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Summary: T cell surface CTLA4 sequesters the costimulatory ligands CD80 and CD86 on antigen-presenting cells (APCs) to prevent autoimmunity. Therapeutic immunosuppression by recombinant CTLA4-immunoglobulin (Ig) fusion proteins, including abatacept, is also attributed to CD80/CD86 blockade. Recent studies show that CTLA4-Ig binding to APC surface cis-CD80:PD-L1 complexes can release the inhibitory ligand PD-L1, but whether this contributes to T cell inhibition remains unclear. Here, we show that PD-L1 liberation by CTLA4-Ig is strictly limited, both in extent and context, relative to PD-L1-competing anti-CD80 antibodies. At APC surface CD80:PD-L1 ratios exceeding 2:1, CTLA4-Ig therapies fail to release PD-L1 regardless of their CD80 affinity. Additionally, introducing flexibility into CTLA4-Ig by modifying its rigid homodimer interface produces biologics that retain bivalent CD80 binding without dissociating cis-bound PD-L1. These findings demonstrate that CTLA4-Ig therapies liberate PD-L1 through a CD80 reorientation mechanism that imposes a strict context dependence to their PD-1 checkpoint agonism and resultant T cell inhibition.

Abstract Thrombopoietin (Tpo) is the primary regulator of megakaryocyte and platelet numbers and is required for haematopoetic stem cell maintenance. Tpo functions by binding its receptor (TpoR, a homodimeric Class I cytokine receptor) and initiating cell proliferation or differentiation. Here we characterise the murine Tpo:TpoR signalling complex biochemically and structurally, using cryo-electron microscopy. Tpo uses opposing surfaces to recruit two copies of receptor, forming a 1:2 complex. Although it binds to the same, membrane-distal site on both receptor chains, it does so with significantly different affinities and its highly glycosylated C-terminal domain is not required. In one receptor chain, a large insertion, unique to TpoR, forms a partially structured loop that contacts cytokine. Tpo binding induces the juxtaposition of the two receptor chains adjacent to the cell membrane. The therapeutic agent romiplostim also targets the cytokine-binding site and the characterisation presented here supports the future development of improved TpoR agonists.

This paper presents new work using an approximate method to find the reliability function for inverse Rayleigh distribution and compares it with two statistical estimation methods. In the approximate method, the reliability function is expanded using Bernstein polynomials to find the approximate value for it. As for statistical estimation methods, the first one is the maximum likelihood estimation by finding the scale parameter estimator to estimate the reliability function. The second one is the Bayes estimator is created under the NLINEX loss function to get the reliability function with the least loss where this estimator is determined utilizing chi-squared informative prior distribution. The simulation technique is used to obtain the results of all methods and compare them depending on the integrated mean squared error (IMSE) to determine which of these methods is best. Finally, to determine theoretical results MATLAB 2015 is used. [ABSTRACT FROM AUTHOR]

Copyright of Jordan Medical Journal is the property of University of Jordan and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Revista del Museo de Antropología is the property of Museo de Antropologia - IDACOR and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

During development, the rate of tissue growth is determined by the relative balance of cell division and cell death. Cell competition is a fitness quality-control mechanism that contributes to this balance by eliminating viable cells that are less fit than their neighbours. The mutations that confer cells with a competitive advantage and the dynamics of the interactions between winner and loser cells are not well understood. Here, we show that embryonic cells lacking the tumour suppressor p53 are 'super-competitors' that eliminate their wild-type neighbours through the direct induction of apoptosis. This elimination is context dependent, as it does not occur when cells are pluripotent and it is triggered by the onset of differentiation. Furthermore, by combining mathematical modelling and cell-based assays we show that the elimination of wild-type cells is not through competition for space or nutrients, but instead is mediated by short-range interactions that are dependent on the local cell neighbourhood. This highlights the importance of the local cell neighbourhood and the competitive interactions within this neighbourhood for the regulation of proliferation during early embryonic development. [ABSTRACT FROM AUTHOR]

