Capivasertib and fulvestrant for patients with hormone receptor-positive advanced breast cancer: characterization, time course, and management of frequent adverse events from the phase III CAPItello-291 study.

BACKGROUND: Capivasertib is a potent, selective pan-AKT inhibitor. In CAPItello-291, the addition of capivasertib to fulvestrant resulted in a statistically significant (P < 0.001) improvement in progression-free survival over fulvestrant monotherapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer and disease progression on or after aromatase inhibitor-based therapy. Characterization of the capivasertib-fulvestrant adverse event (AE) profile as managed in CAPItello-291 can inform future management guidance and optimize clinical benefit. PATIENTS AND METHODS: Seven hundred and eight patients were randomized 1 : 1 to capivasertib (400 mg twice daily; 4 days on, 3 days off) or placebo, plus fulvestrant, on a 4-week cycle. Dose reductions/interruptions for capivasertib/placebo were permitted (up to two dose reductions). Safety analyses included exposure, AE, and clinical laboratory data and were conducted in patients who received at least one dose of capivasertib, fulvestrant, or placebo. Frequent AEs associated with phosphoinositide 3-kinase (PI3K)/protein kinase (AKT) pathway inhibition (diarrhea, rash, hyperglycemia) were characterized using group terms. AEs were summarized using descriptive statistics; time-to-event analyses were conducted. RESULTS: Safety analyses included 705 patients: capivasertib-fulvestrant (n = 355) and placebo-fulvestrant (n = 350). Frequent any-grade AEs with capivasertib-fulvestrant were diarrhea (72.4%), rash (38.0%), and nausea (34.6%); frequent grade ≥3 AEs were rash (12.1%), diarrhea (9.3%), and hyperglycemia (2.3%). Diarrhea, rash, and hyperglycemia occurred shortly after starting capivasertib-fulvestrant [median days to onset (interquartile range) of any grade: 8 (2-22), 12 (10-15), and 15 (1-51), respectively], and were managed with supportive medications, dose reductions, interruptions, and/or discontinuation. Discontinuation rates were 2.0%, 4.5%, and 0.3%, respectively. Overall, 13.0% discontinued capivasertib due to AEs. CONCLUSIONS: Frequent AEs associated with PI3K/AKT pathway inhibition occurred early and were manageable. The low rate of treatment discontinuations suggests that, when appropriately managed, these AEs do not pose a challenge to clinical benefit.

Light-Activatable, Cell-Type Specific Labeling of the Nascent Proteome.

Elucidating the mechanisms by which protein synthesis contributes to complex biological processes has remained a challenging endeavor. This is particularly true in the field of neuroscience, where multiple, tightly regulated periods of new protein synthesis in different cell-types are thought to facilitate intricate neurological functions, such as memory formation. Current methods for labeling the de novo proteome have lacked the spatial and temporal resolution to accurately discriminate these overlapping and often competing windows of mRNA translation. To address this technological limitation, here we describe a novel, light-inducible specific method for labeling newly synthesized proteins within a targeted cell-type.By developing Opto-ANL, a photocaged version of the nonendogenous amino acid azidonorleucine (ANL), we can selectively label newly synthesized proteins in specific cell-types through the targeted expression of a mutant methionyl-tRNA synthetase (L274G-MetRS). We demonstrate that Opto-ANL can be rapidly uncaged by UV light treatment in both cell culture and mouse brain slices, with Opto-ANL labeled proteins being able to be visualized via fluorescent noncanonical amino acid tagging. We also reveal that pretreatment with Opto-ANL not only allows for the period of de novo proteomic labeling to be tightly controlled, but also improves labeling efficiency compared to regular ANL. To demonstrate the potential applications of this novel technique, we use Opto-ANL to detect insulin-induced increases in protein synthesis and to label the excitatory neuronal de novo proteome in mouse brain slices. We believe that this application of photopharmacology will allow researchers to generate novel insights into how the translational landscape is altered across cell-types during complex neurological phenomena such as memory formation.

