Publications by authors named "Anna Giusti"

47 Publications

A Multimethodological Characterization of L. Inflorescences from Seven Dioecious Cultivars Grown in Italy: The Effect of Different Harvesting Stages.

Molecules 2021 May 14;26(10). Epub 2021 May 14.

Institute for Biological Systems, Magnetic Resonance Laboratory "Segre-Capitani", CNR, Via Salaria Km 29.300, 00015 Monterotondo, Italy.

The chemical profile of the female inflorescence extracts from seven L. dioecious cultivars (Carmagnola, Fibranova, Eletta Campana, Antal, Tiborszallasi, Kompolti, and Tisza) was monitored at three harvesting stages (4, 14, and 30 September), reaching from the beginning of flowering to end of flowering/beginning of seed formation, using untargeted nuclear magnetic resonance (NMR) and targeted (ultra-high-performance liquid chromatography (UHPLC) and spectrophotometry) analyses. The tetrahydrocannabinol content was always below the legal limits (<0.6%) in all the analyzed samples. The NMR metabolite profile (sugars, organic acids, amino acids, and minor compounds) subjected to principal components analysis (PCA) showed a strong variability according to the harvesting stages: samples harvested in stage I were characterized by a high content of sucrose and myo-inositol, whereas the ones harvested in stage II showed high levels of succinic acid, alanine, valine, isoleucine, phenylalanine, and threonine. Samples harvested in stage III were characterized by high levels of glucose, fructose, choline, trigonelline, malic acid, formic acid, and some amino acids. The ratio between chlorophylls and carotenoids content indicated that all plants grew up exposed to the sun, the Eletta Campana cultivar having the highest pigment amount. Tiborszallasi cultivar showed the highest polyphenol content. The highest antioxidant activity was generally observed in stage II. All these results suggested that the L. inflorescences of each analyzed dioecious hemp cultivar presented a peculiar chemical profile affected by the harvesting stage. This information could be useful for producers and industries to harvest inflorescences in the appropriate stage to obtain samples with a peculiar chemical profile suitable for proper applications.
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http://dx.doi.org/10.3390/molecules26102912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156653PMC
May 2021

Towards FAIR nanosafety data.

Nat Nanotechnol 2021 Jun 20;16(6):644-654. Epub 2021 May 20.

Joint Research Centre, European Commission, Ispra, Italy.

Nanotechnology is a key enabling technology with billions of euros in global investment from public funding, which include large collaborative projects that have investigated environmental and health safety aspects of nanomaterials, but the reuse of accumulated data is clearly lagging behind. Here we summarize challenges and provide recommendations for the efficient reuse of nanosafety data, in line with the recently established FAIR (findable, accessible, interoperable and reusable) guiding principles. We describe the FAIR-aligned Nanosafety Data Interface, with an aggregated findability, accessibility and interoperability across physicochemical, bio-nano interaction, human toxicity, omics, ecotoxicological and exposure data. Overall, we illustrate a much-needed path towards standards for the optimized use of existing data, which avoids duplication of efforts, and provides a multitude of options to promote safe and sustainable nanotechnology.
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http://dx.doi.org/10.1038/s41565-021-00911-6DOI Listing
June 2021

Fibroblast Activation Protein α-Targeted CD40 Agonism Abrogates Systemic Toxicity and Enables Administration of High Doses to Induce Effective Antitumor Immunity.

Clin Cancer Res 2021 Mar 26. Epub 2021 Mar 26.

Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland.

Purpose: CD40 agonists hold great promise for cancer immunotherapy (CIT) as they enhance dendritic cell (DC) activation and concomitant tumor-specific T-cell priming. However, the broad expression of CD40 accounts for sink and side effects, hampering the efficacy of anti-CD40 antibodies. We hypothesized that these limitations can be overcome by selectively targeting CD40 agonism to the tumor. Therefore, we developed a bispecific FAP-CD40 antibody, which induces CD40 stimulation solely in presence of fibroblast activation protein α (FAP), a protease specifically expressed in the tumor stroma.

Experimental Design: FAP-CD40's activity and FAP specificity were validated by antigen-presenting cell (APC) activation and T-cell priming assays. In addition, FAP-CD40 was tested in subcutaneous MC38-FAP and KPC-4662-huCEA murine tumor models.

Results: FAP-CD40 triggered a potent, strictly FAP-dependent CD40 stimulation . , FAP-CD40 strongly enhanced T-cell inflammation and growth inhibition of KPC-4662-huCEA tumors. Unlike nontargeted CD40 agonists, FAP-CD40 mediated complete regression of MC38-FAP tumors, entailing long-term protection. A high dose of FAP-CD40 was indispensable for these effects. While nontargeted CD40 agonists induced substantial side effects, highly dosed FAP-CD40 was well tolerated. FAP-CD40 preferentially accumulated in the tumor, inducing predominantly intratumoral immune activation, whereas nontargeted CD40 agonists displayed strong systemic but limited intratumoral effects.

Conclusions: FAP-CD40 abrogates the systemic toxicity associated with nontargeted CD40 agonists. This enables administration of high doses, essential for overcoming CD40 sink effects and inducing antitumor immunity. Consequently, FAP-targeted CD40 agonism represents a promising strategy to exploit the full potential of CD40 signaling for CIT.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4001DOI Listing
March 2021

Classic and evolving approaches to evaluating cross reactivity of mAb and mAb-like molecules - A survey of industry 2008-2019.

Regul Toxicol Pharmacol 2021 Apr 22;121:104872. Epub 2021 Jan 22.

Drug Safety Research and Development, Pfizer, Inc, 300 Technology Square, Cambridge, MA, 02139, USA.