Abstract To mitigate the use of antibiotics for many of the multifactorial diseases seen in pigs, horses and cattle, new diagnostic tools are needed. Acute phase protein (APP) measurements can, in humans, be used to guide antibiotic treatment initiation, evaluate treatment efficacy, and make a prognosis. The aim of this review is to collect evidence on the clinical functionality of APP measurements as a tool to guide antibiotic treatment in pigs, horses, and cattle. Literature was retrieved using Medline, CAB Abstracts and Google Scholar. The acute phase response has been investigated for a plethora of diseases and clinical signs and the major acute phase proteins are elevated in diseased compared to healthy animals. Few studies correlated acute phase response with aetiology, antibiotic treatment efficacy, prognosis, or severity of disease. The existing research does not support that APP can be used to guide antibiotic treatment, but the reported studies indicate that C-reactive protein (CRP) might be able to differentiate between bacterial and non-bacterial causes of disease in pigs. Serum amyloid A (SAA) might reflect underlying aetiology in horses and infectious or non-infectious cases of mastitis in cows.

Integrated care systems join up health and care services, so that people have the support they need, in the right place, at the right time. The aims include improving outcomes in healthcare, tackling inequalities in access and enhancing productivity and value for money. This is needed for neuroscience care as the traditional delivery of neuroscience care is inefficient, outdated and expensive, and can involve complex referral pathways and long waiting times.In preparation for the formation of the integrated care system (ICS), a novel innovative collaboration across multiple NHS trusts developed across North Central London in 2021. We developed a model where neuroscience specialists engage in collaborative care with clinicians outside the specialist hospital setting. Pivotal to the pathway is a multidisciplinary meeting, and collaborative working enables joint clinical reviews, diagnostics and medication initiation.This innovative collaboration has already significantly improved access, addressed inequalities due to borough variation and enhanced the delivery and quality of neuroscience care in our ICS. It is a translatable model that can be adapted to suit other regions in the UK. It fulfils many of the objectives of the integrated care system and these benefits are seen without the need for significantly more resource.

Introduction and objectives: Aortic stenosis is the most common valvular heart disease. The number of octogenarians proposed for intervention is growing due to increased lifespan. In this manuscript we aim to evaluate perioperative outcome and long-term survival after surgical aortic valve replacement (SAVR) in octogenarians, comparing patients with low surgical risk (EuroscoreII

In this research, the preparation of licorice extract and the biosynthesis of manganese oxide in the treatment of stomach cancer were investigated by examining the cytotoxicity of the stomach cancer line. The structural properties of manganese oxide were also studied through X-ray examination, scanning electron microscope (SEM), and infrared spectroscopy, where it was found that manganese oxide is polycrystalline, and the average grain size is 62.571 nm, but by SEM, the grain size is 93.49–47.74 nm.

Background: There is a definite shift in assisted reproductive centres from cleavage-stage embryo transfer (ET) toblastocyst transfer that is attributed to improvements in laboratory environments and advances in the development ofembryo culture media. The aim of the study was to investigate the reproductive outcomes of thawed cleavage-stage ET versusblastocysts derived from an extended culture of these embryos.Materials and Methods: This open-label, randomised, parallel group clinical trial study enrolled 182 women aged ≤37years who underwent frozen-thawed ET from November 2015 to June 2020 at Royan Institute Research Centre, Tehran,Iran. The women were randomly assigned to either the thawed cleavage ET group (n=110) or the post-thaw extended cultureblastocysts group (n=72). The primary outcome measure was the clinical pregnancy rate. Secondary outcome measureswere implantation rate, live birth rate (LBR), and miscarriage rate. A P

Background: Myometrial thickness has been expected to be a prognosticator for lower uterine segment function. Anabnormal function of the uterine muscle layer can cause common and important reproductive problems. This studyaimed to evaluate the relationship between the baseline myometrial thickness and assisted reproductive technologies(ART) outcomes.Materials and Methods: In this prospective cohort study, 453 infertile women undergoing ART cycles without anyobvious uterine pathology, participated in this prospective cohort study from February 2013 to May 2015. In order tomeasure the myometrial thickness in the anterior and posterior of the uterine, trans-vaginal ultrasounds were conducted ondays 2-4 of the cycle (menstrual phase) preceding ovarian stimulation and the day of human chorionic gonadotropin(hCG) injection. We defined three groups based on the baseline myometrial thickness in the anterior and posterior, including(A)