Effects of administration of mycobacterium cell wall fraction during the periovulatory period on embryo development following superovulation in virgin dairy heifers.

Proinflammatory cytokines are involved in regulating several reproductive processes that occur during the periovulatory period, including ovulation, corpus luteum formation, and preimplantation embryo development. The objective of this study was to determine whether stimulation of proinflammatory cytokines through administration of mycobacterium cell wall fraction (MCWF; Amplimune, NovaVive) could improve embryo development following superovulation in dairy heifers. A total of 34 independent embryo recovery procedures were performed using nulliparous Holstein heifers (n = 20; age 12-18 mo) as donors. For superovulation, dominant follicle removal was performed and an intravaginal progesterone device was inserted on d -6. Thirty-six hours later, on d -4, FSH (420 IU total) was administered in a decreasing dose regimen consisting of 8 injections given twice daily at 12-h intervals. Prostaglandin F2α was administered in conjunction with the fifth and sixth injections of FSH on d -2 and the intravaginal progesterone device was removed on the morning of d -1. Twenty-four hours later, on d 0, donors received their randomly assigned treatment (sterile saline or MCWF, 5 mL, i.m.) and gonadotropin-releasing hormone was administered to induce ovulation. Donors were artificially inseminated with frozen-thawed semen at 12 and 24 h after induced ovulation. Nonsurgical embryo recovery procedures were performed on d 7. Recovered structures were evaluated using a stereomicroscope to assess embryo development. There was no effect of MCWF treatment on the numbers of total structures, unfertilized oocytes, degenerate embryos, transferable embryos, or blastocysts. However, there was a trend for donors treated with MCWF to have a greater proportion of blastocysts out of total structures recovered. Overall, the efficacy of superovulation in virgin dairy heifer donors was not improved by administration of MCWF during the peri-ovulatory period, but results indicate that MCWF treatment may enhance embryo developmental kinetics.

Cationic Serine-Based Gemini Surfactant:Monoolein Aggregates as Viable and Efficacious Agents for DNA Complexation and Compaction: A Cytotoxicity and Physicochemical Assessment.

Cationic gemini surfactants have emerged as potential gene delivery agents as they can co-assemble with DNA due to a strong electrostatic association. Commonly, DNA complexation is enhanced by the inclusion of a helper lipid (HL), which also plays a key role in transfection efficiency. The formation of lipoplexes, used as non-viral vectors for transfection, through electrostatic and hydrophobic interactions is affected by various physicochemical parameters, such as cationic surfactant:HL molar ratio, (+/-) charge ratio, and the morphological structure of the lipoplexes. Herein, we investigated the DNA complexation ability of mixtures of serine-based gemini surfactants, (nSer)2N5, and monoolein (MO) as a helper lipid. The micelle-forming serine surfactants contain long lipophilic chains (12 to 18 C atoms) and a five CH2 spacer, both linked to the nitrogen atoms of the serine residues by amine linkages. The (nSer)2N5:MO aggregates are non-cytotoxic up to 35-90 µM, depending on surfactant and surfactant/MO mixing ratio, and in general, higher MO content and longer surfactant chain length tend to promote higher cell viability. All systems efficaciously complex DNA, but the (18Ser)2N5:MO one clearly stands as the best-performing one. Incorporating MO into the serine surfactant system affects the morphology and size distribution of the formed mixed aggregates. In the low concentration regime, gemini-MO systems aggregate in the form of vesicles, while at high concentrations the formation of a lamellar liquid crystalline phase is observed. This suggests that lipoplexes might share a similar bilayer-based structure.

Mannan oligosaccharide as an alternative to infeed antibiotics to improve growth performance of broilers: a meta-analysis.