Monoclonal antibodies (mAbs) and mAb derivatives have become mainstay pharmaceutical modalites. A critical assessment is to ascertain the specificity of these molecules prior to human clinical trials. The primary technique for determining specificity has been the immunohistochemistry (IHC)-based "Tissue Cross-Reactivity" (TCR) assay, where the candidate molecule is applied to > 30 tissues to look for unexpected staining. In the last few years, however, non-IHC array-based platforms have emerged that allow for screening 75-80% of the human membrane proteome, indicating a viable alternative and/or addition to the IHC methods. The preclinical sciences subcommittee of the Biotechnology Innovation Organization (BIO), "BioSafe", conducted a survey of 26 BIO member companies to understand current sponsor experience with the IHC and array techniques. In the last ten years, respondents noted they have conducted more than 650 IHC TCR assays, largely on full length mAbs, with varying impacts on programs. Protein/cell arrays have been utilized by almost half of the companies and sponsors are gaining familiarity and comfort with the platform. Initial experience with recent versions of these arrays has been largely positive. While most sponsors are not prepared to eliminate the IHC TCR assay, growing experience with these alternatives allows them to confidently choose other approaches with or without TCR assays.
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http://dx.doi.org/10.1016/j.yrtph.2021.104872DOI Listing
April 2021

A review to support the derivation of a worst-case dermal penetration value for nanoparticles.

Regul Toxicol Pharmacol 2021 Feb 26;119:104836. Epub 2020 Nov 26.

Leitat Technological Center, Innovació 2, 08225, Terrassa, Spain. Electronic address:

Data on dermal penetration of nanoparticles (NPs) was reviewed with the goal to establish a worst-case dermal penetration value for NPs. To this aim, the main focus was on studies providing quantitative dermal penetration data (29 studies). In vivo dermal penetration studies and ex vivo studies based on skin explants were included. These studies used NPs with different compositions, dimensions, and shapes. The overall results showed that skin is an efficient barrier for NPs, indistinctly of their properties. However, some studies reported that a small percentage of the applied NP dose penetrated the skin surface and reached deeper skin layers. The integrity of the skin layer and the product formulation were more critical determinants of dermal penetration than the NP properties. Most quantitative studies were based on elemental analysis such that it cannot be concluded if detected levels are attributable to a dissolved fraction or to the penetration of particles as such. Results of qualitative imaging studies suggest that at least a fraction of the levels reported in quantitative studies could be due to particle penetration. Altogether, based on the data compiled, we propose that 1% could be used as a worst-case dermal penetration value for nanoparticles within the boundaries of the properties of those included in our analysis.
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http://dx.doi.org/10.1016/j.yrtph.2020.104836DOI Listing
February 2021

Chemico-Biological Characterization of Torpedino Di Fondi Tomato Fruits: A Comparison with San Marzano Cultivar at Two Ripeness Stages.

Antioxidants (Basel) 2020 Oct 21;9(10). Epub 2020 Oct 21.

Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P. le Aldo Moro 5, 00185 Rome, Italy.

Torpedino di Fondi (TF) is a hybrid tomato landrace developed in Sicily and recently introduced in the south Lazio area along with the classical San Marzano (SM) cultivar. The present study aimed at characterizing TF tomatoes at both pink and red ripening stages, and at comparing them with traditional SM tomatoes. A multidisciplinary approach consisting of morphological, chemical (FT-ICR MS, NMR, HPLC, and spectrophotometric methods), and biological (antioxidant and antifungal in vitro activity) analyses was applied. Morphological analysis confirmed the mini-San Marzano nature and the peculiar crunchy and solid consistency of TF fruits. Pink TF tomatoes displayed the highest content of hydrophilic antioxidants, like total polyphenols (0.192 mg/g), tannins (0.013 mg/g), flavonoids (0.204 mg/g), and chlorophylls a (0.344 mg/g) and b (0.161 mg/g), whereas red TF fruits were characterized by the highest levels of fructose (3000 mg/100 g), glucose (2000 mg/100 g), tryptophan (2.7 mg/100 g), phenylalanine (13 mg/100 g), alanine (25 mg/100 g), and total tri-unsaturated fatty acids (13% mol). Red SM fruits revealed the greatest content of lipophilic antioxidants, with 1234 mg/g of total carotenoids. In agreement with phenolics content, TF cultivar showed the greatest antioxidant activity. Lastly, red TF inhibited species (, and ) growth.
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http://dx.doi.org/10.3390/antiox9101027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590105PMC
October 2020

Folic acid supplementation in Italian women during pregnancy: A cross-sectional study conducted in general practice.

Nutrition 2020 Nov - Dec;79-80:110886. Epub 2020 Jun 4.

Italian Society of Preventive Medicine and Lifestyles, Rome, Italy.

Objectives: The association between folate insufficiency and congenital neural tube defects has been extensively investigated since the 1990s. To reach an adequate intake of folic acid (FA), improving folate status through periconceptional supplementation with FA, promotion of the consumption of foods rich in natural folates, and appropriate use of fortified foods is recommended. The aim of the present study was to investigate the supplementation of FA in a sample of pregnant women referred to general practice services in Italy, with a focus on the quality of information received by fertile women.

Methods: Participants were recruited from patients admitted to 44 general practice offices enrolled in the Italian Society of Preventive Medicine and Lifestyle study and located in Italy throughout the national territory. A questionnaire for the evaluation of FA supplementation was administered by the general practitioners (GPs). The interviewed subjects were asked to provide information about pregnancy characteristics, nutritional habits, lifestyle and risk factors, information sources, and knowledge about FA.

Results: This study included 328 participants. The percentage of women who did not take any FA supplements was 16.8%, and 66.4% of women started FA supplementation only after finding out they were pregnant. Only 16.8% of women started FA supplementation 12 wk before the beginning of pregnancy. The lack of supplementation with FA, as well as the incorrect adherence to the existing FA supplementation protocol, is attributable to different social (e.g., immigration, place of residence, job employment) and cultural (e.g., educational level, knowledge about FA) factors, the relatively poor planning of pregnancies, and the lack of information concerning the need for FA supplementation in the prepregnancy period. Finally, GPs and gynecologists are the only sources of information on the importance of FA supplementation.

Conclusions: The adherence of women to FA supplementation before pregnancy is still insufficient. The GP role in preconception care, and the promotion of FA supplementation, needs to be emphasized and further promoted.
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http://dx.doi.org/10.1016/j.nut.2020.110886DOI Listing
June 2020

Obesity or BMI Paradox? Beneath the Tip of the Iceberg.

