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1.
Small ; 19(12): e2205961, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36587987

RESUMO

Improving the tumor reoxygenation to sensitize the tumor to radiation therapy is a cornerstone in radiation oncology. Here, the pre-clinical development of a clinically transferable liposomal formulation encapsulating trans sodium crocetinate (NP TSC) is reported to improve oxygen diffusion through the tumor environment. Early pharmacokinetic analysis of the clinical trial of this molecule performed on 37 patients orient to define the optimal fixed dosage to use in a triple-negative breast cancer model to validate the therapeutic combination of radiation therapy and NP TSC. Notably, it is reported that this formulation is non-toxic in both humans and mice at the defined fixed concentration, provides a normalization of the tumor vasculature within 72 h window after systemic injection, leads to a transient increase (50% improvement) in the tumor oxygenation, and significantly improves the efficacy of both mono-fractionated and fractionated radiation therapy treatment. Together, these findings support the introduction of a first-in-class therapeutic construct capable of tumor-specific reoxygenation without associated toxicities.


Assuntos
Neoplasias , Hipóxia Tumoral , Humanos , Camundongos , Animais , Carotenoides , Neoplasias/terapia , Vitamina A/uso terapêutico
2.
Cancer Causes Control ; 33(1): 1-13, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34837156

RESUMO

PURPOSE: This review proposes an overall vision of the protective and therapeutic role of melatonin in breast cancer: from the specific cases of blind women and their reduction of breast cancer incidence to all clinical uses of the sleep hormone in breast cancer. METHODS: We reviewed studies focused on (1) the correlation between blindness and breast cancer, (2) the correlation between melatonin and breast cancer occurrence in the general population, (3) melatonin therapeutic use in breast cancer, and (4) we discussed the properties of melatonin that could explain an anticancer effect. RESULTS: (1) Seven studies of breast cancer risk in blind women related significant incidence decreases, up to 57%, among totally blind women. The limited number of studies and the absence of adjustment for confounding factors in most studies limit conclusions. None of these studies established melatonin profiles to determine whether blind women with a decreased breast cancer incidence produced higher levels of melatonin. (2) In the general population, 5 meta-analyses and 12 prospective-cohort studies focused on melatonin levels at recruitment and breast cancer occurrence. All reported the absence of correlation in premenopausal women, whereas in postmenopausal women, most studies showed significantly decreased risk for women with highest melatonin levels. (3) The therapeutic interest of melatonin associated with chemotherapy, radiotherapy, and hormonotherapy is poorly documented in breast cancer to conclude on a positive effect. (4) Melatonin effects on mammary carcinogenesis were only reported in in vitro and animal studies that demonstrated antiestrogenic, antioxidant, oncostatic, and immunomodulatory properties. CONCLUSION: The preventive role of high endogenous melatonin on breast cancer as well as its beneficial therapeutic use remains to be proven.


Assuntos
Neoplasias da Mama , Melatonina , Animais , Cegueira , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Feminino , Humanos , Incidência , Estudos Prospectivos
3.
Sci Rep ; 13(1): 21875, 2023 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-38072852

RESUMO

Pneumatic transportation systems (PTS) were recently proposed as a method to carry ready-for-injection diluted monoclonal antibodies (mAbs) from the pharmacy to the bedside of patients. This method reduces transportation time and improves the efficiency of drug distribution process. However, mAbs are highly sensitive molecules for which subtle alterations may lead to deleterious clinical effects. These alterations can be caused by various external factors such as temperature, pH, pressure, and mechanical forces that may occur during transportation. Hence, it is essential to ensure that the mAbs transported by PTS remain stable and active throughout the transportation process. This study aims to determine the safety profile of PTS to transport 11 routinely used mAbs in a clinical setting through assessment of critical quality attributes (CQA) and orthogonal analysis. Hence, we performed aggregation/degradation profiling, post-translational modifications identification using complementary mass spectrometry-based methods, along with visible and subvisible particle formation determination by light absorbance and light obscuration analysis. Altogether, these results highlight that PTS can be safely used for this purpose when air is removed from the bags during preparation.