1. The purpose of this meta-analysis was to evaluate the effect of mannan oligosaccharide (MOS) as an alternative to antibiotic growth promoters (AGP) on feed intake (FI), body weight gain (BWG), and feed conversion ratio (FCR) of broilers.2. Data from 75,594 broilers were extracted from 17 articles (19 trials) published between January 2010 and March 2023. The main criteria for the publication selection were as follows, at least three treatments applied (negative control group without MOS or AGP versus MOS or AGP supplementation), presence of performance results, and intra-experimental variation associated with the mean of response (such as standard error). Treatments were classified as control, MOS, or AGP, and adjusted means of treatment were compared. Additionally, the average daily gain (ADG) and average daily feed intake (ADFI) of each type of supplementation were calculated relative (Δ) to the control group (ΔADFI and ΔADG) and expressed as a percentage of the difference.3. Broilers receiving a diet supplemented with MOS had a 3.7% better BWG and 3% better FCR compared to the control diet (P < 0.001), but these variables were similar to the group receiving AGP supplementation. No significant difference was detected in FI among treatments (P > 0.050). The relationship between ΔADG and ΔADFI was linear for the MOS and AGP-supplemented group (P < 0.050). The ΔADG of broilers fed diets supplemented with MOS or AGP was 6.4% and 4.54% when ΔADFI was zero, respectively. The ΔADG of MOS increased by 0.58% for every 1% of increasing observed in ΔADFI. The corresponding value for the increased ΔADG for the AGP group was 0.69%.4. The results of this meta-analysis indicated that MOS supplementation is effective in increasing BWG and reducing FCR, similar to broilers fed a diet supplemented with AGP. Therefore, MOS is a safe and sustainable alternative for AGP-free poultry production.

Exploring the Potential of Anthocyanin-Based Edible Coatings in Confectionery-Temperature Stability, pH, and Biocapacity.

This study aims to develop purple-coloured polymeric coatings using natural anthocyanin and desoxyanthocianidins (3-DXA) colourants for application to chocolate almonds. The objective is to achieve a stable and uniform colour formulation throughout processing and storage, enhancing the appearance and durability of the almonds to appeal to health-conscious consumers and align with market demands. Plant materials like sweet potato pulp, sweet potato peel, radish peel, black carrot, and sorghum were employed to obtain the desired purple hue. Anthocyanidins and 3-DXA were extracted from the matrices using solvent extraction and ultrasound-assisted methods at different pH values. High-performance liquid chromatography with diode array detection (HPLC-DAD) and high-resolution tandem mass spectrometry (HRMS/MS) were used to identify the compounds in the extracts. The highest antioxidant capacities, as measured by the DPPH• and FRAP methods, were observed in purple sweet potato and dye factory extracts, respectively; meanwhile, sorghum extract inhibited both α-amylase and α-glucosidase, indicating its potential for managing postprandial hyperglycemia and type 2 diabetes. The degradation kinetics of coloured coatings in sugar syrup formulations with anthocyanins and 3-DXA revealed that locust bean gum offered the best colour stabilization for plant extracts, with sorghum extracts showing the highest and black carrot extracts the lowest colour variation when coated with Arabic gum. Sweet potato pulp extracts exhibited less colour variation in sugar pastes, both with and without blue spirulina dye, compared to factory dye, highlighting their potential as a more stable and suitable alternative for colouring purple almonds, particularly over a five-month storage period. This study supports sustainable practices in the confectionery industry while aligning with consumer preferences for healthier and environmentally friendly products.

A systematic review and meta-analysis on early-childhood-caries global data.