Los coprolitos, heces mineralizadas o deshidratadas, brindan evidencias que contribuyen a la reconstrucción de los ambientes del pasado. En nuestro grupo de investigación, hace unos años iniciamos el análisis de coprolitos mediante la exploración de diversos elementos contenidos en su interior, como polen, fragmentos vegetales y silicofitolitos. Asimismo, comenzamos a desarrollar y evaluar distintas estrategias metodológicas para maximizar la recuperación de estos elementos. El objetivo de este trabajo es presentar una revisión de distintos casos de estudio realizados por los autores, enfocados en el análisis multiproxy de coprolitos de herbívoros y omnívoros hallados en sitios arqueológicos del noroeste de Santa Cruz, Argentina. Esta revisión muestra que este abordaje permite alcanzar niveles de resolución taxonómica más precisos que cuando se analiza un solo proxy. Asimismo, destaca la importancia de la generación de modelos actualísticos para la interpretación de los hallazgos en coprolitos. En los coprolitos estudiados con una buena preservación de los proxies, se observó la predominancia de taxones de las familias Poaceae y Asteraceae, lo que evidencia directamente los principales elementos de la dieta de la fauna que acompañaba a los cazadores-recolectores. Asimismo, se logró identificar taxones vegetales que estaban disponibles para los cazadores-recolectores que habitaron en el noroeste de Santa Cruz durante el Holoceno.

IntroductionSleep-disordered breathing (SDB) and gas exchange disorders are common in patients with cystic fibrosis (CF). Currently, the impact of the disease on sleep patterns in patients living at high altitude and the relationship of these patterns to lung function are largely unknown. The aim of this study was to determine the frequency of SDB in children with CF aged 6–18 years and the relationship between SDB and lung function (FEV1).MethodsThis is an analytical cross-sectional study of children aged 6–18 years diagnosed with CF. Spirometry before and after bronchodilators and polysomnography with capnography were performed. Descriptive analysis of qualitative and continuous variables was performed. Spearman's correlation coefficient was used to determine the correlation between polysomnogram and lung function (FEV1).ResultsTwenty-four patients with CF were included. The mean age was 10.5 ± 3.1 years and 62.5% were male. Nine children had bronchiectasis on chest CT. The median absolute baseline FEV1 was 1,880 (1,355–2,325) ml and 98% (83%–110%) of predicted value. No significant difference in FEV1% was observed between subjects with obstructive sleep apnea (OSA) and those without OSA (P = 0.56). The prevalence of OSA was 66.7% in children younger than 13 years and 40% in children older than 13 years. The Spearman correlation coefficient between FEV1 and percentage of total sleep time with saturation less than 90% (T90) was rho −0.52 (p-value = 0.018), and between FEV1 and percentage of total sleep time with saturation less than 85% (T85) was statistically significant with rho −0.45 (p-value = 0.041). A positive correlation was observed between FEV1 and SpO2 during sleep with rho 0.53 and a statistically significant p-value (0.014).ConclusionsA high prevalence of sleep apnea was found in children with CF living at high altitude, with a negative correlation between FEV1 and T90 and T85 oxygenation indices, and a positive correlation between FEV1 and SpO2 during sleep.

The impact of vessels on dolphin populations has been extensively studied worldwide. The common dolphin, Delphinus delphis, has been observed in the Tagus estuary for the past two centuries, and during the last several years, these sightings seem to have increased. This area has high levels of maritime traffic throughout the year, both commercial and recreational. To understand the possible effects of vessel traffic on dolphins’ behavior, land-based observations were carried out from March 2022 to March 2023. For a total of 67 events (48.9 h of dolphin sightings), differences in behavioral budgets were noted. Although “neutral reaction” was the most observed response when vessels were in the vicinity of dolphins, “negative reaction” was also common and five times more abundant than “positive reaction”. The GEE model showed statistical differences between these reaction types (positive, neutral, and negative). Markov chains’ analysis revealed distinct patterns in the behavioral transition probabilities, as dolphins were more likely to switch to a traveling state when vessels were nearby. This study is the first step towards understanding a potential impact source in the area since it is expected that tourism companies expand due to the increase in dolphin sightings in the estuary.

