RESUMO
Triceptides are cyclophane-containing ribosomally synthesized and post-translationally modified peptides. The characteristic cross-links are formed between an aromatic ring to Cß on three-residue Ω1X2X3 motifs (Ω1 = aromatic). Here, we explored the promiscuity of the XYE family triceptide maturase, XncB from Xenorhabdus nematophila DSM 3370. Single amino acid variants were coexpressed with XncB in vivo in Escherichia coli, and we show that a variety of amino acids can be incorporated into the Phe-Gly-Asn cyclophane. Aromatic amino acids at the X3 position were accepted by the enzyme but yielded hydroxylated, rather than the typical cyclophane, products. These studies show that oxygen can be inserted but diverges in the final product formed relative to daropeptide maturases. Finally, truncations of the leader peptide showed that it is necessary for complete modification by XncB.
Assuntos
Aminoácidos , Peptídeos , Xenorhabdus , Aminoácidos/metabolismo , Peptídeos/química , Sinais Direcionadores de Proteínas , Xenorhabdus/química , Xenorhabdus/enzimologia , Xenorhabdus/genética , Xenorhabdus/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Especificidade por SubstratoRESUMO
Enzymes catalyzing peptide macrocyclization are important biochemical tools in drug discovery. The three-residue cyclophane-forming enzymes (3-CyFEs) are an emerging family of post-translational modifying enzymes that catalyze the formation of three-residue peptide cyclophanes. In this report, we introduce three additional 3-CyFEs, including ChlB, WnsB, and FnnB, that catalyze cyclophane formation on Tyr, Trp, and Phe, respectively. To understand the promiscuity of these enzymes and those previously reported (MscB, HaaB, and YxdB), we tested single amino acid substitutions at the three-residue motif of modification (Ω1X2X3, Ω1 = aromatic). Collectively, we observe that substrate promiscuity is observed at the Ω1 and X2 positions, but a greater specificity is observed for the X3 residue. Two nonnative cyclophane products were characterized showing a Phe-C3 to Arg-Cß and His-C2 to Pro-Cß cross-links, respectively. We also tested the leader dependence of selected 3-CyFEs and show that a predicted helix region is important for cyclophane formation. These results demonstrate the biocatalytic potential of these maturases and allow rational design of substrates to obtain a diverse array of genetically encoded 3-residue cyclophanes.
Assuntos
Ciclofanos , Peptídeos , Sequência de Aminoácidos , Ciclização , Peptídeos/química , Processamento de Proteína Pós-TraducionalRESUMO
BACKGROUND: Antineoplastic chemotherapies are dramatically efficient when they provoke immunogenic cell death (ICD), thus inducing an antitumor immune response and even tumor elimination. However, activated caspases, the hallmark of most cancer chemotherapeutic agents, render apoptosis immunologically silent. Whether they are dispensable for chemotherapy-induced cell death and the apoptotic clearance of cells in vivo is still elusive. METHODS: A rational cell-based anticancer drug library screening was performed to explore the immunogenic apoptosis pathway and therapeutic targets under apoptotic caspase inhibition. Based on this screening, the potential of caspase inhibition in enhancing chemotherapy-induced antitumor immunity and the mechanism of actions was investigated by various cells and mouse models. RESULTS: Heat shock protein 90 (Hsp90) inhibition activates caspases in tumor cells to produce abundant genomic and mitochondrial DNA fragments and results in cell apoptosis. Meanwhile, it hijacks Caspase-9 signaling to suppress intrinsic DNA sensing. Pharmacological blockade or genetic deletion of Caspase-9 causes tumor cells to secrete interferon (IFN)-ß via tumor intrinsic mitochondrial DNA/the second messenger cyclic GMP-AMP (cGAS) /stimulator of interferon genes (STING) pathway without impairing Hsp90 inhibition-induced cell death. Importantly, both Caspase-9 and Hsp90 inhibition triggers an ICD, leading to the release of numerous damage-associated molecular patterns such as high-mobility group box protein 1, ATP and type I IFNs in vitro and remarkable antitumor effects in vivo. Moreover, the combination treatment also induces adaptive resistance by upregulating programmed death-ligand 1 (PD-L1). Additional PD-L1 blockade can further overcome this acquired immune resistance and achieve complete tumor regression. CONCLUSIONS: Blockade of Caspase-9 signaling selectively provokes Hsp90-based chemotherapy-mediated tumor innate sensing, leading to CD8+ T cell-dependent tumor control. Our findings implicate that pharmacological modulation of caspase pathway increases the tumor-intrinsic innate sensing and immunogenicity of chemotherapy-induced apoptosis, and synergizes with immunotherapy to overcome adaptive resistance.
