From Bench to Bedside: A Team's Approach to Multidisciplinary Strategies to Combat Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is diagnosed in more than 71,000 patients each year in the United States, with nearly 16,000 associated deaths. One significant hurdle in the treatment of HNSCC is acquired and intrinsic resistance to existing therapeutic agents. Over the past several decades, the University of Wisconsin has formed a multidisciplinary team to move basic scientific discovery along the translational spectrum to impact the lives of HNSCC patients.

Immunological effects of radiopharmaceutical therapy.

Radiation therapy (RT) is a pillar of cancer therapy used by more than half of all cancer patients. Clinically, RT is mostly delivered as external beam radiation therapy (EBRT). However, the scope of EBRT is limited in the metastatic setting, where all sites of disease need to be irradiated.

Clinical cell-surface targets in metastatic and primary solid cancers.

Therapies against cell-surface targets (CSTs) represent an emerging treatment class in solid malignancies. However, high-throughput investigations of CST expression across cancer types have been reliant on data sets of mostly primary tumors, despite therapeutic use most commonly in metastatic disease. We identified a total of 818 clinical trials of CST therapies with 78 CSTs.

Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade.

Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray.

Variation and Variability in Skeletal Ossification of the Gray Short-tailed Opossum, .

By reconstructing and comparing the sequence of ontogenetic (embryonic development and post-natal growth) events across species, developmental biologists have gained unique insights into the key processes underlying the evolution of modern lineages and their extinct relatives. However, despite the importance of intraspecific variation to evolutionary transformation and lineage divergence, variation in the sequence of developmental events is seldom acknowledged. Thus, how much variation or variability should be expected during ontogeny remains poorly understood and it is an open question to what extent it impacts interspecific comparisons of developmental patterns.

A combined radio-immunotherapy regimen eradicates late-stage tumors in mice.

Background: The majority of experimental approaches for cancer immunotherapy are tested against relatively small tumors in tumor-bearing mice, because in most cases advanced cancers are resistant to the treatments. In this study, we asked if even late-stage mouse tumors can be eradicated by a rationally designed combined radio-immunotherapy (CRI) regimen.

Methods: CRI consisted of local radiotherapy, intratumoral IL-12, slow-release systemic IL-2 and anti- CTLA-4 antibody.

Large-scale discovery of chromatin dysregulation induced by oncofusions and other protein-coding variants.

Population-scale databases have expanded to millions of protein-coding variants, yet insight into their mechanistic consequences has lagged. Here we present PROD-ATAC, a high-throughput method for discovering the effects of protein-coding variants on chromatin regulation. A pooled variant library is expressed in a disease-agnostic cell line, and single-cell assay for transposase-accessible chromatin resolves each variant's effect on the chromatin landscape.

The Effects of Radiation Dose Heterogeneity on the Tumor Microenvironment and Anti-Tumor Immunity.

Radiotherapy elicits dose- and lineage-dependent effects on immune cell survival, migration, activation, and proliferation in targeted tumor microenvironments. Radiation also stimulates phenotypic changes that modulate the immune susceptibility of tumor cells. This has raised interest in using radiotherapy to promote greater response to immunotherapies.

Development of a Novel Evidence-Based Practice-Specific Competency for Doctor of Physical Therapy Students in Clinical Education: A Modified Delphi Approach.

Introduction: Evidence-based practice (EBP) results in high-quality care and decreases unwarranted variation in practice.

Review Of The Literature: Few performance criteria related to EBP are included in physical therapy clinical education (CE) performance measures, despite EBP requirements in Doctor of Physical Therapy education. The purpose of this study was to develop EBP-specific competencies that may be used for Doctor of Physical Therapy students for use throughout CE.

Body Mass Index and Thoracic Expansion in Post-COVID Dyspnea: A Secondary Analysis.

Dyspnea secondary to lung impairment can persist following the acute phase of COVID-19. Thoracic expansion measurements have been used as a diagnostic tool to evaluate chest wall mobility, respiratory function, and the effects of respiratory muscle strength training. Changes in chest wall mobility may occur because of altered chest biomechanics in individuals with respiratory diseases and an elevated body mass index (BMI).

Administration of intratumoral GD2-directed interleukin-2 immunocytokine and local radiation therapy to activate immune rejection of spontaneous canine melanoma.

Canine malignant melanoma provides a clinically relevant, large animal parallel patient population to study the GD2-reactive hu14.18-IL-2 immunocytokine as it is similar to human melanoma and expresses GD2. The objectives of this study were to evaluate safety, radiation fractionation, and identify informative biomarkers of an in-situ tumor vaccine involving local radiation therapy plus intratumoral-immunocytokine in melanoma tumor-bearing dogs.

Myeloid-derived suppressor cells attenuate the antitumor efficacy of radiopharmaceutical therapy using Y-NM600 in combination with androgen deprivation therapy in murine prostate tumors.

Rationale: Androgen deprivation therapy (ADT) is pivotal in treating recurrent prostate cancer and is often combined with external beam radiation therapy (EBRT) for localized disease. However, for metastatic castration-resistant prostate cancer, EBRT is typically only used in the palliative setting, because of the inability to radiate all sites of disease. Systemic radiation treatments that preferentially irradiate cancer cells, known as radiopharmaceutical therapy or targeted radionuclide therapy (TRT), have demonstrable benefits for treating metastatic prostate cancer.

Initiatives for promoting educator wellbeing: a Delphi study.

