Absence Of Toxicity Research Articles

Simulation and numerical modeling of high‐efficiency CZTS solar cells with a BSF layer

AbstractThe present paper deals with the photovoltaic performance‐based numerical evaluation of copper–zinc–tin–sulfur (CZTS) solar cells embedded with CZTSe as a back surface field (BSF) layer. CZTS has been considered a leading candidate for the fabrication of solar devices owing to its availability and absence of toxicity. Adding a BSF layer to a solar device is a novel way to boost efficiency. It reduces the recombination of the carriers at the back surface, thus increasing the overall current output of the solar cells. SCAPS 1D simulator is used to study the impact of several parameters on electrical properties like temperature, the thickness of the CZTS layer, acceptor doping concentration, and the impact of series and shunt resistances. Considering the optimized parameters in each layer of the solar cells, this work delivers 24.7% efficiency with the BSF layer, which is 8% more than that without the BSF layer. The results of this modeling will facilitate researchers to fabricate a highly efficient CZTS solar cell.

Insulin eye drops for treating corneal ulcer in a non-diabetic patient: regarding a case

Corneal ulcers are included in a heterogeneous group of eye injuries. When patients do not respond to treatment, including even corneal transplant, other alternatives need to be explored.We present a case of a patient who suffered an accidental spillage from the contents of a car battery. This corneal lesion was refractory to both surgical and pharmacological treatment. After four years of a persistent ulcer, insulin topical treatment 50 IU/mL was started. Improvement began to be observed and currently the patient has completely recovered the corneal epithelium.Nowadays, evidence of the topical insulin use for the treatment of corneal ulcers is higher in diabetic patients. In non-diabetic patients, evidence is restricted to a series of cases of neurotrophic corneal ulcers and a case report of a patient who presented a persistent epithelial defect after resection of a neurinoma. This case presents the experience of using an insulin drop formulation with effectiveness and absence of toxicity in a patient non-diabetic with a post-caustic corneal ulcer.

Encapsulating potential and functional properties of exopolysaccharide from Limosilactobacillus reuteri KCTC 14626BP isolated from human breast milk

Exopolysaccharides (EPS) are natural, nontoxic, biocompatible and biodegradable macromolecules produced by microorganisms, including the Lactic acid bacteria, to enhance protection against environmental stress conditions. The current study focused on the encapsulation and functional efficiency of EPS produced by probiotic strains isolated from human milk. Among 27 isolates, the potential high EPS-producing strain Limosilactobacillus reuteri KCTC 14626BP was selected based on biofilm production. The structural Characterization of EPS was performed based on FTIR, NMR and functional properties were determined; further, the encapsulation efficiency of EPS was determined with caffeic acid. The results indicate that L. reuteri produced EPS major component consisting of glucose, galactose and arabinose with the ratio of (0.78:0.16: 0.05). The antioxidant efficiency of EPS-LR was determined on DPPH (60.3 %) and ABTS (48.9 %); EPS showed enhanced functional activities. The absence of toxicity was confirmed based on Caenorhabditis elegans. The EPS-loaded Caffeic acid (CA) EPS-LR indicated spherical capsules with rough surfaces, with sizes ranging from 1.39 to 6.75 μm. These findings indicate that EPS-LR can be applied as a bioactive compound and encapsulating material in food, cosmetics, and pharmaceutical industries.

Anti-Inflammatory Activities of 8-Benzylaminoxanthines Showing High Adenosine A2A and Dual A1/A2A Receptor Affinity.

Chronic inflammation plays an important role in the development of neurodegenerative diseases, such as Parkinson's disease (PD). In the present study, we synthesized 25 novel xanthine derivatives with variable substituents at the N1-, N3- and C8-position as adenosine receptor antagonists with potential anti-inflammatory activity. The compounds were investigated in radioligand binding studies at all four human adenosine receptor subtypes, A1, A2A, A2B and A3. Compounds showing nanomolar A2A and dual A1/A2A affinities were obtained. Three compounds, 19, 22 and 24, were selected for further studies. Docking and molecular dynamics simulation studies indicated binding poses and interactions within the orthosteric site of adenosine A1 and A2A receptors. In vitro studies confirmed the high metabolic stability of the compounds, and the absence of toxicity at concentrations of up to 12.5 µM in various cell lines (SH-SY5Y, HepG2 and BV2). Compounds 19 and 22 showed anti-inflammatory activity in vitro. In vivo studies in mice investigating carrageenan- and formalin-induced inflammation identified compound 24 as the most potent anti-inflammatory derivative. Future studies are warranted to further optimize the compounds and to explore their therapeutic potential in neurodegenerative diseases.

