Prostaglandin D2/J2 signaling pathway in a rat model of neuroinflammation displaying progressive parkinsonian-like pathology: potential novel therapeutic targets

Background: Prostaglandins are products of the cyclooxygenase pathway, which is implicated in Parkinson’s disease (PD). Limited knowledge is available on mechanisms by which prostaglandins contribute to PD neurodegeneration. To address this gap, we focused on the prostaglandin PGD2/J2 signaling pathway, because PGD2 is the most abundant prostaglandin in the brain, and the one that increases the most under pathological conditions. Moreover, PGJ2 is spontaneously derived from PGD2. Methods: In this study, we determined in rats the impact of unilateral nigral PGJ2-microinfusions on COX-2, lipocalin-type PGD2 synthase (L-PGDS), PGD2/J2 receptor 2 (DP2), and 15 hydroxyprostaglandin dehydrogenase (15-PGDH). Nigral dopaminergic (DA) and microglial distribution and expression levels of these key factors of the prostaglandin D2/J2 pathway were evaluated by immunohistochemistry. PGJ2-induced motor deficits were assessed with the cylinder test. We also determined whether oral treatment with ibuprofen improved the PD-like pathology induced by PGJ2. Results: PGJ2 treatment induced progressive PD-like pathology in the rats. Concomitant with DA neuronal loss in the substantia nigra pars compacta (SNpc), PGJ2-treated rats exhibited microglia and astrocyte activation and motor deficits. In DA neurons, COX-2, L-PGDS, and 15-PGDH levelsincreased significantly in PGJ2-treated rats compared to controls, while DP2 receptor levels were unchanged. In microglia, DP2 receptors were basically non-detectable, while COX-2 and L-PGDS levels increased upon PGJ2-treatment, and 15-PGDH remained unchanged. 15-PGDH was also detected in oligodendrocytes. Notably, ibuprofen prevented most PGJ2-induced PD-like pathology. Conclusions: The PGJ2-induced rat model develops progressive PD pathology, which is a hard-to-mimic aspect of this disorder. Moreover, prevention of most PGJ2-induced PD-like pathology with ibuprofen suggests a positive feedback mechanism between PGJ2 and COX-2 that could lead to chronic neuroinflammation. Notably, this is the first study that analyzes the nigral dopaminergic and microglial distribution and levels of factors of the PGD2/J2 signaling pathway in rodents. Our findings support the notions that upregulation of COX-2 and L-PGDS may be important in the PGJ2 evoked PD-like pathology, and that neuronal DP2 receptor antagonists and L-PGDS inhibitors may be novel pharmacotherapeutics to relieve neuroinflammation-mediated neurodegeneration in PD, circumventing the adverse side effects of cyclooxygenase inhibitors

Enhanced anti-tumor effects of combined MDR1 RNA interference and human sodium/iodide symporter (NIS) radioiodine gene therapy using an adenoviral system in a colon cancer model

Using an adenoviral system as a delivery mediator of therapeutic gene, we investigated the therapeutic effects of the use of combined MDR1 shRNA and human NIS (hNIS) radioiodine gene therapy in a mouse colon xenograft model. In vitro uptake of Tc-99m sestamibi was increased approximately two-fold in cells infected with an adenovirus vector that expressed MDR1 shRNA (Ad-shMDR1) and I-125 uptake was 25-fold higher in cells infected with an adenovirus vector that expressed human NIS (Ad-hNIS) as compared with control cells. As compared with doxorubicin or I-131 treatment alone, the combination of doxorubicin and I-131 resulted in enhanced cytotoxicity for both Ad-shMDR1- and Ad-hNIS-infected cells, but not for control cells. In vivo uptake of Tc-99m sestamibi and Tc-99m pertechnetate was twofold and 10-fold higher for Ad-shMDR1 and Ad-hNIS-infected tumors as compared with tumors infected with a control adenovirus construct that expressed β-galactrosidase (Ad-LacZ), respectively. In mice treated with either doxorubicin or I-131 alone, there was a slight delay in tumor growth as compared to mice treated with Ad-LacZ. However, combination therapy with doxorubicin and I-131 induced further significant inhibition of tumor growth as compared with mice treated with Ad-LacZ. We have shown successful therapeutic efficacy of combined MDR shRNA and hNIS radioiodine gene therapy using an adenoviral vector system in a mouse colon cancer model. Adenovirus-mediated cancer gene therapy using MDR1 shRNA and hNIS would be a useful tool for the treatment of cancer cells expressing multi-drug resistant genes