Assuntos
Antineoplásicos , Interferon Tipo I , Neoplasias , Animais , Camundongos , Antineoplásicos/farmacologia , Antígeno B7-H1/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Caspases/metabolismo , DNA Mitocondrial , Proteínas de Choque Térmico HSP90/metabolismo , Interferon Tipo I/metabolismo , Neoplasias/tratamento farmacológicoRESUMO
DICER1 mutations predispose to increased risk for various cancers, particularly pleuropulmonary blastoma (PPB), the commonest lung malignancy of childhood. There is a paucity of directly actionable molecular targets as these tumors are driven by loss-of-function mutations of DICER1. Therapeutic development for PPB is further limited by a lack of biologically and physiologically-representative disease models. Given recent evidence of Dicer's role as a haploinsufficient tumor suppressor regulating RNA polymerase I (Pol I), Pol I inhibition could abrogate mutant Dicer-mediated accumulation of stalled polymerases to trigger apoptosis. Hence, we developed a novel subpleural orthotopic PPB patient-derived xenograft (PDX) model that retained both RNase IIIa and IIIb hotspot mutations and recapitulated the cardiorespiratory physiology of intra-thoracic disease, and with it evaluated the tolerability and efficacy of first-in-class Pol I inhibitor CX-5461. In PDX tumors, CX-5461 significantly reduced H3K9 di-methylation and increased nuclear p53 expression, within 24 hours' exposure. Following treatment at the maximum tolerated dosing regimen (12 doses, 30 mg/kg), tumors were smaller and less hemorrhagic than controls, with significantly decreased cellular proliferation, and increased apoptosis. As demonstrated in a novel intrathoracic tumor model of PPB, Pol I inhibition with CX-5461 could be a tolerable and clinically-feasible therapeutic strategy for mutant Dicer tumors, inducing antitumor effects by decreasing H3K9 methylation and enhancing p53-mediated apoptosis.
Assuntos
Blastoma Pulmonar , RNA Polimerase I , Humanos , RNA Polimerase I/genética , RNA Polimerase I/metabolismo , Proteína Supressora de Tumor p53/genética , Blastoma Pulmonar/genética , Blastoma Pulmonar/metabolismo , Blastoma Pulmonar/patologia , Carcinogênese , Ribonuclease III/genética , Ribonuclease III/metabolismo , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismoRESUMO
BACKGROUND AND AIMS: Dietary factors play an important role in promoting nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) development through regulation of metabolism and inflammation. However, so far there was no evidence regarding how dietary factors may influence different disease outcomes in the NAFLD to HCC progression. Our study aimed to comprehensively evaluate the role of dietary factors on the risk of progression from NAFLD to HCC. METHODS: A comprehensive literature research was conducted in PubMed, Web of Science and Embase databases to identify case-control and cohort studies published up to March 15, 2022 in English. We included studies investigating associations of food and beverage items (excluding alcohol), food groups, dietary patterns, and dietary habits with incidence risk of four main chronic liver diseases involved in the NAFLD-to-HCC progression (i.e., NAFLD, liver fibrosis, liver cirrhosis, and HCC). Three researchers independently performed the literature search, selected eligible articles, performed data abstraction and evaluated study quality. After evaluating adequacy and credibility of the associations reported for each dietary factor and each liver disease outcome, we summarized and evaluated the consistency of associations based on a priori determined criteria considering study design and the proportion of significant associations. RESULTS: There were 109 studies included in this review (47 on NAFLD, 1 on liver fibrosis, 6 on liver cirrhosis, and 55 on HCC). Consistent evidence suggested that higher dietary inflammatory potential was associated with increased risk of both NAFLD and HCC whereas Mediterranean diet was associated with lower risk of both diseases. Additionally, greater conformity to the Healthy Eating Index, Dietary Approaches to Stop Hypertension score, and Mediterranean Diet Score, and dietary patterns with high