OBJECTIVES: The present study systematically reviewed and provided a meta-analysis on early childhood caries (ECC) global prevalence and its association with socioeconomic indicators, both geographical and regarding unemployment rate, national income as well as income inequalities. METHODS: Only cross-sectional or cohort studies covering ECC prevalence and experience in children younger than 71 months, reporting sample size, diagnostic criteria and conducted in urban and rural communities were considered. No language restriction was selected. Studies published from 2011 to 2022 available in PubMed, Web of Science, Embase and Open Grey literature were retrieved by ad hoc prepared search strings. The meta-analyses were conducted for both overall ECC prevalence and experience stratified by country of publication as well as measures of socioeconomic indicators using a random effects model using STATA 18®. RESULTS: One hundred publications reporting ECC data from 49 countries (published from 2011 to 2022) were included and summarized by meta-analysis. The lowest prevalence was reported in Japan (20.6%) and Greece (19.3%). The global estimated random-effect pooled prevalence of ECC was 49% (95%CI: 0.44-0.55). The random-effect pooled caries prevalence (ECC) was 34% (95%CI: 02.20-0.48) (Central/South America), 36% (95%CI: 0.25-0.47) (Europe), 42% (95%CI: 0.32-0.53) (Africa), 52% (95%CI: 0.45-0.60) (Asia-Oceania), 57% (95%CI: 0.36-0.77) (North America) and 72% (95%CI: 0.58-0.85) (Middle East). When stratified by gross national income (GNI) the ECC prevalence ranged from 30% ($20,000-$39,999) to 57% in countries with the lowest GNI (<$5000). Stratification by inequality index (Gini index) resulted in an ECC prevalence range of 39% (low inequality) to 62% (no inequality), while for life expectancy the ECC prevalence ranged from 28% in countries with the highest life expectancy (< 80 years) to 62% in countries with 71-75 years life expectancy. DISCUSSION: Within the limitations of this study (lack of certainty about the results as many countries are not represented and lack of uniformity in prevalence and experience data represented), results from 49 different countries reported a wide range of ECC prevalence. These reports indicated persisting high worldwide distribution of the disease. Both ECC prevalence and experience were associated with geographical areas and GNI. REGISTRATION: PROSPERO: CRD-42,022,290,418.

Signal, detection and estimation using a hybrid quantum circuit.

We investigate a hybrid device allowing a photon-phonon coupling of a transmission line radiation (TLR) and a nanoeletromechanical system (NEMS), mediated by a superconducting qubit population imbalance. We demonstrate the derivation of an effective Hamiltonian for the strongly dispersive regime for this system. The qubit works as a quantum switch, allowing a conditioned transfer of excitations between the TLR and NEMS. We show that this regime allows the system to be employed for signal processing and force estimation. Additionally, we explore the ability of the quantum switch to generate non-classical states.

Reproductive biology of Donax striatus (Linnaeus, 1758) (Mollusca: Bivalvia) on Gado Bravo Beach, municipality of Tibau do Norte, state of Rio Grande do Norte, Brazil.

Aspects of the reproductive biology of Donax striatus were studied from individuals collected from Gado Bravo Beach in the municipality of Tibau do Norte, state of Rio Grande do Norte, Brazil. Donax striatus is a dioic species without external (on the shell) or internal (gonads) macroscopic dimorphism. Thus, a microscopic examination of the reproductive cells is necessary. For the characterization of the gonadal development stages and determination of the size at first sexual maturity (L50), 30 specimens were selected monthly between February 2021 and January 2022 and submitted to histological processing. The condition index (CI) of each individual was estimated and monthly variations were statistically assessed. The size at first maturity (L50) was estimated to be 14.2 mm in shell length. To foster conservation of the species, catches of individuals larger than 14.2 mm is recommended. The lowest condition indices were found in the dry season, with a greater occurrence of organisms in the elimination stage and exhibiting gonad tissue reorganization. Higher indices were found in the rainy season, with the presence of mature individuals. The continuous nature of gametogenesis in Donax stritatus reflects the influence of rainfall in the region. Males and females have peak gamete elimination with pauses during the year, but with the presence of maturing and eliminating individuals throughout the year. As shellfish gathering targeting Donax striatus is excessive on Gado Bravo Beach in the state of Rio Grande do Norte, it is hoped that the results of the present study can contribute to the establishment of management measures for the activity and conservation strategies for the species.

Effects of isoleucine, lysine, valine, and a group of non-essential amino acids on mammary amino acid metabolism in lactating dairy cows.

