Functional differences between rodent and human PD-1 linked to evolutionary divergence.

Mechanistic understanding of the inhibitory immunoreceptor PD-1 is largely based on mouse models, but human and mouse PD-1 share only 59.6% amino acid identity. Here, we found that human PD-1 is more inhibitory than mouse PD-1, owing to stronger interactions with the ligands PD-L1 and PD-L2 and more efficient recruitment of the effector phosphatase Shp2.

Evolutionary fingerprint in rodent PD1 confers weakened activity and enhanced tumor immunity compared to human PD1.

Mechanistic understanding of the immune checkpoint receptor PD1 is largely based on mouse models, but human and mouse PD1 orthologs exhibit only 59.6% identity in amino acid sequences. Here we show that human PD1 is more inhibitory than mouse PD1 due to stronger interactions with the ligands PDL1 and PDL2 and with the effector phosphatase Shp2.

Reducing Radiation Dermatitis for PBS Proton Therapy Breast Cancer Patients Using SpotDelete.

Purpose: The purpose of this work was to reduce the severity of radiation dermatitis for breast cancer patients receiving pencil beam scanning proton therapy. The hypothesis was that eliminating proton spots (SpotDelete) in the 0.5 cm skin rind would reduce the potentially higher relative biological effectiveness (RBE) known to occur at the Bragg Peak.

Perceptions of organizational culture among mental health providers at a Veterans Affairs hospital.

A mixed method approach was utilized to assess the organizational culture of the mental health service line at a large Veterans Affairs (VA) hospital. The goals of the study were to assess the organizational culture, identify how employees differ in perceptions of organizational culture, and identify areas of strength and challenges. Two hundred thirteen participants returned a questionnaire assessing perceptions of organizational culture using the Organizational Culture Assessment Questionnaire (Sashkin & Rosenbach, 2013).

Treating recurrent metastatic breast cancer to the skin with proton therapy.

Proton therapy offers unique physical properties that make it an excellent choice for treating metastatic breast cancer, particularly when recurrent disease occurs near previously irradiated tissues. This case study demonstrates the dosimetric benefits of proton therapy in patients with metastatic breast cancer to the skin. The case consists of one patient with 5 separate areas treated with Pencil Beam Scanning (PBS) proton therapy over a period of 2 years using Monte Carlo calculation and robust optimization.

Transcriptomes and metabolism define mouse and human MAIT cell populations.

Mucosal-associated invariant T (MAIT) cells are a subset of T lymphocytes that respond to microbial metabolites. We defined MAIT cell populations in different organs and characterized the developmental pathway of mouse and human MAIT cells in the thymus using single-cell RNA sequencing and phenotypic and metabolic analyses. We showed that the predominant mouse subset, which produced IL-17 (MAIT17), and the subset that produced IFN-γ (MAIT1) had not only greatly different transcriptomes but also different metabolic states.

A Intronic Element Regulates T Follicular Helper Cell Differentiation.

In response to an intracellular infectious agent, the immune system produces a specific cellular response as well as a T cell-dependent Ab response. Precursor T cells differentiate into effector T cells, including Th1 cells, and T follicular helper (T) cells. The latter cooperate with B cells to form germinal centers and induce the formation of Ab-forming plasmacytes.

Meiotic Cas9 expression mediates gene conversion in the male and female mouse germline.

Highly efficient gene conversion systems have the potential to facilitate the study of complex genetic traits using laboratory mice and, if implemented as a "gene drive," to limit loss of biodiversity and disease transmission caused by wild rodent populations. We previously showed that such a system of gene conversion from heterozygous to homozygous after a sequence targeted CRISPR/Cas9 double-strand DNA break (DSB) is feasible in the female mouse germline. In the male germline, however, all DSBs were instead repaired by end joining (EJ) mechanisms to form an "insertion/deletion" (indel) mutation.

Validation of automated complex head and neck treatment planning with pencil beam scanning proton therapy.

Background: Pencil beam scanning (PBS) proton therapy offers dosimetric advantages for several treatment sites, including head and neck (H&N). However, to achieve the optimal target coverage and robustness, these plans can be complex and time consuming to develop and optimize. Automating the treatment planning process can ensure a high-quality and standardized plan, reduce burden to the planner, and decrease time-to-treatment.

Scripted spot removal in PBS proton therapy planning.

Background: It is well known in proton therapy that the relative biological effectiveness (RBE) is not constant across the entire Bragg peak, with higher RBE at the distal end of the Bragg peak due to higher linear energy transfer (LET). Treatment planning systems are moving toward LET optimization to mitigate this potentially higher biological impact at a track end. However, using a simple script, proton users can begin to simulate this process by deleting spots from critical structures during optimization.

