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1.
J Shoulder Elbow Surg ; 32(7): 1459-1464, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36737032

RESUMO

BACKGROUND: Corticosteroid injections (CSIs) are used for the symptomatic management of osteoarthritis. However, their use may contaminate the joint space and pose an increased risk of periprosthetic joint infection (PJI) following reverse shoulder arthroplasty (RSA). Therefore, the purpose of this study was to assess whether there is any association between the timing of CSI and the incidence of PJI at 90 days, 1 year, and 2 years postoperatively. Specifically, we assessed the risk of PJI in patients who received CSI <1 month, 1-2 months, 2-3 months, and >3 months prior to RSA, as well as associated risk factors for PJI with CSI. METHODS: We queried a national, all-payer database to identify patients who underwent RSA from October 1, 2015, to October 31, 2020 (1.5 million patients). Patients who received an osteoarthritis diagnosis prior to RSA were selected, whereas those with bilateral RSA or >1 injection on the same side were excluded. This resulted in 5 cohorts: cohort receiving CSI within 4 weeks of RSA (n = 5607), cohort receiving CSI 1-2 months prior to RSA (n = 3024), cohort receiving CSI 2-3 months prior to RSA (n = 1572), cohort receiving CSI >3 months prior to RSA (n = 16,302), and control cohort with no injection prior to RSA (n = 21,938). Bivariate χ2 analyses of outcomes were conducted, in addition to multivariate regressions performed to adjust for comorbidities, as well as to assess associated risk factors. RESULTS: The adjusted analyses demonstrated a significantly increased risk of PJI at 90 days in patients who received CSI within 1 month of RSA (P < .001). Additionally, the PJI risk was increased at 1 year postoperatively in patients who received CSI within 1 month of RSA (P = .015). However, no significant increase in the PJI risk was noted at any time point for patients who received CSI >1 month before RSA (all P ≥ .088). Furthermore, alcohol abuse, chronic kidney disease, and depression were identified as risk factors that increased the risk of PJI. CONCLUSION: Intra-articular shoulder CSIs <4 weeks prior to RSA are associated with increased risks of PJI at 90 days and 1 year postoperatively as compared with patients who did not receive CSIs. RSA should be deferred ≥4 weeks after a patient receives a CSI.


Assuntos
Artrite Infecciosa , Artroplastia do Ombro , Osteoartrite , Infecções Relacionadas à Prótese , Articulação do Ombro , Humanos , Infecções Relacionadas à Prótese/epidemiologia , Infecções Relacionadas à Prótese/etiologia , Infecções Relacionadas à Prótese/cirurgia , Artroplastia do Ombro/efeitos adversos , Artroplastia/efeitos adversos , Artrite Infecciosa/cirurgia , Osteoartrite/cirurgia , Corticosteroides/efeitos adversos , Estudos Retrospectivos , Articulação do Ombro/cirurgia
2.
Int J Mol Sci ; 22(4)2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33672263

RESUMO

The 70 kDa and 90 kDa heat shock proteins Hsp70 and Hsp90 are two abundant and highly conserved ATP-dependent molecular chaperones that participate in the maintenance of cellular homeostasis. In Escherichia coli, Hsp90 (Hsp90Ec) and Hsp70 (DnaK) directly interact and collaborate in protein remodeling. Previous work has produced a model of the direct interaction of both chaperones. The locations of the residues involved have been confirmed and the model has been validated. In this study, we investigate the allosteric communication between Hsp90Ec and DnaK and how the chaperones couple their conformational cycles. Using elastic network models (ENM), normal mode analysis (NMA), and a structural perturbation method (SPM) of asymmetric and symmetric DnaK-Hsp90Ec, we extract biologically relevant vibrations and identify residues involved in allosteric signaling. When one DnaK is bound, the dominant normal modes favor biological motions that orient a substrate protein bound to DnaK within the substrate/client binding site of Hsp90Ec and release the substrate from the DnaK substrate binding domain. The presence of one DnaK molecule stabilizes the entire Hsp90Ec protomer to which it is bound. Conversely, the symmetric model of DnaK binding results in steric clashes of DnaK molecules and suggests that the Hsp90Ec and DnaK chaperone cycles operate independently. Together, this data supports an asymmetric binding of DnaK to Hsp90Ec.


