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Magnetic van der Waals (vdW) materials have opened new frontiers for realizing novel many-body phenomena. Recently NiPS3 has received intense interest since it hosts an excitonic quasiparticle whose properties appear to be intimately linked to the magnetic state of the lattice. Despite extensive studies, the electronic character, mobility, and magnetic interactions of the exciton remain unresolved. Here we address these issues by measuring NiPS3 with ultra-high energy resolution resonant inelastic x-ray scattering (RIXS). We find that Hund's exchange interactions are primarily responsible for the energy of formation of the exciton. Measuring the dispersion of the Hund's exciton reveals that it propagates in a way that is analogous to a double-magnon. We trace this unique behavior to fundamental similarities between the NiPS3 exciton hopping and spin exchange processes, underlining the unique magnetic characteristics of this novel quasiparticle.
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BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint blockers (ICBs) ultimately progress either rapidly (primary resistance) or after durable benefit (secondary resistance). The cancer vaccine OSE2101 may invigorate antitumor-specific immune responses after ICB failure. The objective of ATALANTE-1 was to evaluate its efficacy and safety in these patients. PATIENTS AND METHODS: ATALANTE-1 was a two-step open-label study to evaluate the efficacy and safety of OSE2101 compared to standard-of-care (SoC) chemotherapy (CT). Patients with human leukocyte antigen (HLA)-A2-positive advanced NSCLC without actionable alterations, failing sequential or concurrent CT and ICB were randomized (2 : 1) to OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of interim analysis, a decision was taken to prematurely stop the accrual due to coronavirus disease 2019 (COVID-19). Final analysis was carried out in all patients and in the subgroup of patients with ICB secondary resistance defined as failure after ICB monotherapy second line ≥12 weeks. RESULTS: Two hundred and nineteen patients were randomized (139 OSE2101, 80 SoC); 118 had secondary resistance to sequential ICB. Overall, median OS non-significantly favored OSE2101 over SoC {hazard ratio (HR) [95% confidence interval (CI)] 0.86 [0.62-1.19], P = 0.36}. In the secondary resistance subgroup, OSE2101 significantly improved median OS versus SoC [11.1 versus 7.5 months; HR (95% CI) 0.59 (0.38-0.91), P = 0.017], and significantly improved post-progression survival (HR 0.46, P = 0.004), time to Eastern Cooperative Oncology Group (ECOG) performance status deterioration (HR 0.43, P = 0.006) and Quality of Life Questionnaire Core 30 (QLQ-C30) global health status compared to SoC (P = 0.045). Six-month disease control rates and progression-free survival were similar between groups. Grade ≥3 adverse effects occurred in 11.4% of patients with OSE2101 and 35.1% in SoC (P = 0.002). CONCLUSIONS: In HLA-A2-positive patients with advanced NSCLC and secondary resistance to immunotherapy, OSE2101 increased survival with better safety compared to CT. Further evaluation in this population is warranted.
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COVID-19 , Vacinas Anticâncer , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Vacinas Anticâncer/efeitos adversos , Antígeno HLA-A2/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/etiologia , Qualidade de Vida , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , COVID-19/etiologia , ImunoterapiaRESUMO
Necrotizing fasciitis is one of the most common soft tissue infections, with a high risk of major amputation and a mortality ranging from 6 to 33% which has not changed in the past 20 years. Early surgical resection of necrotic tissue plays a key role in determining the prognosis. Nawijn et al. identified an optimal 6 hours window from presentation to surgery. Symptoms of necrotizing fasciitis mimic those of common skin infections, such as erysipelas and cellulitis, making rapid surgical management difficult. In this context, the aid of point-of-care-ultrasound is a valuable tool for early diagnosis, detecting the presence of subcutaneous thickening, gas and perifascial liquid. Other characteristic ultrasound findings include the "cobblestone" appearance of the subcutaneous soft tissues and reverberation artifacts due to hyperechoic outbreaks, defined as "snow globes" due to the presence of heterogeneous swirling material, and "dirty shadowing" due to the foggy shadow created by the gas.
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Fasciite Necrosante , Infecções dos Tecidos Moles , Humanos , Fasciite Necrosante/diagnóstico por imagem , Fasciite Necrosante/cirurgia , Prognóstico , Necrose , Testes Imediatos , Infecções dos Tecidos Moles/diagnósticoRESUMO
Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.
