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Pancreatic cancer is a highly lethal malignancy with a growing incidence reported worldwide. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, which is often diagnosed at advanced stages, making its prognosis and medical management difficult. The identification of histopathological biomarkers has allowed a more precise stratification of pancreatic cancer patients, providing additional information about their prognosis and offering possible therapeutic targets to be explored. The prognostic value of the receptor activator of nuclear factor-kappa B (RANK) and its ligand (RANKL) has been evaluated in breast and prostate tumors, however, their usefulness has not been assessed in pancreatic cancer. In the present work, we analyzed the relationship between the protein expression of RANK and RANKL with the survival of 41 patients with pancreatic cancer followed for 60 months, by performing immunohistochemistry and Kaplan-Meier curves. Our results demonstrate a direct association of high expression levels of RANK and RANKL with poorer survival of pancreatic cancer patients in comparison to those with low/medium and null expression levels of both markers. Further studies should be conducted to explore the carcinogenic role of both components in this type of tumor, as well as additional promising translational uses., (©The Author(s) 2023. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Pancreatic cancer is a type of gastrointestinal tumor with a growing incidence and mortality worldwide. Pancreatic ductal adenocarcinoma (PDAC) constitutes 90% of cases, and late-stage diagnosis is common, leading to a 5-year survival rate of less than 10% in high-income countries. The use of biomarkers has different proven translational applications, facilitating early diagnosis, accurate prognosis and identification of potential therapeutic targets. Several studies have shown a correlation between the tissue expression levels of various molecules, measured through immunohistochemistry (IHC), and survival rates in PDAC. Following the hallmarks of cancer, epigenetic and metabolic reprogramming, together with immune evasion and tumor-promoted inflammation, plays a critical role in cancer initiation and development. In this study, we aim to explore via IHC and Kaplan-Meier analyses the prognostic value of various epigenetic-related markers (histones 3 and 4 (H3/H4), histone acetyl transferase 1 (HAT-1), Anti-Silencing Function 1 protein (ASF1), Nuclear Autoantigenic Sperm Protein (NASP), Retinol Binding Protein 7 (RBBP7), importin 4 (IPO4) and IPO5), metabolic regulators (Phosphoglycerate mutase (PGAM)) and inflammatory mediators (allograft inflammatory factor 1 (AIF-1), interleukin 10 (IL-10), IL-12A and IL-18) in patients with PDAC. Also, through a correlation analysis, we have explored the possible interconnections in the expression levels of these molecules. Our results show that higher expression levels of these molecules are directly associated with poorer survival rates in PDAC patients, except in the case of IL-10, which shows an inverse association with mortality. HAT1 was the molecule more clearly associated with mortality, with a hazard risk of 21.74. The correlogram demonstrates an important correlation between almost all molecules studied (except in the case of IL-18), highlighting potential interactions between these molecules. Overall, our study demonstrates the relevance of including different markers from IHC techniques in order to identify unexplored molecules to develop more accurate prognosis methods and possible targeted therapies. Additionally, our correlation analysis reveals potential interactions among these markers, offering insights into PDAC's pathogenesis and paving the way for targeted therapies tailored to individual patient profiles. Future studies should be conducted to confirm the prognostic value of these components in PDAC in a broader sample size, as well as to evaluate the possible biological networks connecting them.

