Faculty Bibliography

Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), remains a major medical problem. HBV has a high propensity for progressing to chronicity and can result in severe liver disease, including fibrosis, cirrhosis, and hepatocellular carcinoma. CHB patients frequently present with viral coinfection, including human immunodeficiency virus type (HIV) and hepatitis delta virus. About 10% of chronic HIV carriers are also persistently infected with HBV, which can result in more exacerbated liver disease. Mechanistic studies of HBV-induced immune responses and pathogenesis, which could be significantly influenced by HIV infection, have been hampered by the scarcity of immunocompetent animal models. Here, we demonstrate that humanized mice dually engrafted with components of a human immune system and a human liver supported HBV infection, which was partially controlled by human immune cells, as evidenced by lower levels of serum viremia and HBV replication intermediates in the liver. HBV infection resulted in priming and expansion of human HLA-restricted CD8+ T cells, which acquired an activated phenotype. Notably, our dually humanized mice support persistent coinfections with HBV and HIV, which opens opportunities for analyzing immune dysregulation during HBV and HIV coinfection, and preclinical testing of novel immunotherapeutics.

Platelet-rich plasma (PRP) has garnered widespread and increasing attention in recent years. We aimed to characterize the most influential articles in PRP research while clarifying controversies surrounding its use and clinical efficacy and identifying important areas on which to focus future research efforts. The Science Citation Index Expanded subsection of the Web of Science Core Collection was systematically searched to identify the top 50 cited publications on orthopedic PRP research. Publication and study characteristics were extracted, and Spearman's correlations were calculated to assess the relationship between citation data and level of evidence. The top 50 articles were published between the years 2005 and 2016, with 68% published in the year 2010 or later. Of the 33 studies for which level of evidence was assessed, the majority were of level I or II (18, 54.5%). Seventeen articles (34%) were classified as basic science. All clinical studies were prospective, and most (12 studies, 60%) included a high number of metrics related to the PRP preparation protocol and composition. Knee osteoarthritis was the most common topic among clinical studies in the top 50 cited articles (11 studies, 34%). More recent articles were associated with higher citation rates (ρ = 0.46, p < 0.001). The most influential articles on orthopaedic PRP research are recent and consist of high-level of evidence studies mostly. Randomized controlled trials were the most common study type, while basic science articles were relatively less common. The most influential clinical studies reported a high number of metrics related to their PRP preparation protocol and the final PRP composition. These results suggest a rapidly evolving field with the potential to better explain inconsistent clinical results with improved understanding and documentation of basic science concepts such as PRP composition, preparation, and combination techniques.

PURPOSE/OBJECTIVE:The purpose of this study is to compare medium to long term patient reported outcomes to one-year data for patients treated surgically for an aseptic fracture nonunion. METHODS:305 patients surgically treated for a fracture-nonunion were prospectively followed. Data collected included pain scores measured by the Visual Analog Scale (VAS), clinical outcomes assessed by the Short Musculoskeletal Functional Assessment (SMFA), and range of motion. 75% of patients in this study had lower extremity fracture nonunions and 25% had upper extremity fracture nonunions. Femur fracture nonunions were the most common. Data at latest follow-up was compared to one-year follow-up using the independent t-test. RESULTS:Sixty-two patients were available for follow-up data at an average of eight years. There were no differences in patient reported outcomes between one and eight years according to the standardized total SMFA (p = 0.982), functional index SMFA (p = 0.186), bothersome index SMFA (p = 0.396), activity index SMFA (p = 0.788), emotional index SMFA (p = 0.923), or mobility index SMFA (p = 0.649). There was also no difference in reported pain (p = 0.534). Range of motion data was collected for patients who followed up in clinic for an average of eight years after their surgical treatment. 58% of these patients reported a slight increase in range of motion at an average of eight years. CONCLUSION/CONCLUSIONS:Patient functional outcomes, range of motion, and reported pain all normalize after one year following surgical treatment for fracture nonunion and do not change significantly at an average of eight years. Surgeons can feel confident in counseling patients that their results will last and they do not need to follow up beyond one year, barring pain or other complications. LEVEL OF EVIDENCE/METHODS:Level IV.

