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1.
Radiol Med ; 127(4): 449-457, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35247134

RESUMO

PURPOSE: To assess outcomes between salvage radiation therapy (SRT) with curative intent and stereotactic radiotherapy for macroscopic prostate recurrence (SSRT) after radical prostatectomy (RP). In order to compare these two different options, we compared their outcomes with a propensity score-based matched analysis. METHODS: Data from 185 patients in seven Italian centres treated for macroscopic prostate bed recurrence after RP were retrospectively collected. To make a comparison between the two treatment groups, propensity matching was applied to create comparable cohorts. RESULTS: After matching, 90 patients in the SRT and SSRT groups were selected (45 in each arm). Kaplan-Meier analysis did not show any significant differences in terms of BRFS and PFS between matched populations (p = 0.08 and p = 0.8, respectively). Multivariate models show that treatment was not associated with BRFS, neither in the whole or matched cohort, with HR of 2.15 (95%CI 0.63-7.25, p = 0.21) and 2.65 (95%CI 0.59-11.97, p = 0.21), respectively. In the matched cohort, lower rate of toxicity was confirmed for patients undergoing SSRT, with acute GI and GU adverse events reported in 4.4 versus 44.4% (p < 0.001) and 28.9 versus 46.7% (p = 0.08) of patients, and late GI and GU adverse events reported in 0 versus 13.3% (p = 0.04) and 6.7 versus 22.2% (p = 0.03) of patients, respectively. CONCLUSION: Considering the favourable therapeutic ratio of this approach and the lower number of fractions needed, SSRT should be considered as an attractive alternative to conventional SRT in this setting.


Assuntos
Próstata , Neoplasias da Próstata , Humanos , Masculino , Recidiva Local de Neoplasia/radioterapia , Recidiva Local de Neoplasia/cirurgia , Pontuação de Propensão , Próstata/cirurgia , Antígeno Prostático Específico , Prostatectomia/efeitos adversos , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos , Terapia de Salvação
2.
Pharmaceuticals (Basel) ; 15(3)2022 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-35337140

RESUMO

[68Ga]Ga-PSMA-11 PET/CT plays a pivotal role in the diagnosis and staging of prostate cancer because of its higher sensitivity and detection rate compared with traditional choline PET/CT. A highly reproducible radiochemical yield of the radiopharmaceutical to be used in the clinical routine is an important parameter for planning and optimization of clinical activity. During radiometallation of PSMA-11, the presence of metal ion contaminants in the peptide precursor may cause a decrease in the [68Ga]Ga-PSMA-11 radiochemical yield because of metal ion contaminants competition with gallium-68. To optimize the radiochemical yield of [68Ga]Ga-PSMA-11 radiosynthesis, data obtained by preparing the solution of the PSMA-11 precursor with three different methods (A, B, and C) were compared. Methods A and B consisted of the reconstitution of different quantities of precursor (1000 µg and 30 µg, respectively) to obtain a 1 µg/mL solution. In Method A, the precursor solution was aliquoted and stored frozen, while the precursor solution obtained with Method B was entirely used. Method C consisted of the reconstitution of 1000 µg of precursor taking into account net peptide content as described in European Pharmacopoeia. Radiosynthesis data demonstrated that reconstitution methods B and C gave a consistently higher and reproducible radiochemical yield, highlighting the role of metals and precursor storage conditions on the synthesis performance.

