the membrane distal immunoglobulin V (IgV) domain of the CD33 extracellular domain.Methods In this manuscript, we present data on three bispecific antibodies (BsAbs) against the CD33 IgV and membrane proximal immunoglobulin C (IgC) domains. We use in vitro binding and cytotoxicity assays to show the effect of these BsAbs on AML cell lines. We also use immunodeficient mice-bearing leukemias from cell lines and patient-derived xenografts to show the effect of these BsAbs in vivo.Results In vitro, the IgV-targeting BsAb had higher binding to AML cell lines using flow cytometry and delivered more potent cytotoxicity in T-cell-dependent cytotoxicity assays; importantly, the IgC domain-targeting outperformed the IgV domain-targeting BsAb in medullary and extramedullary leukemia animal models.Conclusions These data support further clinical development of this BsAb for first-in-human phase I clinical trial.

The impact bias in affective forecasting—a tendency to overestimate the emotional consequences of future events—may not be a universal phenomenon. This prediction bias stems from a cognitive process known as focalism, whereby predictors focus attention narrowly on the upcoming target event. Three studies supported the hypothesis that East Asians, who tend to think more holistically than Westerners, would be less susceptible to focalism and, consequently-to the impact bias. In Studies 1 and 2, Euro Canadians exhibited the impact bias for positive future events, whereas East Asians did not. A thought focus measure indicated that the cultural difference in prediction was mediated by the extent to which participants focused on the target event (i. e., focalism). In Study 3, a thought focus manipulation revealed that defocused Euro-Canadians and East Asians made equally moderate affective forecasts. [ABSTRACT FROM AUTHOR]