dietary antioxidant capacity reduced NAFLD risk. Some specific foods including soft drinks and red and/or processed meat were associated with increased NAFLD risk while total vegetables and spinach were associated with reduced NAFLD risk. Coffee and white meat consumption were inversely related to HCC risk. CONCLUSIONS: Dietary patterns or individual foods representing a more anti-inflammatory potential were associated with reduced risk of both NAFLD and HCC, which implied diet-induced inflammation may impact NAFLD progression towards HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Antioxidantes , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/epidemiologia , Café , Progressão da Doença , Humanos , Inflamação/complicações , Cirrose Hepática/complicações , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/epidemiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Fatores de RiscoRESUMO
BACKGROUND: Deletion of 1p is associated with poor prognosis in neuroblastoma, however selected 1p-intact patients still experience poor outcomes. Since mutations of 1p genes may mimic the deleterious effects of chromosomal loss, we studied the incidence, spectrum and effects of mutational variants in 1p-intact neuroblastoma. METHODS: We characterized the 1p status of 325 neuroblastoma patients, and correlated the mutational status of 1p tumor suppressors and neuroblastoma candidate genes with survival outcomes among 100 1p-intact cases, then performed functional validation of selected novel variants of 1p36 genes identified from our patient cohort. RESULTS: Among patients with adverse disease characteristics, those who additionally had 1p deletion had significantly worse overall survival. Among 100 tumor-normal pairs sequenced, somatic mutations of 1p tumor suppressors KIF1Bß and CHD5 were most frequent (2%) after ALK and ATRX (8%), and BARD1 (3%). Mutations of neuroblastoma candidate genes were associated with other synchronous mutations and concurrent 11q deletion (P = 0.045). In total, 24 of 38 variants identified were novel and predicted to be deleterious or pathogenic. Functional validation identified novel KIF1Bß I1355M variant as a gain-of-function mutation with increased expression and tumor suppressive activity, correlating with indolent clinical behavior; another novel variant CHD5 E43Q was a loss-of-function mutation with decreased expression and increased long-term cell viability, corresponding with aggressive disease characteristics. CONCLUSIONS: Our study showed that chromosome 1 gene mutations occurred frequently in 1p-intact neuroblastoma, but may not consistently abrogate the function of bonafide 1p tumor suppressors. These findings may augment the evolving model of compounding contributions of 1p gene aberrations toward tumor suppressor inactivation in neuroblastoma.
Assuntos
Genes Supressores de Tumor , Neuroblastoma , Aberrações Cromossômicas , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Estudos de Coortes , DNA Helicases/genética , Humanos , Mutação , Proteínas do Tecido Nervoso/genética , Neuroblastoma/genética , Neuroblastoma/patologiaRESUMO
BACKGROUND: Infective spondylodiscitis has been treated solely with antibiotics based on the pathogen identified. Surgical intervention was used in cases of unidentified pathogens, failed antibiotic treatment, neurological deficit, or instability. The standard surgical procedure was debridement and interbody fusion with a bone graft through the anterior approach, followed by posterior instrumentation. Recently, percutaneous endoscopic surgery has been proven to be safe and effective for treating infectious spondylodiscitis. The results of endoscopy surgery treatment alone for infectious spondylodiscitis with severe bony destruction were analyzed in this study. OBJECTIVE: To describe the clinical and radiological outcomes in patients with infectious spondylodiscitis and severe bony destruction, who were treated with minimally invasive endoscopic surgery alone. STUDY DESIGN: Retrospective observational study (Institutional Review Board: CMUH 105-REC2-101). SETTING: An inpatient surgery center. METHODS: The study included 24 patients with infectious spondylodiscitis and severe bony