Northwestern Medicine

SUMMARYModification by ubiquitination governs the half-lives of thousands of proteins that are fated for elimination by either the proteasome or autophagy pathways, depending on the intricate architectures of ubiquitin modification. This system mediates quality control for individual proteins, protein complexes, and organelles, as well as myriad purely regulatory functions. Here we provide a comprehensive survey of the ubiquitin-proteasome system (UPS), the scope of which is at present poorly defined. The UPS, with the inclusion of pathways involving ubiquitin-like modifiers, comprises in our estimate over 1400 distinct proteins in humans, a vast set of activities whose collective impact on the biology of the cell is pervasive. The UPS is an integral component of the proteostasis network (PN), the remainder of which we have also surveyed in recent studies. With the addition of molecular chaperones, proteins from autophagy-lysosome pathway, and related activities, the PN includes in total over 3100 components by our estimates. Comprehensive and systematic definition of these pathways should support a range of ongoing investigations in the areas of genomics, proteomics, biochemistry, cell biology, and disease research.

Effective July 2022, kidney transplant centers were required to adjust waiting time for Black candidates using a new race-neutral eGFR (estimated glomerular filtration rate) calculation. Little has been reported about the impact and limitations of this policy change on transplant access for Black patients. A retrospective, single-center, cross-sectional study was performed in 04/2024 on adult (> 18years) kidney transplant candidates who were eligible for wait-time modification. Clinicodemographic data and adjusted dialysis start dates were extracted from the medical record. Descriptive statistics were performed. A total of 274 Black patients were eligible for a wait-time modification. Of these, 26 (9.5%) had been delisted, nine (3.3%) were deceased, 26 (9.5%) were already transplanted, and 104 (38.1%) did not have the required laboratory documentation available. In total, 109 (39.8%) candidates ultimately received wait-time modifications. Of the 109, mean age was 56years old and 47 (42.7%) were female. Mean wait-time gained was 2.7years (median, 1.7years; range, 1month-21years). Total wait-time gained by Black patients at this center was 298.5years. Patients who did not receive time back were more likely to have recent bloodwork from maintenance dialysis as the source of evaluated laboratory data (52.7% vs. 33.0%) (p < 0.001). Removing race from the eGFR calculation expanded transplant access for Black patients with eligible patients receiving an average of 2.7years of additional wait time at a large metropolitan center. However, wait-time recovery was limited by the availability of laboratory data, indicating that assistance with finding older lab values may help realize the full potential of this policy.

Clinical phenotypes of neuropathies associated with contactin-associated protein-1 (CASPR1) or isolated CASPR1/contactin-1 (CNTN1)-complex-IgG are not well characterized, and we aimed to describe the same. Patient sera positive for CASPR1 or CASPR1/CNTN1-complex-IgG by cell-based assay (CBA) at Mayo Clinic Neuroimmunology Laboratory (January 1, 2010-May 31, 2024) was identified retrospectively and prospectively. Clinical and paraclinical data were collected. CASPR1/CNTN1-complex-IgG-positive sera were tested using tissue indirect immunofluorescence assay, murine teased nerve fibers, and ELISAs for CASPR1 and CNTN1 to elucidate antigenic targets. Patients were compared with CNTN1-IgG and NF155-IgG4 autoimmune nodopathy cohorts. Among 17 CASPR1 or isolated CASPR1/CNTN1-complex-IgG-seropositive patients identified, 14 had clinical data (CASPR1-IgG = 8 [50% males, median age 50 years], CASPR1/CNTN1-complex-IgG = 6 [67% males, median age 42 years]). Neuropathic pain was more common in CASPR1-IgG (88% vs 33%), while sensory ataxia was more frequent in CASPR1/CNTN1-complex-IgG cases (100% vs 75%). All showed primarily demyelinating electrophysiology (1 CASPR1/CNTN1-complex-IgG case presented as chronic inflammatory sensory polyradiculopathy). Intravenous immunoglobulin (IVIg) refractoriness occurred in 63% of CASPR1-IgG and 40% of CASPR1/CNTN1-complex-IgG. Rituximab was effective in 6 of 7 (86%) treated patients. One patient with CASPR1/CNTN1-complex-IgG who was refractory to multiple immunotherapies underwent allogenic hematopoietic stem cell transplant after which she was off immunotherapies and is in sustained remission for the past 10 years. CASPR1-IgG patients progressed faster to nadir than NF155-IgG4 (p = 0.003). CASPR1/CNTN1-complex-IgG patients had more frequent asymmetric onset (p = 0.009) and greater long-term disability than NF155-IgG4 (p = 0.035). Five of the 7 CASPR1-IgG patients had IgG4 antibodies, compared with 2 of the 5 CASPR1/CNTN1-complex-IgG patients. Four isolated CASPR1/CNTN1-complex-IgG sera tested positive by tissue immunofluorescence assay; 3 also bound paranodes on teased nerve fibers. CASPR1-IgG cases had higher titers compared with CASPR1/CNTN1-complex-IgG cases by CBA. Three of the 5 CASPR1/CNTN1-complex-IgG cases had CASPR1-IgG reactivity by ELISA, while the other 2 were negative by both CASPR1 and CNTN1 ELISA. CASPR1-IgG and CASPR1/CNTN1-complex-IgG neuropathies, though rare, usually have a rapidly progressive course. Both are frequently IVIg-refractory and respond to rituximab. Compared with NF155-IgG4 nodopathies, CASPR1-IgG exhibits faster progression, while some CASPR1/CNTN1-complex-IgG nodopathies can cause greater long-term disability.

In the PROACTIVE-HF trial, remote heart failure (HF) management using comprehensive vital signs and seated mean pulmonary artery pressure (mPAP) was safe and resulted in a low reported rate of HF hospitalization (HFH) and all-cause mortality (HFH/D) through 12 months. In this report, we extend the results from the PROACTIVE-HF study through 2 years, stratified by ejection fraction (EF). PROACTIVE-HF was a prospective, multicenter, open-label, single-arm trial evaluating the safety and efficacy of patient management using the Cordella PA pressure sensor system in patients with New York Heart Association class III symptoms, regardless of EF. In the first 24 months, the incidence of HF events (HFE)/D was 0.89 (95% CI 0.81-0.99) events per patient, driven by HFH. Patients with HF with reduced EF had greater HFE/D rates than those with HF with preserved EF (1.0 vs 0.8 events per patient, P = .048). For patients with HF experiencing moderate-to-severe symptoms, management using the Cordella PA sensor system was associated with low event rates and improved health status at 2 years, regardless of EF. Comprehensive remote monitoring of vital signs, seated PAP, and patient-reported symptoms via a digital platform supports sustained benefit for high-risk patients with HF.