Front Nutr 2020 7;7:53. Epub 2020 May 7.

Department of Experimental Medicine, Sapienza University, Rome, Italy.

The obesity paradox refers to extant evidence showing that obesity in older subjects or in patients with several chronic diseases may be protective and associated with decreased mortality. A number of mechanisms have been postulated to support the existence of obesity paradox; however, marked heterogeneity was found across studies and this has cast doubt on the actual presence of this phenomenon. The aim of the present narrative review is to summarize evidence underlying the concept of obesity paradox, focusing on limitations and bias related to this phenomenon, with emphasis on the use of body mass index (BMI). A major cause of the discrepancy between studies may be related to the use of BMI in the definition of obesity, that should consider, instead, excess body fat as the main characteristic of this disease and as the unique determinant of its complications. In addition, the adjustment for potential confounders (e.g., stage and grade of diseases, smoking habit, inability to capture the presence of signs of undernutrition in the normal-weight comparative group, consideration of body composition) may significantly scale down the protective role of obesity in terms of mortality. However, it is still necessary to acknowledge few biases (e.g., reverse causation, attrition bias, selection bias of healthy obese subjects or resilient survivors) that would still apply to obesity even when defined according with body composition. Further research should be prompted in order to promote correct phenotyping of patients in order to capture properly the trajectories of mortality in a number of diseases.
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http://dx.doi.org/10.3389/fnut.2020.00053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221058PMC
May 2020

Metabolomics profiling to investigate nanomaterial toxicity and .

Nanotoxicology 2020 08 25;14(6):807-826. Epub 2020 May 25.

Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany.

Nanomaterials (NMs) can be produced in plenty of variants posing several challenges for NM hazard and risk assessment. Metabolomic profiling of NM-treated cells and tissues allows for insights into underlying Mode-of-Action (MoA) and offers several advantages in this context. It supports the description of Adverse Outcome Pathways (AOPs) and, therefore, tailored AOP-based hazard testing strategies. Moreover, it bears great potential for biomarker discovery supporting toxicity prediction. Here, we applied metabolomics profiling to cells treated with four well-selected SiO variants, differing in structure, size and surface charge. TiO NM-105 served as a benchmark. Responses were studied in rat lung epithelial cells (RLE-6TN) and alveolar macrophages (NR8383) and compared to responses in rat lung tissues obtained from instillation and short-term inhalation studies (STIS). Time- and concentration-dependent changes were observed in both models but with cell-type specific responses. Overall, the levels of lipids and biogenic amines (BAs) tended to increase in epithelial cells but decreased in macrophages. Many identified metabolites like Met-SO, hydroxy-Pro and spermidine were related to oxidative stress, indicating that oxidative stress contributes to the MoA for the selected NMs. Several biomarker candidates such as Asp, Asn, Ser, Pro, spermidine, putrescine and LysoPCaC16:1 were identified and verified . In this study, we successfully applied a metabolomics workflow for and samples, which proved to be well suited to identify potential biomarkers, to gain insights into NM structure-activity relationship and into the underlying MoA.
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http://dx.doi.org/10.1080/17435390.2020.1764123DOI Listing
August 2020

Phytocomplex Characterization and Biological Evaluation of Powdered Fruits and Leaves from .

Molecules 2020 Apr 26;25(9). Epub 2020 Apr 26.

Department of Drug Chemistry and Technologies, "Sapienza" University of Rome, 00185 Rome, Italy.

Fully ripe fruits and mature leaves of were harvested and analyzed by means of analytical and biological tests to better comprehend the chemical composition and therapeutic/nutraceutical potential of this plant. Fruits and leaves were dried and the obtained powders were analyzed to study their color character and (via headspace gas chromatography) describe the chemical profile. Subsequently, they were submitted to a chloroform-methanol extraction, to a hydroalcoholic extraction procedure assisted or not by microwaves, and to an extraction with supercritical CO, assisted or not by ethanol as the co-solvent, to detect the polyphenolic and the volatile content. The resulting extracts were evaluated in terms of chlorophyll and carotenoid content, polyphenolic content, volatile fraction, total phenolic content, total flavonoid content, antioxidant activity, radical scavenging activity, and enzymatic inhibition activity. The results confirmed the correlation between the chemical composition and the high antioxidant potential of leaf extracts compared to the fruit extracts in terms of the phenolic and pigment content. A promising effect against tyrosinase emerged for all the extracts, suggesting a therapeutic/nutraceutical use for this plant. Conversely, the volatile content from both natural matrices was similar.
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http://dx.doi.org/10.3390/molecules25092021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248930PMC
April 2020

L. Inflorescences from Monoecious Cultivars Grown in Central Italy: An Untargeted Chemical Characterization from Early Flowering to Ripening.

Molecules 2020 Apr 20;25(8). Epub 2020 Apr 20.

Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.

The chemical composition of the inflorescences from four L. monoecious cultivars (Ferimon, Uso-31, Felina 32 and Fedora 17), recently introduced in the Lazio Region, was monitored over the season from June to September giving indications on their sensorial, pharmaceutical/nutraceutical proprieties. Both untargeted (NMR) and targeted (GC/MS, UHPLC, HPLC-PDA/FD and spectrophotometry) analyses were carried out to identify and quantify compounds of different classes (sugars, organic acids, amino acids, cannabinoids, terpenoids, phenols, tannins, flavonoids and biogenic amines). All cultivars in each harvesting period showed a THC content below the Italian legal limit, although in general THC content increased over the season. Citric acid, malic acid and glucose showed the highest content in the late flowering period, whereas the content of proline drastically decreased after June in all cultivars. Neophytadiene, nerolidol and chlorogenic acid were quantified only in Felina 32 cultivar, characterized also by a very high content of flavonoids, whereas alloaromadendrene and -cinnamic acid were detected only in Uso-31 cultivar. Naringenin and naringin were present only in Fedora 17 and Ferimon cultivars, respectively. Moreover, Ferimon had the highest concentration of biogenic amines, especially in July and August. Cadaverine was present in all cultivars but only in September. These results suggest that the chemical composition of L. inflorescences depends on the cultivar and on the harvesting period. Producers can use this information as a guide to obtain inflorescences with peculiar chemical characteristics according to the specific use.
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http://dx.doi.org/10.3390/molecules25081908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221798PMC
April 2020

Impact of Disability, Psychological Status, and Comorbidity on Health-Related Quality of Life Perceived by Subjects with Obesity.