destruction treated with endoscopy surgery. The patients were treated according to the endoscopic surgical protocol and were followed up for at least 5 years. A retrospective chart review was conducted to evaluate the locations, symptoms and signs, comorbidity, pain scale, and functional outcome. Laboratory data, such as erythrocyte sedimentation rate and C-reactive protein level, and clinical outcomes, including the pain scale, visual analogue scale, and functional score of Oswestry disability index, were recorded. All patients underwent a preoperative magnetic resonance imaging (MRI) scan and were carefully reviewed and classified based on the severity, including endplate erosion, bone edema (low T1, high T2), loss of vertebral height, paravertebral inflammation, paravertebral abscess, and epidural abscess. All patients underwent a plain film follow-up at 3, 6, 9, 12, and 18 months after surgery and computed tomography at 12 months postoperatively. RESULTS: The comorbidities of patients were categorized according to the Charlson Comorbidity Index. The results revealed 10 lesions on the thoracic or upper lumbar spine (between T10 and L3) and 14 on the lower lumbar spine (between L3 and S1). Bone destruction as a result of severe infection and loss of disc height was observed in most cases. During the final follow-up, no significant changes were observed in the sagittal alignment, and a kyphotic angle change of less than 10° was observed in 20 cases. Syndesmophyte formation along the anterior longitudinal ligament (ALL), paravertebral syndesmophyte formation, intervertebral bony fusion, and bony ankylosis of the facet joints in the form of osteophyte formation and fusion were noted. No posterior instrumentation surgery was performed for instability in our case series. LIMITATIONS: This was a retrospective observational clinical case series with small sample size. CONCLUSIONS: A trend of spontaneous spinal arthrodesis, including syndesmophyte formation along the ALL, paravertebral ligaments, direct intervertebral bone growth, and bony ankylosis of the facet joint were observed after a minimally invasive endoscopy treatment for infectious spondylodiscitis. The stability of the 3 columns resulted in segmental stability, which prevented the progression of the kyphotic deformity. Percutaneous endoscopic surgery is safe and effective for treating infectious spondylodiscitis even in patients with severe bony destruction.
Assuntos
Anquilose , Discite , Cifose , Fusão Vertebral , Desbridamento/métodos , Discite/cirurgia , Endoscopia , Humanos , Vértebras Lombares/cirurgia , Dor , Estudos Retrospectivos , Fusão Vertebral/métodos , Resultado do TratamentoRESUMO
BACKGROUND: We investigated the superiority of arthroscopy-assisted reduction and internal fixation (ARIF) to open reduction and internal fixation (ORIF) for treating glenoid fracture with scapular involvement. METHODS: We retrospectively enrolled patients with glenoid fracture who underwent ARIF or ORIF from 2010-2020. Radiographic outcomes were assessed, and clinical outcomes (active range of motion [ROM], visual analog scale [VAS], Constant, and Disabilities of the Arm, Shoulder and Hand [DASH]) were evaluated 12 months postoperatively. RESULTS: Forty-four patients with Ideberg type II-VI glenoid fractures (ARIF: 20; ORIF: 24; follow-up 12-22 months) were included. Union was achieved in all patients. Active ROM values were comparable between the approaches. Constant and DASH scores were non-significantly better with ARIF (90.9 ± 9.2 vs. 86.6 ± 18.1 [p = 0.341] and 6.8 ± 9.4 vs. 9.3 ± 21.3 [p = 0.626], respectively). However, VAS scores were significantly lower with ARIF (1.5 ± 0.6 vs. 2.7 ± 1.4, p = 0.001). Associated intra-articular lesions (articular depressions [80%], superior labral anterior-posterior tear [20%], labral tears [30%]) were found in most ARIF cases and were repaired during ARIF. CONCLUSIONS: For glenoid fracture with scapular involvement, ARIF allows accurate diagnosis of fracture pattern and the management of associated intra-articular lesions, with better pain control outcomes than ORIF. Thus, arthroscopy-assistant surgery should be considered in patient with glenoid fracture.