3.
Radiother Oncol ; 168: 69-74, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35101471

RESUMO

BACKGROUND/PURPOSE: To evaluate the usage of RT in trial protocols for anti-cancer drugs approved by the US Food and Drug Administration (FDA). METHODS: Drugs which had been granted an FDA approval between 2010 and 2017 for the treatment of solid tumors in adults were identified. Use of RT in relation to each drug's approval date was reviewed on ClinicalTrials.gov. RESULTS: Out of 42 drugs, none was initially approved for an indication which mandates RT. One drug (2.4%) has a post-approval label extension for sequential usage after RT. 5846 records were screened, exclusion of non-cancer trials and duplicates resulted in 4254 protocols out of which 2919 were industry-sponsored (68.6%). RT was tested in 350 (8.2%) studies. Out of 75 drug/RT trials which were initiated prior to approval, fourteen had not yet started recruitment, 45 were recruiting, one was completed, one prematurely terminated and fourteen fully-recruited but ongoing at approval time. Out of the fully-recruited or completed studies, results from four studies on three drugs were already published. In 52.4% of drugs, no patient had been treated with a drug/RT combination at the approval date. Drug/RT studies were less likely industry-sponsored (p < 0.001) and more likely initiated post-approval (p < 0.001) compared to drug-only trials. Despite this imbalance, pre-approval drug/RT trials were still mostly industry-sponsored (65.3%). CONCLUSION: No drug/RT data were publicly available in over 90% of newly approved anti-cancer drugs. These results indicate that clinicians must rely on postmarketing surveillance to identify drug/RT interactions as data from trials are unavailable at approval.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Estudos Transversais , Aprovação de Drogas/métodos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Preparações Farmacêuticas , Estados Unidos
5.
Eur Urol ; 81(3): 274-282, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34602312

RESUMO

BACKGROUND: Nivolumab showed an overall survival (OS) benefit in pretreated metastatic renal cell carcinoma (mRCC). The role of stereotactic body radiotherapy (SBRT) in mRCC remains to be defined. OBJECTIVE: Our aim was to evaluate the efficacy and safety of SBRT in combination with nivolumab in second- and third-line mRCC patients. DESIGN, SETTING, AND PARTICIPANTS: The NIVES study was a phase II, single-arm, multicenter trial in patients with mRCC with measurable metastatic sites who progressed after antiangiogenic therapy, of whom at least one was suitable for SBRT. INTERVENTION: The patients received SBRT to a lesion at a dose of 10 Gy in three fractions for 7 d from the first infusion of nivolumab. Nivolumab was given at an initial dose of 240 mg every 14 d for 6 mo and then 480 mg q4-weekly in responding patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We hypothesized that nivolumab plus SBRT improves the objective response rate (ORR) compared with nivolumab alone from 25% (derived from historical controls) to 40%. Secondary endpoints were progression-free survival (PFS), OS, disease control rate (DCR) of irradiated and nonirradiated metastases, and safety. RESULTS AND LIMITATIONS: Sixty-nine patients were enrolled from July 2017 to March 2019. The ORR was 17% and the DCR was 55%. The median PFS was 5.6 mo (95% confidence interval [CI], 2.9-7.1) and median OS 20 mo (95% CI, 17-not reached). After 1.5 yr of follow-up, 23 patients died. The median time to treatment response was 2.8 mo and median duration of response was 14 mo. No new safety concerns arose. CONCLUSIONS: We did not find sufficient evidence to suggest that nivolumab in combination with SBRT provides an added benefit in pretreated mRCC patients; it should however be evaluated in patients with oligometastatic or oligoprogressive disease. PATIENT SUMMARY: Nivolumab in combination with stereotactic body radiotherapy does not provide evidence of increased outcomes in metastatic renal cell carcinoma patients. However this approach was safe and showed a good response of the irradiated lesions.


Assuntos
Carcinoma de Células Renais , Quimiorradioterapia , Neoplasias Renais , Carcinoma de Células Renais/terapia , Quimiorradioterapia/efeitos adversos , Feminino , Humanos , Neoplasias Renais/terapia , Masculino , Nivolumabe/uso terapêutico , Radiocirurgia/métodos
7.
Front Oncol ; 11: 744956, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34650927