OBJECTIVES/OBJECTIVE:Obesity is characterized by local and systemic low-grade inflammatory responses. Adipose tissue macrophages (ATM) play decisive roles in inflammation, insulin signaling, and various metabolic dysfunctions. Diets enriched with ω-3 polyunsaturated fatty acids (PUFAs) have been shown to improve health and mitigate pathologic conditions. However, the effects of ω-3 PUFA on adipose tissue inflammation, ATM number, and phenotype are poorly defined in human obesity. The aim of this study was to examine differences in expression of metabolic-inflammatory markers in omental, mesenteric, and subcutaneous fat depots of obese women supplemented with ω-3 PUFAs for 4 wk compared with a low-calorie diet before bariatric surgery. METHODS:In a randomized controlled trial, inflammatory markers in the abdominal adipose tissue and the systemic response in obese women were studied. Patients were treated with a 2-wk low-calorie diet (LCD) or a 4-wk ω-3 PUFA-enriched diet (920 mg eicosapentaenoic acid, 760 mg docosahexaenoic acid daily) before laparoscopic bypass surgery. Omental, mesenteric, and subcutaneous adipose tissue biopsies were collected during surgery and analyzed for quantity and phenotype of ATMs, and profiled for adipokines, cytokines, and signal transduction molecules. RESULTS:The chronic inflammatory state characterized by ATM markers was mostly improved by ω-3 PUFAs in visceral adipose tissue. We observed a decreased expression of CD45, CCL2, and CD68, indicating a lower inflammatory state. In patients with type 2 diabetes, ω-3 PUFAs lowered the expression of Netrin-1. CONCLUSIONS:Compared with an LCD, a diet enriched with ω-3 PUFAs influences the inflammatory state in different adipose tissue depots, by affecting markers of adipose tissue inflammation, macrophage phenotype, and retention. However, this was not reflected in clinical parameters such as insulin resistance and inflammatory cytokines. Subcutaneous adipose tissue and visceral adipose tissue have different responses to an LCD or a ω-3 PUFA-enriched diet. The presence of diabetes modifies the expression of inflammatory markers.

BACKGROUND:The purpose of this study was to compare outcomes following surgical treatment of tibial plateau fractures in an elderly (≥ 65y) and non-elderly (< 65) population. METHODS:Patients with tibial plateau fractures were prospectively followed. Patients were included if they were operatively treated, had an Injury Severity Score of < 16, and had follow-up through 12 months. Clinical, radiographic, and functional outcomes were evaluated at the 3, 6, and 12-month follow-up points. RESULTS:Mean time to radiographic fracture union was by 4.68 and 5.26 months in young and elderly patients, respectively (p = 0.25). There was no difference in self-reported baseline SMFA (p = 0.617). SMFA scores were better in younger patients at 3 months (p = 0.031), however this did not hold when multivariate modeling controlled for other factors. There was no difference at 6 and 12 months (p = 0.475, 0.392). There was no difference in range of knee motion at 3 months. At 6 and 12 months, young patients had statistically but not clinically better range of knee motion (p = 0.045, 0.007). There were no differences in overall reoperation rates, conversion arthroplasty, post-traumatic osteoarthritis or wound complications. CONCLUSIONS:Age greater than 65 does not appear to portend poorer outcomes after surgical repair of a tibial plateau fracture. The complication profiles are similar. Elderly and younger patients had similar function at 12 months compared to their baseline. These data suggest that age should not be a disqualifying factor when considering whether a patient with a tibial plateau fracture should be treated operatively.

