891 research outputs found

    The effects of metabolic indicators and immune biomarkers on pregnancy outcomes in women with recurrent spontaneous abortion: a retrospective study

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    BackgroundThe etiology of recurrent spontaneous abortion (RSA) remains elusive despite specific investigations affirming the association between RSA and thyroid autoimmunity (TAI). This study explores the immunological and metabolic profiles of RSA patients exhibiting positive thyroid antibodies and their connection with the rates of first-trimester miscarriage and live births. The aim is to provide further guidance for clinical interventions.MethodsA retrospective analysis included 478 women with RSA. Thyroid profile, thyroid peroxidase antibodies, and anti-thyroglobulin antibodies were measured in all participants. The clinical characteristics and pregnancy outcomes of RSA women were compared between thyroid autoimmunity (TAI)-positive and TAI-negative patients. Significant factors associated with adverse pregnancy outcomes and risk prediction models were explored in TAI-positive patients. Correlation analysis was used to identify specific metabolic or immune biomarkers associated with thyroid autoantibodies.ResultsThe prevalence of TAI was 18.6%. Compared with women without TAI, the thyroid-stimulating hormone (TSH) concentration of TAI-positive RSA was significantly higher (2.80 ¬Ī 2.98 vs 1.89 ¬Ī 1.17, p=0.006). After 28 weeks, the live birth rate of the TAI-positive group was lower than that of the TAI-negative group, with statistical significance (p<0.05). The immune biomarkers that differed between RSA women with live births and those with first-trimester miscarriages were complement C4 and interleukin-6, respectively, in TAI-negative and TAI-positive women. Then, a risk prediction model for first-trimester miscarriage was constructed for TAI-positive women with an AUC of 0.81. Finally, some factors related to thyroid peroxidase antibody (TPO-Ab) levels were explored, and it was found that TPO-Ab levels were positively correlated with free thyroxine and negatively correlated with 25 hydroxyvitamin D, interleukin-4, and fasting blood glucose in RSA patients.ConclusionTAI-positive RSA patients have higher first-trimester miscarriage rates and a lower live birth rate, which may be related to metabolic immune shifts in TAI-positive RSA patients

    Development of Novel Therapeutic Strategies to Target Therapy Resistance and Cancer Stem Cells

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    This thesis focuses on the core issues of multidrug resistance (MDR) in cancer, a process that hinders the success of chemotherapeutic treatments. MDR involves various mechanisms, including the upregulation of ABC transporter pumps, like MRP1, and increased cancer stemness, which contributes to malignancy and recurrence. The thesis comprises seven chapters: a literature review (Chapter 1), methodology (Chapter 2), results (Chapters 3-5), and discussions on findings and future studies (Chapters 6) and final discussion and overall summary (Chapter 7). Chapter 3 delves into the novel roles of MRP1 in cellular iron metabolism and proliferation, its interaction with c-Myc, and the effects on cellular proliferation. Silencing and inhibition studies reveal MRP1's role in regulating iron regulatory proteins through c-Myc. Chapter 4 investigates the role of ABC transporters in cancer stemness, revealing their connection with stemness states in different tumor types. Chapter 5 explores strategies for targeting drug-resistant cancer cells, demonstrating how doxycycline reduces the stemness marker SOX2 across multiple tumor types through a unique pathway. Chapter 6 examines the alteration of metabolism and stemness in drug-resistant cancer cells and strategies for targeting the cysteine metabolism pathway. The findings provide insights into cancer stemness regulation and potential therapeutic strategies, improving the efficacy of chemotherapeutics. The work reported in this thesis reveals an underlying and unique mechanism in regulation of SOX2-mediated cancer stemness. Moreover, the use of DXC to remove stemness was demonstrated to be a promising therapeutic strategy in combination with other common chemotherapeutics agents. These findings presented in this thesis enables us to understand cancer stemness better and improve the efficacy of current chemotherapeutics, which ultimately improve overall quality of life

    Estudio de biomarcadores en sangre periférica en mujeres con fallo reproductivo recurrente