Obes Facts 2020 24;13(2):191-200. Epub 2020 Mar 24.

Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.

Obesity is a rapidly growing public health problem affecting an increasing number of countries worldwide and creating substantial financial and health burdens. Obesity has a negative impact on health-related quality of life (HRQoL) with reference to physical and mental health status, social relationships, and economic factors. The aim of the present study is to investigate the association of number of comorbidities, psychological status, and disability level with HRQoL in a sample of subjects with obesity.

Methods: A total of 273 subjects with obesity (199 women and 74 men) were recruited. Medical history and anthropometric measurements were carried out. The Italian version of the Laval questionnaire, the TSD-OC (SIO test for obesity-related disabilities), and SCL-90 (Symptom Checklist-90) tests were administered. The association between HRQoL (global and different domains scores of the Laval questionnaire - dependent variable) and age, body mass index (BMI), comorbidity, TSD-OC, and SCL-90 was analysed using a stepwise linear regression model.

Results: BMI, disability (TSD-OC global score), and psychological symptoms (SCL-90 global severity index) were found to be the main determinants of HRQoL. Single domains of HRQoL (symptoms, activity/mobility, personal hygiene/clothing, emotions, social interaction, and sexual life) showed different patterns of associations with each domain of the Laval questionnaire. BMI, pain, and social life disruptions were found to be significantly associated with most of the HRQoL domains while age, comorbidities, psychological problems (depression, interpersonal symptoms, somatization), and disability were associated with only some domains of the Laval questionnaire. Education, psychological symptoms (obsessive-compulsive, anxiety, hostility, phobic anxiety, paranoid ideation), and disability domains (stiffness, housework, outdoor activities, occupational activities) were not associated with any of the dimensions of the Laval questionnaire.

Discussion/conclusion: The present study identified key determinants of QoL in subjects with obesity, which could help in refining the multidimensional diagnostic assessment of obesity as well as designing more effective interventions to improve HRQoL in these patients.
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http://dx.doi.org/10.1159/000506079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250341PMC
September 2020

Phytochemical and biological characterization of Italian "sedano bianco di Sperlonga" Protected Geographical Indication celery ecotype: A multimethodological approach.

Food Chem 2020 Mar 16;309:125649. Epub 2019 Oct 16.

Istituto per i Sistemi Biologici, Laboratorio di Risonanza Magnetica "Annalaura Segre", CNR, 00015 Monterotondo (Rome), Italy. Electronic address:

Celery is a widely used vegetable known for its peculiar sensorial and nutritional properties. Here, the white celery (Apium graveolens L.) "sedano bianco di Sperlonga" PGI ecotype was investigated to obtain the metabolic profile of its edible parts (blade leaves and petioles) also related to quality, freshness and biological properties. A multi-methodological approach, including NMR, MS, HPLC-PDA, GC-MS and spectrophotometric analyses, was proposed to analyse celery extracts. Sugars, polyalcohols, amino acids, organic acids, phenols, sterols, fatty acids, phthalides, chlorophylls, tannins and flavonoids were detected in different concentrations in blade leaf and petiole extracts, indicating celery parts as nutraceutical sources. The presence of some phenols in celery extracts was here reported for the first time. Low contents of biogenic amines and mycotoxins confirmed celery quality and freshness. Regarding the biological properties, ethanolic celery extracts inhibited the oxidative-mediated DNA damage induced by tert-butylhydroperoxide and scavenged DPPH and ABTS radicals.
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http://dx.doi.org/10.1016/j.foodchem.2019.125649DOI Listing
March 2020

Blueberry-Based Meals for Obese Patients with Metabolic Syndrome: A Multidisciplinary Metabolomic Pilot Study.

Metabolites 2019 Jul 10;9(7). Epub 2019 Jul 10.

Sezione di Fisiopatologia Medica, Scienza dell'Alimentazione ed Endocrinologia - Dipartimento di Medicina Sperimentale, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.

A pilot study was carried out on five obese/overweight patients suffering from metabolic syndrome, with the aim to evaluate postprandial effects of high fat/high glycemic load meals enriched by blueberries. Postprandial urine samples were analyzed by H-NMR spectroscopy after 2 and 4 h from ingestion to identify potential markers of blueberry intake. Significant decrease of methylamines, acetoacetate, acetone and succinate, known indicators of type 2 diabetes mellitus, were observed after the intake of meals enriched with blueberries. On the other hand, an accumulation of -hydroxyphenyl-acetic acid and 3-(3'-hydroxyphenyl)-3-hydropropionic acid originating from gut microbial dehydrogenation of proanthocyanidins and procyanidins was detected. Real-time PCR-analysis of mRNAs obtained from mononuclear blood cells showed significant changes in cytokine gene expression levels after meals integrated with blueberries. In particular, the mRNAs expression of interleukin-6 (IL-6) and Transforming Growth Factor-β (TGF-β), pro and anti-inflammation cytokines, respectively, significantly decreased and increased after blueberry supplementation, indicating a positive impact of blueberry ingestion in the reduction of risk of inflammation. The combined analysis of the urine metabolome and clinical markers represents a promising approach in monitoring the metabolic impact of blueberries in persons with metabolic syndrome.
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http://dx.doi.org/10.3390/metabo9070138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680695PMC
July 2019

Amino Acids and Hypertension in Adults.

Nutrients 2019 Jun 27;11(7). Epub 2019 Jun 27.

Department of Experimental Medicine-Medical Pathophysiology, Food Science and Endocrinology Section; Sapienza University of Rome, 00185 Rome, Italy.