Determination of the antifungal activity of Dorema ammonium extract

The current investigation included estimating the efficiency of aqueous and ethanolic plant extracts of Dorema ammoniacum plant in inhibiting the growth of fungi, where the ethanolic extract recorded a higher rate of inhibition than the aqueous extract. It is more effective when the concentration is increased in inhibiting the growth of two types of Candida, C. albicans and C. krusei. The aqueous extracts of Dorema ammoniacum had no toxic effect on human red blood cells at concentrations (100, 200, 300) mg/ml at an incubation period of 3 hours. As a result of the widespread use of medicinal plants as antimicrobial drugs, the absence of toxicity on the host cells is considered essential because it is an inexpensive, easy-to-apply, quick-results method and is safe when used as a drug. Keywords: Dorema ammoniacum, D. Don, cytotoxicity activity, Antimicrobial activity.

Blockade of Rho-associated kinase prevents inhibition of axon regeneration of peripheral nerves induced by anti-ganglioside antibodies.

Anti-ganglioside antibodies are associated with delayed/poor clinical recovery in Guillain-Barrè syndrome, mostly related to halted axon regeneration. Cross-linking of cell surface gangliosides by anti-ganglioside antibodies triggers inhibition of nerve repair in in vitro and in vivo paradigms of axon regeneration. These effects involve the activation of the small GTPase RhoA/ROCK signaling pathways, which negatively modulate growth cone cytoskeleton, similarly to well stablished inhibitors of axon regeneration described so far. The aim of this work was to perform a proof of concept study to demonstrate the effectiveness of Y-27632, a selective pharmacological inhibitor of ROCK, in a mouse model of axon regeneration of peripheral nerves, where the passive immunization with a monoclonal antibody targeting gangliosides GD1a and GT1b was previously reported to exert a potent inhibitory effect on regeneration of both myelinated and unmyelinated fibers. Our results demonstrate a differential sensitivity of myelinated and unmyelinated axons to the pro-regenerative effect of Y-27632. Treatment with a total dosage of 9 mg/kg of Y-27632 resulted in a complete prevention of anti-GD1a/GT1b monoclonal antibody-mediated inhibition of axon regeneration of unmyelinated fibers to skin and the functional recovery of mechanical cutaneous sensitivity. In contrast, the same dose showed toxic effects on the regeneration of myelinated fibers. Interestingly, scale down of the dosage of Y-27632 to 5 mg/kg resulted in a significant although not complete recovery of regenerated myelinated axons exposed to anti-GD1a/GT1b monoclonal antibody in the absence of toxicity in animals exposed to only Y-27632. Overall, these findings confirm the in vivo participation of RhoA/ROCK signaling pathways in the molecular mechanisms associated with the inhibition of axon regeneration induced by anti-GD1a/GT1b monoclonal antibody. Our findings open the possibility of therapeutic pharmacological intervention targeting RhoA/Rock pathway in immune neuropathies associated with the presence of anti-ganglioside antibodies and delayed or incomplete clinical recovery after injury in the peripheral nervous system.

Chicken embryo model for in vivo acute toxicological and antitumor efficacy evaluation of lipid nanocarrier containing doxorubicin

Nanoencapsulation of chemotherapeutics, including doxorubicin, can endow the formulations with unique properties, such as a decrease in adverse effects and toxicity. The chicken embryo model is an alternative and well-accepted strategy for evaluating the toxicity and efficacy of drugs and nanoformulations. Therefore, this study proposes the development of a new lipid nanocarrier for doxorubicin delivery (NanoLip-Dox) and posterior evaluation of toxicological profile and antitumoral efficacy against a breast tumor in chicken embryos. NanoLip-Dox showed a unimodal particle size (< 150 nm), negative zeta potential (−19.5 mV), absence of drug crystals, drug content of 0.099 mg·mL−1, and high entrapment efficiency (95%). NanoLip-Dox did not cause toxicity in the chicken embryos; in contrast, doxorubicin hydrochloride induced moderate irritation in the chorioallantoic membrane (at 862.1 μmol·L−1), a survival rate of 50% (at 1.7 μmol·L−1), and an increase in aspartate aminotransferase (at 862.1, 344.8, and 172.4 μmol·L−1). In addition, NanoLip-Dox (at 1.7 μmol·L−1) showed potent antitumor efficacy with a high tumor remission percentage (40.9 ± 9.7%) compared to the control group (8.6 ± 14.8%). These findings together with the absence of toxicity concerning morphological characteristics, weights of embryos and organs, hematologic parameters, and enzymatic activity (alanine aminotransferase, aspartate aminotransferase, and creatinine) suggest the safety and efficacy of NanoLip-Dox.