Imaging with non-FDG PET tracers: outlook for current clinical applications

Apart from the historical and clinical relevance of positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG), various other new tracers are gaining a remarkable place in functional imaging. Their contribution to clinical decision-making is irreplaceable in several disciplines. In this brief review we aimed to describe the main non-FDG PET tracers based on their clinical relevance and application for patient care

124I-HuCC49deltaCH2 for TAG-72 antigen-directed positron emission tomography (PET) imaging of LS174T colon adenocarcinoma tumor implants in xenograft mice: preliminary results

<p>Abstract</p> <p>Background</p> <p>¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG-PET) is widely used in diagnostic cancer imaging. However, the use of ¹⁸F-FDG in PET-based imaging is limited by its specificity and sensitivity. In contrast, anti-TAG (tumor associated glycoprotein)-72 monoclonal antibodies are highly specific for binding to a variety of adenocarcinomas, including colorectal cancer. The aim of this preliminary study was to evaluate a complimentary determining region (CDR)-grafted humanized C_H2-domain-deleted anti-TAG-72 monoclonal antibody (HuCC49deltaC_H2), radiolabeled with iodine-124 (¹²⁴I), as an antigen-directed and cancer-specific targeting agent for PET-based imaging.</p> <p>Methods</p> <p>HuCC49deltaC_H2 was radiolabeled with ¹²⁴I. Subcutaneous tumor implants of LS174T colon adenocarcinoma cells, which express TAG-72 antigen, were grown on athymic Nu/Nu nude mice as the xenograft model. Intravascular (i.v.) and intraperitoneal (i.p.) administration of ¹²⁴I-HuCC49deltaC_H2 was then evaluated in this xenograft mouse model at various time points from approximately 1 hour to 24 hours after injection using microPET imaging. This was compared to i.v. injection of ¹⁸F-FDG in the same xenograft mouse model using microPET imaging at 50 minutes after injection.</p> <p>Results</p> <p>At approximately 1 hour after i.v. injection, ¹²⁴I-HuCC49deltaC_H2 was distributed within the systemic circulation, while at approximately 1 hour after i.p. injection, ¹²⁴I-HuCC49deltaC_H2 was distributed within the peritoneal cavity. At time points from 18 hours to 24 hours after i.v. and i.p. injection, ¹²⁴I-HuCC49deltaC_H2 demonstrated a significantly increased level of specific localization to LS174T tumor implants (p = 0.001) when compared to the 1 hour images. In contrast, approximately 50 minutes after i.v. injection, ¹⁸F-FDG failed to demonstrate any increased level of specific localization to a LS174T tumor implant, but showed the propensity toward more nonspecific uptake within the heart, Harderian glands of the bony orbits of the eyes, brown fat of the posterior neck, kidneys, and bladder.</p> <p>Conclusions</p> <p>On microPET imaging, ¹²⁴I-HuCC49deltaC_H2 demonstrates an increased level of specific localization to tumor implants of LS174T colon adenocarcinoma cells in the xenograft mouse model on delayed imaging, while ¹⁸F-FDG failed to demonstrate this. The antigen-directed and cancer-specific ¹²⁴I-radiolabled anti-TAG-72 monoclonal antibody conjugate, ¹²⁴I-HuCC49deltaC_H2, holds future potential for use in human clinical trials for preoperative, intraoperative, and postoperative PET-based imaging strategies, including fused-modality PET-based imaging platforms.</p