Accumulating evidence suggests a potential role of dietary protein among nutritional factors interfering with the regulation of blood pressure. Dietary protein source (plant versus animal protein), and especially, protein composition in terms of amino acids has been postulated to interfere with mechanisms underlying the development of hypertension. Recently, mounting interest has been directed at amino acids in hypertension focusing on habitual dietary intake and their circulating levels regardless of single amino acid dietary supplementation. The aim of the present review was to summarize epidemiological evidence concerning the connection between amino acids and hypertension. Due to the large variability in methodologies used for assessing amino acid levels and heterogeneity in the results obtained, it was not possible to draw robust conclusions. Indeed, some classes of amino acids or individual amino acids showed non-causative association with blood pressure as well as the incidence of hypertension, but the evidence was far from being conclusive. Further research should be prompted for a thorough understanding of amino acid effects and synergistic actions of different amino acid classes on blood pressure regulation.
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http://dx.doi.org/10.3390/nu11071459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683075PMC
June 2019

Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy.

Sci Transl Med 2019 06;11(496)

Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.

Endogenous costimulatory molecules on T cells such as 4-1BB (CD137) can be leveraged for cancer immunotherapy. Systemic administration of agonistic anti-4-1BB antibodies, although effective preclinically, has not advanced to phase 3 trials because they have been hampered by both dependency on Fcγ receptor-mediated hyperclustering and hepatotoxicity. To overcome these issues, we engineered proteins simultaneously targeting 4-1BB and a tumor stroma or tumor antigen: FAP-4-1BBL (RG7826) and CD19-4-1BBL. In the presence of a T cell receptor signal, they provide potent T cell costimulation strictly dependent on tumor antigen-mediated hyperclustering without systemic activation by FcγR binding. We could show targeting of FAP-4-1BBL to FAP-expressing tumor stroma and lymph nodes in a colorectal cancer-bearing rhesus monkey. Combination of FAP-4-1BBL with tumor antigen-targeted T cell bispecific (TCB) molecules in human tumor samples led to increased IFN-γ and granzyme B secretion. Further, combination of FAP- or CD19-4-1BBL with CEA-TCB (RG7802) or CD20-TCB (RG6026), respectively, resulted in tumor remission in mouse models, accompanied by intratumoral accumulation of activated effector CD8 T cells. FAP- and CD19-4-1BBL thus represent an off-the-shelf combination immunotherapy without requiring genetic modification of effector cells for the treatment of solid and hematological malignancies.
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http://dx.doi.org/10.1126/scitranslmed.aav5989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181714PMC
June 2019

Desf. Aerial Parts: Extraction Procedures, Secondary Metabolites and Color Analysis.

Molecules 2018 Aug 6;23(8). Epub 2018 Aug 6.

Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.

A method using high-performance liquid chromatography coupled with a photodiode array detector was proposed for the rapid characterization of different phenolic constituents from the extracts of aerial parts. species are known for their multiple biological activities, but no information is available in the literature about . With the aim to firstly characterize the main secondary metabolites of this plant, so as to orient better the biological evaluation, we applied three different extraction procedures and compared the chromatographic results. Microwave-assisted extraction gave the best yield and recovery of important compounds such as gallic acid, catechin, chlorogenic acid, -OH benzoic acid, rutin, sinapinic acid, -ferulic acid, naringenin and benzoic acid. These constituents belong to three important chemical classes: phenolic acids, flavonoids and monoterpenes. Color evaluation and analysis of chlorophylls (a and b) and carotenoids complete the preliminary profile of this plant. From these analyses, is a source of bioactive compounds (especially rutin, -ferulic acid and gallic acid) and could be recommended as a plant of phyto-pharmaceutical relevance, opening new perspectives on this salt-tolerant plant.
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http://dx.doi.org/10.3390/molecules23081962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222348PMC
August 2018

CD20-TCB with Obinutuzumab Pretreatment as Next-Generation Treatment of Hematologic Malignancies.

Clin Cancer Res 2018 10 1;24(19):4785-4797. Epub 2018 May 1.

Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.

Despite promising clinical activity, T-cell-engaging therapies including T-cell bispecific antibodies (TCB) are associated with severe side effects requiring the use of step-up-dosing (SUD) regimens to mitigate safety. Here, we present a next-generation CD20-targeting TCB (CD20-TCB) with significantly higher potency and a novel approach enabling safer administration of such potent drug. We developed CD20-TCB based on the 2:1 TCB molecular format and characterized its activity preclinically. We also applied a single administration of obinutuzumab (Gazyva pretreatment, Gpt; Genentech/Roche) prior to the first infusion of CD20-TCB as a way to safely administer such a potent drug. CD20-TCB is associated with a long half-life and high potency enabled by high-avidity bivalent binding to CD20 and head-to-tail orientation of B- and T-cell-binding domains in a 2:1 molecular format. CD20-TCB displays considerably higher potency than other CD20-TCB antibodies in clinical development and is efficacious on tumor cells expressing low levels of CD20. CD20-TCB also displays potent activity in primary tumor samples with low effector:target ratios. , CD20-TCB regresses established tumors of aggressive lymphoma models. Gpt enables profound B-cell depletion in peripheral blood and secondary lymphoid organs and reduces T-cell activation and cytokine release in the peripheral blood, thus increasing the safety of CD20-TCB administration. Gpt is more efficacious and safer than SUD. CD20-TCB and Gpt represent a potent and safer approach for treatment of lymphoma patients and are currently being evaluated in phase I, multicenter study in patients with relapsed/refractory non-Hodgkin lymphoma (NCT03075696). .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0455DOI Listing
October 2018

Olive Fruit Blends Modulate Lipid-Sensing Nuclear Receptor PPARγ, Cell Survival, and Oxidative Stress Response in Human Osteoblast Cells.

J Am Coll Nutr 2018 Sep-Oct;37(7):589-597. Epub 2018 Apr 13.

b Department of Biochemical Sciences , Sapienza University of Rome , Roma , Italy.

Objective: The aim of the present study was to investigate how different extravirgin olive oils (EVOOs), obtained by blending Olea europea cultivars, could influence the cell growth, the response to inflammatory stimuli, and oxidative stress in a culture of the osteosarcoma cell line Saos-2.