Intracellular amino acids (AA) regulate milk protein synthesis within the mammary glands by modifying mammary plasma flow (MPF) and AA transporter activity. Amino acid transporters catalyze translocation using Na+-gradient, substrate gradient (uniporters), and exchange mechanisms; further, they exhibit specificity for individual AA or groups of AA with similar side-chain properties within each transport system. Non-essential AA are actively transported through Na+-dependent transporters and, thus, are often utilized as intracellular currencies for EAA transport through exchange transporters. Therefore, it was hypothesized that individual EAA supplementation would compete with other EAA for shared transporters, and supplementation with Ala, Gln, and Gly would stimulate EAA transport through exchange transporters. Ten primiparous lactating dairy cows were divided into 2 groups based on milk production and were randomly assigned to treatment sequences within 2 balanced 5 × 5 Latin Squares by group. Period length was 14 d. Treatments were 9-d jugular infusions of 1) saline; 2) 34.5 g Val/d; 3) 32.7 g Ala/d: 40 g Gln/d: 26.7 g Gly/d (AQG); 4) 43 g Lys/d; or 5) 33.5 g Ile/d. All cows were fed a common base diet formulated to contain 15.0% CP. Ile, Lys, or AQG infusions did not affect milk protein or milk production; however, Val infusion decreased both. The effects of Val infusion on milk protein production appeared to be partially driven by decreased DMI. The decline in milk protein percentage indicated that milk lactose production was also affected. Additionally, Val infusion increased MPF efficiency (MPF/Milk; L/L) by approximately 44%. Val infusion tended to decrease or decreased mammary net uptakes of Lys, Leu, Met, and total AA. Ile infusion tended to increase its mammary net uptakes but did not affect any other AA. Lys and AQG infusions did not affect any mammary net uptakes. Val infusion tended to decrease Phe and total NEAA mammary clearance rates. AQG infusion stimulated Tyr clearance rates and tended to decline System N mammary clearance rates. Mammary uptake to milk protein output ratios (U:O) of BCAA did not differ from 1 for Val-infused cows, which indicated that little intramammary catabolism was occurring. Additionally, the average NEAA U:O in response to all treatments except Val was 0.70, but Val-infused cows had NEAA U:O that averaged 0.09 indicating increased synthesis within the glands. The effects of Val on mammary net clearance rates of multiple EAA support the incorporation of AA limitations in ration optimizers to prevent AA imbalances. It is possible that over-supplementation of EAA other than Val may also decrease DMI and mammary activity. Identifying efficiency apexes for each of the EAA will allow more precise diet formulation and supplementation, leading to improved production efficiency.

Robust Photocatalytic MICROSCAFS® with Interconnected Macropores for Sustainable Solar-Driven Water Purification.

Advanced oxidation processes, including photocatalysis, have been proven effective at organic dye degradation. Tailored porous materials with regulated pore size, shape, and morphology offer a sustainable solution to the water pollution problem by acting as support materials to grafted photocatalytic nanoparticles (NPs). This research investigated the influence of pore and particle sizes of photocatalytic MICROSCAFS® on the degradation of methyl orange (MO) in aqueous solution (10 mg/L). Photocatalytic MICROSCAFS® are made of binder-less supported P25 TiO2 NPs within MICROSCAFS®, which are silica-titania microspheres with a controlled size and interconnected macroporosity, synthesized by an adapted sol-gel method that involves a polymerization-induced phase separation process. Photocatalytic experiments were performed both in batch and flow reactors, with this latter one targeting a proof of concept for continuous transformation processes and real-life conditions. Photocatalytic degradation of 87% in 2 h (batch) was achieved, using a calibrated solar light simulator (1 sun) and a photocatalyst/pollutant mass ratio of 23. This study introduces a novel flow kinetic model which provides the modeling and simulation of the photocatalytic MICROSCAFS® performance. A scavenger study was performed, enabling an in-depth mechanistic understanding. Finally, the transformation products resulting from the MO photocatalytic degradation were elucidated by high-resolution mass spectrometry experiments and subjected to an in silico toxicity assessment.

