Genome-wide CRISPR screens identify the YAP/TEAD axis as a driver of persister cells in EGFR mutant lung cancer.

Most lung cancer patients with metastatic cancer eventually relapse with drug-resistant disease following treatment and EGFR mutant lung cancer is no exception. Genome-wide CRISPR screens, to either knock out or overexpress all protein-coding genes in cancer cell lines, revealed the landscape of pathways that cause resistance to the EGFR inhibitors osimertinib or gefitinib in EGFR mutant lung cancer. Among the most recurrent resistance genes were those that regulate the Hippo pathway. Following osimertinib treatment a subpopulation of cancer cells are able to survive and over time develop stable resistance. These 'persister' cells can exploit non-genetic (transcriptional) programs that enable cancer cells to survive drug treatment. Using genetic and pharmacologic tools we identified Hippo signalling as an important non-genetic mechanism of cell survival following osimertinib treatment. Further, we show that combinatorial targeting of the Hippo pathway and EGFR is highly effective in EGFR mutant lung cancer cells and patient-derived organoids, suggesting a new therapeutic strategy for EGFR mutant lung cancer patients.

Current strategies for the management of valuable compounds from hops waste for a circular economy.

World beer production generates large volumes of waste discharged with every brew. Recently, new methods of reducing and reusing hops waste: hot trub (HT), and brewer-spent hops (BSH) are being exploited to improve the circular economy processes. This review outlines the current achievements in the management of hops waste. Following an in-depth review of various scientific publications, current strategies are discussed as a sustainable alternative to food waste exploitation and an inexpensive source of valuable compounds. Moreover, key aspects concerning the nutritional value of hops waste and the potential to enhance the functional properties of food and beverages are highlighted. Due to their nutritional composition, hops residues may be used as prospective sources of added-value co-products or additives for food enrichment, especially for products rich in fat, or as a new source of vegetable protein.

Blackthorn-A Valuable Source of Phenolic Antioxidants with Potential Health Benefits.

Prunus spinosa L. fruit, commonly known as blackthorn, is a rich source of bioactive compounds, including flavonoids, anthocyanins, phenolic acids, vitamins, minerals, and organic acids, which exhibit significant antioxidant and antibacterial properties. Notably, flavonoids such as catechin, epicatechin, and rutin have been reported to have protective effects against diabetes, while other flavonoids, including myricetin, quercetin, and kaempferol, exhibit antihypertensive activity. Solvent extraction methods are widely used for the extraction of phenolic compounds from plant sources, owing to their simplicity, efficacy, and broad applicability. Furthermore, modern extraction techniques, such as microwave-assisted extraction (MAE) and ultrasound-assisted extraction (UAE), have been employed to extract polyphenols from Prunus spinosa L. fruits. This review aims to provide a comprehensive analysis of the biologically active compounds found in blackthorn fruits, emphasizing their direct physiological effects on the human body. Additionally, the manuscript highlights the potential applications of blackthorn fruits in various industries, including the food, cosmetics, pharmaceutical, and functional product sectors.

Doxorubicin-induced acute cardiotoxicity is associated with increased oxidative stress, autophagy, and inflammation in a murine model.

Drug-induced cardiotoxicity is a life-threatening side effect of doxorubicin (DOX) treatment that impacts patient prognosis and survival. In the majority of cases, the acute clinical form often remains asymptomatic, with few patients presenting rather nonspecific electrocardiographic abnormalities. While chronic toxicity has been more widely studied, the alterations appearing in acute cardiotoxicity are much less investigated. Thus, our in vivo study aimed to evaluate the process of DOX-induced acute myocardial toxicity by investigating oxidative stress and autophagy markers as mechanisms of myocardial toxicity in correlation with echocardiography and electrocardiography findings. Our results show that both autophagy and oxidative homeostasis were disrupted as soon as 7 days after DOX treatment, alterations that occurred even before the significant increase of NT-proBNP, a clinical marker for cardiac suffering. Moreover, we found a large number of alterations in the electrocardiography and echocardiography of treated rats. These findings suggest that DOX-induced myocardial toxicity started early after treatment initiation, possibly marking the initial phase of the unfolding process of cardiac damage. Further studies are required to completely decipher the mechanisms of DOX-induced cardiotoxicity.