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Hemangioendotelioma Epitelioide , Sarcoma , Adulto , Criança , Consenso , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/tratamento farmacológico , Humanos , Oncologia , Defesa do Paciente , Sarcoma/diagnóstico , Sarcoma/tratamento farmacológicoRESUMO
BACKGROUND: We evaluated the efficacy and safety of the nontaxane microtubule dynamics inhibitor eribulin plus the humanized anti-VEGF monoclonal antibody bevacizumab in a novel second-line chemotherapy scheme in HER2-negative metastatic breast cancer (MBC) patients progressing after first-line paclitaxel and bevacizumab. PATIENTS AND METHODS: This is a multicenter, single-arm, Simon's two-stage, phase II study. The primary endpoint was the overall response rate, considered as the sum of partial and complete response based on the best overall response rate (BORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and clinical benefit rate. RESULTS: A total of 58 of the 61 patients enrolled in the study were evaluable for efficacy. The BORR was 24.6% (95% CI 14.5-37.3). The clinical benefit rate was 32.8% (95% CI 21.3-46.0). The median PFS was 6.2 months (95% CI 4.0-7.8), and median OS was 14.8 months (95% CI 12.6-22.8). Overall, adverse events (AEs) were clinically manageable and the most common AEs were fatigue, paresthesia, and neutropenia. Quality of life was well preserved in most patients. CONCLUSIONS: The results of this study suggest that second-line therapy with bevacizumab in combination with eribulin has a meaningful clinical activity and may represent a potential therapeutic option for patients with HER2-negative MBC.
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Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Furanos , Humanos , Cetonas , Paclitaxel/efeitos adversos , Qualidade de Vida , Resultado do TratamentoRESUMO
INTRODUCTION: A meningeal solitary fibrous tumor (SFT), also called hemangiopericytoma, is a rare mesenchymal malignancy. Due to anatomic constrains, even after macroscopic complete surgery with curative intent, the local relapse risk is still relatively high, thus increasing the risk of dedifferentiation and metastatic spread. This study aims to better define the role of postoperative radiotherapy (RT) in meningeal SFTs. PATIENTS AND METHODS: A retrospective study was performed across seven sarcoma centers. Clinical information was retrieved from all adult patients with meningeal primary localized SFT treated between 1990 and 2018 with surgery alone (S) compared to those that also received postoperative RT (S + RT). Differences in treatment characteristics between subgroups were tested using independent samples t-test for continuous variables and chi-square tests for proportions. Local control (LC) and overall survival (OS) rates were calculated as time from start of treatment until progression or death from any cause. LC and OS in groups receiving S or S + RT were compared using Kaplan-Meier survival curves. RESULTS: Among a total of 48 patients, 7 (15%) underwent S and 41 (85%) underwent S + RT. Median FU was 65 months. LC was significantly associated with treatment. LC after S at 60 months was 60% versus 90% after S + RT (p = 0.052). Furthermore, R1 resection status was significantly associated with worse LC (HR 4.08, p = 0.038). OS was predominantly associated with the mitotic count (HR 3.10, p = 0.011). CONCLUSION: This retrospective study, investigating postoperative RT in primary localized meningeal SFT patients, suggests that combining RT to surgery in the management of this patient population may reduce the risk for local failures.
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Hemangiopericitoma , Neoplasias Meníngeas , Tumores Fibrosos Solitários , Adulto , Hemangiopericitoma/radioterapia , Hemangiopericitoma/cirurgia , Humanos , Neoplasias Meníngeas/radioterapia , Neoplasias Meníngeas/cirurgia , Recidiva Local de Neoplasia , Estudos Retrospectivos , Tumores Fibrosos Solitários/radioterapia , Tumores Fibrosos Solitários/cirurgiaRESUMO
BACKGROUND: Patients undergoing surgery for soft tissue sarcoma have high morbidity rates, particularly after preoperative radiation therapy (RT). An enhanced recovery after surgery (ERAS) programme may improve perioperative outcomes in abdominal surgery. This study reported outcomes of an ERAS programme tailored to patients with soft tissue sarcoma. METHODS: A prospective ERAS protocol was implemented in 2015 at a high-volume sarcoma centre. Patients treated within the ERAS programme from 2015 to 2018 were case-matched retrospectively with patients treated between 2012 and 2018 without use of the protocol, matched by surgical site, surgeon, sarcoma histology and preoperative RT treatment. Postoperative outcomes, specifically wound complications and duration of hospital stay, were reported. RESULTS: In total, 234 patients treated within the ERAS programme were matched with 237 who were not. The ERAS group had lower wound dehiscence rates overall (2 of 234 (0·9 per cent) versus 31 of 237 (13·1 per cent); P < 0·001), after preoperative RT (0 of 41 versus 11 of 51; P = 0·004) and after extremity sarcoma surgery (0 of 54 versus 6 of 56; P = 0·040) compared with the non-ERAS group. Rates of postoperative ileus or obstruction were lower in the ERAS group (21 of 234 (9·9 per cent) versus 40 of 237 (16·9 per cent); P = 0·016) and in those with retroperitoneal sarcoma (4 of 36 versus 15 of 36; P = 0·007). Duration of hospital stay was shorter in the ERAS group (median 5 (range 0-36) versus 6 (0-67) days; P = 0·003). CONCLUSION: Treatment within an ERAS protocol for patients with soft tissue sarcoma was associated with lower morbidity and shorter hospital stay.
