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Malignant gliomas, including glioblastoma multiforme, constitute the most common and aggressive primary brain tumors in adults. The transcription factor signal transducer and activator of transcription 3 (STAT3) plays an essential role in glioblastoma pathogenesis downstream of the major oncogenic protein epidermal growth factor receptor variant III (EGFRvIII). However, the critical gene targets of STAT3 that mediate EGFRvIII-induced glial transformation have remained unknown. Here, we identify inducible nitric oxide synthase (iNOS) as a novel target gene of STAT3 in EGFRvIII-expressing mouse astrocytes. Endogenous STAT3 occupies the endogenous iNOS promoter and stimulates iNOS transcription in EGFRvIII-expressing astrocytes. STAT3 does not appear to control iNOS transcription in astrocytes deficient in the major glioblastoma tumor suppressor protein phosphatase and tensin homolog (PTEN), suggesting that STAT3 regulates iNOS transcription specifically in EGFRvIII-expressing astrocytes. Importantly, inhibition of iNOS by distinct approaches, including knockdown by RNA interference, reduces cell population growth and invasiveness of EGFRvIII-expressing astrocytes. In addition, upon iNOS knockdown or administration of a small-molecule inhibitor of iNOS, EGFRvIII-expressing astrocytes form smaller tumors in vivo. These findings suggest that inhibition of iNOS may have potential therapeutic value for EGFRvIII-activated brain tumors.
Biofilms are typically studied in bacterial media that allow the study of important properties such as bacterial growth. However, the results obtained in such media cannot take into account the bacterial localization/clustering caused by bacteria-protein interactions in vivo and the accompanying alterations in phenotype, virulence factor production, and ultimately antibiotic tolerance. We and others have reported that methicillin-resistant or methicillin-susceptible Staphylococcus aureus (MRSA or MSSA, respectively) and other pathogens assemble a proteinaceous matrix in synovial fluid. This proteinaceous bacterial aggregate is coated by a polysaccharide matrix as is characteristic of biofilms. In this study, we identify proteins important for this aggregation and determine the concentration ranges of these proteins that can reproduce bacterial aggregation. We then test this protein combination for its ability to cause marked aggregation, antibacterial tolerance, preservation of morphology, and expression of the phenol-soluble modulin (PSM) virulence factors. In the process, we create a viscous fluid that models bacterial behavior in synovial fluid. We suggest that our findings and, by extension, use of this fluid can help to better model bacterial behavior of new antimicrobial therapies, as well as serve as a starting point to study host protein-bacteria interactions characteristic of physiological fluids.
Although activating mutations of the anaplastic lymphoma kinase (ALK) membrane receptor occur in ∼10% of neuroblastoma (NB) tumors, the role of the wild-type (WT) receptor, which is aberrantly expressed in most non-mutated cases, is unclear. Both WT and mutant proteins undergo extracellular domain (ECD) cleavage. Here, we map the cleavage site to Asn654-Leu655 and demonstrate that cleavage inhibition of WT ALK significantly impedes NB cell migration with subsequent prolongation of survival in mouse models. Cleavage inhibition results in the downregulation of an epithelial-to-mesenchymal transition (EMT) gene signature, with decreased nuclear localization and occupancy of β-catenin at EMT gene promoters. We further show that cleavage is mediated by matrix metalloproteinase 9, whose genetic and pharmacologic inactivation inhibits cleavage and decreases NB cell migration. Together, our results indicate a pivotal role for WT ALK ECD cleavage in NB pathogenesis, which may be harnessed for therapeutic benefit.
Clinical guidelines recommend engaging patients in shared decision making for common orthopedic procedures; however, limited work has assessed what is occurring in practice. This study assessed the quality of shared decision making for elective hip and knee replacement and spine surgery at four network-affiliated hospitals.
Although telemedicine visits were essential and adopted by providers and patients alike, few studies have been conducted evaluating orthopedic patient perception of the care delivered during these visits. To our knowledge, no study has evaluated specific factors that affected patient satisfaction with telemedicine and the receptiveness to continue virtual visits post COVID-19 in total joint arthroplasty (TJA) patients. Thus, the purposes of our study are to determine the following: (1) patient satisfaction with using TJA telemedicine services, (2) whether patient characteristics might be associated with satisfaction, and (3) whether virtual clinic visits may be used post-COVID-19.