Integrated Technology for Cereal Bran Valorization: Perspectives for a Sustainable Industrial Approach.

Current research focuses on improving the bioaccessibility of functional components bound to cereal bran cell walls. The main bioactive components in cereal bran that have major biological activities include phenolic acids, biopeptides, dietary fiber, and novel carbohydrates. Because of the bound form in which these bioactive compounds exist in the bran matrix, their bioaccessibility is limited. This paper aims to comprehensively analyze the functionality of an integrated technology comprising pretreatment techniques applied to bran substrate followed by fermentation bioprocesses to improve the bioaccessibility and bioavailability of the functional components. The integrated technology of specific physical, chemical, and biological pretreatments coupled with fermentation strategies applied to cereal bran previously-pretreated substrate provide a theoretical basis for the high-value utilization of cereal bran and the development of related functional foods and drugs.

Protective Effects of Wine Polyphenols on Oxidative Stress and Hepatotoxicity Induced by Acrylamide in Rats.

In recent years, it has been increasingly suggested that the consumption of natural polyphenols, in moderate amounts, is beneficial for health. The aim of this study was to investigate the efficacy of a red wine (the administered dose of 7 mL/kg/day being equivalent to ~16.5 mg/kg/day total polyphenols) compared to a white wine (the administered dose of 7 mL/kg/day being equivalent to ~1.7 mg/kg/day total polyphenols), on the prevention of acrylamide-induced subacute hepatic injury and oxidative stress in Wistar rats. Hepatic damage due to acrylamide intoxication (the administered dose being 250 µg/kg body weight, for 28 days, by intragastric gavage) was assessed by employing biochemical parameters (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) and by histopathological studies. Markers of oxidative damage were measured in terms of plasma malondialdehyde (MDA), hepatic Thiobarbituric Acid Reactive Substances (TBARS) and glutathione (GSH) levels, and liver antioxidant enzyme (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)) activities. Regarding hepatic enzyme activities, treatment with red wine significantly decreased the AST values (p < 0.05), while for the ALT values only a normalization tendency was observed. Treatment with red wine and white wine, respectively, significantly prevented the increase in MDA and TBARS levels (p < 0.05), as well as the depletion of GSH (p < 0.05). Red wine treatment normalized the activities of the antioxidant enzymes CAT and SOD in rats intoxicated with acrylamide, while supplementing the diet with white wine did not produce significant differences in the antioxidant enzyme activities. Histopathological findings revealed a moderate protective effect of red wine after four weeks of daily consumption. Our findings provide evidence that red wine, having a higher phenolic content than white wine, has a significant protective effect on oxidative stress and liver injury induced by acrylamide in rats, through its antioxidative activity.

Anthocyanins from Agro-Industrial Food Waste: Geographical Approach and Methods of Recovery-A Review.

Drastic growth in the amount of global food waste produced is observed every year, not only due to incessant population growth but also economic growth, lifestyle, and diet changes. As a result of their increasing health awareness, people are focusing more on healthy diets rich in fruits and vegetables. Thus, following worldwide fruit and vegetable consumption and their processing in various industries (juice, jams, wines, preserves), significant quantities of agro-industrial waste are produced (pomace, peels, seeds) that still contain high concentrations of bioactive compounds. Among bioactive compounds, anthocyanins have an important place, with their multiple beneficial effects on health; therefore, their extraction and recovery from food waste have become a topic of interest in recent years. Accordingly, this review aims to summarize the primary sources of anthocyanins from food waste and the novel eco-friendly extraction methods, such as pulsed electric field extraction, enzyme-assisted extraction, supercritical fluid extraction, pressurized liquid extraction, microwave-assisted extraction, and ultrasonic-assisted extraction. The advantages and disadvantages of these techniques will also be covered to encourage future studies and opportunities focusing on improving these extraction techniques.

Physico-Chemical, Nutritional, and Sensory Evaluation of Two New Commercial Tomato Hybrids and Their Parental Lines.

