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Relaxin (RLX) is known to induce remodeling of benign stromal tissues through upregulation of matrix metalloproteases (MMPs). Recently, we could show that RLX also induces MMPs in breast cancer cells and enhances in vitro invasiveness. To investigate its potential role for progression of breast cancer in vivo, RLX serum concentrations were determined in 160 breast cancer patients during post-surgical follow-up. RLX concentrations in cancer patients were significantly higher than in a control population of healthy blood donors and patients with various other diseases (0.47 versus 0.29 ng/ml, p < 0.0001). There was a significant difference between patients with metastases (0.62 ng/ml) and those without (0.38ng/ml, p < 0.0001). Overall survival was shorter in RLX-positive ( > 0.4ng/ml) than in RLX-negative patients (p = 0.016). Cox regression analysis showed that RLX was not an independent variable, in contrast to metastatic disease and primary lymph node involvement. Taken together, the detection of elevated RLX concentrations especially in patients with metastases supports the assumption that there is a role for RLX in tissue remodeling during breast cancer progression. [ABSTRACT FROM AUTHOR]

Introduction: Electroconvulsive therapy (ECT) remains a critical intervention for treatment-resistant depression (MDD), yet its neurobiological underpinnings are not fully understood. This pilot study aims to investigate changes in loudness dependence of auditory evoked potentials (LDAEP), a proposed biomarker of serotonergic activity, in patients undergoing ECT. Methods: High-resolution magnetoencephalography (MEG) was utilized to measure LDAEP in nine depressed patients receiving right unilateral ECT. We hypothesized that ECT would reduce the LDAEP slope, reflecting enhanced serotonergic neurotransmission. Depression severity and cognitive performance were assessed using the 24-item Hamilton Depression Rating Scale (HDRS24) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), respectively. Results: Contrary to our hypothesis, findings indicated a significant increase in LDAEP post-ECT (t8 = 3.17, p = .013). The increase in LDAEP was not associated with changes in depression severity or cognitive performance. Discussion: The observed increase in LDAEP suggests a more complex interaction between ECT and neurobiological systems, rather than a direct reflection of serotonergic neurotransmission. Potential mechanisms for this increase include ECT’s impact on serotonergic, dopaminergic, glutamatergic, and GABAergic receptor activity, neuroplasticity involving brain-derived neurotrophic factor (BDNF), and inflammatory modulators such as TNF-α. Our results highlight the multifaceted effects of ECT on brain function, necessitating further research to elucidate these interactions. [ABSTRACT FROM AUTHOR]

We demonstrate femtosecond ultra-stable green laser generation by an ytterbium-doped polarization-maintaining fiber laser with a 2.4 mm long lithium triborate (LBO) crystal. We generated 5.6 W of femtosecond green light at 520 nm for a fundamental power of 12 W, which corresponds to a conversion efficiency of 46.7%. The fiber chirped-pulse amplifier, which has an environmentally immune front end, delivered 170 fs pulses at a 75 MHz repetition rate centered at 1040 nm. According to the dispersion of the optical material in a double-frequency setup, the introduced dispersion had a negligible effect for the green laser, and the pulse duration of the generated green laser was calculated to be 171 fs, resulting in an excellent power stability, with fluctuation as low as 0.16% of the generated green light. This system could be of great interest in ultrafast optical and photobiology research. [ABSTRACT FROM AUTHOR]

EFSA was requested by the European Commission (in accordance with Article 29 of Regulation (EC) No 178/2002) to provide a scientific opinion on the application of new developments in biotechnology (new genomic techniques, NGTs) to viable microorganisms and products of category 4 to be released into the environment or placed on the market as or in food and feed, and to non‐viable products of category 3 to be placed on the market as or in food and feed. A horizon scanning exercise identified a variety of products containing microorganisms obtained with NGTs (NGT‐Ms), falling within the remit of EFSA, that are expected to be placed on the (EU) market in the next 10 years. No novel potential hazards/risks from NGT‐Ms were identified as compared to those obtained by established genomic techniques (EGTs), or by conventional mutagenesis. Due to the higher efficiency, specificity and predictability of NGTs, the hazards related to the changes in the genome are likely to be less frequent in NGT‐Ms than those modified by EGTs and conventional mutagenesis. It is concluded that EFSA guidances are 'partially applicable', therefore on a case‐by‐case basis for specific NGT‐Ms, fewer requirements may be needed. Some of the EFSA guidances are 'not sufficient' and updates are recommended. Because possible hazards relate to genotypic and phenotypic changes introduced and not to the method used for the modification, it is recommended that any new guidance should take a consistent risk assessment approach for strains/products derived from or produced with microorganisms obtained with conventional mutagenesis, EGTs or NGTs. [ABSTRACT FROM AUTHOR]

Using constrained factor mixture models (FMM) for careless response identification is still in its infancy. Existing models have overly restrictive statistical assumptions that do not identify all types of careless respondents. The current paper presents a novel constrained FMM model with more reasonable assumptions that capture both longstring and random careless respondents. We provide a comprehensive comparison of the statistical assumptions between the proposed model and two previous constrained models. The proposed model was evaluated using both real data (N = 1,455) and statistical simulation. The results showed that the model had a superior fit, stronger convergent validity with other indicators of careless responding, more accurate parameter recovery and more accurate identification of careless respondents when compared to its predecessors. The proposed model does not require additional data collection effort, and thus researchers can routinely use it to control careless responses. We provide user-friendly syntax with detailed explanations online to facilitate its use. [ABSTRACT FROM AUTHOR]