LAH, an acetogenin from the Annonaceae family, has demonstrated antitumor activity in several cancer cell lines and in vivo models, where it reduced the tumor size and induced programmed cell death. We focused on the effects of LAH on mitochondrial dynamics, mTOR signaling, autophagy, and apoptosis in colorectal cancer (CRC) cells to explore its anticancer potential. Methods: CRC cells were treated with LAH, and its effects on mitochondrial respiration and glycolysis were measured using Seahorse XF technology. The changes in mitochondrial dynamics were observed through fluorescent imaging, while Western blot analysis was used to examine key autophagy and apoptosis markers. Results: LAH significantly inhibited mitochondrial complex I activity, inducing ATP depletion and a compensatory increase in glycolysis. This disruption caused mitochondrial fragmentation, a trigger for autophagy, as shown by increased LC3-II expression and mTOR suppression. Apoptosis was also confirmed through the cleavage of caspase-3, contributing to reduced cancer cell viability. Conclusions: LAH’s anticancer effects in CRC cells are driven by its disruption of mitochondrial function, triggering both autophagy and apoptosis. These findings highlight its potential as a therapeutic compound for further exploration in cancer treatment.

Caffeic acid (CA) is a phenolic compound, which has a multifaceted role in the response of plants to various abiotic stresses. Plants must adapt to external stimuli, prompting extensive research into phenolic and flavonoid compounds as potential mitigators of environmental stress impacts. Phenylpropanoids are emphasized for their importance in maintaining plant integrity under stress, while the significance of CA, a cinnamic acid, is interpreted as a key component involved in lignin synthesis and regulating physiological processes. CA deals with different kinds of stress, like salinity-induced stress, chilling stress, and especially drought-induced stress in plants. CA helps plants make certain chemicals called phenolics, which protect them from damage caused by oxidative stress. Researchers are investigating the possible ways that CA functions, including its roles in regulating signals, defending against antioxidants, and preserving the integrity of cells. There is a need to understand the response of CA to abiotic stress factors, which can provide information about its adaptive mechanisms and applications in agriculture. This review proposes genetic advances to increase crop tolerance and provides an overview of the complexities surrounding the role of CA in plant responses to various abiotic conditions. This highlights the need for further research to identify specific mechanisms and interactions with other compounds, as well as the importance of comparative analysis of CA responses in different plant species. It emphasized the importance of meeting the challenges of stress response research and encouraged collaborative efforts for sustainable agriculture and human well-being. This demonstrates CA's importance in enhancing stress resistance and provides a blueprint for future research directions, including the study of specific mechanisms, interactions between components, and applications in the development of stress-resistant products.

In Pakistan, tobacco consumption is at an all-time high with the tobacco industry witnessing a boom. According to the Pakistan Tobacco Company, production and sale has taken a sharp leap from Rs.1,000 million rupees to Rs.1,750 million in 2008. The youth remain particularly vulnerable as massive antismoking ad campaigns have failed to drill in the health hazards. The aim of this study is to assess the attitude, perception and practices of youth regarding cigarette smoking. Comparative cross-sectional study was conducted in Ziauddin University and Bahria University. Sample was taken from all years of teaching. Data was collected through self-administered structured questionnaire that was developed in English. It comprised of questions pertaining to their year of study, smoking history, and perception and practices regarding smoking. A total of 450 students were surveyed, medicine (n=260) and engineering (n=190). One-fourth of the survey sample admitted to have tried to smoke at least once in their lifetime (p=0.001), and at least 20% medical students (n=53) and 35% of engineering students (n=66) surveyed had smoked a cigarette (p=0.001). While students studying medicine were better aware of the risks associated with smoking and tobacco consumption, however compared to engineering students their overall knowledge of the health risks was unsatisfactory. A significant number of medical students were unable to list and hence effectively counsel about long and short term health benefits. Peer pressure and media played a large role in students picking up the habit. KEY WORDS: Pakistan/Epidemiology, Smoking, Karachi, Mechanism Medical Students.

