Management of Adverse Events Following Treatment With Anti‐Programmed Death‐1 Agents

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140047/1/onco1230.pd

Immunological consequences of using three different clinical/laboratory techniques of emulsifying peptide-based vaccines in incomplete Freund's adjuvant

Incomplete Freund's adjuvant (IFA) serves as a carrier for water-in-oil emulsion (W/O) vaccines. The stability of such emulsions greatly affects vaccine safety and efficacy since continued presence of antigen depots at lymphoid organs releasing low-level antigens is known to stimulate a potent immune response and high-level systemic release of antigens can lead to tolerance. W/O emulsions for the purpose of clinical and laboratory peptide-based vaccinations have been prepared using the techniques of syringe extrusion, vortex or high-speed homogenization. There is no consensus in the field over which technique would be best to use and no immunological data are available that compare the three techniques. In this study, we compared the immune responses induced by a peptide-based vaccine prepared using vortex, syringe-extrusion and homogenization. The vaccination led to tumor rejection by mice vaccinated with the peptide-based vaccine prepared using all three techniques. The immunological data from the in vivo cytotoxicity assay showed a trend for lower responses and a higher variability and greater range in the immune responses induced by a vaccine that was emulsified by the vortex or homogenizer techniques as compared to the syringe-extrusion technique. There were statistically significant lower numbers of IFNγ-secreting cells induced when the mice were vaccinated with a peptide-based vaccine emulsion prepared using the vortex compared to the syringe-extrusion technique. At a suboptimal vaccine dose, the mice vaccinated with a peptide-based vaccine emulsion prepared using the vortex technique had the largest tumors compared to the syringe-extrusion or the homogenizer technique. In the setting of a busy pharmacy that prepares peptide-based vaccine emulsions for clinical studies, the vortex technique can still be used but we urge investigators to take special care in their choice of mixing vessels for the vortex technique as that can influence the stability of the emulsion. However, in instances where the optimal dose is unknown, we caution investigators against using the vortex technique to prepare the peptide-based vaccine emulsions. Overall, we report that all three techniques can be used to prepare peptide-based vaccine emulsions under optimal dose conditions and we discuss important details regarding the proper preparation of the emulsions

The Next-Generation Multimission U.S. Surveillance Radar Network

The U.S. Government operates seven distinct radar networks, providing weather and aircraft surveillance for public weather services, air traffic control, and homeland defense. In this paper, we describe a next-generation multimission phased-array radar (MPAR) concept that could provide enhanced weather and aircraft surveillance services with potentially lower life cycle costs than multiple single-function radar networks. We describe current U.S. national weather and aircraft surveillance radar networks and show that by reducing overlapping airspace coverage, MPAR could reduce the total number of radars required by approximately one-third. A key finding is that weather surveillance requirements dictate the core parameters of a multimission radar—airspace coverage, aperture size, radiated power, and angular resolution. Aircraft surveillance capability can be added to a phased array weather radar at low incremental cost because the agile, electronically steered beam would allow the radar to achieve the much more rapid scan update rates needed for aircraft volume search missions, and additionally to support track modes for individual aircraft targets. We describe an MPAR system design that includes multiple transmit–receive channels and a highly digitized active phased array to generate independently steered beam clusters for weather, aircraft volume search, and aircraft track modes. For each of these modes, we discuss surveillance capability improvements that would be realized relative to today's radars. The Federal Aviation Administration (FAA) has initiated the development of an MPAR “preprototype” that will demonstrate critical subsystem technologies and multimission operational capabilities. Initial subsystem designs have provided a solid basis for estimating MPAR costs for comparison with existing, mechanically scanned operational surveillance radars.United States. Federal Aviation Administration (FA8721-05-C-0002

Cytotoxic T lymphocyte responses against melanocytes and melanoma

<p>Abstract</p> <p>Background</p> <p>Vitiligo is a common toxicity associated with immunotherapy for melanoma. Cytotoxic T lymphocytes (CTLs) against melanoma commonly target melanoma-associated antigens (MAAs) which are also expressed by melanocytes. To uncouple vitiligo from melanoma destruction, it is important to understand if CTLs can respond against melanoma and melanocytes at different levels.</p> <p>Methods</p> <p>To understand the dichotomous role of MAA-specific CTL, we characterized the functional reactivities of established CTL clones directed to MAAs against melanoma and melanocyte cell lines.</p> <p>Results</p> <p>CTL clones generated from melanoma patients were capable of eliciting MHC-restricted, MAA-specific lysis against melanocyte cell lines as well as melanoma cells. Among the tested HLA-A*0201-restricted CTL clones, melanocytes evoked equal to slightly higher degranulation and cytolytic responses as compared to melanoma cells. Moreover, MAA-specific T cells from vaccinated patients responded directly ex vivo to melanoma and melanocytes. Melanoma cells express slightly higher levels of MART-1 and gp100 than melanocytes as measured by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry.</p> <p>Conclusions</p> <p>Our data suggest that CTLs respond to melanoma and melanocytes equally in vitro and directly ex vivo.</p