Assuntos
Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Proteínas de Choque Térmico HSP70/química , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/química , Proteínas de Choque Térmico HSP90/metabolismo , Regulação Alostérica , Modelos Moleculares , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo
3.
Plast Reconstr Surg Glob Open ; 11(1): e4756, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36655028

RESUMO

The wide awake local anesthesia no tourniquet (WALANT) technique has been proven to be safe and effective for upper extremity surgery. WALANT does not require extensive medical clearance and allows for intraoperative assessment of range of motion. Additionally, it is frequently associated with lower costs and less postoperative pain when compared with traditional methods of anesthesia. Despite its expanded use for hand procedures, there are sparse data to support the use of WALANT in local and regional soft tissue flaps. Methods: A retrospective review was performed. Twenty-one patients who underwent a local or regional soft tissue flap surgery using the WALANT technique from February 2, 2018 to February 25, 2022 were included in our analysis. Results: Overall, one Louvre flap, two posterior tibial artery perforator propeller flaps, two reverse radial forearm flaps, two Quaba flaps, six cross finger flaps, one reverse homodigital island flap, three first dorsal metacarpal artery flaps, two thenar flaps, and two Moberg flaps were performed. Patients were followed up for an average of 11.9 ± 8.1 weeks. During this time, no postoperative complications occurred. All patients demonstrated appropriate healing at donor and recipient sites. Full range of motion was regained for all patients. Conclusions: WALANT is safe and effective for use in local and regional soft tissue flap surgery. Surgeons should consider this technique for more involved procedures such as flap surgery, as preliminary results demonstrate positive outcomes and potentially superior recovery for patients.

4.
Plast Reconstr Surg Glob Open ; 11(3): e4829, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36875924

RESUMO

Thoracic outlet syndrome is a constellation of signs and symptoms due to compression of the neurovascular bundle of the upper limb. In particular, neurogenic thoracic outlet syndrome can present with a wide constellation of clinical manifestations ranging from pain to paresthesia of the upper extremity, resulting in a challenge to correctly diagnose this syndrome. Treatment options range from nonoperative treatment, such as rehabilitation and physical therapy, to surgical correction, such as decompression of the neurovascular bundle. Methods: Following a systematic review of the literature, we describe the need for a thorough patient history, physical examination, and radiologic images which have been reported to correctly diagnose neurogenic thoracic outlet syndrome. Additionally, we review the various surgical techniques recommended to treat this syndrome. Results: Postoperative functional outcomes have been shown to be more favorable in arterial and venous thoracic outlet syndrome (TOS) patients when compared with neurogenic TOS patients, likely due to the ability to completely remove the site of compression in cases of vascular TOS as compared with incomplete decompression in neurogenic TOS. Conclusions: In this review article, we provide an overview of the anatomy, etiology, diagnostic modalities, and current treatment options of correcting neurogenic TOS. Additionally, we offer a detailed step-by-step technique of the supraclavicular approach to the brachial plexus, a preferred approach for decompressing neurogenic TOS.

5.
J Hand Surg Glob Online ; 4(6): 452-455, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36420465

RESUMO

Wide-awake local anesthesia no-tourniquet (WALANT) surgery is an attractive option for hand surgeons, particularly during resource-scarce periods, as it eliminates dependence on main operating rooms or hospital-based procedures. The limited prepping or draping used for WALANT field sterility is as effective, if not more effective, than standard sterile prepping or draping. Patient anxiety surrounding WALANT surgery is similar to or less than that of general or local anesthesia with or without tourniquet. Patients use the same or lower amounts of postoperative narcotics after WALANT as compared to after the other anesthetic methods. Wide-awake local anesthesia no-tourniquet surgery saves significant costs for the same surgeries when performed under general or local anesthesia with or without tourniquet. There are very few complications associated with the WALANT method of anesthesia; rare case reports include vasovagal syncope and cardiac arrhythmia due to inadvertent intravascular injection of epinephrine.