ANTECEDENTES: Los pacientes sometidos a cirugía por sarcoma de tejido blando (soft tissue sarcoma, STS) tienen altas tasas de morbilidad, particularmente después de la radioterapia preoperatoria (RT). El programa de recuperación intensificada después de la cirugía (enhanced recovery after surgery, ERAS) puede mejorar los resultados perioperatorios en la cirugía abdominal. Este estudio analizó los resultados de un programa ERAS diseñado para pacientes con STS. MÉTODOS: Se implementó un protocolo prospectivo ERAS en el año 2015 en un centro de alto volumen de sarcomas. Los pacientes en ERAS desde 2015 hasta 2018 fueron emparejados retrospectivamente con pacientes sin ERAS desde 2012 hasta 2018, según la localización quirúrgica, el cirujano, la histología del sarcoma y el tratamiento con RT preoperatoria. Se analizaron los resultados postoperatorios, específicamente las complicaciones de la herida y la duración de la estancia hospitalaria (length of stay, LOS). RESULTADOS: En total, 234 pacientes tratados con ERAS se compararon con 237 pacientes no tratados con ERAS. Los pacientes con ERAS tuvieron tasas globales más bajas de dehiscencia de la herida (2 (0,9%) versus 31 (13,1%), P < 0,001)), después de la RT preoperatoria (0 versus 11 (21,6%), P = 0,004)), y después de la cirugía de STS de extremidades (0 versus 6 (0,7%), P = 0,04)) en comparación con los pacientes no ERAS. Las tasas de íleo u obstrucción postoperatorias fueron más bajas en el grupo ERAS (21 (9,9%) versus 40 (16,9%), P = 0,02)) y en aquellos pacientes con sarcoma retroperitoneal (4 (11,1%) versus 15 (41,7%), P = 0,007)). La mediana (rango) de la LOS fue más corta en los pacientes con ERAS que fue de 5 (0-36) días que en los pacientes sin ERAS que fue de 6 (0-67) días (P = 0,003). CONCLUSIÓN: ERAS para pacientes con STS se asoció con una menor morbilidad y una estancia hospitalaria más corta.
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Recuperação Pós-Cirúrgica Melhorada , Sarcoma/cirurgia , Procedimentos Clínicos , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos RetrospectivosRESUMO
Approximately one-third of all non-small-cell lung cancer (NSCLC) are locally-advanced at diagnosis, and 15-17% of these tumors are unresectable at presentation. Definitive chemo-radiotherapy (CRT) represents the standard therapeutic approach. However, the literature has shown that only 15% of patients are alive at 5 years and this percentage has remained unchanged despite various attempts of improvement. The recent introduction of immunotherapy has not only strongly changed the clinical scenario but has also drawn attention to a stage of disease apparently forgotten for decades. Stage III NSCLC can represent an interesting setting for the combined use of chemo-radiation and immunotherapy, due to the potential synergistic effect between radiation and immune checkpoint inhibitors. We reviewed the available literature in order to report the state of art of stage III NSCLC, by focusing on trials that evaluate different combinations of CRT and new drugs of PD-1/PD-L1 axis, and anti-CTLA-4. The future goal in the management of unresectable stage III NSCLC will be the optimal patients' selection combined with the use of individualized immuno/chemotherapies that could potentially improve clinical outcomes.