RESUMO
BACKGROUND: Posterior-stabilized antibiotic cement articulating spacers (PS spacers) reduce spacer mechanical complications in prosthetic knee infections (PKIs); however, joint dislocation after femoral cam fracture has been reported. We hypothesized that the rate of post-cam mechanical complications is lower in PS spacers with an endoskeleton-reinforced cam. METHOD: A retrospective study of PKIs using PS spacers with or without a Kirschner wire-reinforced cam (K-PS or nK-PS spacers, respectively) was conducted between 2015 and 2019. The rates of post-cam mechanical complications and reoperation, as well as risk factors for post or cam failure, were analyzed. RESULTS: The cohort included 118 nK-PS and 49 K-PS spacers. All patients were followed up for 2 years. The rate of joint subluxation/dislocation after femoral cam fracture was lower in K-PS (0%) than in nK-PS spacers (17.8%; P = .002). The reoperation rate for spacer mechanical complications was lower in K-PS (0%) than in nK-PS spacers (11.9%; P = .008). The identified risk factors for femoral cam fractures were body mass index ≥25 kg/m2, femoral spacer size ≤2, and surgical volume ≤12 resection arthroplasties per year. CONCLUSION: This preliminary study highlights that K-PS spacers have a lower rate of post-cam mechanical complications than nK-PS spacers. We recommend the use of PS spacers with endoskeleton-reinforced cam when treating PKIs performed by surgeons with lower surgical volumes, especially in patients with higher body mass index and smaller femoral spacer sizes.
Assuntos
Prótese do Joelho , Infecções Relacionadas à Prótese , Antibacterianos/uso terapêutico , Cimentos Ósseos , Humanos , Articulação do Joelho/cirurgia , Prótese do Joelho/efeitos adversos , Infecções Relacionadas à Prótese/tratamento farmacológico , Infecções Relacionadas à Prótese/etiologia , Infecções Relacionadas à Prótese/cirurgia , Reoperação/efeitos adversos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Antibiotic cement articulating spacers are recommended during 2-stage revision for prosthetic knee infection because of increased range of motion (ROM) and improved function; however, spacer mechanical complications have been reported. We aimed to determine the association between different constraints of articulating spacers and the rate of complications and infection eradication, functional outcomes, and ROM. METHODS: A retrospective study of prosthetic knee infection using cruciate-retaining (CR) or posterior-stabilized (PS) spacers was conducted between 2011 and 2018. The rate of spacer mechanical complications, infection eradication after reimplantation and reoperation, Hospital of Special Surgery (HSS) knee score, and ROM during the interim stage were analyzed. All patients were regularly followed up for 2 years. RESULTS: One hundred forty-one patients were included, with 66 CR and 75 PS spacers. Overall mechanical complication rate was lower in PS (9.3%) than in CR spacers (45.5%) (P < .001), especially in joint dislocation (1.3% vs 30.3%, respectively, P < .001). Overall reoperation rate was lower in PS (16.0%) than in CR spacers (36.4%) (P < .001), especially for mechanical complications (1.3% vs 24.2%, respectively, P < .001). HSS knee score was higher in PS (72.3) than in CR spacers (63.8) (P < .001). ROM was greater in PS (90.3°) than in CR spacers (80.6°) (P = .005), especially at maximum flexion (102.4° vs 89.6°, respectively, P = .003). Infection eradication was comparable between the spacers. CONCLUSION: Both spacers can control infection; however, PS spacers had a lower rate of mechanical complications and reoperation, better HSS knee scores, and greater ROM than CR spacers.
Assuntos
Prótese do Joelho , Infecções Relacionadas à Prótese , Antibacterianos/uso terapêutico , Humanos , Prótese do Joelho/efeitos adversos , Infecções Relacionadas à Prótese/tratamento farmacológico , Infecções Relacionadas à Prótese/epidemiologia , Infecções Relacionadas à Prótese/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Cancer has become one of the major diseases threatening human health and life. Circulating tumor DNA (ctDNA) testing, as a practical liquid biopsy technique, is a promising method for cancer diagnosis, targeted therapy and prognosis. Here, for the first time, a field effect transistor (FET) biosensor based on uniformly sized high-response silicon nanowire (SiNW) array was studied for real-time, label-free, super-sensitive detection of PIK3CA E542K ctDNA. High-response 120-SiNWs array was fabricated on a (111) silicon-on-insulator (SOI) by the complementary metal oxide semiconductor (CMOS)-compatible microfabrication technology. To detecting ctDNA, we modified the DNA probe on the SiNWs array through silanization. The experimental results demonstrated that the as-fabricated biosensor had significant superiority in ctDNA detection, which achieved ultralow detection limit of 10 aM and had a good linearity under the ctDNA concentration range from 0.1 fM to 100 pM. This biosensor can recognize complementary target ctDNA from one/two/full-base mismatched DNA with high selectivity. Furthermore, the fabricated SiNW-array FET biosensor successfully detected target ctDNA in human serum samples, indicating a good potential in clinical applications in the future.