Understanding the Potential of CBD for Health Benefits: an Overview.

Cannabinoids are compounds with increasing scientific interest, particularly due to their interaction with the endocannabinoid system via CBR1 and CBR2 receptors. They can interfere with appetite, pain, and sleep or develop mood changes of the individual. Cannabidiol (CBD) is a well-known cannabinoid with potential benefits, including reducing epilepsy seizures, alleviating anxiety, and obsessive-compulsive disorder (OCD) symptoms, aiding in Tourette Syndrome (a neurodevelopmental disorder), depression, sleep disorders, and promising in the treatment of cancer, pain relief, and heart health. Although generally safe, CBD can have side effects, including drug metabolism interference, fertility, and liver function. In addition, it can be administered by oral, sublingual, transdermal or inhalation via, each one with different bioavailability. The application of nanotechnology, specifically through colloidal carrier systems, holds promising potential for maximizing CBD's efficacy and pharmacological profile. There are reported CBD extraction methods using ethanol, carbon dioxide, deionised water, and non-polar oils like olive or coconut oil. The green extraction methods have gained popularity for their higher yields, shorter extraction time, and reduced costs. A specific dose with the desired effects is challenging due to individual factors, with most studies suggesting a range between less than 1 and 50 mg/kg/d. This review aims to explore the principles of CBD-based products development, focusing on extraction methods and purification processes of this cannabinoid for tinctures, topicals, and other pharmaceutical forms, as well as further research to attain the objectives.

OsTH1 is a key player in thiamin biosynthesis in rice.

Thiamin is a vital nutrient that acts as a cofactor for several enzymes primarily localized in the mitochondria. These thiamin-dependent enzymes are involved in energy metabolism, nucleic acid biosynthesis, and antioxidant machinery. The enzyme HMP-P kinase/thiamin monophosphate synthase (TH1) holds a key position in thiamin biosynthesis, being responsible for the phosphorylation of HMP-P into HMP-PP and for the condensation of HMP-PP and HET-P to form TMP. Through mathematical kinetic model, we have identified TH1 as a critical player for thiamin biofortification in rice. We further focused on the functional characterization of OsTH1. Sequence and gene expression analysis, along with phylogenetic studies, provided insights into OsTH1 bifunctional features and evolution. The indispensable role of OsTH1 in thiamin biosynthesis was validated by heterologous expression of OsTH1 and successful complementation of yeast knock-out mutants impaired in thiamin production. We also proved that the sole OsTH1 overexpression in rice callus significantly improves B1 concentration, resulting in 50% increase in thiamin accumulation. Our study underscores the critical role of OsTH1 in thiamin biosynthesis, shedding light on its bifunctional nature and evolutionary significance. The significant enhancement of thiamin accumulation in rice callus upon OsTH1 overexpression constitutes evidence of its potential application in biofortification strategies.

Natural antibiotics against antimicrobial resistance: sources and bioinspired delivery systems.

The current burden associated to multidrug resistance, and the emerging superbugs, result in a decreased and even loss of antibiotic efficacy, which poses significant challenges in the treatment of infectious diseases. This situation has created a high demand for the discovery of novel antibiotics that are both effective and safe. However, while antibiotics play a crucial role in preventing and treating diseases, they are also associated with adverse effects. The emergence of multidrug-resistant and the extensive appearance of drug-resistant microorganisms, has become one of the major hurdles in healthcare. Addressing this problem will require the development of at least 20 new antibiotics by 2060. However, the process of designing new antibiotics is time-consuming. To overcome the spread of drug-resistant microbes and infections, constant evaluation of innovative methods and new molecules is essential. Research is actively exploring alternative strategies, such as combination therapies, new drug delivery systems, and the repurposing of existing drugs. In addition, advancements in genomic and proteomic technologies are aiding in the identification of potential new drug targets and the discovery of new antibiotic compounds. In this review, we explore new sources of natural antibiotics from plants, algae other sources, and propose innovative bioinspired delivery systems for their use as an approach to promoting responsible antibiotic use and mitigate the spread of drug-resistant microbes and infections.