Background/Aim: Aggressive breast cancer (BC) cells show high expression of Rho GTPase activating protein 29 (ARHGAP29), a negative regulator of RhoA. In breast cancer cells in which mesenchymal transformation was induced, ARHGAP29 was the only one of 32 GTPaseactivating enzymes whose expression increased significantly. Therefore, we investigated whether there is a correlation between expression of ARHGAP29 and tumor progression in BC. Since tamoxifen-resistant BC cells exhibit increased mesenchymal properties and invasiveness, we additionally investigated the relationship between ARHGAP29 and increased invasion rate in tamoxifen resistance. The question arises as to whether ARHGAP29 is a suitable prognostic marker for the progression of BC. Materials and Methods: Tissue microarrays were used to investigate expression of ARHGAP29 in BC and adjacent normal breast tissues. Knockdown experiments using siRNA were performed to investigate the influence of ARHGAP29 and the possible downstream actors RhoC and pAKT1 on invasive growth of tamoxifen-resistant BC spheroids in vitro. Results: Expression of ARHGAP29 was frequently increased in BC tissues compared to adjacent normal breast tissues. In addition, there was evidence of a correlation between high ARHGAP29 expression and advanced clinical tumor stage. Tamoxifenresistant BC cells show a significantly higher expression of ARHGAP29 compared to their parental wild-type cells. After knockdown of ARHGAP29 in tamoxifen-resistant BC cells, expression of RhoC was significantly reduced. Further, expression of pAKT1 decreased significantly. Invasive growth of three-dimensional tamoxifen-resistant BC spheroids was reduced after knockdown of ARHGAP29. This could be partially reversed by AKT1 activator SC79. Conclusion: Expression of ARHGAP29 correlates with the clinical tumor parameters of BC patients. In addition, ARHGAP29 is involved in increased invasiveness of tamoxifen-resistant BC cells. ARHGAP29 alone or in combination with its downstream partners RhoC and pAKT1 could be suitable prognostic markers for BC progression. [ABSTRACT FROM AUTHOR]

This article analyses the optimal punishment structure set by a regulator in banking markets under asymmetric information. Relying on a theoretical model, we analyse whether a decreasing, constant, or increasing sanction scheme deters potentially repeated offences in banking. We find that an increasing punishment structure is efficient in reducing gambling bank behaviour. This holds if and only if the regulator's detection probability is low or the amount gambled by the bank, if it would cheat, is high. With this paper, we provide justification for the current policy practice. [ABSTRACT FROM AUTHOR]

The aetiology of acute appendicitis (AA), the most frequent abdominal surgical emergency, is still unclarified. Recent epidemiologic, clinical and laboratorial data point to an allergic component in the pathophysiology of AA. Mastocytes participate in the Th2 immune response, releasing inflammatory mediators from their granules upon stimulation by IgE-specific antigens. Among the well-known mediators are histamine, serotonin and tryptase, which are responsible for the clinical manifestations of allergies. We conducted a prospective single-centre study to measure histamine and serotonin (commercial ELISA kit) and tryptase (ImmunoCAP System) concentrations in appendicular lavage fluid (ALF) and serum. Consecutive patients presenting to the emergency department with a clinical diagnosis of AA were enrolled: 22 patients with phlegmonous AA and 24 with gangrenous AA The control group was composed of 14 patients referred for colectomy for colon malignancy. Appendectomy was performed during colectomy. Tryptase levels were strikingly different between histological groups, both in ALF and serum (p < 0.001); ALF levels were higher than serum levels. Tryptase concentrations in ALF were 109 times higher in phlegmonous AA (APA) (796.8 (194.1–980.5) pg/mL) and 114 times higher in gangrenous AA (AGA) (837.4 (272.6–1075.1) pg/mL) than in the control group (7.3 (4.5–10.3) pg/mL. For the diagnosis of AA, the discriminative power of serum tryptase concentration was good (AUC = 0.825), but discriminative power was weak (AUC = 0.559) for the differential diagnosis between APA and AGA. Mastocytes are involved in AA during clinical presentations of both phlegmonous and gangrenous appendicitis, and no significant differences in concentration were found. No differences were found in serum and ALF concentrations of histamine and serotonin between histological groups. Due to their short half-lives, these might have elapsed by the time the samples were collected. In future research, these determinations should be made immediately after appendectomy. Our findings confirm the hypersensitivity type I reaction as an event occurring in the pathogenesis of AA: tryptase levels in ALF and serum were higher among patients with AA when compared to the control group, which is in line with a Th2 immune response and supports the concept of the presence of an allergic reaction in the pathogenesis of acute appendicitis. Our results, if confirmed, may have clinical implications for the treatment of AA. [ABSTRACT FROM AUTHOR]

Aims: We aimed to investigate whether peripheral T‐cell subsets could be a biomarker to distinguish major depressive disorder (MDD) and bipolar disorder (BD). Methods: Medical records of hospitalized patients in the Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, from January 2015 to September 2020 with a discharge diagnosis of MDD or BD were reviewed. Patients who underwent peripheral blood examination of T‐cell subtype proportions, including CD3+, CD4+, CD8+ T‐cell, and natural killer (NK) cells, were enrolled. The Chi‐square test, t‐test, or one‐way analysis of variance were used to analyze group differences. Demographic profiles and T‐cell data were used to construct a random forest classifier‐based diagnostic model. Results: Totally, 98 cases of BD mania, 459 cases of BD depression (BD‐D), and 458 cases of MDD were included. There were significant differences in the proportions of CD3+, CD4+, CD8+ T‐cell, and NK cells among the three groups. Compared with MDD, the BD‐D group showed higher CD8+ but lower CD4+ T‐cell and a significantly lower ratio of CD4+ and CD8+ proportions. The random forest model achieved an area under the curve of 0.77 (95% confidence interval: 0.71–0.83) to distinguish BD‐D from MDD patients. Conclusion: These findings imply that BD and MDD patients may harbor different T‐cell inflammatory patterns, which could be a potential diagnostic biomarker for mood disorders. [ABSTRACT FROM AUTHOR]

The EU's regulatory framework for genetically modified organisms (GMOs) was developed for "classical" transgenic GMOs, yet advancements in so-called "new genomic techniques (NGTs)" have led to implementation challenges regarding detection and identification. As traceability can complement detection and identification strategies, improvements to the existing traceability strategy for GMOs are investigated in this study. Our results are based on a comprehensive analysis of existing traceability systems for globally traded agricultural products, with a focus on soy. Alternative traceability strategies in other sectors were also analysed. One focus was on traceability strategies for products with characteristics for which there are no analytical verification methods. Examples include imports of "conflict minerals" into the EU. The so-called EU Conflict Minerals Regulation requires importers of certain raw materials to carry out due diligence in the supply chain. Due diligence regulations, such as the EU's Conflict Minerals Regulation, can legally oblige companies to take responsibility for certain risks in their supply chains. They can also require the importer to prove the regional origin of imported goods. The insights from those alternative traceability systems are transferred to products that might contain GMOs. When applied to the issue of GMOs, we propose reversing the burden of proof: All companies importing agricultural commodities must endeavour to identify risks of unauthorised GMOs (including NGTs) in their supply chain and, where appropriate, take measures to minimise the risk to raw material imports. The publication concludes that traceability is a means to an end and serves as a prerequisite for due diligence in order to minimise the risk of GMO contamination in supply chains. The exemplary transfer of due diligence to a company in the food industry illustrates the potential benefits of mandatory due diligence, particularly for stakeholders actively managing non-GMO supply chains. [ABSTRACT FROM AUTHOR]

