Solid tumor immunotherapy using NKG2D-based adaptor CAR T cells.

NKG2D ligands (NKG2DLs) are broadly expressed in cancer. To target these, we describe an adaptor chimeric antigen receptor (CAR) termed NKG2D/Dap10-12. Herein, T cells are engineered to co-express NKG2D with a fusion protein that comprises Dap10 joined to a Dap12 endodomain.

Proliferating macrophages in human tumours show characteristics of monocytes responding to myelopoietic growth factors.

Macrophages play essential roles in maintaining tissue homeostasis and immune defence. However, their extensive infiltration into tumours has been linked to adverse outcomes in multiple human cancers. Within the tumour microenvironment (TME), tumour-associated macrophages (TAMs) promote tumour growth and metastasis, making them prime targets for cancer immunotherapy.

Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors.

Background: Checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies in a range of immunogenic cancer types. Blocking this pathway with an oral therapy could benefit patients through greater convenience, particularly in combination regimens, and allow flexible management of immune-mediated toxicities.

Methods: PD-L1 binding activity was assessed in engineered dimerization and primary cell target occupancy assays.

Analgesia and Sedation Use During Noninvasive Ventilation for Acute Respiratory Failure.

Objectives: To describe U.S. practice regarding administration of sedation and analgesia to patients on noninvasive ventilation (NIV) for acute respiratory failure (ARF) and to determine the association of this practice with odds of intubation or death.

Safety, pharmacodynamics, and antiviral activity of selgantolimod in viremic patients with chronic hepatitis B virus infection.

Background & Aims: Novel finite therapies for chronic hepatitis B (CHB) are needed, since lifelong treatment is usually required with current available oral antivirals. This phase II study (NCT03615066) evaluated the safety, pharmacodynamics, and antiviral activity of selgantolimod (a Toll-like receptor 8 agonist [TLR8]) with tenofovir alafenamide (TAF).

Methods: Viremic patients with CHB not receiving treatment were stratified by HBeAg status and randomized 2:2:1 to TAF 25 mg/day with selgantolimod 3 mg orally once weekly (QW), selgantolimod 1.

Contributing Factors to Adverse Events in Long-Term Care Facilities in Ireland, a Content Analysis.

Objectives: There is substantial research on contributing factors to adverse events (AEs) in acute settings. Little is known about AEs in long-term care facilities (LTCFs). Our aim was to identify contributing factors to AEs from LTCFs for older persons and people with disability to inform quality improvement.

Safety and efficacy of the oral TLR8 agonist selgantolimod in individuals with chronic hepatitis B under viral suppression.

Background & Aims: Selgantolimod (GS-9688) is a Toll-like receptor 8 (TLR8) agonist that suppresses HBV in vitro. In a phase II study, we evaluated the safety and efficacy of weekly selgantolimod treatment in virally suppressed individuals with chronic HBV taking oral antiviral treatment.

Methods: Forty-eight patients were randomized into two cohorts (hepatitis B e antigen [HBeAg]-positive and -negative [n = 24 each]) to receive oral selgantolimod 3 mg, 1.

Rational design of a SOCS1-edited tumor-infiltrating lymphocyte therapy using CRISPR/Cas9 screens.

Cell therapies such as tumor-infiltrating lymphocyte (TIL) therapy have shown promise in the treatment of patients with refractory solid tumors, with improvement in response rates and durability of responses nevertheless sought. To identify targets capable of enhancing the antitumor activity of T cell therapies, large-scale in vitro and in vivo clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens were performed, with the SOCS1 gene identified as a top T cell-enhancing target. In murine CD8+ T cell-therapy models, SOCS1 served as a critical checkpoint in restraining the accumulation of central memory T cells in lymphoid organs as well as intermediate (Texint) and effector (Texeff) exhausted T cell subsets derived from progenitor exhausted T cells (Texprog) in tumors.

The Association of Organizational, Environmental, and Staffing Characteristics of Residential Care Facilities and the Risk Rating of Statutory Notifications: A Cross-Sectional Study in Ireland.

Objectives: Safety incidents (SIs) are an indicator of quality in health and social care services. Safety incident research has largely focused on acute health care settings. We aimed to examine the association of organizational, environmental, and staffing characteristics of residential care facilities (RCFs) and severity of regulatory SI notifications.

AR eGFP reporter mouse enables elucidation of AR expression dynamics during anti-tumor immune responses.

There is significant clinical interest in targeting adenosine-mediated immunosuppression, with several small molecule inhibitors having been developed for targeting the AR receptor. Understanding of the mechanism by which AR is regulated has been hindered by difficulty in identifying the cell types that express AR due to a lack of robust antibodies for these receptors. To overcome this limitation, here an AR eGFP reporter mouse is developed, enabling the expression of AR during ongoing anti-tumor immune responses to be assessed.

Seven-colour multiplex immunochemistry/immunofluorescence and whole slide imaging of frozen sections.