The inhibitor of the redox activity of APE1/REF-1, APX2009, reduces the malignant phenotype of breast cancer cells.

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/REF-1) is a multifunctional protein acting on cellular signaling pathways, including DNA repair and redox activities. APE1/REF-1 has emerged as a target for cancer therapy, and its role in breast cancer models would reveal new strategies for cancer therapy. APX2009 is a specific APE1/REF-1 redox inhibitor whose anticancer properties have not been described in breast cancer cells. Here, we investigated the effect of the APX2009 treatment in the breast cancer cell lines MDA-MB-231 and MCF-7. Breast cancer cell lines were cultured, and WST1 and colony formation assays were performed to evaluate cell proliferation. Annexin V-FITC/7-AAD and LDH-Glo™ assays were performed to evaluate cell death. The wound healing assay and Matrigel transwell assay were performed after APX2009 treatment to evaluate the cellular migration and invasion processes, respectively. Our findings demonstrated that APX2009 treatment decreased breast cancer cell proliferative, migratory, and invasive properties. Furthermore, it induced apoptosis in both cell lines. Our study is the first to show the effects of APX2009 treatment on apoptosis in a breast cancer cell. Therefore, this study suggested that APX2009 treatment is a promising anticancer molecule for breast cancer.

Fish oil supplementation in obese rats ameliorates metabolic syndrome response.

Accumulation of visceral adipose tissue is associated with metabolic syndrome (MS), insulin resistance, and dyslipidemia. Here we examined several morphometric and biochemical parameters linked to MS in a rodent litter size reduction model, and how a 30-day fish oil (FO) supplementation affected these parameters. On day 3 post-birth, pups were divided into groups of ten or three. On day 22, rats were split into control (C) and small litter (SL) until 60 days old. Then, after metabolic disturbance and obesity were confirmed, FO supplementation started for 30 days and the new groups were named control (C), FO supplemented (FO), obese (Ob), and obese FO supplemented (ObFO). Comparison was performed by Student t-test or 2-way ANOVA followed by Tukey post hoc test. At the end of the 60-day period, SL rats were hyperphagic, obese, hypoinsulinemic, normoglycemic, and had high visceral fat depot and high interleukin (IL)-6 plasma concentration. Obese rats at 90 days of age were fatter, hyperphagic, hyperglycemic, hypertriacylgliceromic, hipoinsulinemic, with low innate immune response. IL-6 production ex vivo was higher, but in plasma it was not different from the control group. FO supplementation brought all biochemical changes to normal values, normalized food intake, and reduced body weight and fat mass in obese rats. The innate immune response was improved but still not as efficient as in lean animals. Our results suggested that as soon MS appears, FO supplementation must be used to ameliorate the morpho- and biochemical effects caused by MS and improve the innate immune response.

A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results.

BACKGROUND: SERENA-1 (NCT03616587) is a phase I, multi-part, open-label study of camizestrant in pre- and post-menopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. PATIENTS AND METHODS: Women aged ≥18 years with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy, were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, antitumor efficacy, pharmacokinetics, and impact on mutations in the estrogen receptor gene (ESR1m) circulating tumor (ct)DNA levels were assessed. RESULTS: By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events at doses ≤150 mg. Median tmax was achieved ∼2-4 h post-dose at all doses investigated, with an estimated half-life of 20-23 h. Efficacy was observed at all doses investigated, including in patients with prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. CONCLUSIONS: Camizestrant is a next-generation oral selective ER antagonist and degrader (SERD) and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75-, 150-, and 300-mg QD doses for phase II testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).

Recent advances and strategies for nanocarrier-mediated topical therapy and theranostic for posterior eye disease.