RESUMO

INTRODUCTION: For unresectable stage III non-small cell lung cancer (NSCLC), the standard therapy consists of chemoradiotherapy (CRT) followed by durvalumab maintenance for responding patients. The present study reports on the safety and outcome of durvalumab use after CRT in a real-world, multicenter, retrospective cohort. METHODS: Two hundred thirty-eight patients have been included. We collected data on systemic therapy, radiation therapy, the timing between CRT and durvalumab, number of durvalumab cycles, reasons for non-starting or discontinuation, incidence and grade of adverse events (AEs), and progression-free survival (PFS) and overall survival (OS). RESULTS: One hundred fifty-five patients out of 238 (65.1%) received at least one durvalumab dose: 91 (58.7%) after concomitant CRT (cCRT) and 64 (41.3%) after sequential CRT (sCRT). Programmed-death ligand 1 (PD-L1) status was unknown in 7/155 (4.5%), negative in 14 (9.1%), and positive ≥1% in 134/155 (86.4%). The main reasons for non-starting durvalumab were progression (10.1%), PD-L1 negativity (7.5%), and lung toxicity (4.6%). Median follow-up time was 14 months (range 2­29); 1-year PFS and OS were 65.5% (95%CI: 57.6-74.4) and 87.9% (95%CI: 82.26.6-93.9), respectively. No significant differences in PFS or OS were detected for cCRT vs. sCRT, but the median PFS was 13.5 months for sCRT vs. 23 months for cCRT. Potentially immune-related AEs were recorded in 76/155 patients (49.0%). Pneumonitis was the most frequent, leading to discontinuation in 11/155 patients (7.1%). CONCLUSIONS: Durvalumab maintenenace after concurrent or sequential chemoradiation for unresectable, stage III NSCLC showed very promising short-term survival results in a large, multicenter, restrospective, real-world study. Durvalumab was the first drug obtaining a survival benefit over CRT within the past two decades, and the present study contributes to validating its use in clinical practice.

8.
Biomol NMR Assign ; 15(2): 467-474, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34453696

RESUMO

The stem-loop (SL1) is the 5'-terminal structural element within the single-stranded SARS-CoV-2 RNA genome. It is formed by nucleotides 7-33 and consists of two short helical segments interrupted by an asymmetric internal loop. This architecture is conserved among Betacoronaviruses. SL1 is present in genomic SARS-CoV-2 RNA as well as in all subgenomic mRNA species produced by the virus during replication, thus representing a ubiquitous cis-regulatory RNA with potential functions at all stages of the viral life cycle. We present here the 1H, 13C and 15N chemical shift assignment of the 29 nucleotides-RNA construct 5_SL1, which denotes the native 27mer SL1 stabilized by an additional terminal G-C base-pair.


Assuntos
Regiões 5' não Traduzidas , Ressonância Magnética Nuclear Biomolecular , SARS-CoV-2/genética , Conformação de Ácido Nucleico , RNA Líder para Processamento
9.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299007

RESUMO

Ubiquitin fold modifier 1 (UFM1) is a member of the ubiquitin-like protein family. UFM1 undergoes a cascade of enzymatic reactions including activation by UBA5 (E1), transfer to UFC1 (E2) and selective conjugation to a number of target proteins via UFL1 (E3) enzymes. Despite the importance of ufmylation in a variety of cellular processes and its role in the pathogenicity of many human diseases, the molecular mechanisms of the ufmylation cascade remains unclear. In this study we focused on the biophysical and biochemical characterization of the interaction between UBA5 and UFC1. We explored the hypothesis that the unstructured C-terminal region of UBA5 serves as a regulatory region, controlling cellular localization of the elements of the ufmylation cascade and effective interaction between them. We found that the last 20 residues in UBA5 are pivotal for binding to UFC1 and can accelerate the transfer of UFM1 to UFC1. We solved the structure of a complex of UFC1 and a peptide spanning the last 20 residues of UBA5 by NMR spectroscopy. This structure in combination with additional NMR titration and isothermal titration calorimetry experiments revealed the mechanism of interaction and confirmed the importance of the C-terminal unstructured region in UBA5 for the ufmylation cascade.


