Faculty Bibliography

Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease characterized by keratinized epithelial tunnels that grow deeply into the dermis. Here, we examined the immune microenvironment within human HS lesions. Multi-omics profiling and multiplexed imaging identified tertiary lymphoid structures (TLSs) near HS tunnels. These TLSs were enriched with proliferative T cells, including follicular helper (Tfh), regulatory (Treg), and pathogenic T cells (IL17A+ and IFNG+), alongside extensive clonal expansion of plasma cells producing antibodies reactive to keratinocytes. HS fibroblasts express CXCL13 or CCL19 in response to immune cytokines. Using a microfluidic system to mimic TLS on a chip, we found that HS fibroblasts critically orchestrated lymphocyte aggregation via tumor necrosis factor alpha (TNF-α)-CXCL13 and TNF-α-CCL19 feedback loops with B and T cells, respectively; early TNF-α blockade suppressed aggregate initiation. Our findings provide insights into TLS formation in the skin, suggest therapeutic avenues for HS, and reveal mechanisms that may apply to other autoimmune settings, including Crohn's disease.

BACKGROUND:Vice chairs (VCs) of research play an integral role in orthopaedic departments at academic medical centers; they strategically lead research efforts and support the research careers of faculty and trainees. To our knowledge, no analysis of orthopaedic VCs of research exists in the literature, and no similar analyses have been completed in other medical specialties. We aimed to investigate the academic and demographic characteristics of orthopaedic VCs of research. METHODS:Doximity was used to identify orthopaedic residencies in the U.S. Personal and program websites were queried to identify VCs of research and collect academic and demographic characteristics. The Scopus database, the National Institutes of Health (NIH) RePORTER, and Google Scholar were used to obtain each investigator's Hirsch index (h-index) and the number and type of NIH grants awarded, respectively. RESULTS:Of the 207 orthopaedic residency programs identified, 71 (34%) had a named VC of research in the orthopaedic department. Of the top 50 medical schools, 42 were affiliated with such programs. Most VCs were men (89%). The racial and/or ethnic background of the majority of VCs was White (85%), followed by Asian (14%), and Black (1%). Most held the rank of professor (78%), followed by associate professor (18%), and assistant professor (4%). Over half were PhDs (55%), followed by MDs (37%) and MD/PhDs (8%). On average, the VCs had an h-index of 40.5. Furthermore, 65% had been awarded at least 1 NIH grant for their research, with 43% awarded at least 1 R01 grant. CONCLUSIONS:VCs of research develop research opportunities and shape the brand recognition of academic orthopaedic programs. Most orthopaedic VCs of research are men (89%); 85% each are White and have a rank of professor. Nearly half have been awarded at least 1 R01 grant from the NIH. CLINICAL RELEVANCE/CONCLUSIONS:This study outlines important academic and demographic characteristics among orthopaedic surgery VCs of research. Considering the mentorship aspect of their role, VCs of research have an opportunity to influence the diversity of incoming trainees in the field of academic orthopaedics.

In Mycobacterium tuberculosis (Mtb), proteins that are posttranslationally modified with a prokaryotic ubiquitin-like protein (Pup) can be degraded by bacterial proteasomes. A single Pup-ligase and depupylase shape the pupylome, but the mechanisms regulating their substrate specificity are incompletely understood. Here, we identified a depupylation regulator, a protein called CoaX, through its copurification with the depupylase Dop. CoaX is a pseudopantothenate kinase that showed evidence of binding to pantothenate, an essential nutrient Mtb synthesizes, but not its phosphorylation. In a ∆coaX mutant, pantothenate synthesis enzymes including PanB, a substrate of the Pup-proteasome system (PPS), were more abundant than in the parental strain. In vitro, CoaX specifically accelerated depupylation of Pup~PanB, while addition of pantothenate inhibited this reaction. In culture, media supplementation with pantothenate decreased PanB levels, which required CoaX. Collectively, we propose CoaX regulates PanB abundance in response to pantothenate levels by modulating its vulnerability to proteolysis by Mtb proteasomes.

PURPOSE/OBJECTIVE:To evaluate knee intra-articular cytokine concentrations in patients undergoing isolated meniscectomy and determine if these concentrations are associated with clinical outcomes. METHODS:Concentrations of ten biomarkers were quantified in synovial fluid aspirated from the operative knees of patients who underwent isolated meniscectomy from 10/2011-12/2019. Patients completed a survey at final follow-upincluding VAS, Lysholm, Tegner, and KOOS Physical Function Short Form (KOOS-PS). Failure was defined as subsequent TKA or non-achievement of the Patient Acceptable Symptom State (PASS) for knee pain defined as VAS > 27/100. Regression analysis investigating the relationship between cytokine concentrations and failure was performed. RESULTS:[25.5, 32.4], and a mean follow-up of 8.0 ± 2.2 years. There were no demographic or clinical differences between failures (n = 41) and non-failures (n = 59) at baseline. Monocyte Chemotactic Protein 1 (MCP-1) concentration was significantly higher in failures than in non-failures (344.3 pg/ml vs. 268.6 pg/ml, p = 0.016). In a regression analysis controlling for age, sex, BMI, symptom duration, length of follow-up, and ICRS grade, increased MCP-1 was associated with increased odds of failure (p = 0.002). CONCLUSIONS:The concentration of MCP-1 on the day of arthroscopic meniscectomy was predictive of failure as defined by an unacceptable pain level at intermediate- to long-term follow-up. This finding may help identify patients at high risk for poor postoperative outcomes following isolated meniscectomy and serve as a target for future postoperative immunomodulation research.