Assuntos
Anticorpos Monoclonais , Farmácia , Humanos , Anticorpos Monoclonais/química , Fenômenos Mecânicos , Meios de Transporte/métodos
4.
Front Biosci (Landmark Ed) ; 27(10): 290, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36336868

RESUMO

BACKGROUND: Native mass spectrometry (nMS) approaches appear attractive to complement bottom-up strategies traditionally used in biopharmaceutical industries thanks to their quite straightforward and rapid workflows, especially through online hyphenation of non-denaturing liquid chromatography (LC) to nMS. The present work provides an overview of the state-of-the-art chromatographic tools available for the detailed characterization of monoclonal antibody (mAb) formats, exemplified on the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd). METHODS: T-DXd was first characterized by conventional reversed phase LC (rpLC) and peptide mapping. Couplings of size exclusion chromatography (SEC), cation exchange chromatography (CEX), and hydrophobic interaction chromatography (HIC) to nMS were used to gain further insights into size, hydrophobic, and charge variants of T-DXd and its parental mAb trastuzumab, at intact and middle-up levels. RESULTS: SEC-nMS first offered a direct snapshot of the homogeneous conjugation of T-DXd, with an average drug-to-antibody ratio (DAR) of 8 in agreement with a conjugation on cysteines after reduction of all interchain disulfide bonds. Moreover, SEC-nMS afforded precise identification and quantification of aggregates and fragments. Middle-up level experiments performed after IdeS digestion confirmed that drug conjugation occurs in the Fab region of the mAb, as seen with rpLC. HIC separated two DAR8 species that could not be differentiated by nMS. Although middle-up HIC-nMS proved to be more informative for oxidized forms, the identification of minor variants was still difficult because of poor MS signal quality, showing how the coupling of HIC to nMS remains challenging. Lastly, middle-up CEX-nMS provided accurate determination and localization of post-translational modifications, with several acidic/basic variants within Fab and Fc regions of T-DXd that were also identified by peptide mapping. CONCLUSIONS: This study illustrates the strengths and drawbacks of each LC-nMS coupling. By combining SEC-, HIC-, and CEX-nMS, we were able to achieve a comprehensive characterization of T-DXd without extensive sample preparation prior to MS analysis.


Assuntos
Imunoconjugados , Espectrometria de Massas em Tandem , Cromatografia Líquida/métodos , Imunoconjugados/análise , Imunoconjugados/química , Trastuzumab , Anticorpos Monoclonais/química
5.
Adv Mater ; 34(24): e2110305, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35289003

RESUMO

Tumor-targeted antibody (mAb)/fragment-conjugated nanoparticles (NPs) represent an innovative strategy for improving the local delivery of small molecules. However, the physicochemical properties of full mAb-NPs and fragment-NPs-that is, NP material, size, charge, as well as the targeting antibody moiety, and the linker conjugation strategies-remain to be optimized to achieve an efficient tumor targeting. A meta-analysis of 161 peer-reviewed studies is presented, which describes the use of tumor-targeted mAb-NPs and fragment-NPs from 2009 to 2021. The use of these targeted NPs is confirmed to result in significantly greater tumor uptake of NPs than that of naked NPs (7.9 ± 1.9% ID g-1 versus 3.2 ± 0.6% ID g-1 , respectively). The study further demonstrates that for lipidic NPs, fragment-NPs provide a significantly higher tumor uptake than full mAb-NPs. In parallel, for both polymeric and organic/inorganic NPs, full mAb-NPs yield a significant higher tumor uptake than fragment-NPs. In addition, for both lipidic and polymeric NPs, the tumor uptake is improved with the smallest sizes of the conjugates. Finally, the pharmacokinetics of the conjugates are demonstrated to be driven by the NPs and not by the antibody moieties, independently of using full mAb-NPs or fragment-NPs, confirming the importance of optimizing the NP design to improve the tumor uptake.


Assuntos
Nanopartículas , Neoplasias , Anticorpos/química , Linhagem Celular Tumoral , Humanos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Polímeros
7.
Pharmacol Res Perspect ; 9(4): e00839, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34309241

RESUMO

Prestige Biopharma Ltd (Singapore) has developed HD201, a proposed biosimilar to reference product trastuzumab. As a part of the stepwise approach to ensure comparability between the biosimilar candidate and the reference medicinal product, a phase I study in healthy subjects was conducted to demonstrate the pharmacokinetic (PK) equivalence (NCT03776240). The primary objective of the study was to demonstrate (PK) equivalence of HD201, EU-Herceptin® , and US-Herceptin® given at 6 mg/kg as a 90-min i.v. infusion to healthy male subjects. A pairwise comparisons based on the primary endpoint AUC0-inf and secondary PK endpoints, AUC0-last and Cmax were undertaken. PK equivalence was to be concluded if the 90% confidence interval (CI) for the ratio of geometric means for each criterion were within the equivalence margin of 80% to 125%. Secondary objectives included assessment of other PK parameters, safety, tolerability, and immunogenicity in the three arms. A total of 105 healthy male subjects (35/treatment) were randomized in this study. The 90% CI for the ratios of AUC0-inf , Cmax and AUC0-last , were within 80%-125% for the comparisons of HD201 to EU-Herceptin® or US-Herceptin® and EU-Herceptin® to US-Herceptin® . The frequency of subjects with TEAEs of special interest was slightly lower in the HD201 group (20.0%) compared to the other treatment groups (EU-Herceptin® : 34.3%; US-Herceptin® : 31.4%). Only 1 subject (EU-Herceptin® group) developed anti-drug antibodies prior to dosing. Overall, HD201 demonstrates PK similarity to both EU-Herceptin® and US-Herceptin® . The three study drugs also demonstrated similar safety profiles.