The months prior to elective surgery may present an opportunity for patients to initiate behavior changes that will simultaneously ready them for surgery and improve their overall health status. An upcoming elective total joint arthroplasty (TJA) may serve as motivation for patients with severe obesity (body mass index [BMI]> 40 kg/m2) to lose weight, as it may optimize clinical outcomes following TJA and help them become eligible for TJA since some surgeons use a BMI of 40 kg/m2 as a cut-off for offering surgery in an effort to optimize outcomes.
Multimodal analgesia featuring peripheral nerve blocks decreases postoperative pain for patients undergoing primary total knee arthroplasty (TKA). Many anesthesiologists and surgeons advocate for the use of adductor canal blocks (ACBs) for analgesia, which result in less weakness compared to femoral nerve blocks. Few data exist to guide analgesic management in total knee revision (TKR), considered to be more painful than primary TKA. We hypothesized that TKR patients with a continuous ACB would use more opioids than primary TKA patients who received the same analgesic regimen.
Cancer is the second leading cause of death among women in the United States. Previous studies demonstrate a higher prevalence of cancer among female orthopaedic surgeons. This study aimed to provide an updated prevalence of breast and all-cause cancer among female orthopaedic surgeons using a larger and more current study population.
The study investigated the utilization of odor detection dogs to identify the odor profile of Staphylococcus aureus (S. aureus) biofilms in pure in vitro samples and in in vivo biosamples from animals and humans with S. aureus periprosthetic joint infection (PJI). Biofilms form when bacterial communities aggregate on orthopedic implants leading to recalcitrant infections that are difficult to treat. Identifying PJI biofilm infections is challenging, and traditional microbiological cultures may yield negative results even in the presence of clinical signs.
Massive perioperative blood loss in complex revision total joint arthroplasty (TJA) often requires blood transfusions. Tranexamic acid (TXA) has been used in elective primary TJA to minimize blood loss and transfusions. The purpose of this meta-analysis was to evaluate the safety and efficacy of intravenous TXA in revision TJA.
Osteomyelitis is a devastating condition whose treatment relies on the detection of bacteria. The current standard of microbiology culture may not be adequate. Molecular biology based diagnostic procedures for detecting bacteria in orthopaedic infections was previously established, but has not been applied to the setting of chronic osteomyelitis. We aim to determine the applicability of molecular diagnostic procedures for monitoring chronic osteomyelitis, and to evaluate if these procedures are superior to standard culture methods of osteomyelitis detection.
Physician burnout and its consequences have been recognized as increasingly prevalent and important issues for both organizations and individuals involved in healthcare delivery. The purpose of this study was to describe and compare the patterns of self-reported wellness in orthopaedic surgeons and trainees from multiple nations with varying health systems.
There have been limited advances in the treatment of bone and joint infections, which currently involves a combination of surgery and antibiotic administration. There is a timely need in orthopedics to develop more effective and less invasive forms of antimicrobial prophylaxis and treatment. The antibacterial effect of adult tissue-derived mesenchymal stem cells (MSCs) has recently been investigated against Escherichia coli and Staphylococcus aureus. The main mechanism of action is postulated to be via MSC production of the cationic antimicrobial peptide, LL-37.
Treatment failure in joint infections is associated with fibrinous, antibiotic-resistant, floating and tissue-associated Staphylococcus aureus aggregates formed in synovial fluid (SynF). We explore whether antibiotic activity could be increased against Staphylococcus aureus aggregates using ultrasound-triggered microbubble destruction (UTMD), in vitro and in a porcine model of septic arthritis. In vitro, when bacterially laden SynF is diluted, akin to the dilution achieved clinically with lavage and local injection of antibiotics, amikacin and ultrasound application result in increased bacterial metabolism, aggregate permeabilization, and a 4-5 log decrease in colony forming units, independent of microbubble destruction. Without SynF dilution, amikacin + UTMD does not increase antibiotic activity. Importantly, in the porcine model of septic arthritis, no bacteria are recovered from the SynF after treatment with amikacin and UTMD-ultrasound without UTMD is insufficient. Our data suggest that UTMD + antibiotics may serve as an important adjunct for the treatment of septic arthritis.
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