Assuntos
Técnicas Biossensoriais , DNA Tumoral Circulante , Nanofios , Biomarcadores Tumorais , Humanos , Silício , Transistores EletrônicosRESUMO
Background and Objectives: The proximity of the popliteal vessels in the distal femur may increase the risk of iatrogenic vascular injury during cerclage wiring. In this study, the closest location and distance of the popliteal vessels to the femur was examined using magnetic resonance imaging (MRI). The associations between anthropometric factors and the distance that would guide the placement of wires safely during surgery were also identified. Materials and Methods: We reviewed adult knee magnetic resonance images and recorded: (1) the relation and the shortest horizontal distance (d-H) from the femoral cortex to the popliteal vessels in axial images and (2) the vertical distance (d-V) from the adductor tubercle to the axial level of the d-H values in coronal images. The effects of anthropometric factors (sex, age, body height, body weight, body mass index, thigh circumference, femoral length and femoral width) on these distances were analysed. Results: Analysis of 206 knee magnetic resonance images revealed that the closet locations of popliteal vessels were at the posteromedial aspect of the femur. The d-H and d-V were 7.38 ± 3.22 mm and 57.01 ± 11.14 mm, respectively, and were both shorter in women than in men (p < 0.001). Multivariate analysis identified thigh circumference and femoral length as the most influential factors for the d-H and d-V, respectively (p < 0.001). Linear regression demonstrated a strong positive linear correlation between the thigh circumference and the d-H and between the femoral length and the d-V (Pearson's r = 0.891 and 0.806, respectively (p < 0.001)). Conclusions: The closet location and distance of the popliteal vessels to the femur provide useful information for wire placement during distal femoral fracture surgery while minimising the risk of vascular injury. Given that patients with a smaller thigh circumference and a shorter femoral length are more likely to have a smaller d-H and a shorter d-V, respectively, cautious measures should be taken in such cases.
Assuntos
Fraturas do Fêmur , Adulto , Fios Ortopédicos , Feminino , Fraturas do Fêmur/diagnóstico por imagem , Fraturas do Fêmur/cirurgia , Fêmur/diagnóstico por imagem , Fêmur/cirurgia , Fixação Interna de Fraturas , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
AIMS: Congenital mesoblastic nephroma (CMN) is histologically classified into classic, cellular and mixed subtypes. The aims of this study were to characterise the clinical, pathological and molecular features of a series of CMNs, and to determine the utility of pan-Trk and epidermal growth factor receptor (EGFR) immunohistochemistry as surrogate markers for NTRK gene fusions and EGFR internal tandem duplications (ITDs). METHODS AND RESULTS: Twenty-two archival CMN cases (12 classic, five cellular, and five mixed) were tested for the ETV6-NTRK3 fusion and EGFR ITD transcripts by the use of reverse transcriptase polymerase chain reaction (PCR), and next-generation sequencing-based anchored multiplex PCR. All 12 classic CMNs had EGFR ITD. Of the five cellular CMNs, four had the ETV6-NTRK3 fusion and one had the KLHL7-BRAF fusion. Of the five mixed CMNs, four had EGFR ITD, and one had the ETV6-NTRK3 fusion. Pan-Trk immunoreactivity was 100% sensitive and 94.1% specific for the presence of NTRK rearrangement. However, EGFR staining was only 62.5% sensitive and 33.3% specific for EGFR ITD. CONCLUSIONS: EGFR ITD is a consistent genetic event in classic CMN. A majority of cellular CMNs have the ETV6-NTRK3 fusion. Rare cellular CMNs may harbour non-canonical mutations such as the KLHL7-BRAF fusion, which was found in one case. Mixed CMNs may have either EGFR ITD or the ETV6-NTRK3 fusion. Pan-Trk immunohistochemistry is a sensitive, albeit not perfectly specific, marker for NTRK rearrangement. EGFR immunohistochemistry is not helpful as a marker of EGFR ITD.