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    Tesis in√©dita de la Universidad Complutense de Madrid, Facultad de Medicina, le√≠da el 18-07-2022El fallo reproductivo recurrente engloba dos entidades cl√≠nicas bien diferenciadas como son los abortos de repetici√≥n (AR) y el fallo de implantaci√≥n recurrente (FIR). El AR se define como la p√©rdida de dos o m√°s gestaciones antes de las 24 semanas de edad gestacional, mientras que para FIR no existe un consenso internacional en su definici√≥n, pero la m√°s aceptada ser√≠a la no consecuci√≥n del embarazo en mujeres menores de 40 a√Īos, tras haber transferido al menos 4 embriones de buena calidad, en un m√≠nimo 3 transferencias (incluyendo tanto las realizadas en fresco como las de embriones criopreservados). Ambas patolog√≠as comparten algunas etiolog√≠as como pueden ser: causas anat√≥micas, gen√©ticas, endocrinas, entre otras. Pero, en un gran n√ļmero de pacientes, su origen permanece desconocido pudiendo alcanzar hasta un 50% en las pacientes con AR. El sistema inmunitario ha cobrado en los √ļltimos a√Īos una vital importancia dentro de poder explicar un alto grado de pacientes que previamente permanec√≠an como de causa desconocida. Se ha estudiado extensamente en los √ļltimos 20 a√Īos el papel que las c√©lulas NK tanto en n√ļmero como en funci√≥n, juegan en estas dos patolog√≠as. Asimismo, los monocitos, c√©lulas clave tambi√©n para el desarrollo del embarazo, han cobrado m√°s importancia en los √ļltimos a√Īos, aunque su estudio se ha centrado en su papel en otras patolog√≠as, principalmente en preeclampsia. Inicialmente se pensaba que un estado proinflamatorio durante el embarazo podr√≠a ser perjudicial para el correcto desarrollo del mismo...Recurrent reproductive failure encompasses two well-differentiated entities: recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF). RPL is defined as the loss of two or more pregnancies before 24 weeks of gestational age, while for RIF, there is no international consensus on its definition, but the most accepted would be the non-achievement of pregnancy in women under 40 years of age, after having transferred at least four good quality embryos, in a minimum of 3 transfers (including both those made fresh and those of cryopreserved embryos). Both pathologies share some etiologies, such as anatomical, genetic, and endocrine causes, among others. Therefore, in many patients, its origin remains unknown and can reach up to 50% in patients with RPL. In recent years, the immune system has gained vital importance in explaining a high degree of patients who previously remained as of unknown cause. The role that NK cells play in these two pathologies, both in number and function, has been extensively studied in the last 20 years. Likewise, monocytes, also essential cells for the development of pregnancy, have become more important in recent years, although their study has focused on their role in other pathologies, mainly preeclampsia. Initially, it was thought that a pro-inflammatory state during pregnancy could be detrimental to its proper development...Fac. de MedicinaTRUEunpu

    Acta Siculica 2023

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    Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression

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    The aim of this Special Issue is to collect reports regarding all the recent strategies, directed at the improvement of antineoplastic activity of drugs in cancer progression, engaging all the expertise needed for the development of new anticancer drugs: medicinal chemistry, pharmacology, molecular biology, and computational and drug delivery studies

    Immune microenvironment dynamics in breast cancer during pregnancy: impact of gestational age on tumor-infiltrating lymphocytes and prognosis

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    BackgroundBreast cancer during pregnancy (PrBC) is a rare condition known for its aggressive clinical behavior. The presence of tumor-infiltrating lymphocytes (TILs) has been shown to have a significant impact on the prognosis of these patients. Despite some biological characteristics of the tumor that may differ depending on the gestational age, little is known about the dynamics of the immune landscape within the tumor microenvironment (TME) in PrBC. Therefore, in this study, our objective was to gain comprehensive insights into the relationship between gestational age at breast cancer diagnosis and the composition of the TME.Methodsn = 108 PrBC were selected from our institutional registry and categorized based on the gestational age by trimester. For all cases, TILs were profiled according to the International TILs Working Group recommendations, and subtyped by CD4, CD8, and forkhead box P3 (FOXP3) immunohistochemistry. PD-L1 was tested according to the combined positive score (CPS) using the IHC 22C3 pharmDx assay, with a cutoff value of ‚Č•10 for positivity. The statistical approach encompassed Fisher‚Äôs and Chi-squared tests, with appropriate adjustments for multiple comparisons, logistic regression models, and survival analyses based on the Kaplan‚ÄďMeier method.ResultsThe proportion of patients with poorly differentiated (G3) neoplasms increased as the gestational age advanced (first trimester, n = 25, 56.8%; second trimester, n = 27, 69.2%; third trimester, n = 21, 87.5%; p = 0.03). The histologic subtypes as well as the hormone receptor (HR) and HER2 status did not show significant changes across different pregnancy trimesters. In the HR+/HER2‚Äď subtype, there was a higher proportion of tumors with high/moderate TILs in the early phases of pregnancy, similar to FOXP3 expression (TILs: first trimester, n = 10, 35.7%; second trimester, n = 2, 10.5%; third trimester, n = 0; p = 0.02; FOXP3: first trimester, n = 10, 40%; second trimester, n = 3, 15.8%; third trimester, n = 0; p¬†= 0.03). The median follow-up for our cohort was 81 months. Patients who relapsed after a breast cancer diagnosis during the first trimester were more frequently PD-L1-negative, unlike those with no disease recurrence (n = 9, 100% vs. n = 9, 56.3%; p = 0.03; hormone therapy and n = 9, 100% vs. n = 7, 53.9%; p = 0.02; chemotherapy). No statistically significant differences were seen among the three trimesters in terms of survival outcome.ConclusionThe TME dynamics of HR+/HER2‚ąí PrBC vary based on gestational age, suggesting that immune tolerance expression during later gestational age could explain the increased aggressiveness of tumors diagnosed at that stage