Depression is a heterogeneous syndrome that impacts an individual's emotional, social, cognitive and bodily functioning. Depression is associated with biases in emotional processing, but alterations in basic sensory processing have received less attention in depression research. Here, we measured event-related potentials (ERPs) in response to changes in the intensity of auditory stimuli and the location of somatosensory stimuli in participants with depression and in non-depressed control participants. We tested whether auditory mismatch negativity, P3a or N1 intensity dependence response or somatosensory mismatch response, P3a, P50 or N80 can dissociate depressed participants and non-depressed controls, and we also analysed the effects of depression medication and age in this sample. N1 intensity dependence response was increased in unmedicated depressed participants relative to non-depressed controls. When age was controlled for in the analysis, the effect of depression was only at a trend level. N1 intensity dependence response correlated with depression severity at the whole sample level. We did not observe any depression-related alterations in auditory mismatch negativity or P3a or somatosensory ERPs. Our results may reflect an association between the N1 intensity dependence response and altered neurotransmitter activity in depression, but this should be confirmed in future studies., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Despite targeting different coagulation cascade sites, all Food and Drug Administration-approved anticoagulants present an elevated risk of bleeding, including potentially life-threatening intracranial hemorrhage. Existing studies have not thoroughly investigated the efficacy and safety of sulfonate polymers in animal models and fully elucidate the precise mechanisms by which these polymers act. The activity and safety of sulfonated di- and triblock copolymers containing poly(sodium styrenesulfonate) (PSSS), poly(sodium 2-acrylamido-2-methylpropanesulfonate) (PAMPS), poly(ethylene glycol) (PEG), poly(sodium methacrylate) (PMAAS), poly(acrylic acid) (PAA), and poly(sodium 11-acrylamidoundecanoate) (PAaU) blocks are synthesized and assessed. PSSS-based copolymers exhibit greater anticoagulant activity than PAMPS-based ones. Their activity is mainly affected by the total concentration of sulfonate groups and molecular weight. PEG-containing copolymers demonstrate a better safety profile than PAA-containing ones. The selected copolymer PEG 47 -PSSS 32 exhibits potent anticoagulant activity in rodents after subcutaneous and intravenous administration. Heparin Binding Copolymer (HBC) completely reverses the anticoagulant activity of polymer in rat and human plasma. No interaction with platelets is observed. Selected copolymer targets mainly factor XII and fibrinogen, and to a lesser extent factors X, IX, VIII, and II, suggesting potential application in blood-contacting biomaterials for anticoagulation purposes. Further studies are needed to explore its therapeutic applications fully., (© 2024 Wiley‐VCH GmbH.)

Eph receptor B2 (EPHB2) is overexpressed in some tumors and relevant to unfavorable outcomes of tumor patients. By searching Gene Expression Profiling Interactive Analysis and KM Plot websites, we discovered that EPHB2 was highly expressed in patients with esophageal cancer, leading to poor prognosis. However, the role and molecular mechanism of EPHB2 in esophagus cancer is unknown. Our study aims to unveil the underlying mechanism by which EPHB2 modulates the biological properties of esophagus cancer cells. After si-EPHB2 transfection, the malignant biological properties of esophagus cancer cells were determined by several biological experiments. IWP-4 was applied to block Wnt/β-catenin signaling pathway. The expressions of autophagy and Wnt/β-catenin signaling pathway relevant molecules were tested by western blot assay. An increased expression of EPHB2 was happened in esophagus cancer samples and loss of EPHB2 diminished esophagus cancer cells proliferation, migration, and invasion. Moreover, our data showed that depletion of EPHB2 blocked the autophagy and in-activated Wnt/β-catenin signaling pathway in esophagus cancer cells. While, IWP-4 treatment inhibited the autophagy and limited esophagus cancer cells proliferation, migration, and invasion. Moreover, EPHB2 knocked down strengthened the effect of IWP-4 treatment in regulating esophagus cancer cells proliferation, migration, and invasion. Finally, we illustrated that EPHB2 regulated the biological properties of esophagus cancer cells by modulating autophagy and Wnt/β-catenin signaling pathway. Our study illustrated that EPHB2 might be a worthwhile target considering for the treatment of esophagus cancer., (© 2024 Wiley Periodicals LLC.)

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Depression is one of the most common psychiatric disorders worldwide, affecting approximately 280 million people, with probably much higher unrecorded cases. Depression is associated with symptoms such as anhedonia, feelings of hopelessness, sleep disturbances, and even suicidal thoughts. Tragically, more than 700 000 people commit suicide each year. Although depression has been studied for many decades, the exact mechanisms that lead to depression are still unknown, and available treatments only help a fraction of patients. In the late 1960s, the serotonin hypothesis was published, suggesting that serotonin is the key player in depressive disorders. However, this hypothesis is being increasingly doubted as there is evidence for the influence of other neurotransmitters, such as noradrenaline, glutamate, and dopamine, as well as larger systemic causes such as altered activity in the limbic network or inflammatory processes. In this narrative review, we aim to contribute to the ongoing debate on the involvement of serotonin in depression. We will review the evolution of antidepressant treatments, systemic research on depression over the years, and future research applications that will help to bridge the gap between systemic research and neurotransmitter dynamics using biosensors. These new tools in combination with systemic applications, will in the future provide a deeper understanding of the serotonergic dynamics in depression., (© 2024 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Radiation resistance is a crucial factor influencing therapeutic outcomes in colorectal cancer (CRC). Baicalein (BE), primarily derived from Scutellaria baicalensis, has demonstrated anti-CRC properties. However, the impact of BE on the radiosensitivity of CRC remains unclear. This study aimed to evaluate the radiosensitization effects of BE and elucidate its mechanism in CRC radiotherapy. We established an in vitro radioresistant cell model (CT26-R) using parental CRC cells (CT26) subjected to ionizing radiation (IR). CT26-R cells were pretreated with or without BE, followed by transfection with pcDNA-NC and pcDNA-JAK2. The proliferation of CT26-R cells treated with BE and IR was assessed using a colony formation assay. A CRC animal model was developed in BALB/c mice via CT26-R cell transplantation. The radiosensitizing effect of BE on CRC was evaluated in vivo. TUNEL assay was conducted to detect apoptosis in tumor tissue. The expression levels of p-STAT3, JAK2, PD-L1, and SOCS3 in vitro and in vivo were measured by western blotting. Our results demonstrated that BE significantly increased radiosensitivity in vitro and in vivo and enhanced apoptosis in tumor tissues. Additionally, BE significantly downregulated the expression of p-STAT3, JAK2, and PD-L1, and significantly upregulated SOCS3 expression. These in vivo effects were reversed by pcDNA-JAK2. In summary, our data suggest that BE enhances CRC radiosensitivity by inhibiting the JAK2/STAT3 pathway., (© 2024 The Author(s). Chemical Biology & Drug Design published by John Wiley & Sons Ltd.)