Assuntos
Proteínas/química , Enzimas Ativadoras de Ubiquitina/química , Enzimas de Conjugação de Ubiquitina/química , Varredura Diferencial de Calorimetria , Expressão Gênica , Espectroscopia de Ressonância Magnética , Mutação , Peptídeos/química , Ligação Proteica , Domínios Proteicos , Proteínas/genética , Proteínas/metabolismo , Proteínas Recombinantes , Termodinâmica , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo
10.
Cancers (Basel) ; 13(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070797

RESUMO

BACKGROUND AND PURPOSE: Two previous "Patterns Of Practice" surveys (POP I and POP II), including more than 4000 patients affected by prostate cancer treated with radical external beam radiotherapy (EBRT) between 1980 and 2003, established a "benchmark" Italian data source for prostate cancer radiotherapy. This report (POP III) updates the previous studies. METHODS: Data on clinical management and outcome of 2525 prostate cancer patients treated by EBRT from 2004 to 2011 were collected and compared with POP II and, when feasible, also with POP I. This report provides data on clinical presentation, diagnostic workup, radiation therapy management, and toxicity as collected within the framework of POP III. RESULTS: More than 50% of POP III patients were classified as low or intermediate risk using D'Amico risk categories as in POP II; 46% were classified as ISUP grade group 1. CT scan, bone scan, and endorectal ultrasound were less frequently prescribed. Dose-escalated radiotherapy (RT), intensity modulated radiotherapy (IMRT), image guided radiotherapy (IGRT), and hypofractionated RT were more frequently offered during the study period. Treatment was commonly well tolerated. Acute toxicity improved compared to the previous series; late toxicity was influenced by prescribed dose and treatment technique. Five-year overall survival, biochemical relapse free survival (BRFS), and disease specific survival were similar to those of the previous series (POP II). BRFS was better in intermediate- and high-risk patients treated with ≥ 76 Gy. CONCLUSIONS: This report highlights the improvements in radiotherapy planning and dose delivery among Italian Centers in the 2004-2011 period. Dose-escalated treatments resulted in better biochemical control with a reduction in acute toxicity and higher but acceptable late toxicity, as not yet comprehensively associated with IMRT/IGRT. CTV-PTV margins >8 mm were associated with increased toxicity, again suggesting that IGRT-allowing for tighter margins-would reduce toxicity for dose escalated RT. These conclusions confirm the data obtained from randomized controlled studies.

12.
J Med Chem ; 64(15): 10682-10710, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980013

RESUMO

Histone H3K4 methylation serves as a post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferase (HMT) and its regulatory scaffolding proteins. One of these is the WD-repeat-containing protein 5 (WDR5) that has also been associated with controlling long noncoding RNAs and transcription factors including MYC. The wide influence of dysfunctional HMT complexes and the typically upregulated MYC levels in diverse tumor types suggested WDR5 as an attractive drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might represent an elegant way to target all oncogenic functions. This study presents the design, synthesis, and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds and shows that linker nature and length strongly influence degradation efficacy.


Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Di-Hidropiridinas/farmacologia , Desenho de Fármacos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Células Cultivadas , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Relação Dose-Resposta a Droga , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ligantes , Masculino , Estrutura Molecular , Relação Estrutura-Atividade
13.
Radiol Med ; 126(8): 1117-1128, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33954898