Clustering of Aromatic Amino Acid Residues around Methionine in Proteins

Short-range, non-covalent interactions between amino acid residues determine protein structures and contribute to protein functions in diverse ways. The interactions of the thioether of methionine with the aromatic rings of tyrosine, tryptophan, and/or phenylalanine has long been discussed and such interactions are favorable on the order of 1–3 kcal mol−1. Here, we carry out a new bioinformatics survey of known protein structures where we assay the propensity of three aromatic residues to localize around the [-CH2-S-CH3] of methionine. We term these groups “3-bridge clusters”. A dataset consisting of 33,819 proteins with less than 90% sequence identity was analyzed and such clusters were found in 4093 structures (or 12% of the non-redundant dataset). All sub-classes of enzymes were represented. A 3D coordinate analysis shows that most aromatic groups localize near the CH2&nbsp;and CH3&nbsp;of methionine. Quantum chemical calculations support that the 3-bridge clusters involve a network of interactions that involve the Met-S, Met-CH2, Met-CH3, and the π systems of nearby aromatic amino acid residues. Selected examples of proposed functions of 3-bridge clusters are discussed

Implementation and preliminary clinical outcomes of a pharmacist-managed venous thromboembolism clinic for patients treated with rivaroxaban post emergency department discharge

Objective To describe the implementation, work flow, and differences in outcomes between a pharmacist-managed clinic for the outpatient treatment of venous thromboembolism (VTE) using rivaroxaban versus care by a primary care provider. Interventions Patients in the studied health system that are diagnosed with low-risk VTE in the emergency department are often discharged without hospital admission. These patients are treated with rivaroxban and follow up either in a pharmacist-managed VTE clinic or with their primary care provider. Pharmacists in the VTE clinic work independently under a collaborative practice agreement. An evaluation of thirty-four patients, seventeen in each treatment arm, was conducted to compare the differences in treatment-related outcomes of rivaroxaban when managed by a pharmacist versus a primary care provider. Results The primary endpoint was a six month composite of anticoagulation treatment-related complications that included a diagnosis of major bleeding, recurrent thromboembolism, or fatality due to either major bleeding or recurrent thromboembolism. Secondary endpoints included number of hospitalizations, adverse events, and medication adherence. There was no difference in the primary endpoint between groups with one occurrence of the composite endpoint in each treatment arm (p=1.000), both of which were recurrent thromboembolic events. Medication adherence assessment was formally performed in 8 patients in the pharmacist group versus 0 patients in the control group. No differences were seen amongst other secondary endpoints. Conclusions The pharmacist-managed clinic is a novel expansion of clinical pharmacy services that treats patients with low-risk VTEs with rivaroxaban in the outpatient setting. The evaluation of outcomes provides support that pharmacist-managed care utilizing standardized protocols under a collaborative practice agreement may be as safe as care by a primary care provider

Addressing Research Software Sustainability via Institutes

Research software is essential to modern research, but it requires ongoing human effort to sustain: to continually adapt to changes in dependencies, to fix bugs, and to add new features. Software sustainability institutes, amongst others, develop, maintain, and disseminate best practices for research software sustainability, and build community around them. These practices can both reduce the amount of effort that is needed and create an environment where the effort is appreciated and rewarded. The UK SSI is such an institute, and the US URSSI and the Australian AuSSI are planning to become institutes, and this extended abstract discusses them and the strengths and weaknesses of this approach.Comment: accepted by ICSE 2021 BokSS Workshop (https://bokss.github.io/bokss2021/

RANTES Secretion by Gene-Modified Tumor Cells Results in Loss of Tumorigenicity In Vivo: Role of Immune Cell Subpopulations

Overview summary Members of the chemokine superfamily mediate potent and selective chemoattraction of a variety of immune cell subsets, which is concentration dependent. This important and novel biologic activity raises the possibility of using chemokines as adjuvants in cancer vaccine strategies. We describe here the in vitro chemotactic capacity of RANTES for murine CD8+ tumor-infiltrating lymphocytes (TIL). Moreover, murine fibrosarcoma cells transfected with the cDNA encoding RANTES and secreting high levels of this chemokine become nontumorigenic in immunocompetent mice. The antitumor effect of RANTES is dependent on inherent tumor immunogenicity and is mediated through the participation of host-derived T cells and macrophages. Thus, the general chemoattractant properties exhibited by RANTES in vitro appear to be relevant in an in vivo model. These data warrant further investigation of other distinct members of the chemokine superfamily for their potential use, either alone or in combination, in gene therapy approaches that employ tumor cells as immunogens.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63285/1/hum.1996.7.13-1545.pd

Frontiers in Pigment Cell and Melanoma Research

We identify emerging frontiers in clinical and basic research of melanocyte biology and its associated biomedical disciplines. We describe challenges and opportunities in clinical and basic research of normal and diseased melanocytes that impact current approaches to research in melanoma and the dermatological sciences. We focus on four themes: (1) clinical melanoma research, (2) basic melanoma research, (3) clinical dermatology, and (4) basic pigment cell research, with the goal of outlining current highlights, challenges, and frontiers associated with pigmentation and melanocyte biology. Significantly, this document encapsulates important advances in melanocyte and melanoma research including emerging frontiers in melanoma immunotherapy, medical and surgical oncology, dermatology, vitiligo, albinism, genomics and systems biology, epidemiology, pigment biophysics and chemistry, and evolution