Background: Growing demands on educators have resulted in increased levels of burnout and stress and decreasing wellbeing. This study aimed to establish expert consensus on the key characteristics required in prospective educator wellbeing initiatives.

Methods: The Delphi approach is a process of forecasting that is based on the aggregated opinion of panel members (or experts) within a field of study.

The experience of persons with disabilities as beneficiaries of Ghana's District Assemblies Common Fund.

Ghana's Disability Fund aims to build the capacity of persons with disabilities, particularly those outside of formal employment, to engage in livelihood generation activities as a way to reduce poverty. The objective of this paper is to investigate the kind of knowledge that exists on the District Assemblies Common Fund program, understand the experience of beneficiaries when they access the program, and examine the benefits on beneficiaries' livelihoods. The research consisted of five focus group discussions with 35 beneficiaries, key informant interviews with six member organizations of Ghana Federation of Disability Organizations, and interviews with eleven Disability Fund Management Committees members.

Perspectives of practicing school psychologists during COVID-19: A multi-country, mixed methods investigation.

COVID-19 presented a range of challenges to the delivery of school psychology services in countries around the world. The current study aimed to investigate the practices of school psychologists from the United States of America, Australia, Germany, Canada, and the United Kingdom, including changes to practice and exploration of the factors that supported the delivery of school psychology services during the pandemic. Quantitative and qualitative data were collected from 1,030 school psychologists and analyzed using a mixed methods, multiple case study design.

Functionality of bone marrow mesenchymal stromal cells derived from head and neck cancer patients - A FDA-IND enabling study regarding MSC-based treatments for radiation-induced xerostomia.

Purpose: Salivary dysfunction is a significant side effect of radiation therapy for head and neck cancer (HNC). Preliminary data suggests that mesenchymal stromal cells (MSCs) can improve salivary function. Whether MSCs from HNC patients who have completed chemoradiation are functionally similar to those from healthy patients is unknown.

Comparative Study of the Effect of Radiation Delivered by Lutetium-177 or Actinium-225 on Anti-GD2 Chimeric Antigen Receptor T Cell Viability and Functions.

Chimeric antigen receptor (CAR) T cells have been relatively ineffective against solid tumors. Low-dose radiation which can be delivered to multiple sites of metastases by targeted radionuclide therapy (TRT) can elicit immunostimulatory effects. However, TRT has never been combined with CAR T cells against solid tumors in a clinical setting.

Validation of the Comprehensive Feeding Practices Questionnaire among parents of 5- to 7-year-old children in Sweden.

Introduction: Parents' behaviours towards food and mealtimes, also known as parental feeding practices, are important in the development of children's eating habits. The Comprehensive Feeding Practices Questionnaire (CFPQ) was designed to measure parental feeding practices. The aim of this study was to evaluate the validity of the CFPQ in Sweden and to assess how it performs across different groups of people.

NK cells propagate T cell immunity following in situ tumor vaccination.

We report an in situ vaccination, adaptable to nearly any type of cancer, that combines radiotherapy targeting one tumor and intratumoral injection of this site with tumor-specific antibody and interleukin-2 (IL-2; 3xTx). In a phase I clinical trial, administration of 3xTx (with an immunocytokine fusion of tumor-specific antibody and IL-2, hu14.18-IL2) to subjects with metastatic melanoma increases peripheral CD8 T cell effector polyfunctionality.

Antibody landscape of C57BL/6 mice cured of B78 melanoma via a combined radiation and immunocytokine immunotherapy regimen.

Sera of immune mice that were previously cured of their melanoma through a combined radiation and immunocytokine immunotherapy regimen consisting of 12 Gy of external beam radiation and the intratumoral administration of an immunocytokine (anti-GD2 mAb coupled to IL-2) with long-term immunological memory showed strong antibody-binding against melanoma tumor cell lines via flow cytometric analysis. Using a high-density whole-proteome peptide array (of 6.090.

Combining Dual Checkpoint Immunotherapy with Ablative Radiation to All Sites of Oligometastatic Non-Small Cell Lung Cancer: Toxicity and Efficacy Results of a Phase 1b Trial.

Purpose: Ablative local treatment of all radiographically detected metastatic sites in patients with oligometastatic non-small cell lung cancer (NSCLC) increases progression-free survival (PFS) and overall survival (OS). Prior studies demonstrated the safety of combining stereotactic body radiation therapy (SBRT) with single-agent immunotherapy. We investigated the safety of combining SBRT to all metastatic tumor sites with dual checkpoint, anticytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), and anti-programmed cell death ligand 1 (anti-PD-L1) immunotherapy for patients with oligometastatic NSCLC.

Discovering chromatin dysregulation induced by protein-coding perturbations at scale.

Although population-scale databases have expanded to millions of protein-coding variants, insight into variant mechanisms has not kept pace. We present PROD-ATAC, a high-throughput method for discovering the effects of protein-coding variants on chromatin. A pooled library of variants is expressed in a disease-agnostic cell line, and single-cell ATAC resolves each variant's effect on chromatin.

Cyclophosphamide augments the efficacy of vaccination in a mouse melanoma model.

Introduction: We have previously shown that an intratumoral (IT) injection of the hu14.18-IL2 immunocytokine (IC), an anti-GD2 antibody linked to interleukin 2, can serve as an vaccine and synergize with local radiotherapy (RT) to induce T cell-mediated antitumor effects. We hypothesized that cyclophosphamide (CY), a chemotherapeutic agent capable of depleting T regulatory cells (Tregs), would augment vaccination.