Design, synthesis, and preliminary evaluation of a potential synthetic opioid rescue agent.

Background: One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death.

Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection.

In response to infection, pathogen-specific CD8 T cells differentiate into functionally diverse effector and memory T cell populations critical for resolving disease and providing durable immunity. Through small-molecule inhibition, RNAi studies, and induced genetic deletion, we reveal an essential role for the chromatin modifier and BET family member BRD4 in supporting the differentiation and maintenance of terminally fated effector CD8 T cells during infection. BRD4 bound diverse regulatory regions critical to effector T cell differentiation and controlled transcriptional activity of terminal effector-specific super-enhancers in vivo.

CopyCatchers are versatile active genetic elements that detect and quantify inter-homolog somatic gene conversion.

CRISPR-based active genetic elements, or gene-drives, copied via homology-directed repair (HDR) in the germline, are transmitted to progeny at super-Mendelian frequencies. Active genetic elements also can generate widespread somatic mutations, but the genetic basis for such phenotypes remains uncertain. It is generally assumed that such somatic mutations are generated by non-homologous end-joining (NHEJ), the predominant double stranded break repair pathway active in somatic cells.

The human intermediate prolactin receptor is a mammary proto-oncogene.

The hormone prolactin (PRL) and its receptor (hPRLr) are significantly involved in breast cancer pathogenesis. The intermediate hPRLr (hPRLrI) is an alternatively-spliced isoform, capable of stimulating cellular viability and proliferation. An analogous truncated mouse PRLr (mPRLr) was recently found to be oncogenic when co-expressed with wild-type mPRLr.

FOXO1 constrains activation and regulates senescence in CD8 T cells.

Naive and memory T cells are maintained in a quiescent state, yet capable of rapid response and differentiation to antigen challenge via molecular mechanisms that are not fully understood. In naive cells, the deletion of Foxo1 following thymic development results in the increased expression of multiple AP-1 family members, rendering T cells less able to respond to antigenic challenge. Similarly, in the absence of FOXO1, post-infection memory T cells exhibit the characteristics of extended activation and senescence.

The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain.

Salvinorin A (SA) is a κ-opioid receptor agonist and atypical dissociative hallucinogen found in Salvia divinorum. Despite the resurgence of hallucinogen studies, the effects of κ-opioid agonists on human brain function are not well-understood. This placebo-controlled, within-subject study used functional magnetic resonance imaging for the first time to explore the effects of inhaled SA on strength, variability, and entropy of functional connectivity (static, dynamic, and entropic functional connectivity, respectively, or sFC, dFC, and eFC).

Delineation of a molecularly distinct terminally differentiated memory CD8 T cell population.

Memory CD8 T cells provide durable protection against diverse intracellular pathogens and can be broadly segregated into distinct circulating and tissue-resident populations. Paradigmatic studies have demonstrated that circulating memory cells can be further divided into effector memory (Tem) and central memory (Tcm) populations based on discrete functional characteristics. Following resolution of infection, we identified a persisting antigen-specific CD8 T cell population that was terminally fated with potent effector function but maintained memory T cell qualities and conferred robust protection against reinfection.

A key control point in the T cell response to chronic infection and neoplasia: FOXO1.

T cells able to control neoplasia or chronic infections display a signature gene expression profile similar or identical to that of central memory T cells. These cells have qualities of self-renewal and a plasticity that allow them to repeatedly undergo activation (growth, proliferation, and differentiation), followed by quiescence. It is these qualities that define the ability of T cells to establish an equilibrium with chronic infectious agents, and also preserve the ability of T cells to be re-activated (by checkpoint therapy) in response to malignant cancers.

Validation of the RayStation Monte Carlo dose calculation algorithm using a realistic lung phantom.

Purpose: Our purposes are to compare the accuracy of RaySearch's analytical pencil beam (APB) and Monte Carlo (MC) algorithms for clinical proton therapy and to present clinical validation data using a novel animal tissue lung phantom.

Methods: We constructed a realistic lung phantom composed of a rack of lamb resting on a stack of rectangular natural cork slabs simulating lung tissue. The tumor was simulated using 70% lean ground lamb meat inserted in a spherical hole with diameter 40 ± 5 mm carved into the cork slabs.

Validation of the RayStation Monte Carlo dose calculation algorithm using realistic animal tissue phantoms.

Purpose: The aim of this study is to validate the RayStation Monte Carlo (MC) dose algorithm using animal tissue neck phantoms and a water breast phantom.

Methods: Three anthropomorphic phantoms were used in a clinical setting to test the RayStation MC dose algorithm. We used two real animal necks that were cut to a workable shape while frozen and then thawed before being CT scanned.