RESUMO

INTRODUCTION: Almost 30% of non-small cell lung cancer (NSCLC) patients have locally advanced-stage disease. In this setting, definitive radiotherapy concurrent to chemotherapy plus adjuvant immunotherapy (cCRT + IO) is the standard of care, although only 40% of these patients are eligible for this approach. AIMS: A comparison between cCRT and hypofractionated radiotherapy regimens (hypo-fx RT) with the addition of sequential chemotherapy (sCHT) could be useful for future combinations with immunotherapy. We developed a recommendation about the clinical question of whether CHT and moderately hypo-fx RT are comparable to cCRT for locally advanced NSCLC MATERIALS AND METHODS: The panel used GRADE methodology and the Evidence to Decision (EtD) framework. After a systematic literature search, five studies were eligible. We identified the following outcomes: progression-free survival (PFS), overall survival (OS), freedom from locoregional recurrence (FFLR), deterioration of quality of life (QoL), treatment-related deaths, severe G3-G4 toxicity, late pulmonary toxicity G3-G4, and acute esophageal toxicity G3-G4. RESULTS: The probability of OS and G3-G4 late lung toxicity seems to be worse in patients submitted to sCHT and hypo-fx RT. The panel judged unfavorable the balance benefits/harms. CONCLUSIONS: The final recommendation was that sCHT followed by moderately hypo-fx RT should not be considered as an alternative to cCRT in unresectable stage III NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia , Neoplasias Pulmonares/terapia , Hipofracionamento da Dose de Radiação , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias
14.
Phys Med ; 83: 278-286, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33992865

RESUMO

PURPOSE: A radiomics features classifier was implemented to evaluate segmentation quality of heart structures. A robust feature set sensitive to incorrect contouring would provide an ideal quantitative index to drive autocontouring optimization. METHODS: Twenty-five cardiac sub-structures were contoured as regions of interest in 36 CTs. Radiomic features were extracted from manually-contoured (MC) and Hierarchical-Clustering automatic-contouring (AC) structures. A robust feature-set was identified from correctly contoured CT datasets. Features variation was analyzed over a MC/AC dataset. A supervised-learning approach was used to train an Artificial-Intelligence (AI) classifier; incorrect contouring cases were generated from the gold-standard MC datasets with translations, expansions and contractions. ROC curves and confusion matrices were used to evaluate the AI-classifier performance. RESULTS: Twenty radiomics features, were found to be robust across structures, showing a good/excellent intra-class correlation coefficient (ICC) index comparing MC/AC. A significant correlation was obtained with quantitative indexes (Dice-Index, Hausdorff-distance). The trained AI-classifier detected correct contours (CC) and not correct contours (NCC) with an accuracy of 82.6% and AUC of 0.91. True positive rate (TPR) was 85.1% and 81.3% for CC and NCC. Detection of NCC at this point of the development still depended strongly on degree of contouring imperfection. CONCLUSIONS: A set of radiomics features, robust on "gold-standard" contour and sensitive to incorrect contouring was identified and implemented in an AI-workflow to quantify segmentation accuracy. This workflow permits an automatic assessment of segmentation quality and may accelerate expansion of an existing autocontouring atlas database as well as improve dosimetric analyses of large treatment plan databases.


Assuntos
Processamento de Imagem Assistida por Computador , Planejamento da Radioterapia Assistida por Computador , Coração/diagnóstico por imagem , Radiometria , Tomografia Computadorizada por Raios X
15.
Biomol NMR Assign ; 15(2): 335-340, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33928512

RESUMO

The SARS-CoV-2 virus is the cause of the respiratory disease COVID-19. As of today, therapeutic interventions in severe COVID-19 cases are still not available as no effective therapeutics have been developed so far. Despite the ongoing development of a number of effective vaccines, therapeutics to fight the disease once it has been contracted will still be required. Promising targets for the development of antiviral agents against SARS-CoV-2 can be found in the viral RNA genome. The 5'- and 3'-genomic ends of the 30 kb SCoV-2 genome are highly conserved among Betacoronaviruses and contain structured RNA elements involved in the translation and replication of the viral genome. The 40 nucleotides (nt) long highly conserved stem-loop 4 (5_SL4) is located within the 5'-untranslated region (5'-UTR) important for viral replication. 5_SL4 features an extended stem structure disrupted by several pyrimidine mismatches and is capped by a pentaloop. Here, we report extensive 1H, 13C, 15N and 31P resonance assignments of 5_SL4 as the basis for in-depth structural and ligand screening studies by solution NMR spectroscopy.