Posterior eye disorders, such as age-related macular degeneration, diabetic retinopathy, and glaucoma, have a significant impact on human quality of life and are the primary cause of age-related retinal diseases among adults. There is a pressing need for innovative topical approaches to treat posterior eye disorders, as current methods often rely on invasive procedures with inherent risks. Limited success was attained in the realm of topical ophthalmic delivery through non-invasive means. Additionally, there exists a dearth of literature that delves into the potential of this approach for drug delivery and theranostic purposes, or that offers comprehensive design strategies for nanocarrier developers to surmount the significant physiological ocular barriers. This review offers a thorough and up-to-date state-of-the-art overview of 40 studies on therapeutic loaded nanocarriers and theranostic devices that, to the best of our knowledge, represent all successful works that reached posterior eye segments through a topical non-invasive administration. Most importantly, based on the successful literature studies, this review provides a comprehensive summary of the potential design strategies that can be implemented during nanocarrier development to overcome each ocular barrier.

Localized mammary gland changes in milk composition and venous blood metabolite concentrations result from sterile subclinical mastitis.

Subclinical mastitis reduces milk yield and elicits undesirable changes in milk composition, but the mechanisms resulting in reduced milk production in affected mammary glands are incompletely understood. This study investigated the effects of sterile inflammation on mammary gland metabolism by assessing changes in milk and venous blood composition. Mid-lactation primiparous Holstein cows (n = 4) had udder halves randomly allocated to treatments; quarters of 1 udder half were infused with 2 billion cfu of formalin-fixed Staphylococcus aureus (FX-STAPH) and quarters of the opposite udder half were infused with saline (SAL). Blood samples were collected from the right and left subcutaneous abdominal veins in 2.6 h intervals until 40 h postchallenge and analyzed for blood gas and metabolite concentrations. Milk from FX-STAPH udder halves had significantly increased SCS by the first milking at 8 h postchallenge. By 16 h postchallenge, FX-STAPH udder halves had increased concentrations of protein and lactate and lower lactose concentrations than SAL udder halves. Milk fat concentrations, milk yields, ECM yields, and the ferric reducing antioxidant power of milk were not significantly different between SAL and FX-STAPH udder halves. Venous blood of FX-STAPH halves had marginally greater concentrations of saturated O2, partial pressures of O2, and glucose concentrations than SAL halves. Conversely, total and partial pressures of CO2 did not differ between udder half treatments, suggesting a shift in local metabolite utilization in FX-STAPH udder halves. These results indicate that changes in milk composition resulting from mastitis are accompanied by changes in some key blood metabolite concentrations. The shift in venous blood metabolite concentrations, along with the marked increase in milk lactate, suggests that local mammary tissue or recruited immune cells, or both, alter metabolite usage in mammary tissues. Future studies are needed to quantify the uptake of key milk precursors during mastitis.

Health benefits of bluefin tuna consumption: (Thunnus thynnus) as a case study.

Consumers are increasingly interested in food products with high nutritional value and health benefits. For instance, fish consumption is linked with diverse positive health benefits and the prevention of certain widespread disorders, such as obesity, metabolic syndrome, or cardiovascular diseases. These benefits have been attributed to its excellent nutritional value (large amounts of high-quality fatty acids, proteins, vitamins, and minerals) and bioactive compounds, while being relatively low-caloric. Atlantic bluefin tuna (Thunnus tynnus) is one of the most consumed species worldwide, motivated by its good nutritional and organoleptic characteristics. Recently, some organizations have proposed limitations on its consumption due to the presence of contaminants, mainly heavy metals such as mercury. However, several studies have reported that most specimens hold lower levels of contaminants than the established limits and that their richness in selenium effectively limits the contaminants' bioaccessibility in the human body. Considering this situation, this study aims to provide baseline data about the nutritional composition and the latest evidence regarding the beneficial effects of Atlantic bluefin tuna consumption. A review of the risk-benefit ratio was also conducted to evaluate the safety of its consumption, considering the current suggested limitations to this species' consumption.