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Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia/métodos , Neoplasias Pulmonares/terapia , Ensaios Clínicos como Assunto , Humanos , ImunoterapiaAssuntos
Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Regressão Neoplásica Espontânea , Couro Cabeludo/patologia , Neoplasias Cutâneas/patologia , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Cetuximab/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Masculino , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
The most common endocrine malignancy is thyroid cancer, and researchers have made a great deal of progress in deciphering its molecular mechanisms in the recent years. Many of molecular changes observed in thyroid cancer can be used as biomarkers for diagnosis, prognosis, and therapeutic targets for treatment. MicroRNAs (miRNAs) are important parts in biological and metabolic pathways such as regulation of developmental stages, signal transduction, cell maintenance, and differentiation. Therefore, their dysregulation can expose individuals to malignancies. It has been proved that miRNA expression is dysregulated in different types of tumors, like thyroid cancers, and can be the cause of tumor initiation and progression. In this paper, we have reviewed the available data on miRNA dysregulation in different thyroid tumors including papillary, follicular, anaplastic, and medullary thyroid carcinomas aiming to introduce the last updates in miRNAs-thyroid cancer relation.
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MicroRNAs/genética , MicroRNAs/uso terapêutico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/terapia , Regulação Neoplásica da Expressão Gênica , Humanos , PrognósticoRESUMO
INTRODUCTION: The obturator hernia is a rare pelvic hernia that often comes in the shape of bowel obstruction caused by the presence of an intestinal segment, more often ileum, passing trough the obturator foramen of the pelvic wall (Fig. 1). This type of hernia accounts for 0.5-1.4% of all hernias. CASE PRESENTATION: We report the clinical case of a 84-year-old woman with no previous surgical interventions, who went to the emergency room complaining of vomit and nausea, bowels closed to gas and stool, which she had experienced for three previous days. Routine blood test showed impaired renal function and hydrohelectrolyte imbalance. A CT scan revealed a right ileal, strangulated obturator hernia. The patient underwent an emergency surgical intervention with laparoscopic trans-abdominal peritoneal approach (TAP): after the reduction of the herniated segment, a primary suturing of the parietal defect was performed without ileal resection. DISCUSSION: Because of the non-specific symptoms the diagnosis of this kind of hernia is often unclear; female are 6-9 times more likely than men to be subject to the aforementioned pathology, mostly occurring in multiparous, emaciated, elderly woman so it is also called "the little old lady's hernia". Risk factors are loss of weight, chronic pulmonary disease and ascites which increase the abdominal pressure. An unfrequent presenting sign is a palpable mass, or the Howship-Romberg sign- a pain radiating from the inner tigh and knee - but it could be misleading when confused with symptoms of gonarthrosis or lumbar vertebral disc pathology. CT scan has superior sensitivity and accuracy with respect to other radiological exams to assess the presence of an obturator hernia. CONCLUSION: Obturator hernia is a rare type of hernia due to his diagnosis, which is often unclear; a prompt suspect based for the non-specific symptoms is crucial for the diagnosis. Surgical management depends on early diagnosis and it is the only possible treatment for this pathology.
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OBJECTIVES: We already know that asthma is associated to osteoporosis/osteopenia and characterized by an accelerated lung function decline. Our study aimed at assessing whether lung function decline and bone mineral density (BMD) deterioration in time were associated in a group of female long-standing asthmatics. We also tried to understand whether these two aspects were related to ICS treatment and vitamin D levels. METHODS: 35 female asthmatics were retrospectively analysed. Results of methacholine challenge test at asthma onset, FEV1%, bone density scan at moment of recruitment and after at least 5years later were considered. RESULTS: A significant positive relationship between femoral-t-scores changes and FEV1 decline was found after a median follow-up time of 7 [6-9] years (r=0.43;p=0.04). Femoral-t-score variations and vitamin D values were also significantly related (r=0.669;p=0.024). Furthermore, we found that FEV1 decline was worse in subjects with lower vitamin D levels (-57.5[-80.4-35.9]ml/year), compared to those with normal vitamin D rates (12[-16-23.6]ml/year;p=0.055). Femoral/vertebral t-score changes, as well as FEV1, decline were not associated to the use of medium/high ICS doses when compared to subjects treated with low ICS dosages. CONCLUSIONS: FEV ¹ decline and BMD deterioration in time observed in a group of female asthmatics were associated; low vitamin D levels may be the link.
