Going above and beyond for implementation: the development and validity testing of the Implementation Citizenship Behavior Scale (ICBS).

BackgroundIn line with recent research on the role of the inner context of organizations in implementation effectiveness, this study extends research on organizational citizenship behavior (OCB) to the domain of evidence-based practice (EBP) implementation. OCB encompasses those behaviors that go beyond what is required for a given job that contribute to greater organizational effectiveness. The goal of this study was to develop and test a measure of implementation citizenship behavior (ICB) or those behaviors that employees perform that go above and beyond what is required in order to support EBP implementation.MethodsThe primary participants were 68 supervisors from ten mental health agencies throughout California. Items measuring ICB were developed based on past research on OCB and in consultation with experts on EBP implementation in mental health settings. Supervisors rated 357 of their subordinates on ICB and implementation success. In addition, 292 of the subordinates provided data on self-rated performance, attitudes towards EBPs, work experience, and full-time status. The supervisor sample was randomly split, with half used for exploratory factor analyses and the other half for confirmatory factor analyses. The entire sample of supervisors and subordinates was utilized for analyses assessing the reliability and construct validity of the measure.ResultsExploratory factor analyses supported the proposed two-factor structure of the Implementation Citizenship Behavior Scale (ICBS): (1) Helping Others and (2) Keeping Informed. Confirmatory factor analyses with the other half of the sample supported the factor structure. Additional analyses supported the reliability and construct validity for the ICBS.ConclusionsThe ICBS is a pragmatic brief measure (six items) that captures critical behaviors employees perform to go above and beyond the call of duty to support EBP implementation, including helping their fellow employees on implementation-related activities and keeping informed about issues related to EBP and implementation efforts. The ICBS can be used by researchers to better understand the outcomes of improved organizational support for implementation (i.e., implementation climate) and the proximal predictors of implementation effectiveness. The ICBS can also provide insight for organizations, practitioners, and managers by focusing on key employee behaviors that should increase the probability of implementation success

Defining the potential of mesothelin-directed CAR T cells for the treatment of ovarian cancer

Chimeric antigen receptor (CAR) T cells have revolutionized the field of immunotherapy, by redirecting T cell specificity and effector functions. Co-stimulation has proven to be crucial for therapeutic effectiveness of CAR T cells and remarkable clinical response rates have been achieved with second generation CD19-directed CAR T cells containing either a CD28 or 4-1BB co-stimulatory domain for the treatment of B cell malignancies. Mesothelin (MSLN) has emerged as an attractive target for CAR T cell therapy in solid tumors, including ovarian cancer. Due to the complex tumor microenvironment niche of ovarian cancer, it is crucial to investigate the mechanisms impacting CAR T cell functionality to improve therapeutic effectiveness. The aim of this thesis was to evaluate the therapeutic potential of three different second generation MSLN-directed CAR T cells for the treatment of ovarian cancer. Selection of the most advantageous co-stimulatory segment for functional MSLN-CAR T cell persistence in the relevant disease setting is of great importance for successful clinical application. In paper I and II, MSLN-directed CAR T cells containing either a CD28 (M28z) or 4-1BB (MBBz) co-stimulatory domain followed by the CD3ζ chain were compared in different models of ovarian cancer. M28z and MBBz CAR T cells elicited powerful anti-tumor responses in in vitro and preclinical in vivo models of ovarian cancer, although with different kinetics. Introduction of a CD28 co-stimulatory domain facilitated rapid activation of effector functions, while 4-1BB co-stimulation favored functional persistence of MSLN-CAR T cells. In paper III, a new MSLN-CAR construct was included and evaluated with respect to the classical second generation CAR constructs M28z and MBBz. The novel construct (M1xx) had calibrated activation potential through mutations in the CD3ζ chain combined with CD28 co-stimulation. M1xx CAR T cells displayed superior tumor control as compared to M28z and MBBz CAR T cells in two different in vivo models. Treatment with M1xx CAR T cells resulted in tumor clearance and long-term remission in the orthotopic mice model. However, in a disseminated disease model M1xx CAR T cells treatment delayed tumor progression substantially but mice eventually succumbed to tumor burden. In all papers, I attempted to elucidate the mechanisms affecting MSLN-CAR T cell functionality and several immune escape pathways were highlighted. Tumor cells were capable of evading immune control by downregulation of MSLN surface expression and upregulation of the PD-L1 and HLA-DR co-inhibitory ligands on the remaining MSLN+ tumor cells. Functional persistence of CAR T cells was limited due to exhaustion of MSLN-CAR T cells in vivo. Moreover, MSLN-CAR T cells displayed trogocytotic capacity thereby facilitating fratricide killing as well as tumor antigen escape