Methods: Three different extravirgin olive oils were physicochemically characterized, determining the free acidity, the oxidation status, the polyphenols content, and the antioxidative activity. Moreover, the effects on Saos-2 cell culture were determined, studying the mRNA expression level by real-time polymerase chain reaction (PCR) assays and the antioxidative activity using fluorescent probes.

Results: The cultivars used in the south of Italy, yield extravirgin oils with different amount of fatty acids and polyphenols, which counteract induction of proinflammatory cytokines and regulate free radical production in hydrogen peroxide-stimulated cells. In vitro analysis using the human osteoblast cell line Saos-2 showed that the addition of oils to cell culture simulated a hypoxic stress followed by a reoxygenation period, during which the antioxidant activity of extravirgin olive oils protected cells from oxidative damages. On the other hand, the mRNA expression levels of factors involved in inflammatory processes, cell growth recovery, and antioxidant response, as heme oxygenase-1, were differently stimulated by EVOOs. Moreover, peroxisome proliferator activated receptor γ (PPARγ) was differently modulated by EVOOs.

Conclusion: These findings show that the blending of different extravirgin olive oil can impact an osteoblast cell line, in particular regarding cell growth recovery and oxidative stress.
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http://dx.doi.org/10.1080/07315724.2018.1451409DOI Listing
September 2019

A multi-methodological approach in the study of Italian PDO "Cornetto di Pontecorvo" red sweet pepper.

Food Chem 2018 Jul 10;255:120-131. Epub 2018 Feb 10.

Dipartimento di Fisiologia e Farmacologia "V. Ersparmer", Sapienza Università di Roma, P.le Aldo Moro 5, 00185 Rome, Italy.

A multi-methodological approach was applied to study red sweet peppers (Capsicum annuum L.) ecotype "Cornetto di Pontecorvo" grown in a greenhouse or in open field. This approach includes morphological analysis, chemical composition determination, and biological activity evaluation of different extracts from pepper fruits. Untargeted analyses, namely NMR spectroscopy and mass spectrometry, allowed the comprehensive pepper metabolite profile of pepper pulp, peel and seeds hydroalcoholic and organic extracts to be determined, showing the presence of sugars, organic acids, amino acids and other secondary metabolites. Targeted analyses, such as HPLC-PDA, HPLC-TLC and spectrophotometric analyses allowed polyphenols, tannins, flavonoids and pigments content to be determined. Samples quality and freshness were verified by the low content of biogenic amines and mycotoxins, as determined using HPLC-FLD and HPLC-MS, respectively. Preliminary biological results demonstrated the ability of the organic extracts to inhibit α-amylase, a key enzyme in the control of glucose metabolism.
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http://dx.doi.org/10.1016/j.foodchem.2018.02.050DOI Listing
July 2018

Qualitative and Quantitative Phytochemical Analysis of Different Extracts from Thymus algeriensis Aerial Parts.

Molecules 2018 Feb 20;23(2). Epub 2018 Feb 20.

Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.

This study was performed to evaluate the metabolite recovery from different extraction methods applied to aerial parts. A high-performance liquid chromatographic method using photodiode array detector with gradient elution has been developed and validated for the simultaneous estimation of different phenolic compounds in the extracts and in their corresponding purified fractions. The experimental results show that microwave-assisted aqueous extraction for 15 min at 100 °C gave the most phenolics-enriched extract, reducing extraction time without degradation effects on bioactives. Sixteen compounds were identified in this extract, 11 phenolic compounds and five flavonoids, all known for their biological activities. Color analysis and determination of chlorophylls and carotenoids implemented the knowledge of the chemical profile of this plant.
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http://dx.doi.org/10.3390/molecules23020463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017170PMC
February 2018

Rapid activation of tumor-associated macrophages boosts preexisting tumor immunity.

J Exp Med 2018 03 7;215(3):859-876. Epub 2018 Feb 7.

Roche Pharmaceutical Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany

Depletion of immunosuppressive tumor-associated macrophages (TAMs) or reprogramming toward a proinflammatory activation state represent different strategies to therapeutically target this abundant myeloid population. In this study, we report that inhibition of colony-stimulating factor-1 receptor (CSF-1R) signaling sensitizes TAMs to profound and rapid reprogramming in the presence of a CD40 agonist before their depletion. Despite the short-lived nature of macrophage hyperactivation, combined CSF-1R+CD40 stimulation of macrophages is sufficient to create a proinflammatory tumor milieu that reinvigorates an effective T cell response in transplanted tumors that are either responsive or insensitive to immune checkpoint blockade. The central role of macrophages in regulating preexisting immunity is substantiated by depletion experiments, transcriptome analysis of ex vivo sorted TAMs, and gene expression profiling of whole tumor lysates at an early treatment time point. This approach enabled the identification of specific combination-induced changes among the pleiotropic activation spectrum of the CD40 agonist. In patients, CD40 expression on human TAMs was detected in mesothelioma and colorectal adenocarcinoma.
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http://dx.doi.org/10.1084/jem.20171440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839760PMC
March 2018

Comparative assessment of immune complex-mediated hypersensitivity reactions with biotherapeutics in the non-human primate: Critical parameters, safety and lessons for future studies.

Regul Toxicol Pharmacol 2017 Aug 15;88:125-137. Epub 2017 Jun 15.

Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, 4001 Basel, Switzerland.

With the emergence of novel biotherapeutic formats and immunostimulatory biotherapeutics in cancer immunotherapy, an understanding of immune-complex (IC) mediated hypersensitivity reactions in toxicology studies - and their differentiation from pharmacology - remains key to the preclinical evaluation of these drugs. In this review we provide an in-depth evaluation and comparison of case examples where IC-mediated hypersensitivity reactions were observed in cynomolgus monkeys. We provide details of the parameters evaluated in each study to substantiate and guide the interpretation of these findings. Five study cases (1 therapeutic protein, 4 monoclonal antibodies) are discussed for which effects ranged from minor to fatal. Common characteristics are the high incidence of clinical signs, detectable antidrug antibodies, and accelerated drug clearance up to virtual loss of exposure. In our experience, measurement of cytokine levels in vivo and detection of complement (split products) were supportive markers in situations where coagulopathy was suspected to play a role in the observed effects. Recommendations are outlined to prepare for root-cause analysis of suspected hypersensitivity reactions. Overall, a thorough analysis of the findings has helped to start clinical trials despite major findings. The hypersensitivity reactions with our human(ized) immunoglobulins have not proven to be predictive for humans.
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http://dx.doi.org/10.1016/j.yrtph.2017.06.004DOI Listing
August 2017

Nutraceutical Improvement Increases the Protective Activity of Broccoli Sprout Juice in a Human Intestinal Cell Model of Gut Inflammation.