Breast cancer is characterized by physical changes that occur in the tumor microenvironment throughout growth and metastasis of tumors. Extracellular matrix stiffness increases as tumors develop and spread, with stiffer environments thought to correlate with poorer disease prognosis. Changes in extracellular stiffness and other physical characteristics are sensed by integrins which integrate these extracellular cues to intracellular signaling, resulting in modulation of proliferation and invasion. However, the co-ordination of mechano-sensitive signaling with functional changes to groups of tumor cells within 3-dimensional environments remains poorly understood. Here we provide evidence that increasing the stiffness of collagen scaffolds results in increased activation of ERK1/2 and YAP in human breast cancer cell spheroids. We also show that ERK1/2 acts upstream of YAP activation in this context. We further demonstrate that YAP, matrix metalloproteinases and actomyosin contractility are required for collagen remodeling, proliferation and invasion in lower stiffness scaffolds. However, the increased activation of these proteins in higher stiffness 3-dimensional collagen gels is correlated with reduced proliferation and reduced invasion of cancer cell spheroids. Our data collectively provide evidence that higher stiffness 3-dimensional environments induce mechano-signaling but contrary to evidence from 2-dimensional studies, this is not sufficient to promote pro-tumorigenic effects in breast cancer cell spheroids. [ABSTRACT FROM AUTHOR]

The human rhinovirus (RV) is a positive-stranded RNA virus that causes respiratory tract diseases affecting both the upper and lower halves of the respiratory system. RV enhances its replication by concentrating RNA synthesis within a modified host membrane in an intracellular compartment. RV infections often occur alongside infections caused by other respiratory viruses, and the RV virus may remain asymptomatic for extended periods. Alongside qualitative detection, it is essential to accurately quantify RV RNA from clinical samples to explore the relationships between RV viral load, infections caused by the virus, and the resulting symptoms observed in patients. A reference material (RM) is required for quality evaluation, the performance evaluation of molecular diagnostic products, and evaluation of antiviral agents in the laboratory. The preparation process for the RM involves creating an RV RNA mixture by combining RV viral RNA with RNA storage solution and matrix. The resulting RV RNA mixture is scaled up to a volume of 25 mL, then dispensed at 100 µL per vial and stored at −80 °C. The process of measuring the stability and homogeneity of RV RMs was conducted by employing reverse transcription droplet digital polymerase chain reaction (RT-ddPCR). Digital PCR is useful for the analysis of standards and can help to improve measurement compatibility: it represents the equivalence of a series of outcomes for reference materials and samples being analyzed when a few measurement procedures are employed, enabling objective comparisons between quantitative findings obtained through various experiments. The number of copies value represents a measured result of approximately 1.6 × 105 copies/μL. The RM has about an 11% bottle-to-bottle homogeneity and shows stable results for 1 week at temperatures of 4 °C and −20 °C and for 12 months at a temperature of −80 °C. The developed RM can enhance the dependability of RV molecular tests by providing a precise reference value for the absolute copy number of a viral target gene. Additionally, it can serve as a reference for diverse studies. [ABSTRACT FROM AUTHOR]

Background/Aim: Hormone sensitivity-targeted therapy with selective estrogen receptor modulators (SERMs), such as 4-hydroxytamoxifen (4-OHT), is the mainstay of treatment for breast cancers (BCs) that express estrogen receptor α (ERα). However, development of resistance limits this therapy approach. The question arises whether changes associated with 4-OHT resistance could be exploited therapeutically. Materials and Methods: First, 4-OHT-resistant sublines of ERα-positive breast carcinoma cell lines MCF-7 and T47D were generated. Viability was assessed by the Alamar Blue assay. Cell invasion was quantified in modified Boyden chambers with Matrigel. Changes in expression of CYR61, S100A4, and ERα were examined by RT-qPCR. Expression of CYR61 was suppressed by transient gene silencing using siRNA. Successful suppression was verified by western blot. Efficacy of 4-OHT treatment was analyzed by quantification of viability using Alamar Blue assay. Correlation of CYR61 levels in patients with luminal A BC to distant metastases-free survival was determined by Kaplan-Meier analysis. Results: ERα-positive MCF-7 and T47D BC cells exhibit an extremely weak invasion rate. Acquired tamoxifen resistance significantly increased the invasive behavior of both tamoxifen-resistant MCF-7-TR and T47D-TR sublines. In addition, expression of CYR61 and S100A4 showed significantly increased levels, whereas expression of ERα was decreased. Suppression of CYR61 expression resulted in a significant decreased invasion rate. In addition, expression of S100A4 was reduced, whereas expression of ERα was increased. Furthermore, suppression of CYR61 resulted in resensitization to 4-OHT. High CYR61 levels in patients with luminal A BC resulted in reduced distant metastases-free survival. Conclusion: The prometastatic factor CYR61 appears to play an important role in the increased invasiveness of tamoxifen-resistant ERα-positive BC cells. Its suppression leads to a lower invasion rate. Given the few therapeutic options available for tamoxifen-resistant BC, therapy that reduces CYR61 may improve its treatability in future. [ABSTRACT FROM AUTHOR]