Toxicity of Long-term Bone Therapy in Metastatic Breast Cancer

Purpose: In metastatic breast cancer, bone directed therapies (BDT; bisphosphonates and denosumab) are standard therapies used in the prevention of skeletal-related complications. However, the optimal duration of this treatment is unknown and recommendations suggest continuing indefinitely in the absence of toxicity. We audited the toxicity of prolonged bisphosphonate/denosumab therapy.

Scaffold Using Chitosan, Agarose, Cellulose, Dextran and Protein for Tissue Engineering-A Review.

Biological macromolecules like polysaccharides/proteins/glycoproteins have been widely used in the field of tissue engineering due to their ability to mimic the extracellular matrix of tissue. In addition to this, these macromolecules are found to have higher biocompatibility and no/lesser toxicity when compared to synthetic polymers. In recent years, scaffolds made up of proteins, polysaccharides, or glycoproteins have been highly used due to their tensile strength, biodegradability, and flexibility. This review is about the fabrication methods and applications of scaffolds made using various biological macromolecules, including polysaccharides like chitosan, agarose, cellulose, and dextran and proteins like soy proteins, zein proteins, etc. Biopolymer-based nanocomposite production and its application and limitations are also discussed in this review. This review also emphasizes the importance of using natural polymers rather than synthetic ones for developing scaffolds, as natural polymers have unique properties, like high biocompatibility, biodegradability, accessibility, stability, absence of toxicity, and low cost.

Application of Plant Surfactants as Cleaning Agents in Shampoo Formulations

With the increased demand for sustainable, hypoallergenic products, plant surfactants are a promising, eco-friendly option for cleaning products due to their low toxicity or even the absence of toxicity. In the present study, surfactant-rich extracts from Chenopodium quinoa, Glycine max, and Malpighia emarginata were assessed for their stability, antioxidant capacity, toxic potential, and cleaning potential in shampoo formulations. The surfactants in the extracts were isolated and characterized by NMR, UV-Vis, and FTIR spectroscopy. The results demonstrated that the extracts remained stable within the temperature and pH ranges tested. The antioxidant properties were also determined. In the analysis of irritation potential, G. max and C. quinoa exhibited low toxicity and no toxicity, respectively. The cleaning potential analysis confirmed that the extracts could be used as primary surfactants. Seven shampoo formulations were developed, which showed potential to reduce surface tension to the range of 27.1–31.7 mN/m and interfacial tension to the range of 5.4–7.3 mN/m. The wettability, percentage of solids, density, pH, and dirt dispersion of the formulas were within standard ranges, and the sebum removal capacity of the seven formulations was similar to or even better than that of a commercial shampoo.

Physicochemical, Morphological, and Cytotoxic Properties of Brazilian Jackfruit (Artocarpus heterophyllus) Starch Scaffold Loaded with Silver Nanoparticles.

Due to the physical, thermal, and biological properties of silver nanoparticles (AgNPs), as well as the biocompatibility and environmental safety of the naturally occurring polymeric component, polysaccharide-based composites containing AgNPs are a promising choice for the development of biomaterials. Starch is a low-cost, non-toxic, biocompatible, and tissue-healing natural polymer. The application of starch in various forms and its combination with metallic nanoparticles have contributed to the advancement of biomaterials. Few investigations into jackfruit starch with silver nanoparticle biocomposites exist. This research intends to explore the physicochemical, morphological, and cytotoxic properties of a Brazilian jackfruit starch-based scaffold loaded with AgNPs. The AgNPs were synthesized by chemical reduction and the scaffold was produced by gelatinization. X-ray diffraction (XRD), differential scanning calorimetry (DSC), scanning electron microscopy coupled with energy-dispersive spectroscopy (SEM-EDS), and Fourier-transform infrared spectroscopy (FTIR) were used to study the scaffold. The findings supported the development of stable, monodispersed, and triangular AgNPs. XRD and EDS analyses demonstrated the incorporation of silver nanoparticles. AgNPs could alter the scaffold's crystallinity, roughness, and thermal stability without affecting its chemistry or physics. Triangular anisotropic AgNPs exhibited no toxicity against L929 cells at concentrations ranging from 6.25 × 10-5 to 1 × 10-3 mol·L-1, implying that the scaffolds might have had no adverse effects on the cells. The scaffolds prepared with jackfruit starch showed greater crystallinity and thermal stability, and absence of toxicity after the incorporation of triangular AgNPs. These findings indicate that jackfruit is a promising starch source for developing biomaterials.