Tomato (Solanum lycopersicum) is the globally most consumed vegetable. The objective of this research was to analyze physico-chemical, nutritional and sensorial components (taste and flavor) in two new commercial hybrids (AS 300 F1 and AS 400 F1) and their four F7 parental lines. Two widely grown F1 hybrids (Precos F1 and Addalyn F1) were used as controls. The results obtained for carbohydrates (HPLC-RID) indicated that the highest values (27.82 mg/g) were recorded in the paternal line AS 10 of the new hybrid AS 400 F1. The highest values of total organic acids (HPLC-VWD) were recorded in Addalyn F1 (5.06 m/g), while the highest value of phenolic compounds (HPLC-DAD-ESI⁺) were identified in the maternal line AS 09 of the hybrid AS 400 F1 (96.3 µg/g). Intrinsic sensory values were analyzed by male and female tasters of different ages using a hedonic scale. The tasters' perception revealed obvious taste differences between tomato genotypes. The study allowed determining genetic parameters of interest (heterosis and heterobeltosis) for the new hybrids, as well as a detailed characterization of the chemical composition and organoleptic quality of the parental breeding lines and their hybrids, which is useful in tomato breeding.

Reintegration of Brewers Spent Grains in the Food Chain: Nutritional, Functional and Sensorial Aspects.

Nowadays, the pandemic situation has encouraged the idea of sustainable healthy foods leading to new trends in food consumption. Brewers spent grain (BSG) represents a potential functional food rich in fiber, protein, lipids, mineral and phenols that needs to be further exploited. In this vein, five different BSG types were collected from local breweries and valorized in cookies manufacturing. Thus, proximate composition (protein, minerals, lipids, ash, crude fiber and carbohydrates) was analyzed using AACC (American Association of Cereal Chemists) methods, DPPH (2,2-Diphenyl-1-picrylhydrazyl), and Folin Ciocalteu methods were used to determined antioxidant activity and total phenols, while minerals and aroma volatile compounds were performed using inductively coupled plasma optical emission spectrometry (ICP-OES) and ITEX/GC-MS (in tube extraction gas chromatography-mass spectrometry) respectively. Color and physical characteristics, together with sensorial analysis, were also evaluated. The results highlighted a significant difference between BSG samples, mainly from the total phenols, antioxidant activity and aroma volatile compounds point of view. BSG volatiles compounds from the aldehydes group such as 2-methyl-propanal, 3-methyl-butanal and 2-methyl-butanal were identified also in the final baked goods, leading to a pleasant and appreciated consumers' taste and aroma. Furthermore, cookies sensorial analysis emphasized that the sample manufactured with BSG from light and dark malt mixture was more appreciated by consumers, attaining the highest hedonic scores.

Case Report: Acute Splenic Artery Thrombosis in a COVID 19, Postpartum Patient.

The incidence of thromboembolic disease is reported to be high in SARS-CoV2 disease. Pregnancy, an already physiologically hypercoagulable state, associated to COVID 19, generates even more concern regarding the potentially increased risk of thrombotic events. The exact incidence of such complications is yet unknown, but there is data suggesting that coagulopathy and thromboembolism are both increased in pregnancies affected by COVID-19. Since the outbreak of the COVID 19 pandemics, the most common described thrombotic events associated with SARS-COV2 infection have been venous thromboembolism and disseminated intravascular coagulation, while arterial thrombotic events are less commonly described. Splenic infarction is a rare disorder that can be secondary to a hypercoagulable state. There are only few cases of splenic infraction described, but none with splenic artery thrombosis, in a post-partum patient, on therapeutic anticoagulation regimen. We present the case of a 31-year-old Caucasian, 26 weeks pregnant woman, with no prior medical history, admitted to the hospital with a severe form of COVID 19 pneumonia and who, during the course of the disease, developed a massive splenic infarction with splenic artery thrombosis.

Modern markers for evaluating bone disease in multiple myeloma (Review).