The number of donor atoms available on peptides that can competitively coordinate to metal centers renders the site-selective generation of advanced metal-peptide conjugates in high purity a challenging venture. Herein, we present a transmetalation-based synthetic approach on solid support in which an imidazolium pro-ligand can be used to selectively anchor a range of transition metal half-sandwich complexes onto peptides in the presence of multiple coordinative motifs. Amenable to solid support, a range of N-terminus and/or lysine conjugated metal-peptide conjugates were obtained in high purity after cleavage from the resin. The metalated peptides were evaluated for their anticancer properties against human cancer cell lines. While no cytotoxic activity was observed, this platform has the potential to i) provide a pathway to site-selective peptide labelling, ii) be explored as a biorthogonal handle and/or iii) generate a new strategy for ligand design in transition metal catalysts., (© 2021 Wiley-VCH GmbH.)

Purpose: Previous studies have shown that TBX21 (T-Box Transcription Factor 21) plays a vital role in coordinating multiple aspects of the immune response especially type 1 immune response as well as tumor progression. However, the function of TBX21 in colorectal cancer (CRC) remains unclear. Methods: IHC to investigate TBX21 expression in CRC tissues. Cell proliferation and apoptosis assays to validate TBX21 function in vitro and in vivo. RNA-seq assay to explore target genes of TBX21. Human phospho-kinase array assay to explore down-stream signaling of TBX21. Results: We disclosed that the expression of TBX21 was marked decreased in CRC versus normal tissue, and negatively correlated with CRC TNM stages. Surprisingly, we found that the CRC and normal cell lines show no TBX21 expression levels. Ectopic expression of TBX21 inhibited cell proliferation and promoted cell apoptosis in vitro. Moreover, RNA-sequence data first time showed that ARHGAP29 acts as the target gene of TBX21 to mediate down-stream signaling activation. Human phospho-kinase array data first time displayed that ectopic expression of TBX21 reduced kinase RSK and GSK3β activation. In contrast, knocked down the expression of TBX21 or ARHGAP29 alternatively abolished TBX21 mediated cell proliferation suppression, cell apoptosis enhancement and RSK/GSK3β activation. In addition, xenograft model studies demonstrated that TBX21 inhibits colorectal tumor progression via ARHGAP29/ RSK/ GSK3β signaling in vivo. Conclusions: In summary, the aforementioned findings suggest a model of TBX21 in suppressing CRC progression. This may provide a promising target for CRC therapy. [ABSTRACT FROM AUTHOR]

Careless responding is a pervasive issue that impacts the interpretation and use of responses from survey instruments. Researchers have proposed numerous useful methods for detecting carelessness in survey research, including relatively simple summary statistics such as the frequency of adjacent responses in the same category (e.g., "long-string" analysis) and outlier statistics (e.g., Mahalanobis distance). Researchers have also used methods based on item response theory (IRT) models to identify examinees whose response patterns are unexpected given item parameters. However, researchers have not fully considered the use of nonparametric IRT methods based on Mokken scale analysis (MSA) to detect carelessness in survey research. MSA is a promising framework in which to consider participant carelessness because it is well suited to contexts in which parametric IRT models may not be appropriate, while still maintaining a focus on fundamental measurement requirements. We used a real data analysis and a simulation study to examine the sensitivity of MSA indicators of response quality to examinee carelessness and compared the results to those from standalone indicators. We also examined the impact of carelessness on the sensitivity of MSA item quality indicators. Numeric and graphical indicators of response quality from MSA indicators were sensitive to examinee carelessness. Graphical displays of nonparametric person response functions (PRFs) provided supplementary insight that can alert researchers to potentially problematic responses. Our results also indicated that MSA indicators of item quality are robust to the presence of participant carelessness. We consider the implications of our findings for research and practice. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is regarded as one of the most common cancers diagnosed among the female population and has an extremely high mortality rate. It is known that Fibronectin 1 (FN1) drives the occurrence and development of a variety of cancers through metabolic reprogramming. Aspartic acid is considered to be an important substrate for nucleotide synthesis. However, the regulatory mechanism between FN1 and aspartate metabolism is currently unclear. Methods: We used RNA sequencing (RNA seq) and liquid chromatography-mass spectrometry to analyze the tumor tissues and paracancerous tissues of patients. MCF7 and MDA-MB-231 cells were used to explore the effects of FN1-regulated aspartic acid metabolism on cell survival, invasion, migration and tumor growth. We used PCR, Western blot, immunocytochemistry and immunofluorescence techniques to study it. Results: We found that FN1 was highly expressed in tumor tissues, especially in Lumina A and TNBC subtypes, and was associated with poor prognosis. In vivo and in vitro experiments showed that silencing FN1 inhibits the activation of the YAP1/Hippo pathway by enhancing YAP1 phosphorylation, down-regulates SLC1A3-mediated aspartate uptake and utilization by tumor cells, inhibits BC cell proliferation, invasion and migration, and promotes apoptosis. In addition, inhibition of FN1 combined with the YAP1 inhibitor or SLC1A3 inhibitor can effectively inhibit tumor growth, of which inhibition of FN1 combined with the YAP1 inhibitor is more effective. Conclusion: Targeting the "FN1/YAP1/SLC1A3/Aspartate metabolism" regulatory axis provides a new target for BC diagnosis and treatment. This study also revealed that intratumoral metabolic heterogeneity plays an important role in the progression of different subtypes of breast cancer. [ABSTRACT FROM AUTHOR]