Pharmaceuticals (Basel) 2016 Aug 12;9(3). Epub 2016 Aug 12.

Food and Nutrition Research Centre, Consiglio per la ricerca in agricoltura e l'analisi dell'economia agraria, Via Ardeatina 546, 00178 Rome, Italy.

Benefits to health from a high consumption of fruits and vegetables are well established and have been attributed to bioactive secondary metabolites present in edible plants. However, the effects of specific health-related phytochemicals within a complex food matrix are difficult to assess. In an attempt to address this problem, we have used elicitation to improve the nutraceutical content of seedlings of Brassica oleracea grown under controlled conditions. Analysis, by LC-MS, of the glucosinolate, isothiocyanate and phenolic compound content of juices obtained from sprouts indicated that elicitation induces an enrichment of several phenolics, particularly of the anthocyanin fraction. To test the biological activity of basal and enriched juices we took advantage of a recently developed in vitro model of inflamed human intestinal epithelium. Both sprouts' juices protected intestinal barrier integrity in Caco-2 cells exposed to tumor necrosis factor α under marginal zinc deprivation, with the enriched juice showing higher protection. Multivariate regression analysis indicated that the extent of rescue from stress-induced epithelial dysfunction correlated with the composition in bioactive molecules of the juices and, in particular, with a group of phenolic compounds, including several anthocyanins, quercetin-3-Glc, cryptochlorogenic, neochlorogenic and cinnamic acids.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039501PMC
http://dx.doi.org/10.3390/ph9030048DOI Listing
August 2016

Application of a MABEL Approach for a T-Cell-Bispecific Monoclonal Antibody: CEA TCB.

J Immunother 2016 09;39(7):279-89

*Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Basel †Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Glycart AG, Schlieren, Switzerland.

CEA TCB is a novel T-cell-bispecific (TCB) antibody targeting the carcinoembryonic antigen (CEA) expressed on tumor cells and the CD3 epsilon chain (CD3e) present on T cells, which is currently in Phase 1 clinical trials (NCT02324257) for the treatment of CEA-positive solid tumors. Because the human CEA (hCEA) binder of CEA TCB does not cross-react with cynomolgus monkey and CEA is absent in rodents, alternative nonclinical safety evaluation approaches were considered. These included the development of a cynomolgus monkey cross-reactive homologous (surrogate) antibody (cyCEA TCB) for its evaluation in cynomolgus monkey and the development of double-transgenic mice, expressing hCEA and human CD3e (hCEA/hCD3e Tg), as a potential alternative species for nonclinical safety studies. However, a battery of nonclinical in vitro/ex vivo experiments demonstrated that neither of the previous approaches provided a suitable and pharmacologically relevant model to assess the safety of CEA TCB. Therefore, an alternative approach, a minimum anticipated biological effect level (MABEL), based on an in vitro tumor lysis assay was used to determine the starting dose for the first-in-human study. Using the most conservative approach to the MABEL assessment, a dose of 52 μg was selected as a safe starting dose for clinical study.
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http://dx.doi.org/10.1097/CJI.0000000000000132DOI Listing
September 2016

Improvement of the nutraceutical quality of broccoli sprouts by elicitation.

Food Chem 2016 Jun 20;201:101-9. Epub 2016 Jan 20.

CREA-NUT, Consiglio per la Ricerca in Agricoltura e l'Analisi dell'Economia Agraria, Food and Nutrition Research Centre, Via Ardeatina 546, 00178 Roma, Italy. Electronic address:

Epidemiological studies show an inverse association between Brassica consumption and chronic diseases. Phytochemicals are thought to be beneficial for human health and therefore responsible for this protective effect. Increasing their levels into Brassica food is considered an expedient nutritional strategy that can be achieved through the manipulation of growth conditions by elicitors. In this work we systematically evaluated the influence of treatment with different elicitors (sucrose, mannitol, NaCl, 1-aminocyclopropane-L-carboxylic acid, salicylic acid and methyl jasmonate) on the phytochemical composition of broccoli sprouts. The content of total and single glucosinolates, total phenolic compounds, total flavonoids, total anthocyanins, vitamin C and E and β-carotene was assessed. The exposure to different elicitors produced concentration- and elicitor-dependent specific changes in the content of all the phytochemicals considered. Sucrose, identified as the most effective elicitor by principal component analysis, induced a significant increase of total and specific glucosinolates, vitamin C, total anthocyanins and polyphenols. Sucrose is likely to represent an effective tool to increase the nutritional value of broccoli sprouts.
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http://dx.doi.org/10.1016/j.foodchem.2016.01.063DOI Listing
June 2016

Protective effects of Brassica oleracea sprouts extract toward renal damage in high-salt-fed SHRSP: role of AMPK/PPARα/UCP2 axis.

J Hypertens 2015 Jul;33(7):1465-79

aIRCCS Neuromed, Pozzilli (Isernia) bDepartment of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Ospedale S. Andrea cDepartment of Biology and Biotechnology, Sapienza University dFood and Nutrition Research Center (CRA-NUT), Consiglio per la Ricerca e la Sperimentazione in Agricoltura, Rome eCentro Cardiologico Monzino, IRCCS fDepartment of Pharmacological and Biomolecular Sciences, University of Milan, Milan gDepartment of Experimental Medicine, Medical Physiopathology, Food Science and Endocrinology Section, Sapienza University, Rome, Italy.