Assuntos
Antineoplásicos Imunológicos/farmacocinética , Medicamentos Biossimilares/farmacocinética , Trastuzumab/farmacocinética , Adolescente , Adulto , Anticorpos/sangue , Antineoplásicos Imunológicos/imunologia , Área Sob a Curva , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Trastuzumab/imunologia , Adulto Jovem
8.
Front Oncol ; 11: 714551, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34778031

RESUMO

OBJECTIVE: For most patients suffering from recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC), chemotherapy is the main option after considering surgery and reirradiation. Cetuximab combined with a platinum-fluorouracil regimen (EXTREME) has been the standard of care for over a decade. Nevertheless, a significant number of patients remain unfit for this regimen because of age, severe comorbidities, or poor performance status. The aim of this study is to investigate an alternative regimen with sufficient efficacy and safety. METHODS: We reviewed retrospectively the medical charts of all patients treated with paclitaxel, carboplatin, and cetuximab (PCC) at our institution. Eligibility criteria were as follows: first-line R/M-HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx not suitable for local therapy, cisplatin, and/or 5-FU ineligibility, ECOG-PS: 0-2. PCC consisted of paclitaxel 80 mg/m2, carboplatin AUC 2, and cetuximab at an initial dose of 400 mg/m2 then 250 mg/m2, for 16 weekly administrations followed by cetuximab maintenance for patients for whom a disease control was obtained. The primary endpoint was overall survival (OS), and secondary endpoints were overall response rate (ORR), progression free survival (PFS), and safety. RESULTS: We identified 60 consecutive patients treated with PCC between 2010 and 2016 at our institution. Thirty-one patients (52%) were ECOG-PS 2. Fifty-five patients (92%) were cisplatin ineligible. ORR was 43.3% (95% CI, 30.8-55.8), and disease control rate was 65% (95% CI, 52.9-77.1). With a median follow-up of 35.7 months (IQR 28.6-48.8), median PFS was 5.8 months (95% CI, 4.5-7.2), and median OS was 11.7 months (95% CI, 7.5-14.8). For ECOG-PS 0-1 patients, median OS was 14.8 months (95% CI, 12.2-21.7) while it was only 7.5 months (95%CI: 5.5-12.7) for ECOG-PS 2 patients (p < 0.04). Grades III-IV toxicities occurred in 30 patients (50%). Most toxicities were hematologic. Six patients (10%) had febrile neutropenia. Nonhematologic toxicities were reported such as cutaneous toxicities, neuropathy, infusion-related reactions, or electrolyte disorders. CONCLUSION: The weekly PCC regimen seems to be an interesting option in cisplatin-unfit patients. This study shows favorable PFS and OS when compared with what is achieved with the EXTREME regimen and a high controlled disease rate with predictable and manageable toxicities even in the more fragile population.

9.
PLoS One ; 16(9): e0248222, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34555031

RESUMO

PURPOSE: This first-in-human study was designed to evaluate the pharmacokinetic (PK) equivalence between HD204 and the European Union (EU)-sourced bevacizumab, between HD204 and the United States of America (US)-sourced bevacizumab, and between EU-sourced and US-sourced bevacizumab (NCT03390673). METHODS: In this randomized, double-blind, 3-way parallel group, single-dose comparative PK study, healthy male subjects were randomized to receive a single 1 mg/kg intravenous dose of HD204, EU-sourced bevacizumab or US-sourced bevacizumab. PK parameters were calculated using non-compartmental methods. PK equivalence was determined using the pre-defined equivalence margin of 0.8-1.25 in terms of AUC(0-∞) for the pairwise comparisons. FINDINGS: Baseline demographics for the 119 randomized subjects were similar across the three groups. The 90% CIs for the ratio of the geometric means of HD204 to US-sourced bevacizumab, HD204 to EU-sourced bevacizumab, and EU-sourced to US-sourced bevacizumab were all within the interval of 80% to 125% for AUC0-inf, thus demonstrating equivalency in the PK properties for all three treatment groups. Similarly, the ratio of the geometric means for AUC0-last and Cmax were all within the 80% and 125% margins, supporting the robustness of the primary findings. All other PK parameters, including the half-life (t1/2) clearance (CL), volume of distribution (Vd) and time of maximum concentration (tmax), were comparable. There was no difference between the 3 treatment arms in terms of vital signs, laboratory tests and adverse events. None of the subjects treated with HD204 had positive ADA results. IMPLICATIONS: HD204 demonstrates equivalent pharmacokinetic profiles compared to those of both US-sourced and EU-sourced bevacizumab. (NCT03390673).