Considerations for Drug Development in Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) have historically been challenging diseases for drug development due to their biology, preclinical modeling, and the affected patient population. In April 2022, the FDA convened a panel of regulators and academic experts in MDS to discuss approaches to improve MDS drug development. The panel reviewed challenges in MDS clinical trial design and endpoints and outlined considerations for future trial design in MDS to facilitate drug development to meaningfully meet patient needs. Challenges for defining clinical benefit in patients with MDS include cumbersome response criteria, standardized transfusion thresholds, and application and validation of patient reported outcome instruments. Clinical trials should reflect the biology of disease evolution, the advanced age of patients with MDS, and how patients are treated in real-world settings to maximize the likelihood of identifying active drugs. In patients with lower-risk disease, response criteria for anemic patients should be based on baseline transfusion dependency, improvement in symptoms, and quality of life. For higher-risk patients with MDS, trials should include guidance to prevent dose reductions or delays that could limit efficacy, specify minimal durations of treatment (in the absence of toxicity or progression), and have endpoints focused on overall survival and durable responses. MDS trials should be designed from the outset to allow the practicable application of new therapies in this high-needs population, with drugs that can be administered and tolerated in community settings, and with endpoints that meaningfully improve patients' lives over existing therapies.

Binary Nanodrug-Delivery System Designed for Leukemia Therapy: Aptamer- and Transferrin-Codecorated Daunorubicin- and Luteolin-Coloaded Nanoparticles

This study aimed to develop a binary nanodrug-delivery system decorated with aptamers (APs) and transferrin (Tf) and loaded with daunorubicin (Drn) and luteolin (Lut) for the treatment of leukemia. Oligonucleotide AP- and Tf-contaiing ligands were designed and synthesized separately. AP-decorated Drn-loaded nanoparticles (AP-Drn NPs) and Tf-Lut NPs were prepared by self-assembly. An AP- and Tf-codecorated Drn- and Lut-coloaded nanodrug-delivery system (AP/Tf-Drn/Lut NPs) was prepared by self-assembly of AP-Drn NPs and Tf-Lut NPs. In vitro and in vivo efficiency of the system was evaluated on leukemia cell line and cell-bearing mouse model in comparison with single ligand-decorated, single drug-loaded and free-drug formulations. AP/Tf-Drn/Lut NPs were spherical and nanosized (187.3±5.3 nm) and loaded with about 85% of drugs. In vitro cytotoxicity of AP/Tf-Drn/Lut NPs was remarkably higher than single ligand-decorated ones. Double drug-loaded AP/Tf-Drn/Lut NPs exhibited higher tumor-cell inhibition than single drug-loaded ones, which showed a synergic effect of the two drugs. AP/Tf-Drn/Lut NPs achieved the most efficient antileukemic activity and absence of toxicity in vivo. The present study showed that AP/Tf-Drn/Lut NPs are a promising drug-delivery system for targeted treatment of leukemia, due to the synergic effect of the two drugs in this system. The limitations of this system include stability during large-scale production and application from bench to bedside.

Phytochemical Screening, Antioxidant Activity and Safety of &amp;lt;i&amp;gt;Petroselinum crispum&amp;lt;/i&amp;gt; (Mill.) AW Hill Apiaceae Leaves Grown in Benin

Petroselinum crispum (Mill.) AW Hill Apiaceae (Parsley) is a plant species commonly used for its culinary value, but little is known about its phytochemical composition and antioxidant properties. This study aimed to deepen knowledge of the Petroselinum crispum leaves (LPc) grown and consumed in Benin. The phytochemical screening of the LPc powder was done according to the method of Houghton and Raman at the Laboratory of Pharmacognosy and Essential Oils of the Institute of Applied Biomedical Sciences in Benin. The antioxidant activity (IC50) was evaluated by the DPPH reduction test. Phytochemical screening revealed the presence of chemical groups such as catechin tannins, gallic tannins, flavones, saponins, mucilages, coumarins, reducing agents and O-heterosides with reduced genins in the LPc powder. The aqueous extract of LPc showed antioxidant activity with an IC50 = 63.66 μg/mL and was found to be less active than ascorbic acid (IC50 = 0.111 μg/mL). No acute oral toxicity was observed and the LD50 of the aqueous extract of LPc is estimated to be greater than 5000 mg/kg in the Wistar rat. The absence of toxicity, its antioxidant activity associated with its richness in active ingredients makes Petroselinum crispum a promising species suitable for safe long-term use as food.

