Thomas Connelly

Abstract Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34 + cells and implanting autologous thymus in immune-deficient NOD- scid IL2Rγ null (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3 + Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8 + /Granz B + T cells homeostasis are observed in tumor regions where FOXP3 + Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.

BACKGROUND: Human dignity is an essential value of professional nursing education as well as a component of the American Nurses Association Code of Ethics. Nurses are exhorted to treat patients with dignity, and older adults want to be treated with dignity and die with dignity. Although dignity, particularly the dignity of older adults, is often discussed in the health care literature, its meaning is not always clear. AIM: The aim of this paper is to describe a concept analysis to develop a definition of dignity in older adults. METHODS: Data were collected using a literature review and five focus groups composed of older adults. The literature provided data about professionals' ideas of dignity and the focus groups provided qualitative data about the nature of dignity in older people. The literature review and focus groups were carried out concurrently, followed by synthesis of the findings. FINDINGS: Dignity is an inherent characteristic of being human, it can be subjectively felt as an attribute of the self, and is made manifest through behaviour that demonstrates respect for self and others. Dignity must be learned, and an individual's dignity is affected by the treatment received from others. CONCLUSIONS: A behavioural definition of dignity was constructed and this could provide the theoretical basis for nurses to develop interventions that foster dignity for older people.

The purpose of this study was to evaluate whether lengthening the dwell time of peripheral i.v. catheters from 72 hours to 144 hours resulted in increased rates of phlebitis and/or infiltration. The study was conducted in medical/surgical units at a 110-bed teaching hospital with an i.v. team. Kaplan-Meier estimates of the success and failure and conditional failure probabilities were calculated for phlebitis and infiltration scores. Log rank tests were used to test for an association between the covariates and the time until failure. Drug irritation was the most significant predictor of phlebitis and infiltration rates in this study. The total difference in the estimated failure rates for the catheter lasting 6 days versus a new catheter inserted for another 3 days is 1.3%. Because the conditional failure probability estimates for days 4, 5, and 6 are slightly higher than for days 1, 2, and 3, consideration may be given to extending the dwell time of a peripheral i.v. catheter beyond 72 hours under certain circumstances.

PURPOSE: To examine the relationships among family functioning, hope, and quality of life in children with juvenile rheumatoid arthritis (JRA). STUDY DESIGN AND METHOD: Sixty-eight children (8 to 12 years of age) with a diagnosis of JRA and one of their parents/guardians participated in this descriptive correlational study. Parents completed the Feetham Family Functioning Survey (FFFS), the Parent Report for Children Pediatric Quality of Life Inventory (PedsQL), and the Parent Report for Children PedsQL Rheumatology Module. The children completed the Children's Hope Scale (CHS), the Child Report for PedsQL, and the Child Report PedsQL Rheumatology Module. Data were analyzed using chi-square, t-tests, and correlation analyses. RESULTS: Family functioning and children's hope showed a negative correlation, indicating that a child's hope was lower when the parent reported greater dissatisfaction with family functioning. Hope was not related to parent or child ratings of the child's quality of life. CLINICAL IMPLICATIONS: In caring for children with JRA, nurses can assess the family's satisfaction with relationships to the broader community, subsystems, and individual members and seek ways to promote healthy family functioning. Nurses also can assess the level of hope in children with JRA and facilitate the development of hopefulness by helping children establish goals and develop strategies to meet them.

BACKGROUND: Gamma delta (γδ) T cells are attractive effector cells for cancer immunotherapy. Vδ2 T cells expanded by zoledronic acid (ZOL) are the most commonly used γδ T cells for adoptive cell therapy. However, adoptive transfer of the expanded Vδ2 T cells has limited clinical efficacy. METHODS: We developed a costimulation method for expansion of Vδ2 T cells in PBMCs by activating γδ T-cell receptor (γδTCR) and Toll-like receptor (TLR) 7/8 using isopentenyl pyrophosphate (IPP) and resiquimod, respectively, and tested the functional markers and antitumoral effects in vitro two-dimensional two-dimensional and three-dimensional spheroid models and in vivo models. Single-cell sequencing dataset analysis and reverse-phase protein array were employed for mechanistic studies. RESULTS: We find that Vδ2 T cells expanded by IPP plus resiquimod showed significantly increased cytotoxicity to tumor cells with lower programmed cell death protein 1 (PD-1) expression than Vδ2 T cells expanded by IPP or ZOL. Mechanistically, the costimulation enhanced the activation of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/Akt)-the mammalian target of rapamycin (mTOR) pathway and the TLR7/8-MyD88 pathway. Resiquimod stimulated Vδ2 T-cell expansion in both antigen presenting cell dependent and independent manners. In addition, resiquimod decreased the number of adherent inhibitory antigen-presenting cells (APCs) and suppressed the inhibitory function of APCs by decreasing PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in these cells during in vitro Vδ2 T-cell expansion. Finally, we showed that human Vδ2 T cells can be expanded from PBMCs and spleen of humanized NSG mice using IPP plus resiquimod or ZOL, demonstrating that humanized mice are a promising preclinical model for studying human γδ T-cell development and function. CONCLUSIONS: Vδ2 T cells expanded by IPP and resiquimod demonstrate improved anti-tumor function and have the potential to increase the efficacy of γδ T cell-based therapies.