Multiplex Immunochemistry/Immunofluorescence (mIHC/IF) aims to visualise multiple biomarkers in a single tissue section and is especially powerful when used on slide scanners coupled with digital analysis tools. mIHC/IF is commonly employed in immuno-oncology to characterise features of the tumour microenvironment (TME) and correlate them with clinical parameters to guide prognostication and therapy. However, mIHC/IF can be applied to a wide range of organisms in any physiological or disease context.

To summarise the approach to and findings of the PPIE undertaken as part of a programme of secondary research with a vulnerable, hard to reach population during the COVID-19 pandemic.

Background: Public and patient involvement and engagement (PPIE) is an important part of research. The inclusion of PPIE in research is becoming more widespread, however, there are some areas where it is still uncommon. For example, undertaking PPIE in secondary analysis projects is uncommon and PPIE with difficult to reach populations and vulnerable groups can be seen as being too difficult to facilitate.

Mortality in residential care facilities for people with disability: a descriptive cross-sectional analysis of statutory notifications in Ireland.

Objectives: To determine incidence of death in residential care facilities for people with disability in Ireland, primary cause of death, associations of facility characteristics and deaths, and to compare characteristics of deaths reported as expected and unexpected.

Design: Descriptive cross-sectional study.

Setting: All residential care facilities for people with disability operational in Ireland in 2019 and 2020 (n=1356).

Determinants of regulatory compliance in health and social care services: A systematic review using the Consolidated Framework for Implementation Research.

Background: The delivery of high quality care is a fundamental goal for health systems worldwide. One policy tool to ensure quality is the regulation of services by an independent public authority. This systematic review seeks to identify determinants of compliance with such regulation in health and social care services.

Incidence and type of restrictive practice use in nursing homes in Ireland.

Background: Use of restrictive practices (RP) in care settings may sometimes be warranted but can also conflict with human rights. Research to date has focused primarily on physical and chemical RP, however other forms are also used. Better understanding of practice can inform RP reduction.

Rapid culture of human keratinocytes in an autologous, feeder-free system with a novel growth medium.

Background Aims: The ability to culture human keratinocytes is beneficial in the treatment of skin injury and disease, as well as for testing chemicals in vitro as a substitute for animal testing.

Results: We have identified a novel culture medium for the rapid growth of keratinocytes from human skin. "Kelch's medium" supports keratinocyte growth that is as rapid as in the classical Rheinwald and Green method, but without the need for cholera toxin or xenogeneic feeder cells.

Incidence and type of restrictive practice use in residential disability facilities in Ireland, a cross-sectional study.

Restrictive practices (RPs) are a contentious issue in health and social care services. While use may be warranted in some instances, there are risks and concerns around human rights infringements. There are limited data available on the types and incidences of RPs used in health and social care services internationally.

Prevalence of and Spending on Ear, Nose, Throat, and Respiratory Infections Among Children With Chronic Complex Conditions.

Objective: Ear, nose, throat, and respiratory infections (ENTRI) may affect children with complex chronic conditions (CCC) differently than their peers. We compared ENTRI prevalence and spending in children with and without CCCs.

Methods: Retrospective analysis of 3,880,456 children ages 0-to-18 years enrolled in 9 US state Medicaid programs in 2018 contained in the IBM Watson Marketscan Database.

Management and reporting of safety incidents by residential care facilities in Ireland: A thematic analysis of statutory notifications.

The prevention of safety incidents (SI) in health and social care settings is an ongoing undertaking. Limited research has been conducted on SIs outside of acute care. Internationally residential care facilities (RCFs) are typically regulated to promote quality and safeguarding.

Rhythmic Relating: Bidirectional Support for Social Timing in Autism Therapies.

We propose for autism: a system of supports for friends, therapists, parents, and educators; a system which aims to augment bidirectional communication and complement existing therapeutic approaches. We begin by summarizing the developmental significance of and the challenges observed in early autism. Meta-analyses conclude the early primacy of such challenges, yet cite the lack of focused therapies.

Plasminogen and plasmin can bind to human T cells and generate truncated CCL21 that increases dendritic cell chemotactic responses.

Plasmin is a broad-spectrum protease and therefore needs to be tightly regulated. Active plasmin is formed from plasminogen, which is found in high concentrations in the blood and is converted by the plasminogen activators. In the circulation, high levels of α2-antiplasmin rapidly and efficiently inhibit plasmin activity.

Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance.

Most cancer deaths result from progression of therapy resistant disease, yet our understanding of this phenotype is limited. Cancer therapies generate stress signals that act upon mitochondria to initiate apoptosis. Mitochondria isolated from neuroblastoma cells were exposed to tBid or Bim, death effectors activated by therapeutic stress.

What Types of Hospitals Do Adolescents and Young Adults With Complex Chronic Conditions Use?

Background And Objective: Hospitalizations for children with complex chronic conditions (CCC) at pediatric hospitals have risen over time. Little is known about what hospital types, pediatric or adult, adolescents, and young adults (AYA) with CCCs use. We assessed the types of hospitals used by AYAs with CCCs.