Background: Amino acid racemisation is a reliable method to estimate age in developed countries. This pilot study was designed to determine the coefficient of amino acid racemisation (AAR) with reference to age in our population. Also as no such study has been conducted in our setting, the study also aims to discuss reproducibility of this study on a larger scale. Objective: To determine the coefficient of amino acid racemisation (AAR) with reference to age; To measure the mean error in calculating age using this method; To identify any differences from earlier observation and discuss the reproducibility in our setting. Methods: Teeth were obtained from subjects between the age of 15 and 60 years who had come for routine extraction procedure or for orthodontic procedures. Incisors, canines, premolars and, first and second molars were included. Carious tooth and third molar were excluded. Samples were stored, dried, de-mineralised, hydrolysed, and derivatised. High-Pressure Liquid Chromatography (HPLC) was performed to quantify the L- and D- forms of aspartic acid in dentin. Correlation and regression was then tabulated based on the quantification, and was compared with data from other studies. Results: Based on the analysis of selected samples, a strong positive correlation of 0.93 was observed between co-efficient of racemisation and chronological age. The regression line derived was Age = 200 (KR) + 17.306 (where KR= coefficient of racemisation).The computed regression line was tested by using coefficient of racemisation for 8 samples selected during the study and the mean error (difference between actual and calibrated age) determined came out to be 3.99±5.77. Conclusion: The correlation coefficient was strongly positive. The results strongly suggests that aspartic acid racemisation of human dentine is a precise method for estimation of chronological age in living and in dead. The methodology should be standardized to make the results more accurate and prevent fallacies. However it remains an expensive procedure, especially the laboratory equipment that would not be available in most cities of Pakistan. Key Words: Age Estimation, Amino Acid Racemisation, Forensics Sciences, HPLC, Dentin, Pakistan Epidemiology.

Lithium, a natural element, has been employed as a mental stabilizer in psychiatric treatments; however, some reports indicate it has an anticancer effect, prompting the consideration of repurposing lithium for cancer treatment. The potential anticancer use of lithium may depend on its form (salt type) and the type of cancer cells targeted. Little is known about the effects of Li2CO3 or LiCl on cancer cells, so we focused on exploring their effects on proliferation, apoptosis, migration, and cell cycle as part of the hallmarks of cancer. Firstly, we established the IC50 values on HeLa, SiHa, and HaCaT cells with LiCl and Li2CO3 and determined by crystal violet that cell proliferation was time-dependent in the three cell lines (IC50 values for LiCl were 23.43 mM for SiHa, 23.14 mM for HeLa, and 15.10 mM for HaCaT cells, while the IC50 values for Li2CO3 were 20.57 mM for SiHa, 11.52 mM for HeLa, and 10.52 mM for HaCaT cells.) Our findings indicate that Li2CO3 and LiCl induce DNA fragmentation and caspase-independent apoptosis, as shown by TUNEL, Western Blot, and Annexin V/IP assay by flow cytometry. Also, cell cycle analysis showed that LiCl and Li2CO3 arrested the cervical cancer cells at the G1 phase. Moreover, lithium salts displayed an anti-migratory effect on the three cell lines observed by the wound-healing assay. All these findings imply the viable anticancer effect of lithium salts by targeting several of the hallmarks of cancer.

The mechanisms underlying the sustained activation of the PI3K/AKT and Wnt/β-catenin pathways mediated by HOTAIR in cervical cancer (CC) have not been extensively described. To address this knowledge gap in the literature, we explored the interactions between these pathways by driving HOTAIR expression levels in HeLa cells. Our findings reveal that HOTAIR is a key regulator in sustaining the activation of both signaling pathways. Specifically, altering HOTAIR expression—either by knockdown or overexpression—significantly influenced the transcriptional activity of the PI3K/AKT and Wnt/β-catenin pathways. Additionally, we discovered that HIF1α directly induces HOTAIR transcription, which in turn leads to the epigenetic silencing of the PTEN promoter via DNMT1. This process leads to the sustained activation of both pathways, highlighting a novel regulatory axis involving HOTAIR and HIF1α in cervical cancer. Our results suggest a new model in which HOTAIR sustains reciprocal activation of the PI3K/AKT and Wnt/β-catenin pathways through the HOTAIR/HIF1α axis, thereby contributing to the oncogenic phenotype of cervical cancer.