A series of D-ring modified steroids bearing a vinyl ketone pendant were synthesized and evaluated for antiproliferative activity against breast cancer cell line and cytochromes P450. The lead compound, 21-vinyl 20-keto-pregnene (2f) (IC 50  = 2.4 µM), was shown to be a promising candidate for future anticancer drug design, particularly against estrogen receptor α (ERα)-positive breast cancer. The lead compound was found to have a significant effect on the signaling pathways in parental and 4-hydroxytamoxifen-resistant cells. Compound 2f modulated the ERK, cyclin D1, and CDK4 pathways and blocked the expression of ERα, the main driver of breast cancer growth. Compound 2f significantly reduced 17β-estradiol-induced progesterone receptor expression. Accumulation of cleaved poly(ADP-ribose) polymerase in cells treated with compound 2f indicated induction of apoptosis. The selectivity analysis showed that lead compound 2f produces no significant effects on cytochromes P450, CYP19A1, CYP21A2, and CYP7B1., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Background: Both anastomotic leak (AL) and conduit necrosis (CN) after oesophagectomy are associated with high morbidity and mortality. Therefore, the identification of preoperative, modifiable risk factors is desirable. The aim of this study was to generate a risk scoring model for AL and CN after oesophagectomy., Methods: Patients undergoing curative resection for oesophageal cancer were identified from the international Oesophagogastric Anastomosis Audit (OGAA) from April 2018-December 2018. Definitions for AL and CN were those set out by the Oesophageal Complications Consensus Group. Univariate and multivariate analyses were performed to identify risk factors for both AL and CN. A risk score was then produced for both AL and CN using the derivation set, then internally validated using the validation set., Results: This study included 2247 oesophagectomies across 137 hospitals in 41 countries. The AL rate was 14.2% and CN rate was 2.7%. Preoperative factors that were independent predictors of AL were cardiovascular comorbidity and chronic obstructive pulmonary disease. The risk scoring model showed insufficient predictive ability in internal validation (area under the receiver-operating-characteristic curve [AUROC] = 0.618). Preoperative factors that were independent predictors of CN were: body mass index, Eastern Cooperative Oncology Group performance status, previous myocardial infarction and smoking history. These were converted into a risk-scoring model and internally validated using the validation set with an AUROC of 0.775., Conclusion: Despite a large dataset, AL proves difficult to predict using preoperative factors. The risk-scoring model for CN provides an internally validated tool to estimate a patient's risk preoperatively., Competing Interests: Declaration of competing interest None to declare., (© 2024 Elsevier Ltd, BASO ∼ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Over the past decades, cancer has been a challenging domain for medicinal chemists as it is an international health concern. In association, small molecules such as 2-aminothiophenes and their derivatives showed significant antitumor activity through variable modes of action. Therefore, this article aims to review the advances regarding these core scaffolds over the past 10 years, where 2-aminothiophenes and their fused analogs are classified and discussed according to their biological activity and mode of action, in the interest of boosting new design pathways for medicinal chemists to develop targeted antitumor candidates., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Surgical resection of bone tumors is the primary approach employed in the treatment of bone cancer. Simultaneously, perioperative interventions, particularly postoperative adjuvant anticancer strategies, play a crucial role in achieving satisfactory therapeutic outcomes. However, the occurrence of postoperative bone tumor recurrence, metastasis, extensive bone defects, and infection are significant risks that can result in unfavorable prognoses or even treatment failure. In recent years, there has been significant progress in the development of biomaterials, leading to the emergence of new treatment options for bone tumor therapy and bone regeneration. This progress report aims to comprehensively analyze the strategic development of unique therapeutic biomaterials with inherent healing properties and bioactive capabilities for bone tissue regeneration. These composite biomaterials, classified into metallic, inorganic non-metallic, and organic types, are thoroughly investigated for their responses to external stimuli such as light or magnetic fields, internal interventions including chemotherapy or catalytic therapy, and combination therapy, as well as their role in bone regeneration. Additionally, an overview of self-healing materials for osteogenesis is provided and their potential applications in combating osteosarcoma and promoting bone formation are explored. Furthermore, the safety concerns of integrated materials and current limitations are addressed, while also discussing the challenges and future prospects., (© 2024 Wiley‐VCH GmbH.)

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The airway epithelial barrier dysfunction plays a crucial role in pathogenesis of asthma and causes the amplification of downstream inflammatory signal pathway. S100 calcium binding protein A4 (S100A4), which promotes metastasis, have recently been discovered as an effective inflammatory factor and elevated in bronchoalveolar lavage fluid in asthmatic mice. Vascular endothelial growth factor‐A (VEGFA), is considered as vital regulator in vascular physiological activities. Here, we explored the probably function of S100A4 and VEGFA in asthma model dealt with house dust mite (HDM) extracts. Our results showed that secreted S100A4 caused epithelial barrier dysfunction, airway inflammation and the release of T‐helper 2 cytokines through the activation of VEGFA/VEGFR2 signaling pathway, which could be partial reversed by S100A4 polyclonal antibody, niclosamide and S100A4 knockdown, representing a potential therapeutic target for airway epithelial barrier dysfunction in asthma. [ABSTRACT FROM AUTHOR]

The pro‐inflammatory cytokines IL‐1α, IL‐6 and TNF‐α are associated with major depressive disorder, psychological distress, cardiovascular health and obesity. However, there is limited research that has examined multiple associations between these variables, particularly among individuals with major depressive disorder who are treatment free, in comparison with a control cohort, and including analyses of sex differences. In this study, data were analysed from 60 individuals with major depressive disorder and 60 controls, including plasma IL‐1α, IL‐6 and TNF‐α, adiposity measures (body mass index, waist circumference), cardiovascular health indices (blood pressure, heart rate) and psychological symptoms (depressive severity, anxiety, hostility, stress). The cytokines were compared by group and sex and correlated with measures of adiposity, cardiovascular health indices and psychological health. Plasma IL‐1α and IL‐6 were higher in major depressive disorder group versus control, but with a sex interaction for IL‐6, with this group difference only among females. TNF‐α did not differ between groups. IL‐1α and IL‐6 correlated with depressive severity, anxiety, hostility and stress, whereas TNF‐α correlated only with anxiety and hostility. Psychopathology was associated with IL‐1α in males only and with IL‐6 and TNF‐α in females only. None of the cytokines correlated with body mass index, waist circumference, blood pressure or heart rate. The result of group by sex interaction for IL‐6 and sex‐specific associations between pro‐inflammatory cytokines and psychometrics could be aetiologically important in depression interventions and treatments for females versus males, warranting further investigation. [ABSTRACT FROM AUTHOR]