Assuntos
Regiões 5' não Traduzidas , Ressonância Magnética Nuclear Biomolecular , SARS-CoV-2/genética , Sequências Repetidas Invertidas/genética
16.
Radiother Oncol ; 158: 230-236, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33667585

RESUMO

BACKGROUND: Local treatment of metastases in combination with systemic therapy can prolong survival of oligo-metastasized patients. To fully exploit this potential, safe and effective treatments are needed to ensure long-term metastases control. Stereotactic body radiotherapy (SBRT) is one means, however, for moving liver tumors correct delivery of high doses is challenging. After validating equal in-vivo treatment accuracy, we analyzed a pooled multi-platform liver-SBRT-database for clinical outcome. METHODS: Local control (LC), progression-free interval (PFI), overall survival (OS), predictive factors and toxicity was evaluated in 135 patients with 227 metastases treated by gantry-based SBRT (deep-inspiratory breath-hold-gating; n = 71) and robotic-based SBRT (fiducial-tracking, n = 156) with mean gross tumor volume biological effective dose (GTV-BEDα/ß=10Gy) of 146.6 Gy10. RESULTS: One-, and five-year LC was 90% and 68.7%, respectively. On multivariate analysis, LC was significantly predicted by colorectal histology (p = 0.006). Median OS was 20 months with one- and two-year OS of 67% and 37%. On multivariate analysis, ECOG-status (p = 0.003), simultaneous chemotherapy (p = 0.003), time from metastasis detection to SBRT-treatment (≥2months; p = 0.021) and LC of the treated metastases (≥12 months, p < 0.009) were significant predictors for OS. One- and two-year PFI were 30.5% and 14%. Acute toxicity was mild and rare (14.4% grade I, 2.3% grade II, 0.6% grade III). Chronic °III/IV toxicities occurred in 1.1%. CONCLUSIONS: Patient selection, time to treatment and sufficient doses are essential to achieve optimal outcome for SBRT with active motion compensation. Local control appears favorable compared to historical control. Long-term LC of the treated lesions was associated with longer overall survival.


Assuntos
Radiocirurgia , Seguimentos , Humanos , Fígado , Radiocirurgia/efeitos adversos , Estudos Retrospectivos , Taxa de Sobrevida
17.
Clin Lung Cancer ; 22(5): e767-e773, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33766477

RESUMO

INTRODUCTION: In this observational, retrospective, multicenter study, we aimed to assess the safety of the combination of local metastasis-directed radiotherapy (RT) and immunotherapy (IT) in a cohort of advanced non-small-cell lung cancer (aNSCLC) patients. MATERIAL AND METHODS: We collected clinical data of aNSCLC patients who received concomitant RT and anti-PD-1/PD-L1 inhibitors in seven Italian centers from September 2015 to June 2019. Concomitant RT was defined as delivered ≤4 weeks before or after the first or last administration of immunotherapy, or within two consecutive cycles of ICI. All adverse events apparently related to RT and/or IT were graded according to the Common Terminology Criteria for Adverse Events, version 4.0, and reported in terms of incidence and severity as immune related or RT related, or combined. RESULTS: We analyzed the clinical charts of 187 patients. Median follow-up time was 23 months, and median overall survival was 16.5 months (range, 3-162). Thirteen patients developed pure RT-related side effects, and 43 patients (23.9%) developed immune-related side effects. No additive toxic effects were observed. A case of grade 5 pulmonary toxicity was recorded as a possible consequence of a combined effect. CONCLUSION: This analysis suggests that the combination of concomitant RT and anti-PD-1/PD-L1 agents is safe, and the two toxicity profiles are independent.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Imunoterapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Segurança do Paciente , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
18.
Cell Death Differ ; 28(8): 2499-2516, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33723372

