Rescue of mitochondrial function in parkin-mutant Fibroblasts using drug loaded PMPC-PDPA polymersomes and tubular polymersomes

Mutations in parkin cause autosomal recessive Parkinsonism and mitochondrial defects. A recent drug screen identified a class of steroid-like hydrophobic compounds able to rescue mitochondrial function in parkin-mutant fibroblasts. Whilst these possess therapeutic potential, the size and high hydrophobicity of some may limit their ability to penetrate the blood-brain barrier from systemic circulation, something that could be improved by novel drug formulations. In the present study, the steroid-like compounds Ursolic Acid (UA) and Ursocholanic Acid (UCA) were successfully encapsulated within nanoscopic polymersomes formed by poly(2-(methacryloyloxy)ethyl phosphorylcholine)–poly(2-di-isopropylamino)ethyl methacrylate) (PMPC-PDPA) and separated into spherical and tubular morphologies to assess the effects of nanoparticle mediated delivery on drug efficacy. Following incubation with either morphology, parkin-mutant fibroblasts demonstrated time and concentration dependent increases in intracellular ATP levels, resembling those resulting from treatment with nascent UA and UCA formulated in 0.1% DMSO, as used in the original drug screen. Empty PMPC-PDPA polymersomes did not alter physiological measures related to mitochondrial function or induce cytotoxicity. In combination with other techniques such as ligand functionalisation, PMPC-PDPA nanoparticles of well-defined morphology may prove a promising platform for tailoring the pharmacokinetic profile and organ specific bio-distribution of highly hydrophobic compounds

I Wish Someone had Asked Me Earlier-Perspectives on Advance Care Planning in Surgery.

Recent controversy has called into question the meaning and clinical utility of Advance Care Planning (ACP), however data have consistently shown potential benefit to patients and their surrogate decision makers. We present the concept of surgery-specific advance care planning and a structured, scalable approach to integrating it into clinical practice

Experiences with targeting inpatient advance care planning for emergency general surgery patients: A resident-led quality improvement project.

BACKGROUND: For patients who may permanently or temporarily lose their ability to communicate preferences, advance care planning is a critical mechanism to guide medical decision-making but is currently underused among surgical patients. METHODS: A resident-led quality improvement project, including education and performance measurement, was conducted on an emergency general surgery service to increase the completion of inpatient advance care planning notes using a specialized template in the electronic health record. Advance care planning documentation was defined as either preadmission advance care planning documentation (eg, advance directive) or inpatient advance care planning (use of the electronic health record template). Data from patients admitted to the emergency general surgery service for 12+ hours were analyzed, and baseline data (July 2020 to June 2021) were compared with data from the intervention period (July 2021 to June 2022). The chart review evaluated the content of the inpatient advance care planning documentation from the intervention period. RESULTS: The frequency of inpatient advance care planning documentation increased (9.3%, n = 56 to 16.6%, n = 92, P < .001) with a greater contribution of inpatient advance care planning notes by the surgery team (16.7% to 55.4%) in the intervention period. Content analysis indicated that 79.0% of inpatient advance care planning notes listed preferences for life-sustaining therapy, 78.3% listed surrogacy, 57.3% listed overall health goals, and 50.3% listed treatment goals specific to the surgical encounter. CONCLUSION: Although a resident-led quality improvement project contributed to greater adoption of standardized inpatient advance care planning documentation on an emergency general surgery service, progress was slow, and integration into standard work was not achieved. Future efforts are needed to better understand the integration of essential advance care planning elements into workflows and to establish inclusive educational programming to prepare all team members for conducting and documenting advance care planning conversations

Induction of renal tumorigenesis with elevated levels of somatic loss of heterozygosity in Tsc1+/- mice on a Blm-deficient background

A Bloom’s deficient mouse model (Blmm3/m3) has been shown to induce colorectal tumorigenesis when crossed with Apc+/Min mice. Here, we investigated whether the Blmm3/m3 genotype could induce tumorigenesis in extracolonic tissues in tuberous sclerosis 1–deficient (Tsc1+/) mice that are predisposed to renal cystadenomas and carcinomas. Genotyping of offspring from Tsc1+/ Blm+/m3 intercrosses showed that a f24% excess of Tsc1+/ over Tsc1+/+ mice died before weaning (P = 0.016), although Blm deficiency had no cumulative effect on Tsc1+/ survival. Tsc1+/ Blmm3/m3 mice had significantly more macroscopic and microscopic renal lesions at 3 to 6 months compared with Tsc1+/ Blm+/m3 mice (P =0.0003 and 0.0203, respectively), and their tumors showed significantly increased levels of somatic loss of heterozygosity (LOH) of the wild-type Tsc1 (Tsc1wt) allele compared with those from Tsc1+/ Blm+/+ mice (P < 0.0001). Tsc1+/ Blm+/m3 mice did not show significantly more renal lesions compared with Tsc1+/ Blm+/+ animals; however, their lesions still showed significantly increased levels of somatic LOH of the Tsc1wt allele (P = 0.03). Ninety-five percent (19 of 20) of lesions from Tsc1+/ Blm+/m3 mice retained the wild-type Blm (Blmwt) allele, indicating that the increased somatic LOH at Tsc1 was mediated by Blm haploinsufficiency. Renal lesions from a Blm-deficient background stained positively with anti-phospho-S6 ribosomal protein (Ser240/244), suggesting that these lesions develop through the normal pathway of Tsc-associated tumorigenesis. This work shows the use of the Blmm3/m3 mice for inducing renal tumorigenesis, and the high levels (f87%) of LOH in the resultant tumors will help facilitate mapping of loci involved in tumor progression. (Cancer Res 2005; 65(22): 10179-82