Background: BCR::ABL1 fusion has significant prognostic value and is screened for chronic myeloid leukemia (CML) disease monitoring as a part of routine molecular testing. To overcome the limitations of the current standard real-time quantitative polymerase chain reaction (RQ-PCR), we designed and validated a next-generation sequencing (NGS)-based assay to quantify BCR::ABL1 and ABL1 transcript copy numbers. Methods: After PCR amplification of the target sequence, deep sequencing was performed using an Illumina Nextseq 550Dx sequencer and in-house–designed bioinformatics pipeline. The Next-generation Quantitative sequencing (NQ-seq) assay was validated for its analytical performance, including precision, linearity, and limit of detection, using serially diluted control materials. A comparison with conventional RQ-PCR was performed with 145 clinical samples from 77 patients. Results: The limit of detection of the NQ-seq was the molecular response (MR) 5.6 [BCR::ABL1 0.00028% international scale (IS)]. The NQ-seq exhibited excellent precision and linear range from MR 2.0 to 5.0. The IS value from the NQ-seq was highly correlated with conventional RQ-PCR. Conclusions: We conclude that the NQ-seq is an effective tool for monitoring BCR::ABL1 transcripts in CML patients with high sensitivity and reliability. Prospective assessment of the unselected large series is required to validate the clinical impact of this NGS-based monitoring strategy. [ABSTRACT FROM AUTHOR]

Secretome analysis has gained popularity recently as a very well-designed proteomic approach that is being used to study various interactions and their effects on cellular activity. This analysis is especially helpful while studying the effects of the cells on their microenvironment, paracrine and autocrine processes, their therapeutic purposes, and as a new diagnostic perspective. Cancer is a condition rather than a specific type of disease and is still yet to be fully understood. Cancer secretome is a fairly new concept that is being implemented to examine the interactions taking place in the tumor microenvironment and can help to understand the phenomena like induction of tumorigenesis, stimulation of immune cells, etc. The secretome analysis helps to gain a different perspective on the existing knowledge on cancer and its effects. The recent advances in secretome studies are directed toward secreted components as drug targets, biomarkers, and companion tools for diagnostic and prognostic purposes in cancer. This review aims to find the interactors in different types of cancer and understand the existing unstructured secretome data and its application in prognosis, diagnosis, and in biomarker study. [ABSTRACT FROM AUTHOR]

BACKGROUND: Colon adenocarcinoma (COAD) is a globally prevalent cancer, with hormone secretion playing a crucial role in its progression. Despite this, there is limited understanding of the impact of hormone secretion on COAD prognosis. This study aimed to establish a prognostic signature based on hormone secretion-related genes and to elucidate the potential functional mechanisms of these genes in COAD. METHODS: Using data from The Cancer Genome Atlas COAD cohort (TCGA-COAD), six hormone secretion-related genes were identified (CYP19A1, FOXD1, GRP, INHBB, SPP1, and UCN). These genes were used to develop a Hormone secretion score (HSS), which was then evaluated using the Kaplan-Meier curve and multivariable Cox analysis. The HSS model was further validated with external GEO cohorts (GSE41258, GSE39582, and GSE87211). Functional enrichment analyses were performed, and the CIBERSORT and TIDE algorithms were used to assess tumor infiltration. RESULTS: The study developed a prognostic signature, dividing patients into HSS-high and HSS-low groups. The HSS-high group showed a notably worse prognosis within the TCGA-COAD dataset and in three independent datasets: GSE41258, GSE39582, and GSE87211. Moreover, the HSS-high group predicted a shorter overall survival rate in patients maintaining microsatellite stability (MSS). The functional analysis associated HSS-high with the hypoxic, epithelial-mesenchymal transition (EMT), and TGF- β signaling pathways and correlated with distant and lymph node metastases. The tumor immune microenvironment analysis revealed an elevated CIBERSORT score in the HSS-high group, suggesting an association with tumor metastasis. Further, the HSS-high group showed a higher TIDE score, indicating that patients with high HSS scores are less likely to benefit from Immune Checkpoint Inhibitor (ICI) therapy. CONCLUSIONS: This study demonstrated the prognostic significance of a HSS signature based on six hormone secretion-related genes in COAD. The findings suggest that this gene signature may serve as a reliable biomarker for predicting survival outcomes in COAD patients. [ABSTRACT FROM AUTHOR]

Emerging multifunctional nanoparticulate formulations take advantage of nano-meter scale size and surface chemistry to work as a therapeutic delivery agent and a diagnostic tool for non-invasive real-time monitoring using imaging technologies. Here, we evaluate the selective uptake of 18 nm and 80 nm sized gold nanoparticles (AuNPs) by SKOV3 (4 times higher) ovarian cancer (OC) cells (compared to OVCAR5) in vitro, quantified by inductively coupled plasma (ICP) and MARS spectral photon-counting CT imaging (MARS SPCCT). Based on in vitro analysis, pristine AuNPs (18 nm) and surface modified AuNPs (18 nm) were chosen as a contrast agent for MARS SPCCT. The chemical analysis by FTIR spectroscopy confirmed the luteinizing hormone-releasing hormone (LHRH) conjugation to the AuNPs surface. For the first time, LHRH conjugated AuNPs were used for in vitro and selective in vivo OC targeting. The ICP-MS analysis confirmed preferential uptake of LHRH modified AuNPs by organs residing in the abdominal cavity with OC nodules (pancreas: 0.46 ng mg−1, mesentery: 0.89 ng mg−1, ovary: 1.43 ng mg−1, and abdominal wall: 2.12 ng mg−1) whereas the MARS SPCCT analysis suggested scattered accumulation of metal around the abdominal cavity. Therefore, the study showed the exciting potential of LHRH conjugated AuNPs to target ovarian cancer and also as a potential contrast agent for novel SPCCT imaging technology. [ABSTRACT FROM AUTHOR]