Assuntos
Bevacizumab/farmacocinética , Medicamentos Biossimilares/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Bevacizumab/efeitos adversos , Bevacizumab/sangue , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/sangue , Método Duplo-Cego , União Europeia , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos , Adulto Jovem
10.
J Control Release ; 336: 252-261, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34175365

RESUMO

Current therapeutic treatments improving the impaired transportation of oxygen in acute respiratory distress syndrome (ARDS) have been found to be relevant and beneficial for the therapeutic treatment of COVID-19 patients suffering from severe respiratory complications. Hence, we report the preclinical and the preliminary results of the Phase I/II clinical trial of LEAF-4L6715, a liposomal nanocarrier encapsulating the kosmotropic agent trans-crocetin (TC), which, once injected, enhance the oxygenation of vascular tissue and therefore has the potential to improve the clinical outcomes of ARDS and COVID-19 in severely impacted patients. We demonstrated that the liposomal formulation enabled to increase from 30 min to 48 h the reoxygenation properties of free TCs in vitro in endothelial cells, but also to improve the half-life of TC by 6-fold in healthy mice. Furthermore, we identified 25 mg/kg as the maximum tolerated dose in mice. This determined concentration led to the validation of the therapeutic efficacy of LEAF-4 L6715 in a sepsis mouse model. Finally, we report the preliminary outcomes of an open-label multicenter Phase I/II clinical trial (EudraCT 2020-001393-30; NCT04378920), which was aimed to define the appropriate schedule and dosage of LEAF-4L6715 and to confirm its tolerability profile and preliminary clinical activity in COVID-19 patients treated in intensive care unit.


Assuntos
COVID-19 , Síndrome do Desconforto Respiratório , Animais , Carotenoides , Células Endoteliais , Humanos , Camundongos , Respiração Artificial , Síndrome do Desconforto Respiratório/tratamento farmacológico , SARS-CoV-2 , Vitamina A/análogos & derivados
11.
Cancers (Basel) ; 11(10)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640284

RESUMO

BACKGROUND: management of head and neck squamous cell carcinomas (HNSCC) include anti-Epidermal Growth Factor Receptor (EGFR) antibodies and radiotherapy, but resistance emerges in most patients. RAS mutations lead to primary resistance to EGFR blockade in metastatic colorectal cancer but are infrequent in HNSCC, suggesting that other mechanisms are implicated. Since hypoxia and Hypoxia Inducible Factor-1 (HIF-1) have been associated with treatment failure and tumor progression, we hypothesized that EGFR/mammalian Target Of Rapamycin (mTOR)/HIF-1 axis inhibition could radiosensitize HNSCC. METHODS: We treated the radiosensitive Cal27 used as control, and radioresistant SQ20B and UD-SCC1 cells, in vivo and in vitro, with rapamycin and cetuximab before irradiation and evaluated tumor progression and clonogenic survival. RESULTS: Rapamycin and cetuximab inhibited the mTOR/HIF-1α axis, and sensitized the SQ20B cell line to EGFR-inhibition. However, concomitant delivery of radiation to SQ20B xenografts increased tumor relapse frequency, despite effective HIF-1 inhibition. Treatment failure was associated with the induction of HIF-2α expression by cetuximab and radiotherapy. Strikingly, SQ20B and UD-SCC1 cells clonogenic survival dropped <30% after HIF-2α silencing, suggesting a HIF-2-dependent mechanism of oncogenic addiction. CONCLUSIONS: altogether, our data suggest that resistance to EGFR inhibition combined with radiotherapy in HNSCC may depend on tumor HIF-2 expression and underline the urgent need to develop novel HIF-2 targeted treatments.