BACKGROUND/UNASSIGNED:Bone regeneration following a fracture is dependent on multiple factors including skeletal stem cells (SSCs). Recruitment, proliferation, and differentiation of the SSCs is guided by the proteins and metabolites found within the fracture microenvironment. Understanding how intrinsic factors affect the fracture microenvironment has been a topic of ongoing investigation. This study sought to determine whether the levels of select proteins and metabolites within the fracture hematoma would be differentially expressed depending on the age of the patient. We hypothesized that a distinct set of proteins and metabolites found within the fracture hematoma microenvironment would be present at varying levels depending on patient age. METHODS/UNASSIGNED:The research study was reviewed and approved by an Institutional Review Board. Hematomas were collected from subjects aged 18 years old or older undergoing surgical intervention for a fracture. Hematoma samples were selected from the biorepository and assigned to one of two fracture groups including young ankle/hindfoot and aged ankle/hindfoot. Protein and metabolite levels within each hematoma were analyzed by liquid chromatography-mass spectrometry. RESULTS/UNASSIGNED:A total of seven hematomas were included in each the young ankle/hindfoot and aged ankle/hindfoot groups. From the global metabolomic analysis, creatine, 2-methylindoline, and acetyl-L-carnitine were identified as being differentially expressed between both groups. An untargeted metabolomic analysis of the two groups identified significant differences in the levels of an additional 66 metabolites. Proteomic analysis identified 34 proteins that were expressed at significantly different levels. CONCLUSIONS/UNASSIGNED:The level of metabolites and proteins found within the local fracture environment vary by patient age. Future investigations will focus on identifying a role for these proteins and metabolites in bone homeostasis and fracture healing. LEVEL OF EVIDENCE/UNASSIGNED:N/A, basic science investigation. SUPPLEMENTARY INFORMATION/UNASSIGNED:The online version contains supplementary material available at 10.1007/s43465-024-01284-3.

Immune checkpoint inhibitor (ICI) therapies can increase the risk of cardiovascular events in survivors of cancer by worsening atherosclerosis. Here we map the expression of immune checkpoints (ICs) within human carotid and coronary atherosclerotic plaques, revealing a network of immune cell interactions that ICI treatments can unintentionally target in arteries. We identify a population of mature, regulatory CCR7⁺FSCN1⁺ dendritic cells, similar to those described in tumors, as a hub of IC-mediated signaling within plaques. Additionally, we show that type 2 diabetes and lipid-lowering therapies alter immune cell interactions through PD-1, CTLA4, LAG3 and other IC targets in clinical development, impacting plaque inflammation. This comprehensive map of the IC interactome in healthy and cardiometabolic disease states provides a framework for understanding the potential adverse and beneficial impacts of approved and investigational ICIs on atherosclerosis, setting the stage for designing ICI strategies that minimize cardiovascular disease risk in cancer survivors.

Vascular smooth muscle cells, endothelial cells and macrophages undergo phenotypic conversions throughout atherosclerosis progression, both as a consequence of chronic inflammation and as subsequent drivers of it. The inflammatory hypothesis of atherosclerosis has been catapulted to the forefront of cardiovascular research as clinical trials have shown that anti-inflammatory therapy reduces adverse cardiovascular events. However, no current therapies have been specifically designed to target the phenotype of plaque cells. Fate mapping has revealed that plaque cells convert to detrimental and beneficial cell phenotypes during atherosclerosis, with cumulative evidence highlighting that vascular cell plasticity is intimately linked with plaque inflammation, ultimately impacting lesion stability. Here we review vascular cell plasticity during atherosclerosis in the context of the chronic inflammatory plaque microenvironment. We highlight the need to better understand how plaque cells behave during therapeutic intervention. We then propose modulating plaque cell phenotype as an unexplored therapeutic paradigm in the clinical setting.

The effect of increased triglycerides (TGs) as an independent factor in atherosclerosis development has been contentious, in part, because severe hypertriglyceridemia associates with low levels of low-density lipoprotein cholesterol (LDL-C). To test whether hyperchylomicronemia, in the absence of markedly reduced LDL-C levels, contributes to atherosclerosis, we created mice with induced whole-body lipoprotein lipase (LpL) deficiency combined with LDL receptor (LDLR) deficiency. On an atherogenic Western-type diet (WD), male and female mice with induced global LpL deficiency (iLpl ^-/-) and LDLR knockdown (Ldlr

Mutations in PSEN1 were first discovered as a cause of Alzheimer's disease (AD) in 1995, yet the mechanism(s) by which the mutations cause disease still remains unknown. The generation of novel mouse models assessing the effects of different mutations could aid in this endeavor. Here we report on transgenic mouse lines made with the Δ440 PSEN1 mutation that causes AD with parkinsonism:- two expressing the un-tagged human protein and two expressing a HA-tagged version. Detailed characterization of these lines showed that Line 305 in particular, which expresses the untagged protein, develops age-dependent memory deficits and pathologic features, many of which are consistent with features found in AD. Key behavioral and physiological alterations found in the novel 305 line included an age-dependent deficit in spontaneous alternations in the Y-maze, a decrease in exploration of the center of an open field box, a decrease in the latency to fall on a rotarod, a reduction in synaptic strength and pair-pulse facilitation by electrophysiology, and profound alterations to cerebral blood flow regulation. The pathologic alterations found in the line included, significant neuronal loss in the hippocampus and cortex, astrogliosis, and changes in several proteins involved in synaptic and mitochondrial function, Ca2+ regulation, and autophagy. Taken together, these findings suggest that the transgenic lines will be useful for the investigation of AD pathogenesis.