A multisite cross-sectional study of intercultural competencies

Background Physical therapists (PTs) work in diverse communities with individuals whose identities and beliefs may differ significantly from their own. Academic institutions must include intentional curriculum aimed at graduating PTs who can skillfully navigate intercultural encounters. Being prepared to engage with difference and demonstrate skills related to intercultural competencies (ICC) will prepare entry-level PTs to provide individualized, high-quality care. Intercultural competencies are essential skills that can reduce healthcare disparities, and promote equitable and inclusive healthcare delivery. This study examined the impact of PT curricula, student demographics, and participation in intercultural learning experiences (ILEs) on students’ development of ICC.MethodsA cross-sectional study of 8 Doctor of Physical Therapy (DPT) programs in the United States (US) compared ICC in first-year (F) and third-year students (T), and T who participated in an ILE (T+ILE) to those who did not (T-only). Subjects included 1,038 students. Outcome measures included The Inventory for Assessing the Process of Cultural Competence-among healthcare professionals-Student Version© (IAPCC-SV), and a demographic survey.ResultsIndependent t-tests showed that group T (mean = 64.34 ± 5.95, 95% CI: 63.78-64.90) had significantly higher IAPCC-SV total scores than group F (mean = 60.8 ± 5.54, 95% CI = 60.33-61.27, p \u3c 0.05). Group T+ILE (mean = 65.81 ± 5.71, 95% CI = 64.91-66.71) demonstrated significantly higher IAPCC-SV total scores than group T-only (mean = 63.35 ± 5.8, 95% CI = 62.6-64.1, p = 0.039). A one-way ANOVA and post hoc comparisons showed that the 25 to 34-year age group (mean = 63.80 ± 6.04, 95% CI = 63.25-64.35, p \u3c 0.001) and the≥35-year age group (mean = 64.21 ± 5.88, 95% CI = 62.20-66.22, p \u3c .024) had significantly higher IAPCC-SV total scores, than the 18 to 24-year age group (mean = 60.60 ± 5.41, 95% CI = 60.09-61.11). Students who identified in US census minority ethnic or racial categories (US-Mn) (mean = 63.55 ± 5.78, 95% CI = 62.75-64.35) had significantly higher IAPCC-SV total scores than students who identified in US majority ethnic or racial categories (US-Mj) (mean = 61.98 ± 5.97, 95% CI = 61.55-62.413, p = .0001).ConclusionsResults of the study support the hypothesis that DPT programs can promote the development of intercultural skills in students. The ultimate objective of this academic preparation is to improve the student’s ability to deliver equitable, person-centered healthcare upon entry into practice. Specific ICC for entry-level DPT students are not clearly defined by US physical therapy professional organizations, academic institutions, or accrediting body. Students who participated in an ILE exhibited higher levels of ICC when compared to those who did not. Findings from this study can guide curriculum development, utilization of resources, and outcomes assessment. More research is needed to examine characteristics of an ILE that could inform best practice

A multisite cross-sectional study of intercultural competencies in doctor of physical therapy students

Abstract Background Physical therapists (PTs) work in diverse communities with individuals whose identities and beliefs may differ significantly from their own. Academic institutions must include intentional curriculum aimed at graduating PTs who can skillfully navigate intercultural encounters. Being prepared to engage with difference and demonstrate skills related to intercultural competencies (ICC) will prepare entry-level PTs to provide individualized, high-quality care. Intercultural competencies are essential skills that can reduce healthcare disparities, and promote equitable and inclusive healthcare delivery. This study examined the impact of PT curricula, student demographics, and participation in intercultural learning experiences (ILEs) on students’ development of ICC. Methods A cross-sectional study of 8 Doctor of Physical Therapy (DPT) programs in the United States (US) compared ICC in first-year (F) and third-year students (T), and T who participated in an ILE (T + ILE) to those who did not (T-only). Subjects included 1,038 students. Outcome measures included The Inventory for Assessing the Process of Cultural Competence-among healthcare professionals-Student Version© (IAPCC-SV), and a demographic survey. Results Independent t-tests showed that group T (mean = 64.34 ± 5.95, 95% CI: 63.78-64.90) had significantly higher IAPCC-SV total scores than group F (mean = 60.8 ± 5.54, 95% CI = 60.33-61.27, p < 0.05). Group T + ILE (mean = 65.81 ± 5.71, 95% CI = 64.91-66.71) demonstrated significantly higher IAPCC-SV total scores than group T-only (mean = 63.35 ± 5.8, 95% CI = 62.6-64.1, p = 0.039). A one-way ANOVA and post hoc comparisons showed that the 25 to 34-year age group (mean = 63.80 ± 6.04, 95% CI = 63.25-64.35, p < 0.001) and the ≥ 35-year age group (mean = 64.21 ± 5.88, 95% CI = 62.20-66.22, p < .024) had significantly higher IAPCC-SV total scores, than the 18 to 24-year age group (mean = 60.60 ± 5.41, 95% CI = 60.09-61.11). Students who identified in US census minority ethnic or racial categories (US-Mn) (mean = 63.55 ± 5.78, 95% CI = 62.75-64.35) had significantly higher IAPCC-SV total scores than students who identified in US majority ethnic or racial categories (US-Mj) (mean = 61.98 ± 5.97, 95% CI = 61.55-62.413, p = .0001). Conclusions Results of the study support the hypothesis that DPT programs can promote the development of intercultural skills in students. The ultimate objective of this academic preparation is to improve the student’s ability to deliver equitable, person-centered healthcare upon entry into practice. Specific ICC for entry-level DPT students are not clearly defined by US physical therapy professional organizations, academic institutions, or accrediting body. Students who participated in an ILE exhibited higher levels of ICC when compared to those who did not. Findings from this study can guide curriculum development, utilization of resources, and outcomes assessment. More research is needed to examine characteristics of an ILE that could inform best practice