Evidence shows that inflammatory responses may encompass the onset of severe depressive illness. Traditionally used licorice contains 18β-glycyrrhetinic acid (18βGA), which has been demonstrated to reduce inflammation and oxidative stress. This study investigates the antidepressant effects of 18βGA and the underlying mechanism in rats exposed to chronic unpredictable mild stress (CUMS). Wistar rats were exposed to CUMS for 36 consecutive days to establish depression. 18βGA (10, 20, and 50 mg/kg) or fluoxetine was given once daily (from day 30 to day 36). Thereafter, behavior parameters (sucrose preference test, forced-swimming test, open-field test, body weight), pro-inflammatory cytokines, neurotransmitters, adrenocorticotropic hormone (ACTH), corticosterone (CORT), and liver biomarkers were studied. Immunohistochemistry and western blot analyses were conducted to investigate the protein's expression. 18βGA (20 and 50 mg/kg) treatment increased sucrose intake, locomotion in the open-field test, decreased immobility time in the forced swim test, and improved body weight in CUMS-exposed rats. The therapy of 18βGA dramatically declined cytokines, ACTH and CORT and improved 5HT and norepinephrine in CUMS rats. Furthermore, BDNF and TrkB proteins were down-regulated in CUMS group, which was increased to varying degrees by 18βGA at doses of 20 and 50 mg/kg. Therefore, 18βGA ameliorates depressive-like behavior persuaded by chronic unpredictable mild stress, decreases neuroinflammation, liver biomarkers, stress hormones, and improves body weight, brain neurotransmitter concentration via activating on BDNF/TrkB signaling pathway in both PFC and hippocampus in rats. [ABSTRACT FROM AUTHOR]

Scope: Gastro-AD (GAD) is a soy flour derived product that undergoes an industrial fermentation with Lactobacillus delbrueckii R0187 and has demonstrated clinical effects in gastroesophageal reflux and peptic ulcer symptom resolution. The aim of this study is to describe and link GAD's metabolomic profile to plausible mechanisms that manifest and explain the documented clinical outcomes., Methods and Results: 1 H NMR spectroscopy with multivariate statistical analysis is used to characterize the prefermented soy flour and GAD products. The acquired spectra are screened using various resources and the molecular assignments are confirmed using total correlation spectroscopy (TOCSY). Peaks corresponding to different metabolites are integrated and compared between the two products for relative changes. HPLC and GC are used to quantify some specific molecules. NMR analyses demonstrate significant changes in the composition of various assigned bioactive moieties. HPLC and GC analysis demonstrate deglycation of isoflavones after fermentation, resulting in estrogenically active secondary metabolites that have been previously shown to help to reduce inflammation., Conclusion: The identification of bioactive molecules, such as genistein and SCFAs, capable of modulating anti-inflammatory signaling cascades in the stomach's gastric and neuroendocrine tissues can explain the reported biological effects in GAD and is supported by in vivo data., (© 2024 Lallemand Inc. Molecular Nutrition & Food Research published by Wiley‐VCH GmbH.)

It is common for some participants in self-report surveys to be careless, inattentive, or lacking in effort. Data quality can be severely compromised by responses that are not based on item content (non-content-based [nCB] responses), leading to strong biases in the results of data analysis and misinterpretation of individual scores. In this study, we propose a specification of factor mixture analysis (FMA) to detect nCB responses. We investigated the usefulness and effectiveness of the FMA model in detecting nCB responses using both simulated data (Study 1) and real data (Study 2). In the first study, FMA showed reasonably robust sensitivity (.60 to .86) and excellent specificity (.96 to .99) on mixed-worded scales, suggesting that FMA had superior properties as a screening tool under different sample conditions. However, FMA performance was poor on scales composed of only positive items because of the difficulty in distinguishing acquiescent patterns from valid responses representing high levels of the trait. In Study 2 (real data), FMA detected a minority of cases (6.5%) with highly anomalous response patterns. Removing these cases resulted in a large increase in the fit of the unidimensional model and a substantial reduction in spurious multidimensionality., (© 2023. The Author(s).)

Clinical management of endometrial cancer (EC) is handicapped by the limited availability of second line treatments and bona fide molecular biomarkers to predict recurrence. These limitations have hampered the treatment of these patients, whose survival rates have not improved over the last four decades. The advent of coordinated studies such as The Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA_UCEC) has partially solved this issue, but the lack of proper experimental systems still represents a bottleneck that precludes translational studies from successful clinical testing in EC patients. Within this context, the first study reporting the generation of a collection of endometrioid‐EC‐patient‐derived orthoxenograft (PDOX) mouse models is presented that is believed to overcome these experimental constraints and pave the way toward state‐of‐the‐art precision medicine in EC. The collection of primary tumors and derived PDOXs is characterized through an integrative approach based on transcriptomics, mutational profiles, and morphological analysis; and it is demonstrated that EC tumors engrafted in the mouse uterus retain the main molecular and morphological features from analogous tumor donors. Finally, the molecular properties of these tumors are harnessed to assess the therapeutic potential of trastuzumab, a human epidermal growth factor receptor 2 (HER2) inhibitor with growing interest in EC, using patient‐derived organotypic multicellular tumor spheroids and in vivo experiments. [ABSTRACT FROM AUTHOR]

In recent years, diabetes-associated breast cancer has become a significant clinical challenge. Diabetes is not only a risk factor for breast cancer but also worsens its prognosis. Patients with diabetes usually show hyperglycemia and hyperinsulinemia, which are accompanied by different glucose, protein, and lipid metabolism disorders. Metabolic abnormalities observed in diabetes can induce the occurrence and development of breast cancer. The changes in substrate availability and hormone environment not only create a favorable metabolic environment for tumorigenesis but also induce metabolic reprogramming events required for breast cancer cell transformation. Metabolic reprogramming is the basis for the development, swift proliferation, and survival of cancer cells. Metabolism must also be reprogrammed to support the energy requirements of the biosynthetic processes in cancer cells. In addition, metabolic reprogramming is essential to enable cancer cells to overcome apoptosis signals and promote invasion and metastasis. This review aims to describe the major metabolic changes in diabetes and outline how cancer cells can use cellular metabolic changes to drive abnormal growth and proliferation. We will specifically examine the mechanism of metabolic reprogramming by which diabetes may promote the development of breast cancer, focusing on the role of glucose metabolism, amino acid metabolism, and lipid metabolism in this process and potential therapeutic targets. Although diabetes-associated breast cancer has always been a common health problem, research focused on finding treatments suitable for the specific needs of patients with concurrent conditions is still limited. Most studies are still currently in the pre-clinical stage and mainly focus on reprogramming the glucose metabolism. More research targeting the amino acid and lipid metabolism is needed. [ABSTRACT FROM AUTHOR]