Multiple myeloma (MM) is a bone marrow neoplasia with increasing incidence compared to previous years. Although new therapeutic molecules have been introduced, it remains an incurable disease with severe repercussions to patients. For many patients, bone disease represents a severe problem often causing pain, pathological bone fractures, and spinal cord compression, which affects the quality of life. This article analyzes the main markers of bone destruction in MM as well as risk factors for severe bone damage. Bone complications have a negative impact on the quality of life of patients with MM, along with other associated complications (renal failure, hypogammaglobulinemia, osteolytic bone disease, hypercalcemia, anemia). The markers of bone destruction described in this article include: interleukin (IL)-6, tumor necrosis factor (TNF)-α, receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin (OPG), amino- and carboxy-terminal cross-linking telopeptide of type I collagen (NTX, CTX), human bone sialoprotein (BSP) and dickkopf-1 secreted glycoprotein (DKK1). The future practical applicability of this literature review would be the large-scale determination of markers of bone destruction that correlate with the negative evolution to complications of bone disease or the implications that these markers have in regards to treatment.

Novel Delivery Systems of Polyphenols and Their Potential Health Benefits.

Liposome-based delivery systems have been studied and used more frequently in recent years due to their advantages, such as low toxicity, specificity, and the ability to protect the encapsulated substance from environmental factors, which could otherwise degrade the active compound and reduce its effectiveness. Given these benefits, many researchers have encapsulated polyphenols in liposomes, thus increasing their bioavailability and stability. Similarly, polyphenols encapsulated in liposomes are known to produce more substantial effects on targeted cells than unencapsulated polyphenols, while having minimal cytotoxicity in healthy cells. Although polyphenols play a role in preventing many types of disease and generally have beneficial effects on health, we solely focused on their chemopreventive effects on cancer through liposomes in this review. Our goal was to summarize the applicability and efficacy of liposomes encapsulated with different classes of polyphenols on several types of cancer, thus opening the opportunity for future studies based on these drug delivery systems.

Arguments for Using Direct Oral Anticoagulants in Cancer-Related Venous Thromboembolism.

(1) Background: Patients with cancer with a hypercoagulable state present an increased incidence of venous thromboembolism (VTE). Neoplastic patients with concurrent VTE undergoing anticoagulant treatment face a series of issues. (2) The aim of the present paper is to systematically summarize current VTE management in patients with neoplasia and to review the current clinical evidence from meta-analyses of randomized controlled trials and guidelines regarding the administration of direct oral anticoagulants (DOACs) for cancer-associated VTE. (3) Search Strategy: We performed a review on meta-analyses of randomized controlled trials and guidelines in favor of the administration of DOACs in patients with cancer-associated VTE published in the last 6 years in the Medline (PubMed) and Embase databases. (4) Results: 21 meta-analyses, 14 randomized controlled studies comparing DOACs to VKAs and LMWH, and 7 national and international guidelines were identified. We identified five studies that show the antineoplastic effect of DOAC on experimental models. (5) Conclusions: DOACs can be seen as the first choice for VTE treatment in neoplastic patients who have a low risk of bleeding, who do not have severe renal impairment, and who are not undergoing treatments that could interact with DOAC's mechanism of action.

Immune Checkpoint Inhibitors and the Heart.

Immune checkpoint inhibitors (ICIs) represent a break-through treatment for a large number of cancer types. This treatment is increasingly being recommended. ICIs are prescribed for primary tumours and for metastases, adjuvant/neo-adjuvant therapy. Thus, there is an increased need for expertise in the field, including the ways of response and toxicities related to them. ICIs become toxic because of the removal of self-tolerance, which in turn induces autoimmune processes that affect every organ. However, when relating to the heart, it has been noticed to be leading to acute heart failure and even death caused by various mechanisms, such as: myocarditis, pericarditis, arrhythmia, and Takotsubo cardiomyopathy. This review aims to address the above issues by focusing on the latest findings on the topic, by adding some insights on the mechanism of action of ICIs with a special focus on the myocardial tissue, by providing information on clinical manifestations, diagnosis and (wherever possible) treatment of the cardiotoxic events related to this therapy. The information is expanding and in many cases, the articles we found refer mainly to case-presentations and studies conducted on small populations. However, we consider that it is worthwhile to raise awareness of this new treatment, especially since it is widely now and it provides a significant increase in the survival rate in patients who receive it.

Macrophage activation syndrome: A diagnostic challenge (Review).