Objectives: Renal damage precedes occurrence of stroke in high-sodium/low-potassium-fed stroke-prone spontaneously hypertensive rat (SHRSP). We previously reported a marked suppression of uncoupling protein-2 (UCP2) upon high-salt Japanese-style diet in SHRSP kidneys. Vegetable compounds are known to exert protective effects in cardiovascular diseases. We aimed at evaluating the impact of Brassica oleracea sprouts juice toward renal damage in Japanese diet-fed SHRSP and exploring the role of 5'-adenosine monophosphate-activated protein kinase (AMPK)/NAD-dependent deacetylase sirtuin-1 (SIRT1)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α)/peroxisome proliferator-activated receptor-α (PPARα)/UCP2 axis.

Methods: SHRSP received Japanese diet for 4 weeks. A group of SHRSP received Japanese diet and B. oleracea. A third group received Japanese diet, B. oleracea, and PPARα inhibitor (GW6471). A group of SHRSP fed with regular diet served as control.

Results: Japanese diet induced marked increases of oxidative stress, inflammation, and proteinuria, along with glomerular and tubular damage, as compared with regular diet. A significant suppression of AMPK/UCP2 pathway was observed. Despite Japanese diet feeding, concomitant administration of B. oleracea prevented oxidative stress accumulation, inflammation, renal damage, and proteinuria. All components of the UCP2 regulatory pathway were significantly increased by B. oleracea. Superoxide dismutase 2 and phosphoendothelial nitric oxide synthase were also stimulated. Addition of PPARα inhibitor to B. oleracea and Japanese diet significantly reduced the B. oleracea beneficial effects. SBP levels were comparable among the different groups of rats.In vitro, UCP2 inhibition by genipin offset the antioxidant effect of B. oleracea in renal mesangial and proximal tubular cells.

Conclusion: B. oleracea administration prevented renal damage in salt-loaded SHRSP, independently from SBP, with parallel stimulation of AMPK/SIRT1/PGC1α/PPARα/UCP2 axis. Stimulation of the latter mechanism may provide relevant renal protective effect and play a therapeutic role in target organ damage progression in hypertension.
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http://dx.doi.org/10.1097/HJH.0000000000000562DOI Listing
July 2015

Untargeted NMR-based methodology in the study of fruit metabolites.

Molecules 2015 Mar 4;20(3):4088-108. Epub 2015 Mar 4.

Magnetic Resonance Laboratory "Annalaura Segre", Institute of Chemical Methodologies, National Research Council (CNR), I-00015 Monterotondo (RM), Italy.

In this review, fundamental aspects of the untargeted NMR-based methodology applied to fruit characterization are described. The strategy to perform the structure elucidation of fruit metabolites is discussed with some examples of spectral assignments by 2D experiments. Primary ubiquitous metabolites as well as secondary species-specific metabolites, identified in different fruits using an untargeted 1H-NMR approach, are summarized in a comprehensive way. Crucial aspects regarding the quantitative elaboration of spectral data are also discussed. The usefulness of the NMR-based metabolic profiling was highlighted using some results regarding quality, adulteration, varieties and geographical origin of fruits and fruit-derived products such as juices.
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http://dx.doi.org/10.3390/molecules20034088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272596PMC
March 2015

Environmental and economic sustainability of the Mediterranean Diet.

Int J Food Sci Nutr 2014 Dec 4;65(8):1008-12. Epub 2014 Aug 4.

Department of Experimental Medicine, RU of Food Science and Human Nutrition, Sapienza University of Rome , Rome , Italy.

The Mediterranean diet (MD) has been proposed as a healthy dietary pattern for disease prevention. However, little information exists on the cost and on the environmental impact of such a dietary model. We compared the environmental impact and the costs of the current food consumption pattern of the Italian population and the Mediterranean model in order to investigate its overall sustainability. The environmental impact was calculated on the basis of three indexes, i.e. Carbon, Ecological and Water Footprint. The costs (Euro) per person of the MD and of the current Italian household food expenditure were considered on a weekly basis according to the 2013 data from the Observatory prices and tariffs of the Ministry of Economic Development and the service SMS consumers of the Ministry of Agriculture, Food and Forestry. The MD resulted to produce a lower environmental impact than the current food consumption of the Italian population. The monthly expenditure of the MD is slightly higher in the overall budget compared to the current expenditure allocated to food by the Italian population, but there is a substantial difference in the distribution of budget according to the different food groups.
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http://dx.doi.org/10.3109/09637486.2014.945152DOI Listing
December 2014

177Lu-DOTA-HH1, a novel anti-CD37 radio-immunoconjugate: a study of toxicity in nude mice.

PLoS One 2014 28;9(7):e103070. Epub 2014 Jul 28.

Nordic Nanovector AS, Oslo, Norway.

Background: CD37 is an internalizing B-cell antigen expressed on Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia cells (CLL). The anti-CD37 monoclonal antibody HH1 was conjugated to the bifunctional chelator p-SCN-Bn-DOTA and labelled with the beta-particle emitting radionuclide 177Lu creating the radio-immunoconjugate (RIC) 177Lu-DOTA-HH1 (177Lu-HH1, trade name Betalutin). The present toxicity study was performed prior to initiation of clinical studies with 177Lu-HH1.

Methodology/principal Findings: Nude mice with or without tumor xenografts were treated with 50 to 1000 MBq/kg 177Lu- HH1 and followed for clinical signs of toxicity up to ten months. Acute, life threatening bone marrow toxicity was observed in animals receiving 800 and 1000 MBq/kg 177Lu-HH1. Significant changes in serum concentrations of liver enzymes were evident for treatment with 1000 MBq/kg 177Lu-HH1. Lymphoid depletion, liver necrosis and atrophy, and interstitial cell hyperplasia of the ovaries were also observed for mice in this dose group.

Conclusions/significance: 177Lu-DOTA-HH1 was well tolerated at dosages about 10 times above those considered relevant for radioimmunotherapy in patients with B-cell derived malignancies.The toxicity profile was as expected for RICs. Our experimental results have paved the way for clinical evaluation of 177Lu-HH1 in NHL patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103070PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113375PMC
November 2015