Parkinson’s disease, characterized by motor dysfunction due to the loss of nigrostriatal dopaminergic neurons, is one of the most prevalent age-related neurodegenerative disorders. Given there is no current cure, the stem cell approach has emerged as a viable therapeutic option to replace the dopaminergic neurons that are progressively lost to the disease. The success of the approach is likely to depend upon accessible, renewable, immune compatible, and non-tumorigenic sources of neural progenitors from which stable dopaminergic neurons can be generated efficaciously. Here, we demonstrate that neural progenitors derived from limbus, a regenerative and accessible ocular tissue, represent a safe source of dopaminergic neurons. When the limbus-derived neural progenitors were subjected to a well-established protocol of directed differentiation under the influence of Shh and FGF8, they acquired the biochemical and functional phenotype of dopaminergic neurons that included the ability to synthesize dopamine. Their intrastriatal transplantation in the rat model of hemi-Parkinsonism was associated with a reduction in the amphetamine-induced rotation. No tumor formation was observed 6 weeks post-transplantation. Together, these observations posit limbus-derived neural progenitors as an accessible and safe source of dopaminergic neurons for a potential autologous ex-vivo stem cell approach to Parkinson’s disease.
Background: Real-world data regarding the use of poly (ADP-ribose) polymerase (PARP) inhibitors in recurrent ovarian cancer patients with non-BRCA homologous recombination (HR) mutations or somatic BRCA mutations are lacking. Objective: The purpose of our study is to evaluate the response rate, duration of treatment, time to progression (TTP), and toxicities of olaparib, niraparib, and rucaparib in somatic BRCAm and non-BRCA HR-mutated patients. Methods: This was a retrospective study using the electronic medical record to identify patients across our health system who were initiated on a PARP inhibitor for ovarian cancer between December 2014 and December 2019. Patients were screened for the presence of a somatic BRCA1/2 mutation or a mutation in non-BRCA HR genes. Data were collected via chart review. Results: For the efficacy analysis, 8 patients had somatic BRCA mutations and 12 patients had HR mutations. The overall response rate (ORR) was 50% for BRCA-mutated (BRCAm) patients and 9.1% for non-BRCA HR-mutated (non-BRCA HRm) patients. 72.7% of patients with non-BRCA HR mutations had stable disease. The duration of therapy ranged from 2 to 66 months. The median TTP was 9.5 months. Overall, 66.7% of patients in the entire cohort started on a reduced dose of PARP inhibitor. Dose reductions due to AEs were observed in 52.4% of patients, while AEs requiring treatment interruption occurred in 61.9%. Conclusion and Relevance: We found that PARP inhibitors provided stable disease in a high proportion of recurrent ovarian cancer patients who had pathogenic HR mutations, with toxicities comparable to major trials. Patients with non-BRCA HR and somatic BRCA mutations could benefit from PARP inhibitors.
BackgroundHSCT patients are at an increased risk of developing infections after transplant due to the loss of immunogenicity from prior vaccinations. Current national and international guidelines recommend routine revaccinations at a fixed dosing schedule for HSCT patients post-transplant. Although immunization adherence is vital to prevent infections, compliance with post-transplant vaccinations is unknown. The primary endpoint of this study was the completion rate of the post-transplant vaccination series. Secondary endpoints included identifying reasons for noncompliance, rates of breakthrough vaccine-preventable infections, and assessing post-vaccination antibody responses based on titers.MethodsA single-center, retrospective study of adult HSCT patients at Yale New Haven Hospital between January 2010 and September 2015 was performed. Patients were excluded if: <18 years of age, deceased prior to one year post-transplant, transferred care to an outside facility, or were lost to follow-up.ResultsA total of 512 HSCT patients were evaluated. 390 (76%) patients were initiated on the vaccination series. Of the 390 patients, 275 (71%) patients were started at one year follow-up per institutional guidelines. The most common reasons for non-initiation or delayed initiation of the vaccine series included disease relapse (14%), active graft vs. host disease (9%), and the need for immunosuppressive therapy (5%). Of the patients initiated on the vaccination series, only 187 (48%) patients completed the entire vaccination series; with the majority of whom were autologous HSCT patients (72%). The most common reasons for an incomplete vaccination series included maintenance chemotherapy (19%), disease relapse (16%), and lost to follow-up (10%). Of the patients who completed the vaccination series, 19% had the appropriate post-vaccination titers obtained. Of the patients who received at least one or more doses of pneumococcal vaccine post-transplant, 8 patients (2%) developed a breakthrough infection with S. pneumoniae.ConclusionThis study adds important data to the limited body of literature on HSCT vaccine compliance rates. Future studies on the best interventions to improve compliance rates are warranted.Disclosures All authors: No reported disclosures.
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