The 17-residue-long N terminus in huntingtin controls stepwise aggregation in solution and on membranes via different mechanisms.

Aggregation of huntingtin protein arising from expanded polyglutamine (polyQ) sequences in the exon-1 region of mutant huntingtin plays a central role in the pathogenesis of Huntington's disease. The huntingtin aggregation pathways are of therapeutic and diagnostic interest, but obtaining critical information from the physiologically relevant htt exon-1 (Httex1) protein has been challenging. Using biophysical techniques and an expression and purification protocol that generates clean, monomeric Httex1, we identified and mapped three distinct aggregation pathways: 1) unseeded in solution; 2) seeded in solution; and 3) membrane-mediated. In solution, aggregation proceeded in a highly stepwise manner, in which the individual domains (N terminus containing 17 amino acids (N17), polyQ, and proline-rich domain (PRD)) become ordered at very different rates. The aggregation was initiated by an early oligomer requiring a pathogenic, expanded Gln length and N17 α-helix formation. In the second phase, ß-sheet forms in the polyQ. The slowest step is the final structural maturation of the PRD. This stepwise mechanism could be bypassed by seeding, which potently accelerated aggregation and was a prerequisite for prion-like spreading in vivo Remarkably, membranes could catalyze aggregation even more potently than seeds, in a process that caused significant membrane damage. The N17 governed membrane-mediated aggregation by anchoring Httex1 to the membrane, enhancing local concentration and promoting collision via two-dimensional diffusion. Considering its central roles in solution and in membrane-mediated aggregation, the N17 represents an attractive target for inhibiting multiple pathways. Our approach should help evaluate such inhibitors and identify diagnostic markers for the misfolded forms identified here.

Severe Immune-Mediated Colitis Induced by Checkpoint Inhibitors in an Adolescent With Lynch Syndrome.

Lynch syndrome is a hereditary colorectal cancer caused by mutations in DNA mismatch repair genes. Immune checkpoint therapies have shown promise in treating Lynch syndrome-associated cancers but can lead to immune-related adverse events, such as colitis. In this report, we present a severe case of immune-mediated colitis (IMC) induced by checkpoint inhibitors in a young patient with Lynch syndrome. This 20-year-old male with Lynch syndrome and a history of glioblastoma underwent dual checkpoint therapy, after initial treatment with systemic steroids. Despite this, his condition worsened, resulting in complications, such as toxic megacolon and small bowel obstruction. He was subjected to various treatments, including infliximab and vedolizumab, but ultimately required total abdominal colectomy with J-pouch creation. This case highlights the challenges of managing severe IMC in patients with Lynch syndrome. The patient's suboptimal response to standard treatments and the development of complications emphasizes the need for a better understanding and alternative therapeutic options for IMC. This case also calls into question whether a subset of patients with IMC should be "treated to target," even though the current standard of care for IMC is guided by symptom response, and if so, further research is necessary to identify potential therapeutic targets. Further research is also required to understand the mechanisms of IMC and develop effective treatment strategies tailored to patients with Lynch syndrome and immune-related adverse events.

Episode-Based Payment and Direct Employer Purchasing of Healthcare Services: Recent Bundled Payment Innovations and the Geisinger Health System Experience.

One significant driver of the disjointed healthcare often observed in the United States is the traditional fee-for-service payment model which financially incentivizes the volume of care delivered over the quality and coordination of care. This problem is compounded by the wide, often unwarranted variation in healthcare charges that purchasers of health services encounter for substantially similar episodes of care. The last 10 years have seen many stakeholder organizations begin to experiment with novel financial payment models that strive to obviate many of the challenges inherent in customary quantity-based cost paradigms. The Patient Protection and Affordable Care Act has allowed many care delivery systems to partner with Medicare in episode-based payment programs such as the Bundled Payments for Care Improvement (BPCI) initiative, and in patient-based models such as the Medicare Shared Savings Program. Several employer purchasers of healthcare services are experimenting with innovative payment models to include episode-based bundled rate destination centers of excellence programs and the direct purchasing of accountable care organization services. The Geisinger Health System has over 10 years of experience with episode-based payment bundling coupled with the care delivery reengineering which is integral to its ProvenCare® program. Recent experiences at Geisinger have included participation in BPCI and also partnership with employer-purchasers of healthcare through the Pacific Business Group on Health (representing Walmart, Lowe's, and JetBlue Airways). As the shift towards value-focused care delivery and patient experience progresses forward, bundled payment arrangements and direct purchasing of healthcare will be critical financial drivers in effecting change.