6.
J Asian Health ; 2(1)2022.
Artigo em Inglês | MEDLINE | ID: mdl-36381954

RESUMO

BACKGROUND/AIMS: To understand how social media can be used to improve Asian subgroup engagement in a research registry. METHODS: A 10-week social media campaign was implemented with the goal of increasing the percentage of Asian participants in the Stanford Research Registry - platforms utilized include Facebook, Instagram, and Twitter through the Stanford Center for Asian Health Research and Education accounts. Participant data was disaggregated by race and ethnicity in order to better understand the diversity among Asian subgroups. RESULTS: The percentage of Asian participants increased from 14.3% at baseline to 23.8% at the end of the campaign (525 Asian identifying individuals to 1,871). The greatest increase occurred during the general outreach phase which utilized all channels of outreach available. Frequencies of some ethnicities, such as Japanese, Korean, and Vietnamese, were higher in the Multi-Ethnic and/or Multi-Racial categories compared to their corresponding monoethnic groups. CONCLUSIONS: Social media is a powerful tool that can be leveraged for targeted recruitment - in this study we see how it can increase diversity amongst research participants and potentially be used as an effective tool for information dissemination. This work can be expanded in the future by examining other social media platforms more targeted toward Asian populations, and more thorough disaggregation to fully understand the diversity present in the Asian population.

7.
Hand (N Y) ; : 15589447221105542, 2022 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-35815611

RESUMO

BACKGROUND: Previous studies have suggested that proximal row carpectomy (PRC) results in increased contact pressures and decreased contact areas in the radiocarpal joint. Such experiments, however, used older technologies that may be associated with considerable measurement errors. The purpose of this study was to determine whether there was a significant difference in contact pressure and contact area before and after PRC using Tekscan, a newer pressure sensing technology. METHODS: Ten nonpaired cadaveric specimens were dissected proximal to the carpal row and potted. An ultra-thin Tekscan sensor was secured in the lunate fossa of the radius. The wrists were loaded with 200 N of force for 60 seconds to simulate clenched-fist grip; contact pressure and area was assessed before and after PRC. RESULTS: Performing a PRC did not significantly increase mean contact pressure at the lunate fossa compared to the native state (mean increase of 17.4 ± 43.2 N/cm2, P = .184). Similarly, the PRC did not significantly alter peak contact pressures at the lunate fossa (intact: 617.2 ± 233.46 N/cm2, median = 637.5 N/cm2; PRC: 707.8 ± 156.6 N/cm2, median = 728.5 N/cm2; P = .169). In addition, the PRC (0.46 ± 0.15 cm2, median = 0.48 cm2) and intact states (0.49 ± 0.25 cm2, median = 0.44 cm2) demonstrated similar contact areas (P = .681). CONCLUSIONS: In contrast to prior studies that demonstrated significant increases in contact pressure and decreases in contact area after PRC, our findings propose that performing a PRC does not significantly alter the contact pressures or area of the lunate fossa of the radiocarpal joint.

8.
J Wrist Surg ; 11(3): 250-256, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35845237

RESUMO

Background The scapholunate interosseous ligament (SLIL) couples the scaphoid and lunate, preventing motion and instability. Prior studies suggest that damage to the SLIL may significantly alter contact pressures of the radiocarpal joint. Questions/Purposes The purpose of this study was to investigate the contact pressure and contact area in the scaphoid and lunate fossae of the radius prior to and after sectioning the SLIL. Methods Ten cadaveric forearms were dissected distal to 1-cm proximal to the radiocarpal joint and a Tekscan sensor was placed in the radiocarpal joint. The potted specimen was mounted and an axial load of 200 N was applied over 60 seconds. Results Sectioning of the SLIL did neither significantly alter mean contact pressure at the lunate fossa ( p = 0.842) nor scaphoid fossa ( p = 0.760). Peak pressures were similar between both states at the lunate and scaphoid fossae ( p = 0.301-0.959). Contact areas were similar at the lunate fossa ( p = 0.508) but trended toward an increase in the SLIL sectioned state in the scaphoid fossa ( p = 0.055). No significant differences in the distribution of contact pressure ( p = 0.799), peak pressure ( p = 0.445), and contact area ( p = 0.203) between the scaphoid and lunate fossae after sectioning were observed. Conclusion Complete sectioning of the SLIL in isolation may not be sufficient to alter the contact pressures of the wrist. Clinical Relevance Injury to the secondary stabilizers of the SL joint, in addition to complete sectioning of the SLIL, may be needed to induce altered biomechanics and ultimately degenerative changes of the radiocarpal joint.