12.
Cancer Lett ; 440-441: 145-155, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30339780

RESUMO

Targeting specific tumor metabolic needs represents an actively investigated therapeutic strategy to bypass tumor resistance mechanisms. In this study, we describe an original approach to impact the cancer metabolism by exploiting the redox properties of a ruthenium organometallic compound. This organometallic complex induced p53-independent cytotoxicity and reduced size and vascularization of patients-derived tumor explants that are resistant to platinum drugs. At the molecular level, the ruthenium complex altered redox enzyme activities and the intracellular redox state by increasing the NAD+/NADH ratio and ROS levels. Pathway analysis pointed to HIF-1 as a top deregulated metabolite pathway. Unlike cisplatin, treatment with the ruthenium complex decreased HIF1A protein levels and expression of HIF1A target genes. The rapid downregulation of HIF1A protein levels involved a direct interaction of the ruthenium compound with the redox enzyme PHD2, a HIF1A master regulator. HIF1A inhibition led to decreased angiogenesis in patient-derived xenografted using fragments of primary human colon tumors. Altogether, our results show that a ruthenium compound impacts metabolic pathways acting as anticancer agents in colon cancer via an original mechanism of action that affects redox enzymes differently than platinum-based drugs.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Neoplasias Colorretais/irrigação sanguínea , Feminino , Células HCT116 , Células Endoteliais da Veia Umbilical Humana , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Compostos Organometálicos/química , Oxirredução , Rutênio/química , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Oncotarget ; 9(101): 37581-37588, 2018 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-30680071

RESUMO

BACKGROUND: The EXTREME protocol is the standard of care for recurrent or metastatic head and neck squamous-cell carcinoma (R/M HNSCC) in first line. Beyond the first-line except immunotherapy, poor efficacy was reported by second-line chemotherapy. Re-challenge strategies based on a repetition of the first line with platinum and cetuximab regimens might have been an option to consider. METHODS: We performed a retrospective study in order to assess the efficacy of the cetuximab plus platinum doublet-based chemotherapy regimen in patients with R/M HNSCC progressing after at least 3 months of cetuximab maintenance (EXTREME protocol). We complete a retrospective review of all medical records from R/M HNSCC patients treated after 16 weeks with the EXTREME regimen and treated with a re-challenge strategy between January 2010 and December 2014 in our institution (Centre Paul Strauss, Strasbourg, France). RESULTS: 33 patients were identified. The re-challenged strategy provided an ORR in 33.3% of cases and a DCR of 69.6% of cases. The median OS and PFS observed from the second line were 11.2 months and 6.5 months for the subset re-challenged by EXTREME or PCC regimens respectively. The response rate between patients with a platin free interval within 3 and 6 months and greater than 6 months were equal. Drugs dose intensity were better with the PCC protocol than the EXTREME regimen used as a rechallenge. CONCLUSIONS: This study suggest re-challenging strategy by these regimens could be considered beyond the first line as an option when the platin free interval is greater than 3 months.

14.
Oral Oncol ; 51(9): 848-56, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26121938

RESUMO

OBJECTIVES: Human Papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OSCC) patients have improved prognosis compared to other head and neck (HNSCC) cancers. Since poor prognosis is associated with tumour hypoxia, we studied whether the hypoxic response is different in HPV-related cells and tumours. MATERIAL AND METHODS: HPV-positive and -negative cells were incubated in hypoxia and analyzed by qRTPCR, western blotting and cell proliferation assays. Tumours formed by xenografting these cells in nude mice were studied by IHC. HNSCC patient samples were analyzed by unsupervised clustering of hypoxia-related gene expression, quantitative real-time PCR (qRTPCR) and immunohistochemical (IHC) detection of neo-blood vessels. RESULTS AND CONCLUSION: HPV-positive and -negative cells responded differently to hypoxia, in terms of gene expression (HIF-1α, PHD-3, GLUT-1 and VEGF-A) and cell survival. Tumour xenografts formed by HPV-positive cells had fewer hypoxic areas than those formed by HPV-negative cells. HPV related tumours were less hypoxic, expressed lower levels of hypoxia-responsive genes, and had a higher density of neo-blood vessels. HPV-related OSCC display lower tumour hypoxia, which could be linked to the distinct intrinsic abilities of HPV-positive tumour cells to adapt to hypoxia and to their better prognosis.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Orofaríngeas/metabolismo , Infecções por Papillomavirus/metabolismo , Animais , Western Blotting , Hipóxia Celular/fisiologia , Sobrevivência Celular/fisiologia , Feminino , Expressão Gênica/fisiologia , Humanos , Masculino , Camundongos , Camundongos Nus , Reação em Cadeia da Polimerase em Tempo Real
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