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Asma/sangue , Densidade Óssea , Deficiência de Vitamina D/complicações , Adulto , Asma/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/etiologia , Testes de Função Respiratória , Estudos Retrospectivos , Vitamina D/sangue , Deficiência de Vitamina D/sangueRESUMO
In systems having an anisotropic electronic structure, such as the layered materials graphite, graphene, and cuprates, impulsive light excitation can coherently stimulate specific bosonic modes, with exotic consequences for the emergent electronic properties. Here we show that the population of E_{2g} phonons in the multiband superconductor MgB_{2} can be selectively enhanced by femtosecond laser pulses, leading to a transient control of the number of carriers in the σ-electronic subsystem. The nonequilibrium evolution of the material optical constants is followed in the spectral region sensitive to both the a- and c-axis plasma frequencies and modeled theoretically, revealing the details of the σ-π interband scattering mechanism in MgB_{2}.
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Anatase TiO2 is among the most studied materials for light-energy conversion applications, but the nature of its fundamental charge excitations is still unknown. Yet it is crucial to establish whether light absorption creates uncorrelated electron-hole pairs or bound excitons and, in the latter case, to determine their character. Here, by combining steady-state angle-resolved photoemission spectroscopy and spectroscopic ellipsometry with state-of-the-art ab initio calculations, we demonstrate that the direct optical gap of single crystals is dominated by a strongly bound exciton rising over the continuum of indirect interband transitions. This exciton possesses an intermediate character between the Wannier-Mott and Frenkel regimes and displays a peculiar two-dimensional wavefunction in the three-dimensional lattice. The nature of the higher-energy excitations is also identified. The universal validity of our results is confirmed up to room temperature by observing the same elementary excitations in defect-rich samples (doped single crystals and nanoparticles) via ultrafast two-dimensional deep-ultraviolet spectroscopy.Here the authors combine steady-state angle-resolved photoemission spectroscopy, ellipsometry and ultrafast two-dimensional ultraviolet spectroscopy to examine the role of many-body correlations in anatase TiO2, revealing the existence of strongly bound excitons in single crystals and nanoparticles.
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Transition metal oxides are among the most promising solar materials, whose properties rely on the generation, transport and trapping of charge carriers (electrons and holes). Identifying the latter's dynamics at room temperature requires tools that combine elemental and structural sensitivity, with the atomic scale resolution of time (femtoseconds, fs). Here, we use fs Ti K-edge X-ray absorption spectroscopy (XAS) upon 3.49 eV (355 nm) excitation of aqueous colloidal anatase titanium dioxide nanoparticles to probe the trapping dynamics of photogenerated electrons. We find that their localization at Titanium atoms occurs in <300 fs, forming Ti(3+) centres, in or near the unit cell where the electron is created. We conclude that electron localization is due to its trapping at pentacoordinated sites, mostly present in the surface shell region. The present demonstration of fs hard X-ray absorption capabilities opens the way to a detailed description of the charge carrier dynamics in transition metal oxides.
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Small Ubiquitinlike MOdifier (SUMO) proteins are small protein modifiers capable of regulating cellular localization and function of target proteins. Over the last few years, a relevant role has been demonstrated for sumoylation in the modulation of important cellular processes, including gene transcription, DNA repair, cell-cycle regulation and apoptosis. Components of the sumoylation machinery have been found deregulated in different human cancers, and are thought to significantly affect cancer cell progression. In the present study we sought to analyze the expression of all the components of the sumoylation machinery in a case study comprising 77 papillary thyroid cancers (PTC) and normal matched tissues. In particular, we evaluated the expression of the SENP1 to SENP8 (SENtrin-specific proteases), SAE1 (SUMO1 activating enzyme subunit 1), UBA2 (UBiquitin-like modifier activating enzyme 2), UBC9 (UBiquitin conjugating enzyme 9), RanBP2 (RAN binding protein 2), MSMCE2 (Non- SMC element 2), CBX4 (ChromoBoX homolog 4), PIAS1 to PIAS4 (protein inhibitor of activated STAT), ZMIZ1 (zinc finger, MIZ-type containing 1) and ZMIZ2 (Zinc finger, MIZ-type containing 2) by means of quantitative RT-PCR. In most of the PTC examined we observed a significant alteration in the mRNAs of SENP8, ZMIZ1, SAE1, PIAS1 and PIAS2. These tended to be reduced in about 50 to 66% of cases, and unchanged or increased in the remaining ones. Univariate and Kaplan-Mayer analyses documented the lack of association between the expression of the above 5 genes and clinicopathological parameters. Only SAE1 was significantly higher in female PTC tissues, in respect to male PTC tissues (p=0.021), and SENP8 was significantly lower in TNM stages III-V, with respect to stages I-II (p=0.047). In conclusion, we demonstrated that the expression of SENP8, SAE1, PIAS1, PIAS2 and ZMIZ1 is deregulated in the majority of PTC tissues, likely contributing to the PTC phenotype. However, differently from other human cancers, their mRNA level does not represent a prognostic biomarker in PTC patients.