Macrophage activation syndrome (MAS) represents an acute and severe inflammatory syndrome, idiopathic (primary) or secondary to infections, rheumatic diseases, malignancies, or drugs. MAS is underdiagnosed, being confused with sepsis, adverse effects of anti-arthritic drugs or exacerbated symptoms of evolving rheumatologic or infectious diseases. Because of the late diagnosis, most patients do not benefit from effective therapy, leading to death. Elucidation of valid early diagnostic criteria of MAS would be a particularly important step in reducing the mortality due to this pathology. Thus, the purpose of this review based on 40 studies centered on the diagnostic criteria of MAS. We detailed the main diagnostic criteria and the few diagnostic scores or sets of criteria that have been recently published. The criteria most frequently encountered in the literature include: Fever, hepatosplenomegaly, hyperferritinemia, hepatopathy, coagulopathy, thrombocytopenia, hypertriglyceridemia, decrease in erythrocyte sedimentation rate and bone marrow hemophagocytosis. The most elaborate diagnostic score will result following an ongoing international project and consensus, the Delphi International Survey.

ACE2 and Apelin-13: Biomarkers with a Prognostic Value in Congestive Heart Failure.

The progression of heart failure is the result of the interaction of several pathogenetic processes that involve the activation of biomarkers belonging to the renin angiotensin aldosterone system (RAAS), to its counterregulatory mechanisms, to the sympathetic nervous system and inflammation, and to oxidative stress. This study is aimed at determining the prognostic role of biomarkers in the evolution of patients with heart failure. These biomarkers are representative of different pathogenetic pathways involved in the progression of heart failure and the possible interrelationships between them and heart remodelling. Method. This is a progressive observational study on 53 hospitalized patients with low ejection fraction heart failure, who were followed up for 12 months. The aetiology of heart failure was ischemic heart disease and dilated cardiomyopathy. The patients were clinically and biochemically evaluated by EKG (echocardiography) on admission and at 6 and 12 months. The biomarkers included in the present study were angiotensin-converting enzyme type 2 (ACE2), apelin-13, NT-proBNP (biomarkers involved in the counterregulation of RAAS), interleukin 17 (IL-17), hsCRP (inflammatory biomarkers), and urinary 8-iso-PGF2α (oxidative stress biomarker). The evolution was considered unfavourable if the patients presented complications during hospitalization, were readmitted for decompensated heart failure, or died. Results. From the study group, 14 patients (24.52%) presented an unfavourable clinical evolution. The biomarkers that were associated with the evolution of patients during hospitalization were ACE2, apelin-13, NT-proBNP, and hsCRP. Multivariate logistic regression analysis identified ACE2 and apelin-13 as independent, predictive biomarkers for the unfavourable evolution of patients over the study period. Values of ACE2 above 4000.75 pg/mL and of apelin-13 less than 402.5 pg/mL were associated with an unfavourable evolution (poor clinical outcomes). Conclusion. The serum values of ACE2 and apelin-13 correlate with the unfavourable evolution of patients with reduced ejection fraction heart failure.

Partnering bevacizumab with irinotecan as first line-therapy of metastatic colorectal cancer improves progression free survival-A retrospective analysis.

Colorectal cancer remains one of the most frequent malignancies (third place at both genders) worldwide in the last decade, owing to significant changes in modern dietary habits. Approximately half of the patients develop metastases during the course of their disease. The available therapeutic armamentarium is constantly evolving, raising questions regarding the best approach for improving survival. Bevacizumab remains one of the most widely used therapies for treating metastatic colorectal cancer and can be used after progression. This study aimed to identify the best chemotherapy partner for bevacizumab after progression. We performed a retrospective analysis of patients with metastatic colorectal cancer who were treated with bevacizumab as first- and second-line chemotherapy. Data were collected for 151 patients, 40 of whom were treated with double-dose bevacizumab after the first progression. The two standard chemotherapy regimens combined with bevacizumab were FOLFIRI/CAPIRI and FOLFOX4/CAPEOX. The initiation of first-line treatment with irinotecan-based chemotherapy improved progression-free survival and time to treatment failure but not overall survival. After the first progression, retreatment with the same regimen as that used in the induction phase was the best approach for improving overall survival (median overall survival: 46.5 vs. 27.0 months for the same vs. switched strategy, respectively). No correlations were observed between the dose intensity of irinotecan, oxaliplatin, 5-fluorouracil, or bevacizumab and the overall survival, progression-free survival in the first-/second-line treatment, and time to treatment failure. Interaction between an irinotecan-based regimen as a second-line treatment and double-dose bevacizumab after progression was associated with an improved overall survival (p = 0.06). Initiating systemic treatment with an irinotecan-based regimen in combination with bevacizumab improved the progression-free survival in the first-line treatment and time to treatment failure. In terms of overall survival, bevacizumab treatment after the first progression is better partnered with the same regimen as that used in the induction phase.