The Italian Agreement between the Government and the Regional Authorities: National Guidelines for AAI and Institutional Context

Animal-assisted interventions (AAI) have developed considerably in the last half century, prompting various private and public realities dealing with AAI worldwide to work on and establish standards and best practice. However, AAI are still far from being regulated harmoniously. In this context, Italy offers a unique example at world level: here the spread of AAI has set in motion an ethical and legal reflection that led to the creation of the Italian National Reference Centre for AAI (NRC AAI) by ministerial decree in 2009 and the approval of National Guidelines for AAI in 2015. The Italian legislation on AAI is based on the One Health approach, which has been part of Italian health culture and institutions since the Renaissance. The synergy between human and veterinary medicine is the core of this theme: in other words, One Health represents a multidisciplinary approach aimed at best protecting the health and well-being of all those who share our planet. In Italy, human and veterinary medicine have both been placed under the umbrella of the Ministry of Health since its establishment in 1958. The same idea of collaboration is at the heart of the Italian legislative approach to the AAI field, given the inherent multidisciplinarity of these interventions. This applies to all indications provided by the National Guidelines, for example the distinction between the various types of interventions, the animal species involved, the roles within the multidisciplinary team, and the training programs for each professional figure. In addition, the National Guidelines are intended to be amendable according to the needs arising over time from daily practice: in fact, the constant contact and dialogue between institutions and AAI professionals is another pillar of the Italian approach

Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers.

Melanoma is the least common but deadliest type of skin cancer. Melanomagenesis is driven by a series of mutations and epigenetic alterations in oncogenes and tumor suppressor genes that allow melanomas to grow, evolve, and metastasize. Epigenetic alterations can also lead to immune evasion and development of resistance to therapies. Although the standard of care for melanoma patients includes surgery, targeted therapies, and immune checkpoint blockade, other therapeutic approaches like radiation therapy, chemotherapy, and immune cell-based therapies are used for patients with advanced disease or unresponsive to the conventional first-line therapies. Targeted therapies such as the use of BRAF and MEK inhibitors and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 only improve the survival of a small subset of patients. Thus, there is an urgent need to identify alternative standalone or combinatorial therapies. Epigenetic modifiers have gained attention as therapeutic targets as they modulate multiple cellular and immune-related processes. Due to melanoma\u27s susceptibility to extrinsic factors and reversible nature, epigenetic drugs are investigated as a therapeutic avenue and as adjuvants for targeted therapies and immune checkpoint inhibitors, as they can sensitize and/or reverse resistance to these therapies, thus enhancing their therapeutic efficacy. This review gives an overview of the role of epigenetic changes in melanoma progression and resistance. In addition, we evaluate the latest advances in preclinical and clinical research studying combinatorial therapies and discuss the use of epigenetic drugs such as HDAC and DNMT inhibitors as potential adjuvants for melanoma patients

Bringing macrophages to the frontline against cancer: current Immunotherapies targeting macrophages

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Macrophages are found in all tissues and display outstanding functional diversity. From embryo to birth and throughout adult life, they play critical roles in development, homeostasis, tissue repair, immunity, and, importantly, in the control of cancer growth. In this review, we will briefly detail the multi-functional, protumoral, and antitumoral roles of macrophages in the tumor microenvironment. Our objective is to focus on the ever-growing therapeutic opportunities, with promising preclinical and clinical results developed in recent years, to modulate the contribution of macrophages in oncologic diseases. While the majority of cancer immunotherapies target T cells, we believe that macrophages have a promising therapeutic potential as tumoricidal effectors and in mobilizing their surroundings towards antitumor immunity to efficiently limit cancer progression.This work was supported by an iMM-Laço research grant and the Fundacão para a Ciência e Tecnologia through a research grant (PTDC/MED-IMU/30948/2017) and a personal fellowship (CEECIND/00697/2018) received by K.S. and a PhD fellowship (SFRH/BD/144792/2019) to C.J. This work was also kindly backed by the COST Action BM1404 Mye-EUNITER (http://www.mye-euniter.eu accessed on 26 November 2018). COST is supported by the EU Framework Program Horizon 2020.info:eu-repo/semantics/publishedVersio