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Biomarcadores Tumorais/biossíntese , Carcinoma/metabolismo , Carcinoma/mortalidade , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Sumoilação , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/patologia , Carcinoma/terapia , Carcinoma Papilar , Criança , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapiaRESUMO
The three members of the Aurora kinase family, Aurora-A, -B and -C, regulate several aspects of the mitotic process, and their aberrant expression and/or function causes mitotic abnormalities leading either to cell death or aneuploidy. They are found overexpressed in several human malignancies, including the papillary thyroid carcinoma (PTC). In the present study, we sought to establish whether Aurora kinase inhibition could be of any therapeutic value in the treatment of aggressive forms of PTC, enduring to radioactive iodide (RAI) ablation. To this end, the effects of selective inhibitors of Aurora-A (MLN8237) and Aurora-B (AZD1152) were analyzed on 3 human PTC cell lines expressing either wild-type (K1 and TPC1) or mutant p53 (BCPAP). The two inhibitors were capable of reducing cell proliferation in a time- and dose-dependent manner, with IC50 comprised between 65.4 and 114.9 nM for MLN8237, and between 26.6 and 484.6 nM for AZD1152. Immunofluorescence experiments confirmed that AZD1152 inhibited Aurora-B phosphorylation of histone H3 on Ser10, however, it did not affect Aurora-A autophosphorylation. MLN8237 inhibited Aurora-A autophosphorylation as expected, but at concentrations required to achieve the maximum antiproliferative effects it also abolished H3 (Ser10) phosphorylation. Time-lapse videomicroscopy evidenced that both inhibitors prevented the completion of cytokinesis, and cytofluorimetric analysis showed accumulation of cells in G2/M phase and/or polyploidy. Apoptosis was induced in all the cells by both inhibitors independently from the p53 status. In conclusion, in the present preclinical study MLN8237 and AZD1152 have emerged as promising drug candidates for RAI-insensitive PTC.
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Aurora Quinases/antagonistas & inibidores , Carcinoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Azepinas/uso terapêutico , Carcinoma/patologia , Carcinoma Papilar , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Organofosfatos/uso terapêutico , Pirimidinas/uso terapêutico , Quinazolinas/uso terapêutico , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/patologiaRESUMO
The anaplastic thyroid cancer (ATC) is among the most aggressive human tumors which fail to respond to all the currently available therapeutic approaches. As a consequence most patients die within a few months from diagnosis. In the present preclinical study, the effects of the ZM447439, a functional inhibitor of Aurora kinases, on the growth and tumorigenicity of a panel of ATC derived cell lines (CAL-62, 8305C, 8505C and BHT-101) were evaluated. The treatment of the different ATC cells with ZM447439 inhibited proliferation in a time- and dose-dependent manner, with IC50 comprised between 0.5 mM and 5 mM. Moreover, the drug remarkably impaired the formation of colonies in soft agar of all the cell lines. Consistently with Aurora inhibition, immunofluorescence and immunoblotting experiments demonstrated that Aurora auto-phosphorylation following drug treatment was completely abrogated, and treated cells were characterized by the presence of multiple spindles with short microtubules. In the same experiments we observed the loss of histone H3 phosphorylation on Ser10, specifically due to Aurora-B, after ZM447439 treatment. Time-lapse videomicroscopy and flow cytometric analysis demonstrated that in presence of ZM447439 the cells were able to enter mitosis but not to complete it, becoming polyploid. Almost all the ATC cell lines studied showed increased apoptosis after only 48 h of treatment. In conclusion, our data demonstrate that ZM447439 is effective in reducing cell growth and tumorigenicity of different ATC derived cell lines, and further investigations are needed to exploit its potential therapeutic value for ATC treatment.