9.
Phys Sportsmed ; 50(5): 388-393, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-34030578

RESUMO

BACKGROUND: This study documented injury types, rates and mechanisms for female youth ice hockey players reporting to US emergency departments to inform safety measures and sideline medical preparedness. METHODS: The National Electronic Injury Surveillance System (NEISS) database was queried for ice hockey injuries (product code 1279) from 1 January 2002 to 31 December 2019. Incidence rate ratios (IRR) were calculated using OpenEpi and compared between age divisions. Spearman's rank correlation was utilized to evaluate the correlation between age and injury incidence. USA Hockey membership statistics were used to establish the population at risk and calculate incidence rates (IR). RESULTS: An estimated 20,384 ice hockey injuries presented to participating United States emergency departments. The number of female youth ice hockey players increased significantly from 36,258 in 2002 to 65,072 in 2019 (p < 0.01). The most commonly injured body parts were the head (n = 5,519, IR = 62.1 [95%CI 54.3-70.0 per 10,000 athletes), trunk (n = 2,364, IR = 26.6 [95%CI 21.2-32.0] per 10,000 athletes), and wrist (n = 1,824, IR = 20.5 [95%CI 15.7-25.4] per 10,000 athletes). The most commonly reported mechanisms of injury were player-to-player collision (n = 4,746, IR = 53.4 [95%CI 46.4-60.5] per 10,000 athletes) and falls (n = 4,585, IR = 51.6 [95%CI 44.1-59.1] per 10,000 athletes). The most common diagnoses were traumatic brain injury (n = 5,333, IR = 60.0 [95%CI 52.3-67.8] per 10,000 athletes), contusion (n = 4,204, IR = 47.3 [95%CI 40.3-54.4] per 10,000 athletes) and strain/sprain (n = 3,601, IR = 40.5 [95%CI 34.1-47.0] per 10,000 athletes). A positive correlation was found between age and injury incidence, as well as increasing age and injuries from player-to-player collision and TBI's. CONCLUSIONS: Though body checking is illegal at all levels of women's ice hockey, player-to-player collision prevailed as the leading mechanism on injury. Hopefully this study informs players, parents, coaches, trainers and clinicians about the impact of player-to-player collisions on overall injury burden in the older age divisions of youth female hockey.


Assuntos
Traumatismos em Atletas , Concussão Encefálica , Hóquei , Entorses e Distensões , Adolescente , Traumatismos em Atletas/epidemiologia , Traumatismos em Atletas/etiologia , Concussão Encefálica/complicações , Serviço Hospitalar de Emergência , Feminino , Hóquei/lesões , Humanos , Incidência , Entorses e Distensões/complicações , Estados Unidos/epidemiologia
10.
Orthopedics ; 44(3): 187-191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34039213

RESUMO

Negative pressure wound therapy (NPWT) has shown promise in reducing postoperative complications in several applications in orthopedic surgery, including trauma and arthroplasty. To the authors' knowledge, no study has evaluated its use in multiligament knee reconstruction. Multiligament knee reconstruction is often fraught with arthrofibrosis and wound-healing complications. This retrospective study assessed complications requiring reoperation in patients who underwent multiligament knee reconstruction and received either NPWT (n=14) or a dry sterile dressing (DSD) (n=44). There were significantly more reoperations in the cohort of patients who received a DSD (P=.011). Arthrofibrosis in particular showed a significantly lower rate of occurrence in the NPWT cohort compared with the DSD cohort (P=.025). There was a trend toward a lower infection rate in the NPWT cohort (P=.322). This study provides evidence that NPWT may be effective in reducing reoperation after multiligament knee reconstruction. Further investigations with prospective studies are needed to draw stronger conclusions about the benefits of NPWT. [Orthopedics. 2021;44(3):187-191.].


