👤 Ann Moyer

Amyloidosis derived from apolipoprotein C-II (AApoCII) is a recently discovered, rare form of amyloidosis. Data on clinical presentations and natural history are very limited. This study defines the clinicopathologic, proteomic, and outcome characteristics of renal AApoCII. Case series. Twenty-five renal AApoCII cases were identified from the Mayo Clinic Tissue Proteomics Laboratory archives from January 2008 through January 2024. All patients were White, 19 were≥65 years old at diagnosis, and 18 were female. Seven had a family history of chronic kidney disease (CKD). Patients presented with proteinuria (median 3.3g/day) and reduced kidney function (n=16; median creatinine, 1.6mg/dL). No patients had clinical evidence of other organ involvement by amyloidosis or features of monogenic hypertriglyceridemia. Histologically, amyloid deposits were often weakly positive for Congo red and involved glomeruli in all cases (with a nodular pattern in 22), whereas extraglomerular involvement was less common and generally mild. Proteomic analysis revealed abundant spectra for Apo C-II and for all 3 amyloid signature proteins (apolipoprotein E, apolipoprotein A-IV, and serum amyloid P) in all cases and detected an Apo C-II variant in 14 (K19T [p.Lys41Thr] in 12 and E47V [p.Glu69Val] in 2). Among 22 patients with follow-up information available, there were 12 end-stage kidney disease (ESKD) events and 2 deaths without ESKD during an average follow-up period of 75.5±12.5 (SE) months. Retrospective design, small sample size, APOC2 gene sequencing performed in a smaller subset. AApoCII mostly affects the kidney and manifests in the elderly with proteinuria and CKD. A minority of these patients had a family history of kidney disease. Kidney failure occurred in about half, whereas overall survival was more favorable. Amyloidosis derived from apolipoprotein C-II (AApoCII) is very rare, and data on clinicopathologic and outcome characteristics are scant. This study of 25 patients with AApoCII diagnosed by mass spectrometry at the Mayo Clinic Tissue Proteomics Laboratory revealed that most patients were elderly White females who presented with proteinuria and reduced kidney function, without involvement of other organs. A family history of kidney disease was often lacking. Pathologically, most cases exhibited nodular glomerular involvement. Proteomic analysis revealed abundant protein spectra for Apo C-II and amyloid signature proteins, and identified an Apo C-II variant in over half of cases (most commonly the p.Lys41Thr variant). The cumulative incidence of kidney failure was over 50% at 5 years follow-up. Only 4 deaths occurred over an average follow-up period of 76 months. Show less

Precision medicine approaches to cancer treatment aim to exploit genomic alterations that are specific to individual patients to tailor therapeutic strategies. Yet, some targetable genes and pathways are essential for tumor cell viability even in the absence of direct genomic alterations. In underrepresented populations, the mutational landscape and determinants of response to existing therapies are poorly characterized because of limited inclusion in clinical trials and studies. One way to reveal tumor essential genes is with genetic screens. Most screens are conducted on cell lines that bear little resemblance to patient tumors, after years of culture under nonphysiologic conditions. To address this problem, we aimed to develop a CRISPR screening pipeline in three-dimensionally grown patient-derived tumor organoid (PDTO) models. A breast cancer PDTO biobank that focused on underrepresented populations, including West African patients, was established and used to conduct a negative-selection kinome-focused CRISPR screen to identify kinases essential for organoid growth and potential targets for combination therapy with EGFR or MEK inhibitors. The screen identified several previously unidentified kinase targets, and the combination of FGFR1 and EGFR inhibitors synergized to block organoid proliferation. Together, these data demonstrate the feasibility of CRISPR-based genetic screens in patient-derived tumor models, including PDTOs from underrepresented patients with cancer, and identify targets for cancer therapy. Significance: Generation of a breast cancer patient-derived tumor organoid biobank focused on underrepresented populations enabled kinome-focused CRISPR screening that identified essential kinases and potential targets for combination therapy with EGFR or MEK inhibitors. See related commentary by Trembath and Spanheimer, p. 407. Show less

The purpose of this study was to investigate the longitudinal association of replacing stationary time (ST) with either light (LPA) or moderate-to-vigorous (MVPA) physical activity and replacing LPA with MVPA on 2-year clinical outcomes in individuals with varying severities of knee osteoarthritis. This retrospective cohort study used isotemporal substitution models to investigate the association of replacing 10-60 min of ST with LPA or MVPA and of LPA with MVPA on Western Ontario and McMaster Universities Osteoarthritis Index pain, stiffness, function, and gait speed at 2 years. Device-based stationary and physical activities were monitored using accelerometry within the Osteoarthritis Initiative cohort (n = 848). All analyses were completed separately for mild-to-moderate (Kellgren-Lawrence grade = 1-2) and severe (Kellgren-Lawrence grade = 3-4) knee osteoarthritis groups. In individuals with mild-to-moderate osteoarthritis, substituting 30-60 min of ST or LPA with MVPA improved pain and gait speed at 2 years but worsened stiffness. Replacing 60 min of ST with LPA improved Western Ontario and McMaster Universities Osteoarthritis Index function. For severe osteoarthritis, substituting 30-60 min of ST or LPA with MVPA led to worsened Western Ontario and McMaster Universities Osteoarthritis Index pain and function at 2 years, whereas substituting ST or LPA with MVPA minimally impacted stiffness. Improvements in gait speed were observed with 10-to-60-min ST or LPA substitutions with MVPA. Stationary and physical activity substitutions had varying longitudinal effects in individuals with mild-to-moderate versus severe knee osteoarthritis. Individuals with mild-to-moderate and severe knee osteoarthritis may require differing physical activity prescription to improve functional and overall health outcomes. Significance/Implications: These findings underscore the importance of severity-specific physical activity recommendations to support clinical outcomes in knee osteoarthritis management. Show less

Mast cells' association with fibrosis is known, but the mechanics of that association are unclear. The hypothesis is that mast cells promote fibroblast profibrotic activities through heterocellular gap junctional intercellular communications. Casting populated collagen lattices with both human mastocytoma cell line (HMC-1), an established mast cell line, and fibroblasts enhances lattice contraction via gap junctional intercellular communications. Unfortunately, in monolayer culture, HMC-1 cells and fibroblasts do not form heterocellular gap junctional intercellular communications. Freshly isolated rat peritoneal mast cells, however, establish these communications with fibroblasts in monolayer culture. Isolated rat peritoneal mast cells, however, survive only 7 days. Establishing a rat mast cell line that grows in the same medium as fibroblasts advances the study of mast cell-fibroblast interactions. HMC-1 cells thrive without supplements, suggesting that they release the factor(s) necessary for their viability. Spent HMC-1 medium may contain the factor(s) that generate a viable rat mast cell line. Rat peritoneal-isolated mast cells grew in culture medium containing spent HMC-1 medium for 4 weeks. At 4 weeks, rat mast cells (RMC-1) were successfully maintained in Dulbecco's Modified Eagle Medium with 10% serum. RMC-1 cells formed heterocellular gap junctional intercellular communications with fibroblasts, enhancing both fibroblast proliferation and co-cultured RMC-1/fibroblast/populated collagen lattice contraction. Enhanced fibroblast proliferation and lattice contraction failed to occur by including RMC-1 cells unable to establish gap junctional intercellular communications with fibroblasts, but cell proliferation was not affected by including degranulated RMC-1 cells. Heterocellular gap junctional intercellular communications with mast cells increase in fibroblast proliferation and fibroblast PCL contraction, two hypertrophic scar fibroblast activities. Show less