RESUMO

The role of mitophagy, a process that allows the removal of damaged mitochondria from cells, remains unknown in multiple sclerosis (MS), a disease that is found associated with dysfunctional mitochondria. Here we have qualitatively and quantitatively studied the main players in PINK1-mediated mitophagy in peripheral blood mononuclear cells (PBMCs) of patients with relapsing-remitting MS. We found the variant c.491G>A (rs550510, p.G140E) of NDP52, one of the major mitophagy receptor genes, associated with a MS cohort. Through the characterization of this variant, we discovered that the residue 140 of human NDP52 is a crucial modulator of NDP52/LC3C binding, promoting the formation of autophagosomes in order to drive efficient mitophagy. In addition, we found that in the PBMC population, NDP52 is mainly expressed in B cells and by ensuring efficient mitophagy, it is able to limit the production of the proinflammatory cytokine TNF-α following cell stimulation. In sum, our results contribute to a better understanding of the role of NDP52 in mitophagy and underline, for the first time, a possible role of NDP52 in MS.


Assuntos
Mitocôndrias/genética , Mitofagia/genética , Proteínas Nucleares/metabolismo , Proteínas Quinases/metabolismo , Humanos
19.
EMBO J ; 40(6): e106094, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33576509

RESUMO

The assembly of a specific polymeric ubiquitin chain on a target protein is a key event in the regulation of numerous cellular processes. Yet, the mechanisms that govern the selective synthesis of particular polyubiquitin signals remain enigmatic. The homologous ubiquitin-conjugating (E2) enzymes Ubc1 (budding yeast) and Ube2K (mammals) exclusively generate polyubiquitin linked through lysine 48 (K48). Uniquely among E2 enzymes, Ubc1 and Ube2K harbor a ubiquitin-binding UBA domain with unknown function. We found that this UBA domain preferentially interacts with ubiquitin chains linked through lysine 63 (K63). Based on structural modeling, in vitro ubiquitination experiments, and NMR studies, we propose that the UBA domain aligns Ubc1 with K63-linked polyubiquitin and facilitates the selective assembly of K48/K63-branched ubiquitin conjugates. Genetic and proteomics experiments link the activity of the UBA domain, and hence the formation of this unusual ubiquitin chain topology, to the maintenance of cellular proteostasis.


Assuntos
Poliubiquitina/biossíntese , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitinação/fisiologia , Simulação por Computador , Modelos Estruturais , Domínios Proteicos , Proteômica , Proteínas de Saccharomyces cerevisiae/genética , Transdução de Sinais/fisiologia , Enzimas de Conjugação de Ubiquitina/genética
20.
Biomol NMR Assign ; 15(1): 129-135, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33270159

RESUMO

The current outbreak of the highly infectious COVID-19 respiratory disease is caused by the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). To fight the pandemic, the search for promising viral drug targets has become a cross-border common goal of the international biomedical research community. Within the international Covid19-NMR consortium, scientists support drug development against SARS-CoV-2 by providing publicly available NMR data on viral proteins and RNAs. The coronavirus nucleocapsid protein (N protein) is an RNA-binding protein involved in viral transcription and replication. Its primary function is the packaging of the viral RNA genome. The highly conserved architecture of the coronavirus N protein consists of an N-terminal RNA-binding domain (NTD), followed by an intrinsically disordered Serine/Arginine (SR)-rich linker and a C-terminal dimerization domain (CTD). Besides its involvement in oligomerization, the CTD of the N protein (N-CTD) is also able to bind to nucleic acids by itself, independent of the NTD. Here, we report the near-complete NMR backbone chemical shift assignments of the SARS-CoV-2 N-CTD to provide the basis for downstream applications, in particular site-resolved drug binding studies.


Assuntos
Proteínas do Nucleocapsídeo de Coronavírus/química , Espectroscopia de Ressonância Magnética , SARS-CoV-2/química , Isótopos de Carbono , Cristalografia por Raios X , Dimerização , Desenho de Fármacos , Hidrogênio , Concentração de Íons de Hidrogênio , Isótopos de Nitrogênio , Fosfoproteínas/química , Ligação Proteica , Domínios Proteicos , Mapeamento de Interação de Proteínas , Estrutura Secundária de Proteína
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