Estimated Costs of the Ipilimumab-Nivolumab Therapy and Related Adverse Events in Metastatic Melanoma.

Combined ipilimumab and nivolumab significantly improve outcomes in metastatic melanoma patients but bear an important financial impact on the healthcare system. Here, we analyze the treatment costs, focusing on irAE. We conducted a retrospective analysis of 62 melanoma patients treated with ipilimumab-nivolumab at the Lausanne University Hospital between 1 June 2016 and 31 August 2019. The frequency of irAEs and outcomes were evaluated. All melanoma-specific costs were analyzed from the first ipilimumab-nivolumab dose until the therapy given subsequently or death. A total of 54/62 (87%) patients presented at least one irAE, and 31/62 (50%) presented a grade 3-4 irAE. The majority of patients who had a complete response 12/14 (86%) and 21/28 (75%) of overall responders presented a grade 3-4 toxicity, and there were no responses in patients without toxicity. Toxicity costs represented only 3% of the total expenses per patient. The most significant contributions were medication costs (44%) and disease costs (39%), mainly disease-related hospitalization costs, not toxicity-related. Patients with a complete response had the lowest global median cost per week of follow up (EUR 2425) and patients who had progressive disease (PD), the highest one (EUR 8325). Except for one patient who had a Grade 5 toxicity (EUR 6043/week), we observe that less severe toxicity grades (EUR 9383/week for Grade 1), or even the absence of toxicity (EUR 9922/week), are associated with higher median costs per week (vs. EUR 3266/week for Grade 4 and EUR 2850/week for Grade 3). The cost of toxicities was unexpectedly low compared to the total costs, especially medication costs. Patients with higher toxicity grades had better outcomes and lower total costs due to treatment discontinuation.

Optical pulse labeling studies reveal exogenous seeding slows α-synuclein clearance

The accumulation of α-synuclein (α-syn) in intracellular formations known as Lewy bodies (LBs) is associated with several neurodegenerative diseases including Parkinson’s disease and Lewy Body Dementia. There is still limited understanding of how α-syn and LB formation is associated with cellular dysfunction and degeneration in these diseases. To examine the clearance and production dynamics of α-syn we transduced organotypic murine brain slice cultures (BSCs) with recombinant adeno-associated viruses (rAAVs) to express Dendra2-tagged human wild-type (WT) and mutant A53T α-syn, with and without the addition of exogenous α-syn fibrillar seeds and tracked them over several weeks in culture using optical pulse labeling. We found that neurons expressing WT or mutant A53T human α-syn show similar rates of α-syn turnover even when insoluble, phosphorylated Ser129 α-syn has accumulated. Taken together, this data reveals α-syn aggregation and overexpression, pSer129 α-syn, nor the A53T mutation affect α-syn dynamics in this system. Prion-type seeding with exogenous α-syn fibrils significantly slows α-syn turnover, in the absence of toxicity but is associated with the accumulation of anti-p62 immunoreactivity and Thiazin Red positivity. Prion-type induction of α-syn aggregation points towards a potential protein clearance deficit in the presence of fibrillar seeds and the ease of this system to explore precise mechanisms underlying these processes. This system facilitates the exploration of α-syn protein dynamics over long-term culture periods. This platform can further be exploited to provide mechanistic insight on what drives this slowing of α-syn turnover and how therapeutics, other genes or different α-syn mutations may affect α-syn protein dynamics.

