Effects of a True Prophylactic Treatment on Hippocampal and Amygdala Synaptic Plasticity and Gene Expression in a Rodent Chronic Stress Model of Social Defeat.

Post-traumatic stress disorder (PTSD) is a complex stress-related disorder induced by exposure to traumatic stress that is characterized by symptoms of re-experiencing, avoidance, and hyper-arousal. While it is widely accepted that brain regions involved in emotional regulation and memory-e.g., the amygdala and hippocampus-are dysregulated in PTSD, the pathophysiology of the disorder is not well defined and therefore, pharmacological interventions are extremely limited. Because stress hormones norepinephrine and cortisol (corticosterone in rats) are heavily implicated in the disorder, we explored whether preemptively and systemically antagonizing ß-adrenergic and glucocorticoid receptors with propranolol and mifepristone are sufficient to mitigate pathological changes in synaptic plasticity, gene expression, and anxiety induced by a modified social defeat (SD) stress protocol. Young adult, male Sprague Dawley rats were initially pre-screened for anxiety. The rats were then exposed to SD and chronic light stress to induce anxiety-like symptoms. Drug-treated rats were administered propranolol and mifepristone injections prior to and continuing throughout SD stress. Using competitive ELISAs on plasma, field electrophysiology at CA1 of the ventral hippocampus (VH) and the basolateral amygdala (BLA), quantitative RT-PCR, and behavior assays, we demonstrate that our SD stress increased anxiety-like behavior, elevated long-term potentiation (LTP) in the VH and BLA, and altered the expression of mineralocorticoid, glucocorticoid, and glutamate receptors. These measures largely reverted to control levels with the administration of propranolol and mifepristone. Our findings indicate that SD stress increases LTP in the VH and BLA and that prophylactic treatment with propranolol and mifepristone may have the potential in mitigating these and other stress-induced effects.

Restructuring lung cancer care to accelerate diagnosis and treatment in patients vulnerable to healthcare disparities using an innovative care model.

The diagnosis and treatment of lung cancer is challenged by complex diagnostic pathways and fragmented care that can lead to disparities for vulnerable patients. Our model involved a multi-institutional, multidisciplinary conference to address the complexity of lung cancer care in vulnerable patient populations. The conference was conducted using a process adapted from the problem-solving method entitled FastTrack, pioneered by General Electric. Conference attendees established critical social determinants of health specific to lung cancer and designed a practical care model to accelerate diagnosis and treatment in this population. The resulting care delivery model, the Lung Cancer Strategist Program (LCSP), was led by a lung cancer trained advanced practice provider (APP) to expedite diagnosis, surgical and oncologic consultation, and treatment of a suspicious lung nodule. We compared the timeliness of care, care efficiency, and oncologic outcomes in 100 LCSP patients and 100 routine referral patients at the same thoracic surgery clinic. Patient triage through our integrated care model transitioned initial referral evaluation to a lung cancer trained APP to coordinate multidisciplinary patient-centered care that was highly individualized and significantly reduced the time to diagnosis and treatment among vulnerable patients at high-risk for treatment delay due to healthcare disparities.•To develop the Lung Cancer Strategist Program care model, we used a three-step (Design, Meeting, and Culmination), team-based, problem-solving process entitled FastTrack.•An advantage of FastTrack is its ability to overcome barriers embedded within hierarchal and institutional social systems, empowering those closest to the relevant issue to propose and enact meaningful change.•Under this framework, we engaged a diverse field of experts to assess systemic barriers in lung cancer care and design an innovative care pathway to improve the timeliness and efficiency of lung cancer care in patients at risk for healthcare disparities.

Porous Paclitaxel Mesh Reduces Local Recurrence in Patient-Derived Xenograft Resection Model.

BACKGROUND: Drug-loaded meshes offer a promising delivery strategy for the prevention of local recurrence. Patient-derived xenograft (PDX) models are representative of individual patient tumors and predictive of clinical outcomes. METHODS: A PDX model was established in NSG (NOD-scid IL2Rgammanull) mice using tumor tissue from a patient with aggressive lung adenocarcinoma. Polyglycolic acid (PGA) meshes loaded with paclitaxel (PGA+PTX) were electrospun. Tumor-bearing mice were randomized into 4 groups after macroscopic complete resection: (1) no treatment (n = 10); (2) intraperitoneal PTX at 20 mg/kg (n = 10); (3) PGA mesh without drug (n = 14); and (4) PGA+PTX mesh at 12 mg/kg (n = 14). A 1-cm2 mesh was placed onto the tumor resection beds. Groups were observed for local recurrence for 120 postoperative days. RESULTS: PDX mice treated with PGA+PTX meshes after resection exhibited a >5-fold increase in recurrence-free survival (P < .0001) compared with systemically treated and untreated control groups. Median recurrence-free survival was 24 days for untreated and intraperitoneal PTX groups, 28 days for unloaded PGA mesh group, and undefined for the PGA+PTX mesh group. CONCLUSIONS: Development of a PDX surgical resection model of non-small cell lung cancer permits robust assessment of postresection local recurrence for preclinical studies of patient-derived tumors. Intraoperative placement of drug-loaded meshes demonstrates superior local disease treatment, suggesting that this approach may improve recurrence-free survival in early-stage non-small cell lung cancer patients undergoing limited resection.

Ultra-high drug loading improves nanoparticle efficacy against peritoneal mesothelioma.

Peritoneal mesothelioma is an aggressive disease with a median survival of under three years, due to a lack of effective treatment options. Mesothelioma is traditionally considered a "chemoresistant" tumor; however, low intratumoral drug levels coupled with the inability to administer high systemic doses suggests that therapeutic resistance may be due to poor drug delivery rather than inherent biology. While patient survival may improve with repetitive local intraperitoneal infusions of chemotherapy throughout the perioperative period, these regimens carry associated toxicities and significant peri-operative morbidity. To circumvent these issues, we describe ultra-high drug loaded nanoparticles (NPs) composed of a unique poly(1,2-glycerol carbonate)-graft-succinate-paclitaxel (PGC-PTX + PTX) conjugate. PGC-PTX + PTX NPs are cytotoxic, localize to tumor in vivo, and improve survival in a murine model of human peritoneal mesothelioma after a single intraperitoneal (IP) injection compared to multiple weekly doses of the clinically utilized formulation PTX-C/E. Given their unique pharmacokinetics, a second intraperitoneal dose of PGC-PTX + PTX NPs one month later more than doubles the overall survival compared to the clinical control (122 versus 58 days). These results validate the clinical potential of prolonged local paclitaxel to treat intracavitary malignancies such as mesothelioma using a tailored polymer-mediated nanoparticle formulation.