Currently, there are various physical and mechanical agents that can cause skin wounds, which are still traditionally treated with plant extracts. It has been reported that the genus Tagetes has a wide range of biological properties, including antibacterial and wound healing activity. Likewise, Agave americana extract and Aloe vera gel have shown potential in the treatment of burn wounds and other skin conditions both in vitro and in vivo. In this study, the antibacterial and wound healing activities of each of these plants were investigated, as well as the possibility of enhancing these activities by combining them. First, the secondary metabolites of the extracts were quantified, the antibacterial activity was evaluated using the Kirby-Bauer method, and their cytotoxicity was measured in 3T3 and HaCaT cells using the sulforhodamine B assay. The results revealed that Tagetes nelsonii extract had a higher amount of secondary metabolites, which is why it exhibited antibacterial activity. Finally, the scratch assay showed that the individual extracts of T. nelsonii and A. americana demonstrated greater cell migration and proliferation starting from 12 h, as well as when using the combination of A. americana extract and A. vera gel, which almost completely closed the wound compared to the control.

Enterobacterales resistant to extended-spectrum cephalosporins (ESC) are a marker of the antimicrobial resistance (AMR) burden. They are infecting humans, but the intestinal microbiota can also be transiently colonized without developing symptoms. Healthy carriage can promote silent dissemination of resistant bacteria, and data on this colonization are often lacking. Between 2021 and 2023, a sampling of healthy Tunisian people was carried out. Fecal samples (n = 256) were plated on selective agar, and all collected isolates were characterized by phenotypic (antibiograms) and genomic (whole-genome sequencing) methods. A total of 26 (26/256, 10.2%) isolates were collected, including 24 Escherichia coli and 2 Klebsiella pneumoniae. In total, 17 isolates (15 E. coli and 2 K. pneumoniae) presented an ESBL phenotype conferred by the blaCTX-M-15 gene, and 9 E. coli isolates presented an AmpC phenotype conferred by the blaDHA-1 gene. K. pneumoniae belonged to ST1564 and ST313, while E. coli belonged to diverse STs including the pandemic ST131 clone. Clonally related ST349 E. coli isolates carrying the blaDHA-1 gene were found in nine individuals. In parallel, four blaCTX-M-15 -positive E. coli isolates carried this ESC-resistance gene on an epidemic plasmid IncF/F-:A-:B53 previously identified in Tunisian pigeons and fish. These findings highlight the spread of genetically diverse ESC-resistant Enterobacterales as well as an epidemic plasmid in Tunisia, emphasizing the need for antimicrobial stewardship to limit the transmission of these resistances in the Tunisian population.

Cervical cancer (CC) remains among the most frequent cancers worldwide despite advances in screening and the development of vaccines against human papillomavirus (HPV), involved in virtually all cases of CC. In mid-income countries, a substantial proportion of the cases are diagnosed in advanced stages, and around 40% of them are diagnosed in women under 49 years, just below the global median age. This suggests that members of this age group share common risk factors, such as chronic inflammation. In this work, we studied samples from 46 patients below 45 years old, searching for a miRNA profile regulating cancer pathways. We found 615 differentially expressed miRNAs between tumor samples and healthy tissues. Through bioinformatic analysis, we found that several of them targeted elements of the JAK/STAT pathway and other inflammation-related pathways. We validated the interactions of miR-30a and miR-34c with JAK1 and STAT3, respectively, through dual-luciferase and expression assays in cervical carcinoma-derived cell lines. Finally, through knockdown experiments, we observed that these miRNAs decreased viability and promoted proliferation in HeLa cells. This work contributes to understanding the mechanisms through which HPV regulates inflammation, in addition to its canonical oncogenic function, and brings attention to the JAK/STAT signaling pathway as a possible diagnostic marker for CC patients younger than 45 years. To our knowledge to date, there has been no previous description of a panel of miRNAs or even ncRNAs in young women with locally advanced cervical cancer.