Assuntos
Autoantígenos/genética , Neoplasias Renais/genética , Nefroma Mesoblástico/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas B-raf/genética , Receptores ErbB/genética , Feminino , Duplicação Gênica , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Fusão OncogênicaAssuntos
Proteínas de Ligação a DNA/genética , Proteínas Nucleares/genética , Coativador 2 de Receptor Nuclear/genética , Rabdomiossarcoma/genética , Neoplasias de Tecidos Moles/genética , Fatores de Transcrição/genética , Pé , Humanos , Lactente , Masculino , Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/genética , Rabdomiossarcoma/congênito , Rabdomiossarcoma/patologia , Neoplasias de Tecidos Moles/congênito , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição de Domínio TEARESUMO
Primary glomus tumors of the kidney are rare and have never been reported in children under 16 years of age. Tuberous sclerosis complex (TSC) is an extremely variable genetic condition that can affect virtually any organ in the body. Only a single case of glomus tumor associated with TSC was reported in 1964. In this article, we describe the clinical, radiologic, and pathological features of a primary renal glomus tumor in an 8-year-old girl with TSC. This tumor is large, has a deep location, and has infiltrative margins and numerous mitoses. However, there was no disease progression in a 16-month period of follow-up. To our knowledge, this is the second report of primary renal glomus tumor in childhood, the youngest one in the literature.
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Tumor Glômico/patologia , Neoplasias Renais/patologia , Esclerose Tuberosa/complicações , Criança , Feminino , Tumor Glômico/etiologia , Humanos , Neoplasias Renais/etiologiaRESUMO
BACKGROUND: In comparison to static spacers, articulating spacers have been shown to result in a similar infection eradication rate in two-stage revision of periprosthetic knee infections. However, the optimal construct for articulating spacers has not been identified yet. The aim of this study was to present a preliminary result of treatment for periprosthetic knee infection using a novel computer-aided design (CAD)-articulating spacer. METHODS: We retrospectively reviewed 32 consecutive cases of chronic periprosthetic knee infection occurring from January 2015 to December 2015. In these cases, we used an antibiotic-loaded, optimized CAD-articulating spacer based on the retrieved knee prosthesis. Evaluation included infection eradication rate, the Hospital of Special Surgery (HSS) knee score, range of motion (ROM), and spacer-related mechanical complications. All cases were regularly followed-up for 2 years minimum. RESULTS: Twenty-eight of 32 patients (87.5%) had infection eradication; 18 patients (56.3%) received reimplantation successfully. The mean interval between spacer insertion and reimplantation was 8.8 months (range 4.0-12.5 months). The mean HSS knee score and ROM significantly increased during each interval (p < 0.0001 for both). The mean HSS knee scores were 31.2 (range 20-48) at initial visit, 65.4 (range 60-78.8) at 1 month after spacer insertion, and 84.2 (range 78-90) at 3 months after reimplantation (p < 0.0001). The mean ROM were 72.0° (range 15-100°), 85.6° (range 35-110°), and 102.0° (range 80-122°), respectively (p = 0.002). Two (6.3%) spacer-related mechanical complications occurred. CONCLUSIONS: The CAD-articulating spacer in two-staged revision of periprosthetic knee infection significantly controlled infection, improved clinical outcomes, increased ROM, and decreased mechanical complications in the preliminary study. Further larger clinical studies are needed to confirm the findings presented here.