Determination of the tolerability of the combined vaccine against Rhinopneumonia and Strangles on young horses

Infectious diseases are registered annually in herd horse breeding. One of the most common diseases among young horses are rhinopneumonia and strangles. According to the Department of Veterinary Medicine of the Republic of Sakha Yakutia and its own research, rhinopneumonia is registered annually in many districts of the republic, and the incidence of horse strangles is 57.8-62.7% annually, and the mortality from these diseases reaches up to 20%. One of the effective methods of combating these diseases is vaccination. In this regard, we have developed a new combined vaccine against rhinopneumonia and strangles for young horses. Preclinical studies on white mice have established harmlessness, absence of toxicity and pyrogenicity. The preclinic was completed by determining the tolerability on young horses (target animals) with single and multiple administration in preventive and increased doses. After immunization, the foals of all experimental groups in the blood, regardless of the multiplicity and number of doses of the vaccine, developed antibodies to the rhinopneumonia virus in titers 1:800 and 1:1600. The morphological composition of the blood of animals of all experimental groups exceeded the indicators of animals of the control group in terms of the content of erythrocytes and leukocytes. However, it should be noted that the indicators of the morphological composition of the blood of the control and experimental groups were within the physiological norm. Biochemical studies have shown that, in all groups (control, experimental), a decrease in total protein and its fractions was noted after vaccination. We attribute the decrease in these indicators to the influence of the method of keeping and feeding, since in the spring the young do not receive the necessary nutrients, vitamins and mineral elements. Thus, we have established the safety of a combined vaccine against rhinopneumonia and strangles for young horses in tested doses.

Development of potent and selective FAAH inhibitors with improved drug-like properties as potential tools to treat neuroinflammatory conditions

The neuroprotective performance against neuroinflammation of the endocannabinoid system (ECS) can be remarkably improved by indirect stimulation mediated by the pharmacological inhibition of the key ECS catabolic enzyme fatty acid amide hydrolase (FAAH). Based on our previous works and aiming to discover new selective FAAH inhibitors , we herein reported a new series of carbamate-based FAAH inhibitors (4a-t) which showed improved drug disposition properties compared to the previously reported analogues 2a-b. The introduction of ionizable functions allowed us to obtain new FAAH inhibitors of nanomolar potency characterized by good water solubility and chemical stability at physiological pH. Interesting structure-activity relationships (SARs), deeply analyzed by molecular docking and molecular dynamic (MD) simulations, were obtained. All the newly developed inhibitors showed an excellent selectivity profile evaluated against monoacylglycerol lipase and cannabinoid receptors. The reversible mechanism of action was determined by a rapid dilution assay. Absence of toxicity was confirmed in mouse fibroblasts NIH3T3 (for compounds 4e, 4g, 4n-o, and 4s) and in human astrocytes cell line 1321N1 (for compounds 4e, 4n, and 4s). The absence of undesired cardiac effects was also confirmed for compound 4n. Selected analogues (compounds 4e, 4g, 4n, and 4s) were able to reduce oxidative stress in 1321N1 astrocytes and exhibited notable neuroprotective effects when tested in an ex vivo model of neuroinflammation.

Can Growth of Nannochloropsis oculata under Modulated Stress Enhance Its Lipid-Associated Biological Properties?

Nannochloropsis oculata is well-recognized as a potential microalgal source of valuable compounds such as polyunsaturated fatty acids, particularly, eicosapentaenoic acid (EPA). The content and profile of these lipids is highly dependent on the growth conditions and can, therefore, be tailored through modulation of the growth parameters, specifically, temperature. Moreover, biological activities are composition dependent. In the present work, lipid extracts obtained from N. oculata, grown under constant temperature and under modulated temperature stress (to increase EPA content; Str) were characterized by GC-FID and several bioactivities were evaluated, namely, antioxidant (L-ORACFL), cytotoxic (MTT), adipolytic, anti-hepatic lipid accumulation (steatosis), and anti-inflammatory properties. Both extracts exhibited antioxidant activity (c.a. 49 µmol Troloxequivalent/mgextract) and the absence of toxicity (up to 800 µg/mL) toward colon and hepatic cells, adipocytes, and macrophages. They also induced adipolysis and the inhibition of triglycerides hepatic accumulation, with a higher impact from Str. In addition, anti-inflammatory activity was observed in the lipopolysaccharide-induced inflammation of macrophages in the presence of either extract, since lower levels of pro-inflammatory interleukin-6 and interferon-β were obtained, specifically by Str. The results presented herein revealed that modulated temperature stress may enhance the health effects of N. oculata lipid extracts, which may be safely utilized to formulate novel food products.