Assuntos
Joelho/cirurgia , Tratamento de Ferimentos com Pressão Negativa , Procedimentos de Cirurgia Plástica/efeitos adversos , Adulto , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/prevenção & controle , Reoperação , Estudos Retrospectivos , Cicatrização
11.
Plast Reconstr Surg Glob Open ; 9(12): e3983, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35070612

RESUMO

BACKGROUND: Favorable rates of meaningful recovery (≥M3/S3) of processed nerve allografts (PNAs) for mixed and motor nerve injuries have been reported, but there are few reports of patients having complete PNA failure (M0/S0). The purpose of this study was to describe the outcomes, including rate of complete failures, in a case series of patients who underwent PNA for peripheral mixed nerve reconstructions. METHODS: A retrospective review of outcomes between May 2018 to September 2020 was performed. Consecutive patients who underwent nerve reconstruction (>15 mm) with PNA for a peripheral mixed nerve injury of the upper or lower extremity were eligible. Those who returned to clinic for a 10-month postoperative visit were included in this study. The primary outcome was whether the patient was defined as having a complete failure (M0/S0). RESULTS: A total of 22 patients underwent a PNA during the time period; 14 patients participated in follow-up and were included (average age: 34.7 years) with a mean follow-up of 11.9 months. The average gap length was 46.4 mm (range 15-110 mm). At their 10-month postoperative visit, no patients had any motor or sensory improvement; all patients were deemed as having complete failure. Four patients underwent or were planned for subsequent revision surgery. CONCLUSIONS: In this study, we demonstrated a high number of complete failures, with all 14 included patients sustaining a complete failure (100% failure rate) at a minimum 10-month follow-up visit. Failure in this case series was not observed to affect one nerve type, location, or be related to preoperative injury size.

12.
J Orthop ; 25: 129-133, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34025056

RESUMO

PURPOSE: The purpose of this study is to evaluate the reliability of magnetic resonance imaging (MRI) in predicting the location of ACL tears in preoperative planning for anterior cruciate ligament (ACL) repair. METHODS: Thirty-four patients who underwent ACL repair were retrospectively analyzed to compare intraoperative arthroscopic findings with preoperative MRIs. RESULTS: For identifying type I tears, the sensitivity of MRI was 9.0% and the accuracy of MRI was 8.8%. There was moderate interrater agreement between MRI findings for tear location and tear degree. CONCLUSION: MRI alone may not necessarily be accurate in identifying which ACL tears are amenable to repair. STUDY DESIGN: Retrospective case series; Level of Evidence: IV.

13.
Tech Hand Up Extrem Surg ; 25(3): 142-147, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33122495

RESUMO

Fasciotomy of the forearm is a well-described technique for the treatment of compartment syndrome in adults; however, it has not been discussed with sufficient details in the setting of neonatal compartment syndrome. When performing a fasciotomy, it is imperative to decompress all compartments within the forearm to limit the ischemic damage and prevent the progression of the disease. Although it is common to utilize both volar and dorsal incisions to release these compartments, we describe a method that potentially allows for total decompression through a single volar incision with minimal to no morbidity. This novel technique provides sufficient soft-tissue exposure while improving upon the cosmesis that results from a traditional approach.


Assuntos
Síndromes Compartimentais , Antebraço , Adulto , Síndromes Compartimentais/cirurgia , Descompressão Cirúrgica , Fasciotomia , Antebraço/cirurgia , Humanos , Recém-Nascido
14.
Cancer Res ; 63(16): 5073-83, 2003 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-12941837

RESUMO

An antagonistic monoclonal antibody, designated EM164, has been developed which binds specifically to the human insulin-like growth factor I receptor (IGF-IR) and inhibits the proliferation and survival functions of the receptor in cancer cells. EM164 was initially selected by a rapid cell-based screen of hybridoma supernatants to identify antibodies that bind to IGF-IR but not to the homologous insulin receptor and that show maximal inhibition of IGF-I-stimulated autophosphorylation of IGF-IR. EM164 binds tightly to IGF-IR with a dissociation constant K(d) of 0.1 nM, inhibits binding of IGF-I and antagonizes its effects on cells completely, and has no agonistic activity on its own. EM164 inhibits IGF-I-, IGF-II-, and serum-stimulated proliferation and survival of diverse human cancer cell lines in vitro, including breast, lung, colon, cervical, ovarian, pancreatic, melanoma, prostate, neuroblastoma, rhabdomyosarcoma, and osteosarcoma cancer lines. It also suppresses the autocrine or paracrine proliferation of several cancer cell lines. EM164 was the most potent antagonistic anti-IGF-IR antibody tested when compared with several commercially available antibodies. The in vitro inhibitory effect could be extended to in vivo tumor models, where EM164 caused regression of established BxPC-3 human pancreatic tumor xenografts in SCID mice. The antitumor effect of treatment with EM164 could be enhanced by combining it with the cytotoxic agent gemcitabine. These data support the development of EM164 as a candidate therapeutic agent that targets IGF-IR function in cancer cells.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Experimentais/terapia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Anticorpos Monoclonais/farmacologia , Ciclo Celular , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Neoplasias Experimentais/patologia , Fosforilação , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Transplante Heterólogo , Células Tumorais Cultivadas
15.
J Vis Exp ; (118)2016 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-28060251