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Antibacterianos/administração & dosagem , Cimentos Ósseos , Desenho Assistido por Computador , Prótese do Joelho/efeitos adversos , Infecções Relacionadas à Prótese/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Liberação Controlada de Fármacos , Seguimentos , Humanos , Prótese do Joelho/microbiologia , Pessoa de Meia-Idade , Infecções Relacionadas à Prótese/diagnóstico por imagem , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Primary paediatric epidural sarcomas are extremely rare. Overall, there remains a paucity of knowledge in paediatric epidural sarcomas owing to the infrequent number of cases. The Archer FusionPlex Sarcoma Kit (ArcherDX, Inc) is a next-generation sequencing assay that has been reported to be a useful technique to detect recurrent fusion in sarcomas. We report the molecular exploration of 3 primary paediatric epidural sarcomas-one in the cranium (mesenchymal chondrosarcoma) and 2 in the spine (mesenchymal chondrosarcoma and Ewing sarcoma respectively). CASE PRESENTATION: This is a study approved by the hospital ethics board. Clinico-pathological information from 3 consenting patients with primary epidural sarcomas was collected. These selected tumours are interrogated via Archer FusionPlex Sarcoma Kit (ArcherDX, Inc) for genomic aberrations. Results were validated with RT-PCR and Sanger sequencing. All findings are corroborated and discussed in concordance with current literature. Our findings show 2 variants of the HEY1-NCOA2 gene fusion: HEY1 (exon 4)-NCOA2 (exon 13) and HEY1 (exon 4)-NCOA2 (exon 14), in both mesenchymal chondrosarcoma patients. Next, the Ewing sarcoma tumour is found to have EWSR1 (exon 10)-FLI1 (exon 8) translocation based on NGS. This result is not detected via conventional fluorescence in situ testing. CONCLUSIONS: This is a molecularly-centered study based on 3 unique primary paediatric epidural sarcomas. Our findings to add to the growing body of literature for these exceptionally rare and malignant neoplasms. The authors advocate global collaborative efforts and in-depth studies for targeted therapy to benefit affected children.
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Neoplasias Epidurais/diagnóstico , Sarcoma/diagnóstico , Fatores Etários , Biomarcadores Tumorais , Biópsia , Criança , Condrossarcoma Mesenquimal/diagnóstico , Condrossarcoma Mesenquimal/genética , Análise Mutacional de DNA , Neoplasias Epidurais/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Sarcoma/genética , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/genética , Avaliação de SintomasAssuntos
Proteínas Proto-Oncogênicas c-raf/genética , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Ubiquitina-Proteína Ligases/genética , Antígenos CD34/metabolismo , Pré-Escolar , Humanos , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas S100/metabolismoRESUMO
In 2008, we presented three cases of ALK-positive histiocytosis as a novel systemic histiocytic proliferation of early infancy with hepatosplenomegaly and dramatic hematological disturbances. This series of 10 cases (including the original three cases) describes an expanded clinicopathological spectrum and the molecular findings of this histiocytic proliferation. Six patients had disseminated disease: five presented in early infancy with eventual disease resolution, and the sixth presented at 2 years of age and died of intestinal, bone marrow, and brain involvement. The other four patients had localized disease involving nasal skin, foot, breast, and intracranial cavernous sinus - the first three had no recurrence after surgical resection, while the cavernous sinus lesion showed complete resolution with crizotinib therapy. The lesional histiocytes were very large, with irregularly folded nuclei, fine chromatin, and abundant eosinophilic cytoplasm, sometimes with emperipolesis. There could be an increase in foamy histiocytes and Touton giant cells with time, resembling juvenile xanthogranuloma. Immunostaining showed that the histiocytes were positive for ALK, histiocytic markers (CD68, CD163) and variably S100, while being negative for CD1a, CD207, and BRAF-V600E. Next-generation sequencing-based anchored multiplex PCR (Archer® FusionPlex®) performed in six cases identified KIF5B-ALK gene fusion in five and COL1A2-ALK fusion in one. There was no correlation of gene fusion type with disease localization or dissemination. The clinicopathological spectrum of ALK-positive histiocytosis is broader than originally described, and this entity is characterized by frequent presence of KIF5B-ALK gene fusion. We recommend that every unusual histiocytic proliferative disorder, especially disseminated lesions, be tested for ALK expression because of the potential efficacy of ALK inhibitor therapy in unresectable or disseminated disease.