Results from a Phase I Trial Using Nivolumab in Combination with Dose Adjusted EPOCH in Newly Diagnosed Peripheral T-Cell Lymphomas

Introduction: Dose adjusted (DA)-EPOCH (etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide) is a first line chemotherapy option for peripheral T-cell lymphomas (PTCLs), but only a minority of patients (pts) are cured. Immune checkpoint blockade (CPB) demonstrated an overall response rate (ORR) of 30% in heavily pre-treated PTCLs in phase I/II studies but rapid or hyperprogression has also been observed in some non-responders. Cytotoxic chemotherapy may be additive to CPB by increasing the expression of neoantigens and therefore overcoming resistance due to weak tumor immunogenicity (Blood Advances. 2021). Methods: We conducted a phase I trial using a flat dose of the anti-PD1 antibody nivolumab (Nivo) in combination with DA-EPOCH in newly diagnosed PTCLs. Pts were allowed to receive one cycle of chemotherapy prior to enrollment. Pts received Nivo (360 mg) followed by DA-EPOCH every 21 days for 6 or 5 cycles (if prior chemotherapy) in the absence of toxicity or lack of efficacy. For immune related adverse event (irAE), Nivo was held until resolution to grade (G)1 and on ≤10 mg prednisone. For any G3 irAE, Nivo was withheld during the subsequent cycle, and if recurrence, Nivo was permanently discontinued. For protocol defined serious G3 irAEs (e.g., pneumonitis) or G4 irAE, Nivo was omitted from remaining cycles. After completing chemotherapy, pts had the option to proceed with autologous stem cell transplant (ASCT). Responses were assessed by PET/CT after 2 cycles of Nivo + DA-EPOCH and after the last cycle, using RECIL criteria. The primary objective was investigator-assessed ORR to Nivo + DA-EPOCH. Secondary objectives included toxicity, event free survival (EFS), progression free survival (PFS), and overall survival (OS). Selected baseline pt and tumor characteristics, as well as targeted next generation sequencing and multiplex immunohistochemistry of diagnostic tumor tissue were assessed and matched to response, EFS, and PFS in an exploratory analysis. Results: Table 1 displays pt characteristics of the 18 pts enrolled. Nine of 18 pts received treatment prior to enrollment as follows: one cycle of anthracycline based chemotherapy (N=6), oral methotrexate (N=1, SPTCL), and systemic steroids (N=2). The EPOCH dose level ranged from -6 to +3 (median dose level -1). All dose level reductions occurred due to G4 thrombocytopenia. In total, 10% (N=8 of 77) of treatment cycles were delayed >3 days; no delays were due to inadequate hematologic recovery. Immune related AEs of all grades occurred in 78% (N=14) of pts and 39% (N=7) of pts experienced ≥ grade 3 irAEs. 44% (N=8) of pts required discontinuation of Nivo due to irAEs. In the 8 pts whose irAEs resulted in discontinuation of Nivo, the irAE occurred prior to the second or third cycle of Nivo + DA-EPOCH. None of the 6 pts who received a cycle of anthracycline based chemotherapy prior to enrolling on trial experienced an irAE that resulted in dose hold or discontinuation of Nivo, whereas 8 of 12 pts who did not receive a prior cycle of anthracycline based chemotherapy experienced an irAE requiring a dose hold or discontinuation of Nivo. Interim and end of induction ORR were 94% (6 CR, 11 PR; 1 (6%) had SD) and 89%, respectively. We observed 11 CR, 5 PR, and 2 PD at the end of induction. Figure 1 displays response to Nivo + DA-EPOCH and duration of response. 2 pts received consolidation with ASCT. The number of doses of Nivo was significantly associated with improved response (CR vs. PR vs. PD); pts who received more doses of Nivo were more likely to achieve CR (p=0.0066). With a median follow up of 707 days (95% CI: 399-962), median EFS is 373 days (95% CI: 214-616), median PFS is 434 days (95% CI: 225-666), and median OS is 714 days (95% CI: 309-NR). Exploratory analyses, including expression of PD-1 and PDL-1 is ongoing. Discussion: As expected, in the entire cohort irAEs were common, often leading to discontinuation of CPB. However, no hyperprogression events were observed and dose-limiting irAEs did not occur in pts who received prior chemotherapy. Pts who were able to receive more Nivo had better efficacy outcomes. Given the high-risk characteristics of this cohort, the observed responses in rare subtypes, the encouraging PFS with a long median follow up, and the acceptable toxicity profile, further investigation of chemoimmunotherapeutic treatment strategies is warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal