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Carob pulp is a valuable source of cellulose-rich fraction (CRF) for many food applications. This study aimed to obtain and characterize a CRF derived from carob pulp waste after sugar removal and to evaluate its potential use in the 3D printing of cellulose-rich foods. Thus, the extraction of the CRF present in carob pulp (by obtaining the alcohol-insoluble residue) was carried out, accounting for nearly 45% dm (dry matter) of this byproduct. The CRF contained about 24% dm of cellulose. The functional properties (swelling capacity, water retention, and fat adsorption) related to this fraction were determined, showing a value of 5.9 mL/g of CRF and 4.0 and 6.5 g/g of CRF, respectively. Different gels were formulated with a total solids content of 15% wm (wet matter), using potato peel flour as a base and partially substituting with CRF (0% to 8% wm). The cellulose-based gels were characterized in terms of viscosity, water distribution (low-field Nuclear Magnetic Resonance), and printability, while the 3D printed samples were assessed for their textural properties. As the percentage of added CRF increased, the viscosity decreased while the water retention increased. Printability improved when small proportions of CRF (2% to 4%) were used, while it deteriorated for higher percentages (6% to 8%). The textural properties (hardness, adhesiveness, cohesiveness, and gumminess) showed significant changes caused by the addition of CRF, with gels containing 3% to 4% CRF exhibiting the most suitable printing values. In summary, this study demonstrates the significant potential of carob cellulose-based gel as an ingredient in the 3D printing of novel fiber-rich foods, contributing to reducing food waste and promoting sustainable practices within the framework of the circular economy. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to investigate differences in the three-dimensional (3D) upper airway dimensions in Vietnamese participants. Methods: This study included 341 Vietnamese participants grouped based on the vertical growth pattern (ANB angle) (skeletal Class I, 123; Class II, 124; Class III, 94). The patients were categorized into subgroups based on the horizontal growth pattern according to the Frankfort mandibular angle (hypodivergent, 35; normodivergent, 175; hyperdivergent, 131) to compare the frequency distribution of the three growth patterns in each skeletal class. The airway dimensions of the three skeletal classes were divided into four volumes using 3D virtual software (In VivoDental Software 6.0). The height, width, and cross-sectional area (CSA) of each part, as well as the total volume and minimum CSA, were measured and analyzed. Results: The airway space was reduced in hyperdivergent Class II individuals, underscoring an important connection between upper airway dimensions and vertical skeletal patterns, which suggests that vertical growth patterns contribute to pharyngeal narrowing and subsequent upper airway obstruction. Significant differences (p < 0.001) in the minimum CSAs and volumes of the middle and inferior pharyngeal airways were observed based on Angle's skeletal classification. Conclusions: Our insights are valuable for orthodontics, especially in diverse populations, such as the Vietnamese, due to differences in the influence of genetic and environmental factors on skeletal and airway characteristics. [ABSTRACT FROM AUTHOR]

Simple Summary: This study raises the question whether all breast cancer patients need axillary lymph node dissection (ALND) after neoadjuvant chemotherapy (NAC). Researchers assessed a novel clinical variable: the sentinel lymph node ratio (SLN-R) to predict additional cancerous lymph nodes during ALND. SLN-R was defined as total number of positive sentinel nodes among all sentinel nodes removed during axillary staging after NAC. Axillary surgery included Targeted Axillary Dissection (TAD) technique for cN1 breast cancer patients. We analyzed data from 1521 patients, focusing on 118 with specific cancer stages and positive sentinel /TAD nodes results after NAC. The results indicated that an SLN-R value below 0.35 could suggest a lower chance of finding more cancerous nodes, with a 10.2% false-negative rate. This means SLN-R could help identify patients who might avoid unnecessary surgeries. By combining SLN-R with other clinical factors, the study aims to create a predictive tool, enhancing personalized care and improving patients' quality of life. Background/Objectives: The aim of the study was to determine the clinical value of the sentinel lymph node ratio (SLN-R) in predicting additional positive lymph nodes during axillary lymph node dissection (ALND) in breast cancer patients following neoadjuvant chemotherapy (NAC). Methods: A cross-sectional study was performed at a single institution evaluating data from 1521 BC patients. Inclusion criteria comprised cT1/cT4, cN0/cN1 status with positive post-NAC axillary staging by SLN/TAD, respectively, and subsequent ALND. Results: The study included 118 patients, divided into two groups based on the presence or absence of additional node metastasis at ALND: 39 in the residual disease group (RD) and 79 in the non-residual disease group (nRD). Univariate logistic regression analysis of SLN-R was conducted to assess its predictive value, yielding an odds ratio (OR) of 7.79 (CI 1.92–29.5, p = 0.003). An SLN-R cut-off point of <0.35 was identified using ROC curve analysis, with a false-negative rate of 10.2%, as a predictor for no additional metastasis at ALND following post-NAC SLN/TAD positivity. Conclusions: The study concludes that SLN-R is a valuable predictor for determining the omission of ALND in cases where SLN/TAD is positive after NAC. This metric, in combination with other clinical variables, could help develop a nomogram to spare patients from ALND. [ABSTRACT FROM AUTHOR]

Omega-3 fatty acids are essential fatty acids that are not synthesised by the human body and have been linked with the prevention of chronic illnesses such as cardiovascular and neurodegenerative diseases. However, the current dietary habits of the majority of the population include lower omega-3 content compared to omega-6, which does not promote good health. To overcome this, pharmaceutical and nutraceutical companies aim to produce omega-3-fortified foods. For this purpose, various approaches have been employed to obtain omega-3 concentrates from sources such as fish and algal oil with higher amounts of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Among these techniques, enzymatic enrichment using lipase enzymes has gained tremendous interest as it is low in capital cost and simple in operation. Microorganism-derived lipases are preferred as they are easily produced due to their higher growth rate, and they hold the ability to be manipulated using genetic modification. This review aims to highlight the recent studies that have been carried out using marine lipases for the enrichment of omega-3, to provide insight into future directions. Overall, the covalent bond-based lipase immobilization to various support materials appears most promising; however, greener and less expensive options need to be strengthened. [ABSTRACT FROM AUTHOR]

This article explores the use of citrus residues as a source of different pectic materials for packaging film production: a water-soluble orange residue extract (WSE) (~5% pectin), semi-pure pectins extracted in citric acid (SP) (~50% pectin), and commercial pure citrus pectins (CP). First, these materials were characterized in terms of chemical composition. Then, films were produced using them pure or mixed with chitosan or glycerol through solvent-casting. Finally, antioxidant activity, functional properties (e.g., mechanical and gas barrier properties), and visual appearance of the films were assessed. WSE films showed the highest antioxidant activity but the lowest mechanical strength with the highest elongation at break (EB) (54%); incorporating chitosan increased the films’ strength (Young’s modulus 35.5 times higher). SP films showed intermediate mechanical properties, reinforced by chitosan addition (Young’s modulus 4.7 times higher); they showed an outstanding dry O2 barrier. CP films showed a similar O2 barrier to SP films and had the highest Young’s modulus (~29 MPa), but their brittleness required glycerol for improved pliability, and chitosan addition compromised their surface regularity. Overall, the type of pectic material determined the film’s properties, with less-refined pectins offering just as many benefits as pure commercial ones. [ABSTRACT FROM AUTHOR]

Snake gourd is a seasonal vegetable with a high water content and medicinal value, but the short harvest period limits the large-scale application of snake gourd. Therefore, the effects of freeze–thaw pretreatment (FT) combined with hot air (HD) on the drying characteristics, active ingredients and bioactivities of snake gourd were investigated. The results showed that FT pretreatment reduced browning and shortened the drying time by 44%; the Page model was the best fit for describing the drying process. The polysaccharide contents (21.70% in alcoholic extract (TG1) and 44.34% in water extract (TG2)) and total phenol contents (1.81% in TG1 and 0.88% in TG2) of snake gourd pretreated by FT-HD were higher than those of snake gourd pretreated by the corresponding HD treatment. The FT pretreatment decreased the molecular weight of snake gourd polysaccharides and increased the molar ratio of glucose. The extracts pretreated by FT-HD showed greater chemical, cellular antioxidant capacity and α-amylase and α-glucosidase inhibition than those pretreated by HD. FT-HD can be recommended for achieving a short drying time and high quality of snake gourd and can be used for the drying of other fruits and vegetables. [ABSTRACT FROM AUTHOR]

The citrus processing industry is responsible for the generation of large volumes of waste side streams, represented principally by fruit peels. These tissues are exceptionally rich in polyphenolic bioactive phytochemicals, and there has been a great industrial interest for their valorization. The examination presented herein targeted at developing a fast and straight-forward aqueous extraction process, based on ultrasonication, for the efficacious recovery of polyphenolic compounds from waste orange peels. After an initial single-factor examination, the response surface optimization showed that a maximum total polyphenol yield of 12.81 mg chlorogenic acid equivalents (GAE) per g−1 dry mass could be achieved by setting sonicator amplitude at 80%, for 15 min, using a duty cycle of 2/2 (2 s on/2 s off). Comparison of this methodology with a stirred-tank extraction demonstrated that the ultrasonication technique was equally effective, requiring ambient temperature and considerably shorter resident time. The combination of both techniques using the ultrasonication process as a pretreatment step did not boost extraction yield, and the extracts produced had similar polyphenolic composition and antioxidant activity. However, a slight enhancement of the recovery of individual constituents was noted. It is proposed that efficient extraction of polyphenolic substances from waste orange peels may be accomplished using the present methodology, which is a low-cost (ambient temperature, short time) and sustainable (water as solvent) process. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent advances in cancer therapy have spotlighted immune checkpoint inhibitors (ICIs) as a breakthrough in treating various cancers. These treatments, however, can lead to immune-related adverse events (irAEs) that mirror the body's heightened immune response, affecting multiple organs. Recognizing and managing these irAEs is critical, and imaging modalities such as 18F-FDG PET/CT have emerged as a potential tool for early detection. This review delves into the capability of 18F-FDG PET/CT to identify irAEs, exploring the patterns of metabolic activation indicative of these events. While highlighting the current utility of PET/CT scans in oncology for tracking therapy response and irAEs, the review also speculates on future directions, suggesting a potential role in refining immunotherapy strategies and enhancing patient care. The insights obtained could transform patient monitoring during ICI therapy, potentially improving outcomes by facilitating prompt management of irAEs. Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized contemporary oncology, presenting efficacy in various solid tumors and lymphomas. However, ICIs may potentially overstimulate the immune system, leading to immune-related adverse events (irAEs). IrAEs may affect multiple organs, such as the colon, stomach, small intestine, kidneys, skin, lungs, joints, liver, lymph nodes, bone marrow, brain, heart, and endocrine glands (e.g., pancreas, thyroid, or adrenal glands), exhibiting autoimmune inflammation. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is commonly used in oncology for staging and assessment of therapy responses, but it may also serve as a tool for detecting irAEs. This review aims to present various patterns of metabolic activation associated with irAEs due to ICI treatment, identifiable through 18F-FDG PET/CT. It describes the advantages of early detection of irAEs, but also presents the challenges in differentiating them from tumor progression. It also delves into aspects of molecular response assessment within the context of pseudoprogression and hyperprogression, along with typical imaging findings related to these phenomena. Lastly, it summarizes the role of functional PET imaging in oncological immunotherapy, speculating on its future significance and limitations. [ABSTRACT FROM AUTHOR]

This work evaluated the green extraction of oleoresin from pink pepper fruits (ORPPF) using ultrasound-assisted extraction (UAE) and ethanol as a solvent. The effects of temperature, ultrasound power intensity, sample to solvent ratio and time on the global extraction yield (YGE) and phenolic compounds yield (YPC) were evaluated. The oleoresin samples were characterized and its antimicrobial activity determined, and the obtained results were compared to conventional extraction in Soxhlet. From the results it was found that the application of the highest levels of the independent variables favored the extraction process. The maximum values of YGE and YPC were 28.60 wt% and 6.37 mg GAE per g fruit, respectively, obtained at 60 °C, 100% of ultrasound power (165 W), 1:20 g mL−1 (sample:solvent) and 45 min. Under maximized conditions, the ORPPF obtained by UAE showed a content of phenolic compounds and antioxidant activity inferior to soxhlet–ethanol extraction. However, the time and solvent consumption were reduced. Oleic and linoleic acids predominated in the fatty acid composition of ORPPF, in addition to sesquiterpenes and gallic and syringic acids. The ORPPF presented weak antibacterial activity, with minimum inhibitory concentration ranging from 31.25 to 125 mg mL−1. [ABSTRACT FROM AUTHOR]

Citrus processing side-streams are largely represented by waste orange peels (WOP), and there are several techniques developed for polyphenol extraction from WOP; yet, there are a significant lack of methodologies based on non-conventional, green solvents. On this basis, this study was performed to assess a deep eutectic solvent (DES) synthesized with glycerol and sodium butyrate, for its capacity to extract WOP polyphenols. Optimization of the process was carried out using a response surface methodology, which revealed that a maximum total polyphenol yield of 73.36 mg gallic acid equivalent (GAE) g−1 dry mass (DM) could be achieved with a solvent system of DES/water (80% w/w), a residence time of 120 min, and a temperature of 90 °C. Using these settings, the polyphenol extraction from WOP with the DES/water solvent system was found to have outstanding performance compared to aqueous or hydroethanolic extraction, while the extracts generated possessed significantly enhanced antioxidant properties. The chromatographic analyses of the extracts demonstrated that the DES/water extract was particularly enriched in hesperidin (21.81 mg g−1 dry mass), a bioflavonoid with promising pharmaceutical potential. This is a first report on the use of this particular DES for WOP polyphenol extraction, which may be used to produce hesperidin-enriched extracts, by implementing the methodology developed. [ABSTRACT FROM AUTHOR]

The pursuit for better skin health, driven by collective and individual perceptions, has led to the demand for sustainable skincare products. Environmental factors and lifestyle choices can accelerate skin aging, causing issues like inflammation, wrinkles, elasticity loss, hyperpigmentation, and dryness. The skincare industry is innovating to meet consumers' requests for cleaner and natural options. Simultaneously, environmental issues concerning waste generation have been leading to sustainable strategies based on the circular economy. A noteworthy solution consists of citrus by-product valorization, as such by-products can be used as a source of bioactive molecules. Citrus processing, particularly, generates substantial waste amounts (around 50% of the whole fruit), causing unprecedented environmental burdens. Hesperidin, a flavonoid abundant in orange peels, is considered to hold immense potential for clean skin health product applications due to its antioxidant, anti-inflammatory, and anticarcinogenic properties. This review explores hesperidin extraction and purification methodologies as well as key skincare application areas: (i) antiaging and skin barrier enhancement, (ii) UV radiation-induced damage, (iii) hyperpigmentation and depigmentation conditions, (iv) wound healing, and (v) skin cancer and other cutaneous diseases. This work's novelty lies in the comprehensive coverage of hesperidin's promising skincare applications while also demonstrating its potential as a sustainable ingredient from a circular economy approach. [ABSTRACT FROM AUTHOR]

In this work, the peels of red and blonde oranges as well as lemons were efficiently (5.75–9.65% yield) extracted by hydroalcoholic solution with ultrasound assistance and employed as active molecule sources in the preparation of functional gummies. Antioxidant performances of the hydroalcoholic extracts were characterized by colorimetric assays, whereas LC–HRMS analyses identified the main bioactive compounds (phenolic acids and flavonoids). The highest scavenging activity was recorded for lemon extract in an aqueous environment (IC50 = 0.081 mg mL−1). An ecofriendly grafting procedure was performed to anchor polyphenols to gelatin chains, providing macromolecular systems characterized by thermal analysis and antioxidant properties. Scavenger abilities (IC50 = 0.201–0.454 mg mL−1) allowed the employment of the conjugates as functional ingredients in the preparation of gummies with remarkable antioxidant and rheological properties over time (14 days). These findings confirmed the possible employment of highly polluting wastes as valuable sources of bioactive compounds for functional gummies preparation. [ABSTRACT FROM AUTHOR]

Enzymatic biodiesel production is a potential eco-friendly alternative to the conventional chemical route which requires extensive study to reduce the costs associated with the application of commercial enzymes. Thus, this study aimed to develop a bioprocess using residues from macauba (Acrocomia aculeata) as raw material for lipase production in solid-state fermentation (SSF) by Yarrowia lipolytica. Then, the product obtained was used as a biocatalyst for the conversion (hydrolysis/esterification) of macauba acidic oil to biodiesel esters. Firstly, different SSF parameters (inoculum concentration, initial moisture content, and carbon and nitrogen levels) were investigated in a factorial design approach, using the cake from macauba fruit. Afterwards, moisture and urea concentration were shown to be statistically significant variables for lipase production. Lipase productnivities were 12.6 ± 0.6 U g−1 h−1 (at 24 h) for macauba fruit cake and 11.6 ± 1 U g−1 h−1 (at 20 h) for macauba pulp and peel cake. The solid enzymatic preparation (biocatalyst) showed optimized values at pH 6–7 at 37 °C, remaining stable (>70% retention) for 90 days at room temperature. Finally, enzymatic hydrolysis of the acidic oil from macauba reached 96% conversion (72 h) to fatty acids, and esterification of fatty acids reached 72% (biodiesel yield of 67%). The bioprocess described is a promising alternative for an integral and self-sufficient valorization of the macauba products. [ABSTRACT FROM AUTHOR]

A novel series of hybrid compounds comprising quinazolin-4-one and 3-cyanopyridin-2-one structures has been developed, with dual inhibitory actions on both EGFR and BRAFV600E. These hybrid compounds were tested in vitro against four different cancer cell lines. Compounds 8, 9, 18, and 19 inhibited cell proliferation significantly in the four cancer cells, with GI50 values ranging from 1.20 to 1.80 µM when compared to Doxorubicin (GI50 = 1.10 µM). Within this group of hybrids, compounds 18 and 19 exhibited substantial inhibition of EGFR and BRAFV600E. Molecular docking investigations provided confirmation that compounds 18 and 19 possess the capability to inhibit EGFR and BRAFV600E. Moreover, computational ADMET prediction indicated that most of the newly synthesized hybrids have low toxicity and minimal side effects. [ABSTRACT FROM AUTHOR]

Simple Summary: The MET gene is crucial for cell growth and has shown promise as a cancer treatment target. However, distinguishing between focal amplification and polysomy, different types of gene multiplication, is challenging. Accurate differentiation requires techniques such as in situ hybridization (ISH) or next generation sequencing (NGS). As the effectiveness of MET inhibitors can vary, careful patient selection and defining the perfect amplification threshold are critical. Future studies should focus on determining optimal therapy combinations and innovating new treatments targeting MET amplification. The MET gene plays a vital role in cellular proliferation, earning it recognition as a principal oncogene. Therapies that target MET amplification have demonstrated promising results both in preclinical models and in specific clinical cases. A significant obstacle to these therapies is the ability to distinguish between focal amplification and polysomy, a task for which simple MET copy number measurement proves insufficient. To effectively differentiate between the two, it is crucial to utilize comparative measures, including in situ hybridization (ISH) with the centromere or next generation sequencing (NGS) with adjacent genes. Despite the promising potential of MET amplification treatment, the judicious selection of patients is paramount to maximize therapeutic efficacy. The effectiveness of MET inhibitors can fluctuate depending on the extent of MET amplification. Future research must seek to establish the ideal threshold value for MET amplification, identify the most efficacious combination therapies, and innovate new targeted treatments for patients exhibiting MET amplification. [ABSTRACT FROM AUTHOR]

This research explored the effects of the addition of low doses of aromatic plant biomasses (APBs) on the microbial community and carbon source decomposition in compost. APBs were reported to be capable of altering the composition and function of microbial communities in many environments. However, the effects of APB addition on the compost carbon source metabolism, a process highly linked to the microbial community of compost, were still unclarified, especially when added in small doses. In this study, Cinnamomum camphora biomass was added to the initial compost of Stropharia rugosoannulata cultivation materials, in a mass ratio of 0%, 1%, 2%, and 3%, respectively. The variation in the carbon source contents, the microbial community composition, and the related enzyme activities of the end compost products were measured. The results showed that Cinnamomum camphora biomass addition significantly altered the content of cellulose, hemicellulose, lignin, and protein of compost products, but did not affect the starch and soluble sugar content. Meanwhile, the addition significantly reduced lignin peroxidase and cellulase activities, but increased xylanase and laccase activities, and had no effect on magnesium peroxidase and polyphenol oxidase. Both the bacterial and fungal community compositions were significantly altered by the addition, though the alpha diversity indexes were not significantly changed. The relative abundance of Proteobacteria and Sordariomycetes was significantly increased by the addition, while Acidobacteria, Chloroflexi and Eurotiomycetes significantly decreased. Structural equation modeling found that the variation in the bacterial community composition (0.464 standard total effect) provided a higher contribution to lignocellulose degradation, rather than the fungal community (0.365 standard total effect). A co-occurrence network analysis further revealed that the trade-off between lignin peroxidase and laccase activity, which was induced by the relative abundance variation in Proteobacteria, Actinobacteriota, and Firmicute members, was the main driver in the lignocellulose decomposition variation. This research provides a new insight into the recycling of APB waste, and offers an improvement to mushroom cultivation material compost. [ABSTRACT FROM AUTHOR]

Breast cancer is considered the second-leading cancer after lung cancer and is the most prevalent cancer among women globally. Currently, cancer immunotherapy via vaccine has gained great attention due to specific and targeted immune cell activity that creates a potent immune response, thus providing long-lasting protection against the disease. Despite peptides being very susceptible to enzymatic degradation and poor immunogenicity, they can be easily customized with selected epitopes to induce a specific immune response and particulate with carriers to improve their delivery and thus overcome their weaknesses. With advances in nanotechnology, the peptide-based vaccine could incorporate other components, thereby modulating the immune system response against breast cancer. Considering that peptide-based vaccines seem to show remarkably promising outcomes against cancer, this review focuses on and provides a specific view of peptide-based vaccines used against breast cancer. Here, we discuss the benefits associated with a peptide-based vaccine, which can be a mainstay in the prevention and recurrence of breast cancer. Additionally, we also report the results of recent trials as well as plausible prospects for nanotechnology against breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Stromal tumor infiltrating lymphocytes (sTIL) are a validated predictive and prognostic biomarker in non-luminal breast cancer. Our aim was to evaluate their clinical relevance in luminal (hormone receptor positive, HER2 negative) early breast cancer. Our results show that, although sTIL are associated with a better response to neoadjuvant chemotherapy, they are also associated with worse biological features (proliferation, higher stage) and poorer prognosis in luminal B breast cancer. TIL might improve prognostic stratification and contribute to therapeutic decision-making in the early high-risk setting of luminal B breast cancer. Luminal breast cancer (BC) is associated with less immune activation, and the significance of stromal lymphocytic infiltration (sTIL) is more uncertain than in other BC subtypes. The aim of this study was to investigate the predictive and prognostic value of sTIL in early luminal BC. The study was performed with an observational design in a prospective cohort of 345 patients with predominantly high-risk luminal (hormone receptor positive, HER2 negative) BC and with luminal B features (n = 286), in which the presence of sTIL was analyzed with validated methods. Median sTIL infiltration was 5% (Q1–Q3 range (IQR), 0–10). We found that sTIL were associated with characteristics of higher biological and clinical aggressiveness (tumor and lymph node proliferation and stage, among others) and that the percentage of sTIL was predictive of pathologic complete response in patients treated with neoadjuvant chemotherapy (OR: 1.05, 95%CI 1.02–1.09, p < 0.001). The inclusion of sTIL (any level of lymphocytic infiltration: sTIL > 0%) in Cox regression multivariable prognostic models was associated with a shorter relapse-free interval (HR: 4.85, 95%CI 1.33–17.65, p = 0.016) and significantly improved its performance. The prognostic impact of sTIL was independent of other clinical and pathological variables and was mainly driven by its relevance in luminal B BC. [ABSTRACT FROM AUTHOR]

The primary focus in the production of quality red wine is the extraction of grape components, which can be achieved in a variety of ways. This work investigates the extraction yield of biologically active compounds from crushed Merlot grapes, as a result of ultrasound treatment applied before maceration, and optimizes the process parameters of a laboratory scale using response surface methodology (RSM) within a central composite design (CCD) model. The two factors whose response was studied were amplitude (A) % and treatment time (t), while the dependent variables were the total phenolic compounds (TPC), monomeric anthocyanins (MA), and antioxidant activity expressed as ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity. The results showed that the application of high-power ultrasound treatment to crushed grapes for a few minutes increased both the extraction rate of bioactive compounds and the antioxidant activity by a maximum of 12 times for the TPC, 14 times for the MA, 3.6 times for the FRAP value, and 18.77% for the DPPH. The optimized solution had an amplitude of 90% and a treatment time of 4 min and 24 s. The validation experiments yielded errors between—8.70% and 3.14%, confirming the proposed model. Thus, the RSM model is recommended as a tool to optimize a procedure for enhancing both the extraction rate of the bioactive compounds from grapes and the antioxidant properties of grape must. Our results demonstrate the ultimate benefits of using ultrasonic treatment on crushed grapes at the beginning of the winemaking process, as a highly effective technique for improving the extraction of high-value bioactive chemicals, with significant application potential. [ABSTRACT FROM AUTHOR]

Therapeutic oligonucleotides are powerful tools for the inhibition of potential targets involved in cancer. We describe the effect of two Polypurine Reverse Hoogsteen (PPRH) hairpins directed against the ERBB2 gene, which is overexpressed in positive HER-2 breast tumors. The inhibition of their target was analyzed by cell viability and at the mRNA and protein levels. The combination of these specific PPRHs with trastuzumab was also explored in breast cancer cell lines, both in vitro and in vivo. PPRHs designed against two intronic sequences of the ERBB2 gene decreased the viability of SKBR-3 and MDA-MB-453 breast cancer cells. The decrease in cell viability was associated with a reduction in ERBB2 mRNA and protein levels. In combination with trastuzumab, PPRHs showed a synergic effect in vitro and reduced tumor growth in vivo. These results represent the preclinical proof of concept of PPRHs as a therapeutic tool for breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Radiation therapy is routinely prescribed for women who undergo breast-sparing surgery for early breast cancers. Over the years, advancements in diagnosis and treatments have dramatically improved breast cancer outcomes, now approaching 100% survival at 5 years for those diagnosed at stage I with favorable clinical and molecular features. In this review, we discuss the investigations that are underway to identify women with low-risk cancers in whom radiation therapy can either be completely avoided or delivered in lower intensities. We also review ongoing clinical trials that are assessing if radiation therapy can increase the capacity of patients' anticancer immune responses and discuss if cancer cells that are shed in the blood can guide radiation decisions. Adjuvant whole breast irradiation after breast-conserving surgery is a well-established treatment standard for early invasive breast cancer. Screening, early diagnosis, refinement in surgical techniques, the knowledge of new and specific molecular prognostic factors, and now the standard use of more effective neo/adjuvant systemic therapies have proven instrumental in reducing the rates of locoregional relapses. This underscores the need for reliably identifying women with such low-risk disease burdens in whom elimination of radiation from the treatment plan would not compromise oncological safety. This review summarizes the current evidence for radiation de-intensification strategies and details ongoing prospective clinical trials investigating the omission of adjuvant whole breast irradiation in molecularly defined low-risk breast cancers and related evidence supporting the potential for radiation de-escalation in HER2+ and triple-negative clinical subtypes. Furthermore, we discuss the current evidence for the de-escalation of regional nodal irradiation after neoadjuvant chemotherapy. Finally, we also detail the current knowledge of the clinical value of stromal tumor-infiltrating lymphocytes and liquid-based biomarkers as prognostic factors for locoregional relapse. [ABSTRACT FROM AUTHOR]

High-power ultrasound in gas-phase (28.8 kW/m3 for 120 min at 17.5 ± 0.3 °C) has been evaluated as a pre-treatment to enhance the release of antioxidants and phenolic compounds from red bell pepper during digestion. The moisture content decreased (34 ± 4%) while both the antioxidant activity (between 4 ± 1% and 21 ± 1%) and the phenolic compounds content (37 ± 4%) increased after the treatment. Moreover, microstructural changes were observed in the treated sample, with the appearance of breaks in the plant tissue, cell shrinkage, and an increased number of cells per area unit (28 ± 2%). Bioaccessibility was determined by in vitro gastrointestinal digestion. The total release of antioxidants and phenolic compounds after gastrointestinal digestion was 22–55% higher and 45 ± 7% higher, respectively, in the sonicated sample, with cell swelling and a 9.2 ± 0.1% higher number of cells per area unit. Therefore, the ultrasound treatment caused microstructural changes in the red bell pepper tissue, which could help to explain the higher release of bioactive compounds. [ABSTRACT FROM AUTHOR]

Simple Summary: The addition of bevacizumab or ramucirumab to systemic therapy for EGFR-mutated non-small-cell lung cancer (NSCLC) patients provides survival benefits. No study to date has compared the efficacy and safety of these two antiangiogenic therapies (AATs). This study enrolled patients with stage IIIB to IV EGFR-mutated NSCLC who were treated with first-line EGFR-TKIs between January 2014 and May 2022. The progression-free survival (PFS) of patients who received front-line AATs combined with EGFR-TKI therapy was longer than that of patients receiving later-line AATs combined with other therapies (19.6 vs. 10.0 months, p < 0.001). Bevacizumab and ramucirumab did not differ in PFS (24.1 vs. 15.7 months, p = 0.454). No difference in overall survival (OS) was observed between front-line and later-line therapy (non-reach vs. 44.0 months, p = 0.261) or between the two AATs (48.6 vs. 43.0 months, p = 0.924). The incidence of some adverse events such as bleeding and hepatitis was higher for bevacizumab than for ramucirumab but it was not significant. The effectiveness and safety of the two AATs were similar. The combination of bevacizumab or ramucirumab with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy, chemotherapy, or immunotherapy for non-small-cell lung cancer (NSCLC) patients with EGFR mutations could have survival benefits. However, no study, to date, has been conducted to compare the efficacy and safety of these two antiangiogenic therapies (AATs). Stage IIIB to IV EGFR-mutated NSCLC patients who received first-line EGFR-TKIs between January 2014 and May 2022 were enrolled. These patients were divided into two groups: those receiving bevacizumab and those receiving ramucirumab as a combination therapy in any line of treatment. Ninety-six patients were enrolled in this study's final analysis. The progression-free survival (PFS) of patients who received front-line AATs combined with EGFR-TKI therapy was longer than that of patients receiving later-line AATs combined with other therapies (19.6 vs. 10.0 months, p < 0.001). No difference in overall survival (OS) was observed between front-line and later-line therapy (non-reach vs. 44.0 months, p = 0.261). Patients who received these two different AATs did not differ in PFS (24.1 vs. 15.7 months, p = 0.454) and OS (48.6 vs. 43.0 months, p = 0.924). In addition, these two AATs showed similar frequencies of the T790M mutation (43.6% vs. 38.2%; p = 0.645). Multivariate Cox regression analysis indicated several AAT cycles as an independent good prognostic factor in OS. The incidence of some adverse events such as bleeding and hepatitis was higher for bevacizumab than for ramucirumab but it was not significant. Front-line AAT and EGFR-TKI combination therapy improved the PFS of stage IV EGFR-mutated NSCLC patients. The effectiveness and safety of the two AATs were similar. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most prevalent cancer in women and the leading cause of cancer-associated deaths. Although several therapeutic approaches are available, systemic chemotherapy remains the primary choice, especially for the treatment of advanced breast cancers. Unfortunately, systemic chemotherapy causes numerous side effects and damage to distal organs and requires high doses of drugs to achieve a therapeutic concentration in the tumor region. The use of nanosystems for drug delivery is a promising strategy to overcome these drawbacks. In this study, we developed Poly (lactic-co-glycolic acid) nanoparticles (PLGA-NPs) containing the chemotherapeutic drug Docetaxel, functionalized with a cyclic RGD tripeptide to allow the active targeting of αvβ3 integrins, which are overexpressed in breast cancer. We demonstrated that PLGAs effectively deliver the drug to breast cancer cells in preclinical models, and are more effective than free Docetaxel in hampering tumor progression, while reducing side effects. Breast cancer is the leading cause of cancer-related death in women. Although many therapeutic approaches are available, systemic chemotherapy remains the primary choice, especially for triple-negative and advanced breast cancers. Unfortunately, systemic chemotherapy causes serious side effects and requires high doses to achieve an effective concentration in the tumor. Thus, the use of nanosystems for drug delivery may overcome these limitations. Herein, we formulated Poly (lactic-co-glycolic acid) nanoparticles (PLGA-NPs) containing Docetaxel, a fluorescent probe, and a magnetic resonance imaging (MRI) probe. The cyclic RGD tripeptide was linked to the PLGA surface to actively target αvβ3 integrins, which are overexpressed in breast cancer. PLGA-NPs were characterized using dynamic light scattering, fast field-cycling 1H-relaxometry, and 1H-nuclear magnetic resonance. Their therapeutic effects were assessed both in vitro in triple-negative and HER2+ breast cancer cells, and in vivo in murine models. In vivo MRI and inductively coupled plasma mass spectrometry of excised tumors revealed a stronger accumulation of PLGA-NPs in the RGD_PLGA group. Targeted PLGAs have improved therapeutic efficacy and strongly reduced cardiac side effects compared to free Docetaxel. In conclusion, RGD-PLGA is a promising system for breast cancer treatment, with positive outcome in terms of therapeutic efficiency and reduction in side effects. [ABSTRACT FROM AUTHOR]

Waste orange peels (WOP) are a food processing residue rich in bioactive polyphenols. However, data on aqueous extraction processes for efficient polyphenol recovery are rather limited. The present study dealt with the optimization of WOP polyphenols, using a batch stirred-tank mode and water as solvent. After a preliminary single-factor examination, the implementation of response surface methodology revealed that optimum extraction time and temperature were 60 min and 55 °C, respectively. Under these conditions, the extraction afforded a total polyphenol yield of 26.13 ± 0.78 mg gallic acid equivalents per g dry mass. The use of aqueous solutions of citric, tartaric and lactic acid showed that total polyphenol yield may be significantly increased with 1% tartaric acid or equally with 2.5% citric acid. However, the effect on individual polyphenolic constituents was rather negligible, as determined by high-performance liquid chromatography. The discrepancies observed in the antioxidant properties of the extracts produced with water and acidified water were putatively attributed to some differences in the polyphenolic composition. The extraction methodology proposed is environmentally green and of low cost, and it could certainly be used as an effective means of recovering WOP polyphenols. [ABSTRACT FROM AUTHOR]

The use of artificial neural networks (ANNs) is proposed to optimize the formulation of stable oil-in-water emulsions (oil 6% w/w) with a flour made from orange by-products (OBF), rich in pectins (21 g/100 g fresh matter), in different concentrations (0.95, 2.38, and 3.40% w/w), combined with or without soy proteins (0.3 and 0.6% w/w). Emulsions containing OBF were stable against coalescence and flocculation (with 2.4 and 3.4% OBF) and creaming (3.4% OBF) for 24 h; the droplets' diameter decreased up to 44% and the viscosity increased up to 37% with higher concentrations of OBF. With the protein addition, the droplets' diameter decreased by up to 70%, and flocculation increased. Compared with emulsions produced with purified citrus pectins (0.2 and 0.5% w/w), OBF emulsions exhibited up to 32% lower viscosities, 129% larger droplets, and 45% smaller Z potential values. Optimization solved with ANNs minimizing the droplet size and the emulsion instability resulted in OBF and protein concentrations of 3.16 and 0.14%, respectively. The experimental characteristics of the optimum emulsion closely matched those predicted by ANNs demonstrating the usefulness of the proposed method. [ABSTRACT FROM AUTHOR]

Breast cancer is the most frequent cancer in women. Despite recent clinical advances, new therapeutic approaches are still required. The cystine-glutamate antiporter xCT, encoded by the SLC7A11 gene, which imports cystine in exchange with glutamate, is a potentially new target for breast cancer therapy, being involved in tumor cell redox balance and resistance to therapies. xCT expression is regulated by the oncosuppressor p53, which is mutated in many breast cancers. Indeed, mutant p53 (mut-p53) can induce xCT post-transcriptional down modulation, rendering mut-p53 tumors susceptible to oxidative damage. Interestingly, the drug APR-246, developed to restore the wild-type function of p53 in tumors harboring its mutation, alters the cell redox balance in a p53-independent way, possibly rendering the cells more sensitive to xCT inhibition. Here, we propose a combinatorial treatment based on xCT immunetargeting and APR-246 treatment as a strategy for tackling breast cancer. We demonstrate that combining the inhibition of xCT with the APR-246 drug significantly decreased breast cancer cell viability in vitro and induced apoptosis and affected cancer stem cells' self-renewal compared to the single treatments. Moreover, the immunetargeting of xCT through DNA vaccination in combination with APR-246 treatment synergistically hinders tumor progression and prevents lung metastasis formation in vivo. These effects can be mediated by the production of anti-xCT antibodies that are able to induce the antibody dependent cellular cytotoxicity of tumor cells. Overall, we demonstrate that DNA vaccination against xCT can synergize with APR-246 treatment and enhance its therapeutic effect. Thus, APR-246 treatment in combination with xCT immunetargeting may open new perspectives in the management of breast cancer. [ABSTRACT FROM AUTHOR]

The Southeastern United States is facing agriculture crises, such as the ongoing epidemic of citrus greening disease that has forced the region to begin looking into alternative crops. Some of these belong to the Rosaceae genus Prunus, which encompasses many economically important species such as peaches, almonds, cherries, plums, and more. Peach production in Florida has become a very promising alternative to citrus; however, there are different limitations and challenges that peach production faces in this region. Differing climates coupled with edaphic challenges such as salinity, alkalinity, and waterlogging have been the focus of much of the research into the viability of peach production in the region. Using the genetic diversity of the Prunus genus is crucial to the success of peach as an alternative crop, due to the nature of its propagation on rootstocks. The development of new rootstock cultivars has been—and continues to be—the most efficient way not only to deal with the variety of problems associated with the climate and soil mentioned above but also to mitigate the effects of pests and diseases. The vegetative propagation of stone fruit rootstocks also has distinct advantages that seed propagation cannot achieve, including tree performance uniformity and the multiplication of interspecific hybrids. Tools used to select the best-performing rootstocks for the area such as the root system architecture (RSA) analysis are fundamental to this development process to ensure that the rootstock cultivars with the traits needed for success in the region are selected. This narrative review lays out all the challenges facing southeastern peach production in detail, discussing the research into these challenges and highlighting the tools that are most crucial to the success of peach production in the region to create a resource for researchers, growers, and breeders to more easily access this information. [ABSTRACT FROM AUTHOR]

Simple Summary: This retrospective observational study aims at highlighting the response to pertuzumab, trastuzumab and docetaxel treatment (THP), without using anthracycline, in patients with HER2-positive early breast cancer. We add evidence to the suitability of THP in real life to reach higher pathological complete response rates, with a good safety profile for patients. An exploratory analysis of the mutational status of PIK3CA was performed as well, and 21% mutated samples were identified, with overall higher pCR rates in PIK3CA mutant patients and, particularly, in those who were THP-treated. Our original results open the door to further studies focused on more in-depth analysis of the molecular and clinical features related to the response to anthracycline-free neoadjuvant treatment in HER2-positive early breast cancer patients. HER2 is considered one of the most traditional prognostic and predictive biomarkers in breast cancer. Literature data confirmed that the addition of pertuzumab to a standard neoadjuvant chemotherapy backbone (either with or without anthracyclines), in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), leads to a higher pathological complete response (pCR) rate, which is known to correlate with a better prognosis. In this retrospective analysis, 47 consecutive patients with HER2-positive EBC received sequential anthracyclines and taxanes plus trastuzumab (ATH) or pertuzumab, trastuzumab and docetaxel (THP). Despite the limited sample size, this monocentric experience highlights the efficacy (in terms of pCR) and safety of THP in the neoadjuvant setting of HER2-positive EBC as an anthracycline-free approach. Given the role of PIK3CA as a prognostic and therapeutic target in breast cancer, tumors were also analyzed to assess the PIK3CA mutational status. Thirty-eight out of forty-seven patients were evaluated, and PIK3CA variants were identified in 21% of tumor samples: overall, one mutation was detected in exon 4 (2.6%), two in exon 9 (5.3%) and four in exon 20 (10.5%). Of note, one sample showed concurrent mutations in exons 9 (codon 545) and 20 (codon 1047). Among patients reaching pCR (n = 13), 38.5% were PIK3CA mutants; on the other hand, among those lacking pCR (n = 25), just 12% showed PIK3CA variants. Regarding THP-treated mutant patients (n = 5), 80% reached pCR (three hormone-receptor-negative, one hormone-receptor-positive). Interestingly, the only patient not achieving pCR had a tumor with two co-occurring PIK3CA mutations. In conclusion, this study provides new evidence about the efficacy and good safety profile of THP, compared to the ATH regimen, as an anthracycline-free neoadjuvant treatment of HER2-positive EBC. Further studies on larger/multicentric cohorts are planned for more in-depth analysis to confirm our molecular and clinical results. [ABSTRACT FROM AUTHOR]

This study was focused on the simultaneous organosolv treatment/extraction of waste orange peels (WOP) for the effective recovery of polyphenolic antioxidants. The treatments were performed with aqueous glycerol mixtures, which were acidified either with citric acid or hydrochloric acid (HCl). Process optimization was carried out using response surface methodology and comparative appraisal of the different processes tested, based on both the extraction efficiency factor (FEE), severity factor (SF) or combined severity factor (CSF). Metabolite stability was also of major concern, and it was examined by deploying liquid chromatography-mass spectrometry. The results drawn suggested 90% (w/w) glycerol to be the highest-performing system, providing a yield in total polyphenols of 44.09 ± 5.46 mg GAE g−1 DM at 140 °C for 50 min, with a FEE of 2.20 and an SF of 2.88. Acidification with 1% citric acid was proven less efficient and equally severe, whereas acidification with 1% HCl was less severe but also less efficient. The major disadvantage associated with the use of HCl was its detrimental impact on the polyphenolic composition of WOP since major metabolites, such as narirutin, hesperidin and didymin, did not survive the process. By contrast, the formation of lower molecular weight compounds was observed. With regard to antioxidant properties, the extract obtained with aqueous glycerol displayed significantly higher antiradical activity and reducing power, which was in line with its higher concentration in total polyphenols. It was concluded that organosolv treatment with aqueous glycerol under the conditions employed may boost polyphenol recovery from WOP, thus giving extracts with powerful antioxidant characteristics. [ABSTRACT FROM AUTHOR]

Simple Summary: The miR200 family is involved in breast cancer progression. Our aim was to evaluate the predictive and prognostic role of miR-200c-3p, both in plasma and in tumor, in women with locally advanced and metastatic breast cancer. Our results show that plasma levels of miR-200c-3p are higher in these patients and might be used as a breast cancer marker. In patients treated with neoadjuvant chemotherapy, miR-200c-3p expression may also improve prognostic stratification beyond pathologic response and clinical stage. While the role of miR-200c in cancer progression has been established, its expression and prognostic role in breast cancer is not completely understood. The predictive role of miR-200c in response to chemotherapy has also been suggested by some studies, but only limited clinical evidence is available. The purpose of this study was to investigate miR-200c-3p in the plasma and primary tumor of BC patients. The study design included two cohorts involving women with locally advanced (LABC) and metastatic breast cancer. Tumor and plasma samples were obtained before and after treatment. We found that miR-200c-3p was significantly higher in the plasma of BC patients compared with the controls. No correlation of age with plasma miR-200c-3p was found for controls or for BC patients. MiR-200c-3p tumor expression was also associated with poor overall survival in LABC patients treated with neoadjuvant chemotherapy, independently of pathological complete response or clinical stage. Our findings suggest that plasmatic miR-200c-3p levels could be useful for BC staging, while the tumor expression of miR-200c-3p might provide further prognostic information beyond residual disease in BC treated with neoadjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Wastewater reclamation and reuse have the potential to supplement water supplies, offering resiliency in times of drought and helping to meet increased water demands associated with population growth. Non-potable water reuse represents the largest potential reuse market. Yet, economic constraints for new water reuse infrastructure and safety concerns due to microbial water quality, especially viral pathogen exposure, limit the widespread implementation of water reuse. Cost-effective, real-time methods to measure or indicate the viral quality of recycled water would do much to instill greater confidence in the practice. This manuscript discusses advancements in monitoring and modeling viral health risks in the context of water reuse. First, we describe current wastewater reclamation processes and treatment technologies with an emphasis on virus removal. Second, we review technologies for the measurement of viruses, both culture- and molecular-based, along with their advantages and disadvantages. We outline promising viral surrogates and specific pathogenic viruses that can serve as indicators of viral risk for water reuse. We suggest metagenomic analyses for viral screening and flow cytometry for quantification of virus-like particles as new approaches to complement more traditional methods. Third, we describe modeling to assess health risks through quantitative microbial risk assessments (QMRAs), the most common strategy to couple data on virus concentrations with human exposure scenarios. We then explore the potential of artificial neural networks (ANNs) to incorporate suites of data from wastewater treatment processes, water quality parameters, and viral surrogates. We recommend ANNs as a means to utilize existing water quality data, alongside new complementary measures of viral quality, to achieve cost-effective strategies to assess risks associated with infectious human viruses in recycled water. Given the review, we conclude that technologies will be ready to identify and implement viral surrogates for health risk reduction in the next decade. Incorporating modeling with monitoring data would likely result in a more robust assessment of water reuse risk. [ABSTRACT FROM AUTHOR]

In Canada, the therapeutic management of patients with advanced non-small cell lung cancer (NSCLC) with rare actionable mutations differs between provinces, territories, and individual centres based on access to molecular testing and funded treatments. These variations, together with the emergence of several novel mesenchymal-epithelial transition (MET) factor-targeted therapies for the treatment of NSCLC, warrant the development of evidence-based consensus recommendations for the use of these agents. A Canadian expert panel was convened to define key clinical questions, review evidence, discuss practice recommendations and reach consensus on the treatment of advanced MET-altered NSCLC. Questions addressed by the panel include: 1. How should the patients most likely to benefit from MET-targeted therapies be identified? 2. What are the preferred first-line and subsequent therapies for patients with MET exon 14 skipping mutations? 3. What are the preferred first-line and subsequent therapies for advanced NSCLC patients with de novo MET amplification? 4. What is the preferred therapy for patients with advanced epidermal growth factor receptor (EGFR)- mutated NSCLC with acquired MET amplification progressing on EGFR inhibitors? 5. What are the potential strategies for overcoming resistance to MET inhibitors? Answers to these questions, along with the consensus recommendations herein, will help streamline the management of MET-altered NSCLC in routine practice, assist clinicians in therapeutic decision-making, and help ensure optimal outcomes for NSCLC patients with MET alterations. [ABSTRACT FROM AUTHOR]

There is, to-date, an expanding interest concerning the use of cyclodextrins as green food-grade co-solvents in the aqueous extraction of polyphenols, however, data regarding polyphenol extraction from waste orange peels (WOP) are lacking. On this ground, hydroxypropyl β-cyclodextrin (HP-β-CD), a highly water-soluble cyclodextrin, was used to develop a simple and straightforward methodology for the effective recovery of WOP polyphenols. Process optimization by response surface showed that maximum total polyphenol recovery (26.30 ± 1.49 mg gallic acid equivalents g-1 dry mass) could be accomplished with 15 mM HP-β-CD at 40 °C. On the other hand, integration of ultrasonication pretreatment was found unsuitable, as it resulted in reduced polyphenol yield. Examination of solvent acidity indicated that polyphenol extraction may be enhanced at pH 4, but the difference was non-significant (p > 0.05) compared to yields attained at pH 2, 3, and 5. Extraction of WOP polyphenols with HP-β-CD was shown to provide significantly higher hesperidin yield compared to 60% (v/v) aqueous ethanol, which suggested selectivity of HP-β-CD toward this polyphenolic metabolite. [ABSTRACT FROM AUTHOR]

Small molecules found in natural products provide therapeutic benefits due to their pharmacological or biological activity, which may increase or decrease the expression of human epidermal growth factor receptor (HER), a promising target in the modification of signaling cascades involved in excessive cellular growth. In this study, in silico molecular protein-ligand docking protocols were performed with AutoDock Vina in order to evaluate the interaction of 800 natural compounds (NPs) from the NatProd Collection (http://www.msdiscovery.com/natprod.html), with four human HER family members: HER1 (PDB: 2ITW), HER2 (PDB: 3PP0), HER3 (PDB: 3LMG) and HER4 (PDB: 2R4B). The best binding affinity values (kcal/mol) for docking pairs were obtained for HER1-podototarin (-10.7), HER2-hecogenin acetate (-11.2), HER3-hesperidin (-11.5) and HER4-theaflavin (-10.7). The reliability of the theoretical calculations was evaluated employing published data on HER inhibition correlated with in silico binding calculations. IC50 values followed a significant linear relationship with the theoretical binding Affinity data for HER1 (R = 0.656, p < 0.0001) and HER2 (R = 0.543, p < 0.0001), but not for HER4 (R = 0.364, p > 0.05). In short, this methodology allowed the identification of several NPs as HER inhibitors, being useful in the discovery and design of more potent and selective anticancer drugs. [ABSTRACT FROM AUTHOR]

Two groups of bacteriophages that infect Escherichia coli, somatic and F-specific coliphages, have been used in academia as both fecal and viral indicators for many years. Regulatory authorities in different parts of the world are beginning to consider coliphages as indicators of water quality in a range of settings. However, issues such as their potential replication in natural water environments, the cumbersome detection and enumeration methods, a lack of definition concerning which of the two groups should be included in future regulations, and the lack of a clear correlation between coliphages and human viruses and health risks in different water settings remain controversial. This review attempts to shed some light on these contentious issues. The conclusions are that: 1) supposing that they can replicate in some natural water settings, the contribution of coliphages replicated outside the gut will not affect the numbers contributed by fecal pollution and detected by strains recommended for standardized methods; 2) there are easy, fast, and cost-effective methods that can be used in routine laboratories after a little training; 3) perhaps the best option is to determine both groups in a single step; and 4) the low correlation of coliphages with human viruses and health risks is no worse than the correlation between different human viruses. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate cancer size measurement by computer-aided diagnosis (CAD) and radiologist on breast magnetic resonance imaging (MRI) relative to histopathology and to determine clinicopathologic and MRI factors that may affect measurements. Methods: Preoperative MRI of 208 breast cancers taken between January 2017 and March 2021 were included. We evaluated correlation between CAD-generated size and pathologic size as well as that between radiologist-measured size and pathologic size. We classified size discrepancies into accurate and inaccurate groups. For both CAD and radiologist, clinicopathologic and imaging factors were compared between accurate and inaccurate groups. Results: The mean sizes as predicted by CAD, radiologist and pathology were 2.66 ± 1.68 cm, 2.54 ± 1.68 cm, and 2.30 ± 1.61 cm, with significant difference (p < 0.001). Correlation coefficients of cancer size measurement by radiologist and CAD in reference to pathology were 0.898 and 0.823. Radiologist's measurement was more accurate than CAD, with statistical significance (p < 0.001). CAD-generated measurement was significantly more inaccurate for cancers of larger pathologic size (>2 cm), in the presence of an extensive intraductal component (EIC), with positive progesterone receptor (PR), and of non-mass enhancement (p = 0.045, 0.045, 0.03 and 0.002). Radiologist-measured size was significantly more inaccurate for cancers in presence of an in situ component, EIC, positive human epidermal growth factor receptor 2 (HER2), and non-mass enhancement (p = 0.017, 0.008, 0.003 and <0.001). Conclusion: Breast cancer size measurement showed a very strong correlation between CAD and pathology and radiologist and pathology. Radiologist-measured size was significantly more accurate than CAD size. Cancer size measurement by CAD and radiologist can both be inaccurate for cancers with EIC or non-mass enhancement. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoadjuvant chemotherapy in HER2-positive breast cancer has become the standard of care. Systemic treatment allows, in many cases, a reduction in the scope of surgical treatment. The aim of our retrospective study was to confirm the efficacy and safety of neoadjuvant chemotherapy in the TCbH-P program. All study patients received six courses of chemotherapy. All patients achieved a reduction in breast tumour size. There were no cardiac complications in any of the patients that prevented the continuation of treatment. A complete pathological response was achieved in 52.9% of patients. No pCR was achieved in any patient over 60 years of age with luminal B HER2-positive cancer, which questions the use of the TCbH-P regimen in this group of patients. Neoadjuvant systemic therapy has now become the standard in early breast cancer management. Chemotherapy in combination with trastuzumab +/− pertuzumab targeted therapy can improve the rates of pathologic complete response (pCR) in patients with HER2-positive breast cancer. Achieving a pCR is considered a good prognostic factor, in particular, in patients with more aggressive breast cancer subtypes such as TNBC or HER2-positive cancers. Furthermore, most studies demonstrate that chemotherapy in combination with trastuzumab and pertuzumab is well tolerated. The retrospective analysis presented here concentrates on neoadjuvant therapy with the TCbH-P regimen, with a particular emphasis on patients over 60 years of age. We analysed the factors affecting the achievement of pCR and present the adverse effects of the applied therapies, opening discussion about optimizing the therapy of older patients with HER-2 positive breast cancer. [ABSTRACT FROM AUTHOR]

Lung cancer has a high prevalence, with a growing number of new cases and mortality every year. Furthermore, the survival rate of patients with non-small-cell lung carcinoma (NSCLC) is still quite low in the majority of cases. Despite the use of conventional therapy such as tyrosine kinase inhibitor for Epidermal Growth Factor Receptor (EGFR), which is highly expressed in most NSCLC cases, there was still no substantial improvement in patient survival. This is due to the drug's ineffectiveness and high rate of resistance among individuals with mutant EGFR. Therefore, the development of new inhibitors is urgently needed. Understanding the EGFR structure, including its kinase domain and other parts of the protein, and its activation mechanism can accelerate the discovery of novel compounds targeting this protein. This study described the structure of the extracellular, transmembrane, and intracellular domains of EGFR. This was carried out along with identifying the binding pose of commercially available inhibitors in the ATP-binding and allosteric sites, thereby clarifying the research gaps that can be filled. The binding mechanism of inhibitors that have been used clinically was also explained, thereby aiding the structure-based development of new drugs. [ABSTRACT FROM AUTHOR]

Simple Summary: We extracted known interactions between metastasis suppressors and their regulators from scientific studies. Next, we used publically available data of drug treatments to identify which of them potentially perturbs these interactions. Finally, we studied the effect of several of these drugs on a particular metastasis suppressor called RKIP and found that our model accurately predicted its regulation in breast cancer cells. Our approach can discover alternative mechanisms of existing cancer drugs and repurpose them in different disease types. Drug screening strategies focus on quantifying the phenotypic effects of different compounds on biological systems. High-throughput technologies have the potential to understand further the mechanisms by which these drugs produce the desired outcome. Reverse causal reasoning integrates existing biological knowledge and measurements of gene and protein abundances to infer their function. This approach can be employed to appraise the existing biological knowledge and data to prioritize targets for cancer therapies. We applied text mining and a manual literature search to extract known interactions between several metastasis suppressors and their regulators. We then identified the relevant interactions in the breast cancer cell line MCF7 using a knockdown dataset. We finally adopted a reverse causal reasoning approach to evaluate and prioritize pathways that are most consistent and responsive to drugs that inhibit cell growth. We evaluated this model in terms of agreement with the observations under treatment of several drugs that produced growth inhibition of cancer cell lines. In particular, we suggested that the metastasis suppressor PEBP1/RKIP is on the receiving end of two significant regulatory mechanisms. One involves RELA (transcription factor p65) and SNAI1, which were previously reported to inhibit PEBP1. The other involves the estrogen receptor (ESR1), which induces PEBP1 through the kinase NME1. Our model was derived in the specific context of breast cancer, but the observed responses to drug treatments were consistent in other cell lines. We further validated some of the predicted regulatory links in the breast cancer cell line MCF7 experimentally and highlighted the points of uncertainty in our model. To summarize, our model was consistent with the observed changes in activity with drug perturbations. In particular, two pathways, including PEBP1, were highly responsive and would be likely targets for intervention. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian high-grade serous carcinoma is the deadliest ovarian cancer. Cancer cells develop resistance to anti-cancer regimens leading to poor prognosis. Previous studies showed that the progesterone receptor was associated with better rates of survival of ovarian cancer patients. We aimed to investigate the association between the progesterone receptor and its isoform-B and platinum sensitivity of ovarian high-grade serous carcinoma. We found that strong progesterone receptor-B expression was associated with better platinum sensitivity and better survival in high-grade serous ovarian cancer patients. Our clinical data also showed that a high expression of progesterone receptor-B and optimal debulking were the independent factors associated with better platinum sensitivity. In a cell model, enhancing progesterone receptor-B expression and progesterone treatment increased platinum sensitivity and platinum-related apoptosis of the ovarian cancer cells. These might be potential therapeutic targets of ovarian high-grade serous carcinoma. Background: Expression of the progesterone receptor (PR) has been reported to influence survival outcomes in patients with ovarian high-grade serous carcinoma (HGSC). In the present study, we attempted to investigate the association among PR and its isoforms' expression, platinum sensitivity, and survival in ovarian HGSC. Material and methods: This retrospective study reviewed ovarian HGSC patients who received surgery followed by adjuvant chemotherapy. We analyzed total PR and PR isoform-B (PR-B) expression by immunohistochemical staining and quantified using the H-score. Then, we compared platinum sensitivity and survival outcomes between those patients with weak and strong PR-B expression. Cisplatin viability assays were carried out in ovarian HGSC cell lines (OC-3-VGH and OVCAR-3) with different PR-B expression. Results: Among 90 patients, 49 and 41 patients were considered to have platinum-sensitive and platinum-resistant disease, respectively. Pearson's correlation model showed that the H-score of total PR correlated positively with PR-B (r = 0.813). The PR-B H-score of tumors was significantly higher in the platinum-sensitive group (p = 0.004). Multivariate analysis revealed that the PR-B H-score and optimal debulking status were independent factors predicting platinum sensitivity. When compared with strong PR-B expression, patients with weak PR-B had significantly poorer progression-free (p = 0.021) and cancer-specific survival (p = 0.046). In a cell model, cisplatin-resistant OC-3-VGH cells expressed a lower level of PR-B than wild-type cells. Overexpression of PR-B or progesterone could increase cisplatin sensitivity in both OC-3-VGH and OVCAR-3 cells via the mechanism of promoting cisplatin-related apoptosis. Conclusions: When compared to weak PR-B, ovarian HGSC patients with a strong PR-B expression had a better chance of platinum sensitivity and survival, and this finding was compatible with our experimental results. Progesterone seemed to be a platinum sensitizer, but the value of adding progesterone in the treatment of ovarian HGSC should be further investigated. [ABSTRACT FROM AUTHOR]

Simple Summary: Recently, the role of vaccination has been expanded in the management of HER2/neu-positive breast cancer. Data from various clinical trials indicated that an effective breast cancer vaccine must be able to induce both humoral and cellular immune responses. One approach is the use of a multi-epitope peptide vaccine comprising B, T helper and CTL epitopes. In this study, we have successfully developed a vaccine construct based on a chimeric HER2/neu-derived antigenic peptide possessing B- and T-cell epitopes conjugated to the KLH protein as a source of T-helper epitopes. A similar vaccine construct, but without the presence of a B-cell peptide epitope, was also prepared to examine the role of the humoral immune response in antitumor immunity. Multi-epitope peptide vaccine with additional B-cell epitope was found to be superior in inhibiting the tumor growth and prolongation of survival in tumor mice model compared to vaccine construct without the presence of B-cell epitope. Breast cancer is the most common invasive cancer diagnosed among women. A cancer vaccine has been recognized as a form of immunotherapy with a prominent position in the prevention and treatment of breast cancer. The majority of current breast cancer vaccination strategies aim to stimulate antitumor T-cell responses of the HER2/neu oncogene, which is abnormally expressed in breast cancer cells. However, the role of the B-cell humoral response is often underappreciated in the cancer vaccine design. We have advanced this idea by elucidating the role of B-cells in cancer vaccination by designing a chimeric antigenic peptide possessing both cytotoxic T lymphocytes (GP2) and B-cell (P4) peptide epitopes derived from HER2/neu. The chimeric peptide (GP2–P4) was further conjugated to a carrier protein (KLH), forming a KLH–GP2–P4 conjugate. The immunogenicity of KLH–GP2–P4 was compared with KLH–GP2 (lacking the B-cell epitope) in BALB/c mice. Mice immunized with KLH–GP2–P4 elicited more potent antigen-specific neutralizing antibodies against syngeneic TUBO cells (cancer cell line overexpressing HER2/neu) that was governed by a balanced Th1/Th2 polarization in comparison to KLH–GP2. Subsequently, these immune responses led to greater inhibition of tumor growth and longer survival in TUBO tumor-bearing mice in both prophylactic and therapeutic challenge experiments. Overall, our data demonstrated that the B-cell epitope has a profound effect in orchestrating an efficacious antitumor immunity. Thus, a multi-epitope peptide vaccine encompassing cytotoxic T-lymphocytes, T-helper and B-cell epitopes represents a promising strategy in developing cancer vaccines with a preventive and therapeutic modality for the effective management of breast cancer. [ABSTRACT FROM AUTHOR]

Bacteriophages are promising tools for the detection of fecal pollution in different environments, and particularly for viral pathogen risk assessment. Having similar morphological and biological characteristics, bacteriophages mimic the fate and transport of enteric viruses. Enteric bacteriophages, especially phages infecting Escherichia coli (coliphages), have been proposed as alternatives or complements to fecal indicator bacteria. Here, we provide a general overview of the potential use of enteric bacteriophages as fecal and viral indicators in different environments, as well as the available methods for their detection and enumeration, and the regulations for their application. [ABSTRACT FROM AUTHOR]

Simple Summary: Currently, it is unclear which kind of axillary staging surgery breast cancer patients with lymph node metastasis should receive after neoadjuvant chemotherapy. For decades, these patients have been treated with a full axillary lymph node dissection, even if they converted to clinical node negativity. However, the removal of a large number of lymph nodes during the procedure can increase arm morbidity and impact quality of life. Therefore, several studies investigated less radical surgical strategies in this setting, such as sentinel lymph node biopsy or targeted axillary dissection, i.e., removal of a previously marked node combined with sentinel node removal. In this review, we summarize current evidence on the different surgical techniques and compare national and international recommendations. We show that many questions regarding oncological safety of different surgery types and the optimal marking technique remain unanswered and present the multinational prospective cohort study AXSANA that will address these open issues. In the last two decades, surgical methods for axillary staging in breast cancer patients have become less extensive, and full axillary lymph node dissection (ALND) is confined to selected patients. In initially node-positive patients undergoing neoadjuvant chemotherapy, however, the optimal management remains unclear. Current guidelines vary widely, endorsing different strategies. We performed a literature review on axillary staging strategies and their place in international recommendations. This overview defines knowledge gaps associated with specific procedures, summarizes currently ongoing clinical trials that address these unsolved issues, and provides the rationale for further research. While some guidelines have already implemented surgical de-escalation, replacing ALND with, e.g., sentinel lymph node biopsy (SLNB) or targeted axillary dissection (TAD) in cN+ patients converting to clinical node negativity, others recommend ALND. Numerous techniques are in use for tagging lymph node metastasis, but many questions regarding the marking technique, i.e., the optimal time for marker placement and the number of marked nodes, remain unanswered. The optimal number of SLNs to be excised also remains a matter of debate. Data on oncological safety and quality of life following different staging procedures are lacking. These results provide the rationale for the multinational prospective cohort study AXSANA initiated by EUBREAST, which started enrollment in June 2020 and aims at recruiting 3000 patients in 20 countries (NCT04373655; Funded by AGO-B, Claudia von Schilling Foundation for Breast Cancer Research, AWOgyn, EndoMag, Mammotome, and MeritMedical). [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite numerous efforts to target epidermal growth factor receptor (EGFR), commonly dysregulated in GBM, approaches directed against EGFR have not achieved the same degree of success as seen in other tumor types, particularly as compared to non-small cell lung cancer (NSCLC). EGFR alterations in glioblastoma lie primarily in the extracellular domain, unlike the kinase domain alterations seen in NSCLC. Small molecule inhibitors are difficult to develop for the extracellular domain. Monoclonal antibodies can be developed to target the extracellular domain but must contend with the blood brain barrier (BBB). We review the role of EGFR in GBM, the history of trialed treatments, and the potential paths forward to target the pathway that may have greater success. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) accounts for 15% of overall breast cancer. A lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2 receptor) makes TNBC more aggressive and metastatic. Wnt signaling is one of the important pathways in the cellular process; in TNBC it is aberrantly regulated, which leads to the progression and metastasis. In this study, we designed a therapeutic strategy using a combination of a low dose of paclitaxel and a Wnt signaling inhibitor (XAV939), and examined the effect of the paclitaxel-combined XAV939 treatment on diverse breast cancer lines including TNBC cell lines (MDA-MB-231, MDA-MB-468, and BT549) and ER+ve cell lines (MCF-7 and T-47D). The combination treatment of paclitaxel (20 nM) and XAV939 (10 µM) exerted a comparable therapeutic effect on MDA-MB-231, MDA-MB-468, BT549, MCF-7, and T-47D cell lines, relative to paclitaxel with a high dose (200 nM). The paclitaxel-combined XAV939 treatment induced apoptosis by suppressing Bcl-2 and by increasing the cleavage of caspases-3 and PARP. In addition, the in vivo results of the paclitaxel-combined XAV939 treatment in a mice model with the MDA-MB-231 xenograft further confirmed its therapeutic effect. Furthermore, the paclitaxel-combined XAV939 treatment reduced the expression of β-catenin, a key molecule in the Wnt pathway, which led to suppression of the expression of epithelial-mesenchymal transition (EMT) markers and angiogenic proteins both at mRNA and protein levels. The expression level of E-cadherin was raised, which potentially indicates the inhibition of EMT. Importantly, the breast tumor induced by pristane was significantly reduced by the paclitaxel-combined XAV939 treatment. Overall, the paclitaxel-combined XAV939 regimen was found to induce apoptosis and to inhibit Wnt signaling, resulting in the suppression of EMT and angiogenesis. For the first time, we report that our combination approach using a low dose of paclitaxel and XAV939 could be conducive to treating TNBC and an external carcinogen-induced breast cancer. [ABSTRACT FROM AUTHOR]

Recent studies showed that Fatty Acid Synthase (FASN), a lipogenic enzyme overexpressed in several carcinomas, plays an important role in drug resistance. Furthermore, the enrichment of Breast Cancer Stem Cell (BCSC) features has been found in breast tumors that progressed after chemotherapy. Hence, we used the triple negative breast cancer (TNBC) cell line MDA-MB-231 (231) to evaluate the FASN and BCSC population role in resistance acquisition to chemotherapy. For this reason, parental cell line (231) and its derivatives resistant to doxorubicin (231DXR) and paclitaxel (231PTR) were used. The Mammosphere-Forming Assay and aldehyde dehydrogenase (ALDH) enzyme activity assay showed an increase in BCSCs in the doxorubicin-resistant model. Moreover, the expression of some transcription factors involved in epithelial-mesenchymal transition (EMT), a process that confers BCSC characteristics, was upregulated after chemotherapy treatment. FASN inhibitors C75, (−)-Epigallocatechin 3-gallate (EGCG), and its synthetic derivatives G28, G56 and G37 were used to evaluate the effect of FASN inhibition on the BCSC-enriched population in our cell lines. G28 showed a noticeable antiproliferative effect in adherent conditions and, interestingly, a high mammosphere-forming inhibition capacity in all cell models. Our preliminary results highlight the importance of studying FASN inhibitors for the treatment of TNBC patients, especially those who progress after chemotherapy. [ABSTRACT FROM AUTHOR]