Validation of Normal P-Wave Parameters in a Large Unselected Pediatric Population of North-Western Romania: Results of the CARDIOPED Project.

AIMS: Reference values of the P-wave on 12 lead electrocardiograms are lacking for children and adolescents in Eastern Europe. Hence, the present study is aimed at determining the standard values of the P-wave in children and adolescents based on ECG data from the CARDIOPED project, a large-scale general population of children who participated in a screening program in Transylvania, Romania. METHODS AND RESULTS: A total of 22,411 ECGs of participants aged 6 to 18 years old from a school-based ECG screening were obtained between February 2015 and December 2015 in Transylvania, Romania. Three pediatric cardiologists manually reviewed each ECG. P-wave duration, voltage, axis, and correlation with gender and age were analyzed. The mean P-wave duration was 88 ± 10.7 ms, with a maximum duration of 128 ms. P-wave showed a positive correlation with age but did not differ between sexes. There was a positive correlation between the P-wave duration and the heart rate, but not with the body max index. The mean P-wave axis was 40.4 ± 31.1, and the mean P-wave amplitude was 0.12 ± 0.03 mV. CONCLUSION: In this study on many pediatric subjects, we have provided normal limits for the P-wave in Romanian children aged 6-18 years. Our findings are useful for creating interpretation guidelines for pediatric ECG.

TET2 is a component of the estrogen receptor complex and controls 5mC to 5hmC conversion at estrogen receptor cis-regulatory regions.

Estrogen receptor-α (ER) drives tumor development in ER-positive (ER+) breast cancer. The transcription factor GATA3 has been closely linked to ER function, but its precise role in this setting remains unclear. Quantitative proteomics was used to assess changes to the ER complex in response to GATA3 depletion. Unexpectedly, few proteins were lost from the ER complex in the absence of GATA3, with the only major change being depletion of the dioxygenase TET2. TET2 binding constituted a near-total subset of ER binding in multiple breast cancer models, with loss of TET2 associated with reduced activation of proliferative pathways. TET2 knockdown did not appear to change global methylated cytosine (5mC) levels; however, oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) was significantly reduced, and these events occurred at ER enhancers. These findings implicate TET2 in the maintenance of 5hmC at ER sites, providing a potential mechanism for TET2-mediated regulation of ER target genes.

Changes in Physicochemical and Microbiological Properties, Fatty Acid and Volatile Compound Profiles of Apuseni Cheese during Ripening.

The evolution during ripening on the quality of Apuseni cheese was studied in this research. The cheese samples were controlled and evaluated periodically (at 4 months) during 16 months of storage (at 2-8 °C) for physicochemical parameters (pH, moisture, fat, fat in dry matter, total protein, ash, NaCl), microbiological (total combined yeasts and molds count (TYMC), total viable count (TVC), Escherichia coli, Staphylococcusaureus, Salmonella, lactic acid bacteria (LAB)), fatty acids (FA) and volatile compounds. For better control of the quality of the cheese, the storage space was evaluated for TYMC and TVC. The ripening period showed improved effects on the quality of the cheese, showing lower values for moisture and pH and an increase in macronutrients. Both the cheese samples and the storage space were kept within the allowed microbiological limits. Lipids are predominant, the predominant FAs being saturated fatty acids (SFAs), which decrease, while monounsaturated fatty acids (MUFAs) increase. During ripening, the microbiological and chemical changes result in the development of flavor. Major volatile compounds such as 2-heptanone show accumulations, while acetophenone, limonene, or thymol show a decrease. In conclusion, Apuseni ripening cheese clearly involves a complex series of transformations, leading to a ripening cheese with improved nutritional and aromatic characteristics.