PURPOSE/OBJECTIVE:To determine if the type of approach used for treatment of lateral split-depression tibial plateau fractures affects clinical outcome and complications rate. METHODS:This is a retrospective review of 169 patients who presented between 01/2005 and 12/2020 to a Level-I trauma center for operative management of an isolated lateral Schatzker II tibial plateau fractures (AO/OTA Type 41B3.1) treated through a single anterolateral approach: a 90-degree "L" (L), longitudinal vertical (V), or "lazy S" (S). Postoperative radiographic, clinical, and functional outcomes were assessed at 3, 6, 12 months, and beyond. RESULTS:Average time to radiographic healing was longer in the S incision cohort (p < 0.05). Furthermore, patients within the S incision cohort developed more postoperative wound complications at follow-up when compared to those within the L and V incision cohorts (p < 0.05). Additionally, reoperation rates were greater in the S incision cohort (p < 0.05). Lastly, on physical examination of the knee, patients within the S incision cohort had significantly poorer knee range of motion (p < 0.05). CONCLUSIONS:Our study demonstrates that skin incision type in the anterolateral approach to the proximal tibia has an association with outcomes following operative repair of tibial plateau fractures. The information from this study can be used to inform surgeons about the potential complications and long-term outcomes that patients may experience when undergoing operative repair of a tibial plateau fracture through a specific incision type. LEVEL OF EVIDENCE/METHODS:III.

RAS proteins are small GTPases that transduce signals from membrane receptors to signaling pathways that regulate growth and differentiation. Four RAS proteins are encoded by three genes - HRAS, KRAS, NRAS. Among them, KRAS is mutated in human cancer more frequently than any other oncogene. The KRAS pre-mRNA is alternatively spliced to generate two transcripts, KRAS4A and KRAS4B, that encode distinct proto-oncoproteins that differ almost exclusively in their C-terminal hypervariable regions (HVRs) that controls subcellular trafficking and membrane association. The KRAS4A isoform arose 475 million years ago in jawed vertebrates and has persisted in all vertebrates ever since, strongly suggesting non-overlapping functions of the splice variants. Because KRAS4B is expressed at higher levels in most tissues, it has been considered the principal KRAS isoform. However, emerging evidence for KRAS4A expression in tumors and splice variant-specific interactions and functions have sparked interest in this gene product. Among these findings, the KRAS4A-specific regulation of hexokinase I is a stark example. The aim of this mini-review is to provide an overview of the origin and differential functions of the two splice variants of KRAS.

A subtype of myeloid monocyte mediates the transition from autoimmunity to joint destruction in rheumatoid arthritis.

The adhesion G-protein-coupled receptor GPR133 (ADGRD1) supports growth of the brain malignancy glioblastoma. How the extracellular interactome of GPR133 in glioblastoma modulates signaling remains unknown. Here, we use affinity proteomics to identify the transmembrane protein PTK7 as an extracellular binding partner of GPR133 in glioblastoma. PTK7 binds the autoproteolytically generated N-terminal fragment of GPR133 and its expression in trans increases GPR133 signaling. This effect requires the intramolecular cleavage of GPR133 and PTK7's anchoring in the plasma membrane. PTK7's allosteric action on GPR133 signaling is additive with but topographically distinct from orthosteric activation by soluble peptide mimicking the endogenous tethered Stachel agonist. GPR133 and PTK7 are expressed in adjacent cells in glioblastoma, where their knockdown phenocopies each other. We propose that this ligand-receptor interaction is relevant to the pathogenesis of glioblastoma and possibly other physiological processes in healthy tissues.

Systems-level assessments of protein-protein interaction (PPI) network dysfunctions are currently out-of-reach because approaches enabling proteome-wide identification, analysis, and modulation of context-specific PPI changes in native (unengineered) cells and tissues are lacking. Herein, we take advantage of chemical binders of maladaptive scaffolding structures termed epichaperomes and develop an epichaperome-based 'omics platform, epichaperomics, to identify PPI alterations in disease. We provide multiple lines of evidence, at both biochemical and functional levels, demonstrating the importance of these probes to identify and study PPI network dysfunctions and provide mechanistically and therapeutically relevant proteome-wide insights. As proof-of-principle, we derive systems-level insight into PPI dysfunctions of cancer cells which enabled the discovery of a context-dependent mechanism by which cancer cells enhance the fitness of mitotic protein networks. Importantly, our systems levels analyses support the use of epichaperome chemical binders as therapeutic strategies aimed at normalizing PPI networks.