Molecular and Metabolic Regulation of Immunosuppression in Metastatic Pancreatic Ductal Adenocarcinoma

Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared to the localized tumors, current standard-of-care therapies have failed to improve the survival of patients with metastatic PDAC, that necessecitates exploration of novel therapeutic approaches. While immunotherapies such as immune checkpoint blockade (ICB) and therapeutic vaccines have emerged as promising treatment modalities in certain cancers, limited responses have been achieved in PDAC. Therefore, specific mechanisms regulating the poor response to immunotherapy must be explored. The immunosuppressive microenvironment driven by oncogenic mutations, tumor secretome, non-coding RNAs, and tumor microbiome persists throughout PDAC progression, allowing neoplastic cells to grow locally and metastasize distantly. The metastatic cells escaping the host immune surveillance are unique in molecular, immunological, and metabolic characteristics. Following chemokine and exosomal guidance, these cells metastasize to the organ-specific pre-metastatic niches (PMNs) constituted by local resident cells, stromal fibroblasts, and suppressive immune cells, such as the metastasis-associated macrophages, neutrophils, and myeloid-derived suppressor cells. The metastatic immune microenvironment differs from primary tumors in stromal and immune cell composition, functionality, and metabolism. Thus far, multiple molecular and metabolic pathways, distinct from primary tumors, have been identified that dampen immune effector functions, confounding the immunotherapy response in metastatic PDAC. This review describes major immunoregulatory pathways that contribute to the metastatic progression and limit immunotherapy outcomes in PDAC. Overall, we highlight the therapeutic vulnerabilities attributable to immunosuppressive factors and discuss whether targeting these molecular and immunological hot spots could improve the outcomes of PDAC immunotherapies

Detection of legionella in dental unit waterlines using different techniques

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science in Medicine. Johannesburg, 2002Water stagnation in dental waterlines may cause contaminating organisms including Legionella and amoeba to multiply to potentially hazardous levels. The purpose of this study was to determine the presence of Legionella in the dental unit waterlines at the Dental Teaching Hospital, University of the Witwatersrand using different techniquesIT201

Cancer cell plasticity defines response to immunotherapy in cutaneous squamous cell carcinoma

Immune checkpoint blockade (ICB) approaches have changed the therapeutic landscape for many tumor types. However, half of cutaneous squamous cell carcinoma (cSCC) patients remain unresponsive or develop resistance. Here, we show that, during cSCC progression in male mice, cancer cells acquire epithelial/mesenchymal plasticity and change their immune checkpoint (IC) ligand profile according to their features, dictating the IC pathways involved in immune evasion. Epithelial cancer cells, through the PD-1/PD-L1 pathway, and mesenchymal cancer cells, through the CTLA-4/CD80 and TIGIT/CD155 pathways, differentially block antitumor immune responses and determine the response to ICB therapies. Accordingly, the anti-PD-L1/TIGIT combination is the most effective strategy for blocking the growth of cSCCs that contain both epithelial and mesenchymal cancer cells. The expression of E-cadherin/Vimentin/CD80/CD155 proteins in cSCC, HNSCC and melanoma patient samples predicts response to anti-PD-1/PD-L1 therapy. Collectively, our findings indicate that the selection of ICB therapies should take into account the epithelial/mesenchymal features of cancer cells. Immune surveillance is critical to prevent the development and progression of cutaneous squamous cell carcinoma (cSCC). Here, the authors show that epithelial-mesenchymal plasticity in cancer cells is associated with changes in their immune checkpoint ligand profile during mouse cSCC progression, which dictates differential responses to immune checkpoint blockade