Breast cancer expressing the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) is known as triple-positive (TPBC). TPBC represents 9–11% of breast cancer cases worldwide and is a heterogeneous subtype. Notably, TPBC presents a therapeutic challenge due to the crosstalk between the hormonal (ER and PR) and HER2 pathways. Patients with TPBC are treated with trastuzumab (TTZ); however, several patients treated with TTZ tend to relapse. The present study aimed to investigate the effect of the PR on inhibitory effect of TTZ on cell viability. BT474 cells (a model of TPBC) and BT474 PR-silenced cells were treated with either TTZ, progesterone (Pg), the PR antagonist mifepristone (RU486) or estradiol (E2) alone or in combination for 144 h (6 days). Cell viability assays and western blotting were subsequently performed. The results showed that Pg and E2 interfered with the inhibitory effect of TTZ on cell viability and this effect was potentiated when both hormones were combined. Pg was revealed to act through the PR, mainly activating the PR isoform B (PR-B) and inducing the protein expression levels of CDK4 and cyclin D1; however, it did not reactivate the HER2/Akt pathway. By contrast, E2 was able to increase PR isoform A (PR-A) expression, which was inhibited by Pg. Notably, in most of the experiments, RU486 did not antagonize the effects of Pg. In conclusion, Pg and E2 may interfere with the inhibitory effect of TTZ on cell viability through PR-B activation and PR-A inactivation. [ABSTRACT FROM AUTHOR]

In vitro digestion methods have been utilized in food research to reduce in vivo studies. Although previous studies have related in vitro and in vivo data, there is no consensus on how to establish an in vitro - in vivo relationship (IVIVR) for food digestion. A framework that serves as a tool to evaluate the utility and limitations of in vitro approaches in simulating in vivo processes is proposed to develop IVIVRs for food digestion, with a focus on the gastric phase as the main location of food structural breakdown during digestion. The IVIVR consists of three quantitative levels (A, B, and C) and a qualitative level (D), which relate gastric digestion kinetic data on a point-to-point basis, parameters derived from gastric digestion kinetic data, in vitro gastric digestion parameters with in vivo absorption or appearance parameters, and in vitro and in vivo trends, respectively. Level A, B, and C IVIVRs can be used to statistically determine the agreement between in vitro and in vivo data. Level A and B IVIVRs can be utilized further evaluate the accuracy of the in vitro approach to mimic in vivo processes. To exemplify the utilization of this framework, case studies are provided using previously published static and dynamic gastric in vitro digestion data and in vivo animal study data. Future food digestion studies designed to establish IVIVRs should be conducted to refine and improve the current framework, and to improve in vitro digestion approaches to better mimic in vivo phenomena.

Introduction: In this study, we aim to refine the value of a statistical life (VSL) framework to align with hospice care's focus on quality over quantity of life, recognising the necessity for age-sensitive economic assessments., Methods: We developed an adapted VSL model that incorporates patient and family preferences, which may guide resource distribution and policymaking in end-of-life care. Methods include a multidisciplinary analysis that merges economic and humanistic perspectives to advocate for policies that support adequate funding and compassionate care., Results: Results indicate that our adjusted VSL model promotes a more equitable assessment of hospice care, advocating for enhanced patient dignity and comfort., Conclusions: This paper presents a novel, ethically and economically balanced approach to evaluating hospice care, emphasising dignity and comfort in terminal care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

During development, the rate of tissue growth is determined by the relative balance of cell division and cell death. Cell competition is a fitness quality-control mechanism that contributes to this balance by eliminating viable cells that are less fit than their neighbours. The mutations that confer cells with a competitive advantage and the dynamics of the interactions between winner and loser cells are not well understood. Here, we show that embryonic cells lacking the tumour suppressor p53 are 'super-competitors' that eliminate their wild-type neighbours through the direct induction of apoptosis. This elimination is context dependent, as it does not occur when cells are pluripotent and it is triggered by the onset of differentiation. Furthermore, by combining mathematical modelling and cell-based assays we show that the elimination of wild-type cells is not through competition for space or nutrients, but instead is mediated by short-range interactions that are dependent on the local cell neighbourhood. This highlights the importance of the local cell neighbourhood and the competitive interactions within this neighbourhood for the regulation of proliferation during early embryonic development., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)