    Magyar nyelvj√°r√°sok 2023

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    The Influence of Early Onset Preeclampsia on Perinatal Red Blood Cell Characteristics of Neonates

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    Preeclampsia is the leading cause of complicated neonatal adaptation. The present investigation aimed to study the hemorheological factors during the early perinatal period (cord blood, 24 and 72 h after delivery) in newborns of early-onset preeclamptic mothers (n = 13) and healthy neonates (n = 17). Hematocrit, plasma, and whole blood viscosity (WBV), red blood cell (RBC) aggregation, and deformability were investigated. There were no significant differences in hematocrit. WBV was significantly lower in preterm neonates at birth than in the term 24 and 72 h samples. Plasma viscosity was significantly lower in preterm neonates’ cord blood than in healthy controls. RBC aggregation parameters were significantly lower in preterm newborns’ cord blood than in term neonates’ cord blood 24 and 72 h samples. RBC elongation indices were significantly lower in the term group than in preterm neonates 72 h’ sample at the high and middle shear stress range. Changes in the hemorheological parameters, especially RBC aggregation properties, refer to better microcirculation of preterm neonates at birth, which could be an adaptation mechanism to the impaired uteroplacental microcirculation in preeclampsia

    Contaminant containment for sustainable remediation of persistent contaminants in soil and groundwater

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    Contaminant containment measures are often necessary to prevent or minimize offsite movement of contaminated materials for disposal or other purposes when they can be buried or left in place due to extensive subsurface contamination. These measures can include physical, chemical, and biological technologies such as impermeable and permeable barriers, stabilization and solidification, and phytostabilization. Contaminant containment is advantageous because it can stop contaminant plumes from migrating further and allow for pollutant reduction at sites where the source is inaccessible or cannot be removed. Moreover, unlike other options, contaminant containment measures do not require the excavation of contaminated substrates. However, contaminant containment measures require regular inspections to monitor for contaminant mobilization and migration. This review critically evaluates the sources of persistent contaminants, the different approaches to contaminant remediation, and the various physical-chemical-biological processes of contaminant containment. Additionally, the review provides case studies of contaminant containment operations under real or simulated field conditions. In summary, contaminant containment measures are essential for preventing further contamination and reducing risks to public health and the environment. While periodic monitoring is necessary, the benefits of contaminant containment make it a valuable remediation option when other methods are not feasible

    A unique maternal and placental galectin signature upon SARS-CoV-2 infection suggests galectin-1 as a key alarmin at the maternal‚Äďfetal interface

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    The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic imposed a risk of infection and disease in pregnant women and neonates. Successful pregnancy requires a fine-tuned regulation of the maternal immune system to accommodate the growing fetus and to protect the mother from infection. Galectins, a family of ő≤-galactoside‚Äďbinding proteins, modulate immune and inflammatory processes and have been recognized as critical factors in reproductive orchestration, including maternal immune adaptation in pregnancy. Pregnancy-specific glycoprotein 1 (PSG1) is a recently identified gal-1 ligand at the maternal‚Äďfetal interface, which may facilitate a successful pregnancy. Several studies suggest that galectins are involved in the immune response in SARS-CoV-2‚Äďinfected patients. However, the galectins and PSG1 signature upon SARS-CoV-2 infection and vaccination during pregnancy remain unclear. In the present study, we examined the maternal circulating levels of galectins (gal-1, gal-3, gal-7, and gal-9) and PSG1 in pregnant women infected with SARS-CoV-2 before vaccination or uninfected women who were vaccinated against SARS-CoV-2 and correlated their expression with different pregnancy parameters. SARS-CoV-2 infection or vaccination during pregnancy provoked an increase in maternal gal-1 circulating levels. On the other hand, levels of PSG1 were only augmented upon SARS-CoV-2 infection. A healthy pregnancy is associated with a positive correlation between gal-1 concentrations and gal-3 or gal-9; however, no correlation was observed between these lectins during SARS-CoV-2 infection. Transcriptome analysis of the placenta showed that gal-1, gal-3, and several PSG and glycoenzymes responsible for the synthesis of gal-1-binding glycotopes (such as linkage-specific N-acetyl-glucosaminyltransferases (MGATs)) are upregulated in pregnant women infected with SARS-CoV-2. Collectively, our findings identify a dynamically regulated ‚Äúgalectin-specific signature‚ÄĚ that accompanies the SARS-CoV-2 infection and vaccination in pregnancy, and they highlight a potentially significant role for gal-1 as a key pregnancy protective alarmin during virus infection
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