RESUMO

Hypoxia has been implicated in the metastasis of Ewing sarcoma (ES) by clinical observations and in vitro data, yet direct evidence for its pro-metastatic effect is lacking and the exact mechanisms of its action are unclear. Here, we report an animal model that allows for direct testing of the effects of tumor hypoxia on ES dissemination and investigation into the underlying pathways involved. This approach combines two well-established experimental strategies, orthotopic xenografting of ES cells and femoral artery ligation (FAL), which induces hindlimb ischemia. Human ES cells were injected into the gastrocnemius muscles of SCID/beige mice and the primary tumors were allowed to grow to a size of 250 mm3. At this stage either the tumors were excised (control group) or the animals were subjected to FAL to create tumor hypoxia, followed by tumor excision 3 days later. The efficiency of FAL was confirmed by a significant increase in binding of hypoxyprobe-1 in the tumor tissue, severe tumor necrosis and complete inhibition of primary tumor growth. Importantly, despite these direct effects of ischemia, an enhanced dissemination of tumor cells from the hypoxic tumors was observed. This experimental strategy enables comparative analysis of the metastatic properties of primary tumors of the same size, yet significantly different levels of hypoxia. It also provides a new platform to further assess the mechanistic basis for the hypoxia-induced alterations that occur during metastatic tumor progression in vivo. In addition, while this model was established using ES cells, we anticipate that this experimental strategy can be used to test the effect of hypoxia in other sarcomas, as well as tumors orthotopically implanted in sites with a well-defined blood supply route.


Assuntos
Hipóxia/patologia , Metástase Neoplásica/patologia , Sarcoma de Ewing/patologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos SCID , Transplante de Neoplasias
16.
Oncotarget ; 6(9): 7151-65, 2015 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-25714031

RESUMO

Ewing sarcoma (ES) develops in bones or soft tissues of children and adolescents. The presence of bone metastases is one of the most adverse prognostic factors, yet the mechanisms governing their formation remain unclear. As a transcriptional target of EWS-FLI1, the fusion protein driving ES transformation, neuropeptide Y (NPY) is highly expressed and released from ES tumors. Hypoxia up-regulates NPY and activates its pro-metastatic functions. To test the impact of NPY on ES metastatic pattern, ES cell lines, SK-ES1 and TC71, with high and low peptide release, respectively, were used in an orthotopic xenograft model. ES cells were injected into gastrocnemius muscles of SCID/beige mice, the primary tumors excised, and mice monitored for the presence of metastases. SK-ES1 xenografts resulted in thoracic extra-osseous metastases (67%) and dissemination to bone (50%) and brain (25%), while TC71 tumors metastasized to the lungs (70%). Bone dissemination in SK-ES1 xenografts associated with increased NPY expression in bone metastases and its accumulation in bone invasion areas. The genetic silencing of NPY in SK-ES1 cells reduced bone degradation. Our study supports the role for NPY in ES bone invasion and provides new models for identifying pathways driving ES metastases to specific niches and testing anti-metastatic therapeutics.


Assuntos
Neoplasias Ósseas/metabolismo , Neuropeptídeo Y/química , Sarcoma de Ewing/metabolismo , Animais , Neoplasias Ósseas/patologia , Neoplasias Encefálicas/secundário , Linhagem Celular Tumoral , Movimento Celular , Meios de Cultivo Condicionados , Modelos Animais de Doenças , Feminino , Inativação Gênica , Humanos , Hipóxia , Neoplasias Pulmonares/secundário , Camundongos , Camundongos SCID , Metástase Neoplásica , Transplante de Neoplasias , Proteínas de Fusão Oncogênica/metabolismo , Fenótipo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/metabolismo , Sarcoma de Ewing/patologia
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