Pancreatic cancer is a malignant neoplasm that, despite its low frequency, has a 5-year survival rate of less than 10%. The study of different histopathological markers has allowed a better understanding of the onset and development of this type of tumor as well as facilitating an approach to clinical variables based on their diagnostic, prognostic, and predictive value. In this sense, the NLRP3 protein of the inflammasome has been shown to be a component of great relevance in the initiation and progression of pancreatic cancer, although the value of this biomarker in patients has not yet been clarified. In this study, we selected 41 patients with pancreatic cancer and followed them for 60 months (5 years), evaluating their NLRP3 expression using immunohistochemical techniques. Furthermore, by performing Kaplan-Meier curves, we evaluated the survival of these patients in relation to their NLRP3 expression. Our results show that a significant percentage of our cohort had high expression of this component (90.74%) and that there is an inverse relationship between the expression of NLRP3 and patient survival. High levels of NLRP3 expression are related to lower survival and worse prognosis in these patients, possibly due to an ineffective immune system response and increased tumor-promoted inflammation. Future studies should be aimed at confirming these results in larger groups and evaluating various clinical strategies based on this knowledge., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Chronic Venous Disease (CVD) refers to a wide variety of venous disorders being the varicose veins its most common manifestation. It is well-established the link between pregnancy and the risk of suffering CVD, due to hormonal or haematological factors, especially during the third trimester. In the same manner, previous studies have demonstrated the detrimental effect of this condition in the placental tissue of pregnant women, including in the normal physiology and the metabolomic profile of this organ. In this context, the aim of this study was to evaluate the glucose homeostasis in the placental tissue of women presenting CVD. Through immunohistochemistry, we studied the protein expression of the glucose transporter 1 (GLUT-1), Phosphoglycerate kinase 1 (PGK1), aldolase (ALD), Glyceraldehyde-3-phosphate dehydrogenase (GA3PDH) and lactate dehydrogenase (LDH). Our results have reported a significative increase in the expression of GLUT-1, PGK1, ALD, GA3PDH and the isoenzyme LDHA in placentas of women with CVD. This work has proven for the first-time an altered glucose metabolism in the placental tissue of women affected by CVD, what may aid to understand the pathophysiological mechanisms of this condition in more distant organs such as placenta. Furthermore, our research also supports the basis for further studies in the metabolic phenotyping of the human placenta due to CVD, which may be considered during the late pregnancy in these women., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Mesenchymal cells (MSCs) are considered to be cellular populations of common embryological origin. For clinical research applications, MSCs are expanded and increased with cells obtained from a primary culture. By extracting cells from tissue and encouraging them to reproduce, the stem cell population ends up dominating the culture due to a high proliferation rate and self-renewal. The first subcultures between the third and sixth are chosen in order to obtain the maximum number of cells with optimal differentiation capacity. However, few studies have reported long-term cultivation of MSCs. The objective of this study was to advance the knowledge on the characteristics of MSCs by assessing their capacity for self-renewal and phenotypic maintenance beyond 50 cell subcultures, which is defined as the normal limit for cellular survival. Rat subcutaneous adipose tissue was the source of mesenchymal adipose stem cells (MASCs) cultured over 175 subcultures. Early 1 to 5 and late 25 to 30 subcultures were used to induce cellular differentiation to become adipogenic, chondrogenic and osteogenic connective tissue cells. MASCs characteristics were studied using flow cytometry, transmission electron microscopy (TEM), and immunohistochemical and reverse transcription polymerase chain reaction (RT-qPCR) assays. The MASCs maintained cell differentiation capacity for more than 30 subcultures but lost potentiality starting at 60 up to 175 subcultures. MASCs showed the embryonic phenotypes OCT3/4 and Nanog indefinitely, and developed compensatory mechanisms, such as autophagy, to achieve cell survival over a long time period. Therefore, long-term subcultures showed that MASCs could maintain their potential for clinical research use.

Polymer-based composites are a group of biomaterials that exert synergic and combined activity. There are multiple reported uses of these composites in multiple biomedical areas, such as drug carriers, in wound dressings, and, more prominently, in tissue engineering and regenerative medicine. Bone grafting is a promising field in the use of polymeric composites, as this is the second most frequently transplanted organ in the United States. Advances in novel biomaterials, such as polymeric composites, will undoubtedly be of great aid in bone tissue engineering and regeneration. In this paper, a general view of bone structure and polymeric composites will be given, discussing the potential role of these components in bone tissue. Moreover, the most relevant jawbone and maxillofacial applications of polymeric composites will be revised in this article, collecting the main knowledge about this topic and emphasizing the need of further clinical studies in humans.

Chronic venous insufficiency (CVI), in which blood return to the heart is impaired, is a prevalent condition worldwide. Valve incompetence is a complication of CVI that results in blood reflux, thereby aggravating venous hypertension. While CVI has a complex course and is known to produce alterations in the vein wall, the underlying pathological mechanisms remain unclear. This study examined the presence of DNA damage, pro-inflammatory cytokines and extracellular matrix remodelling in CVI-related valve incompetence. One hundred and ten patients with CVI were reviewed and divided into four groups according to age (<50 and ≥50 years) and a clinical diagnosis of venous reflux indicating venous system valve incompetence (R) (n = 81) or no reflux (NR) (n = 29). In vein specimens (greater saphenous vein) from each group, PARP, IL-17, COL-I, COL-III, MMP-2 and TIMP-2 expression levels were determined by RT-qPCR and immunohistochemistry. The younger patients with valve incompetence showed significantly higher PARP, IL-17, COL-I, COL-III, MMP-2 and reduced TIMP-2 expression levels and a higher COL-I/III ratio. Young CVI patients with venous reflux suffer chronic DNA damage, with consequences at both the local tissue and systemic levels, possibly associated with ageing., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Chronic venous disease (CVD) is the response to a series of hemodynamic changes in the venous system and the onset of this disease is often triggered by pregnancy. Placental tissue is particularly sensitive to the characteristic changes which occurs in venous hypertension. In this regard, changes in the extracellular matrix (ECM), that occur to adapt to this situation, are fundamental to controlling elastogenesis. Therefore, the aim of the present study was to analyze the changes that occur in the mRNA and protein expression level of proteins related to elastogenesis in the placental villi of women diagnosed with CVD, in the third trimester of pregnancy. An observational, analytical and prospective cohort study was conducted, in which the placenta from 62 women with CVD were compared with that in placenta from 52 women without a diagnosis of CVD. Gene and protein expression levels were analyzed using reverse transcription‑quantitative PCR and immunohistochemistry, respectively. The results showed a significant decrease in the gene and protein expression level of EGFL7 in the placental villi of women with CVD. By contrast, significant increases in the gene and protein expression level of ECM‑related proteins, such as tropoelastin, fibulin 4, fibrillin 1 and members of the lysyl oxidase family (LOX and LOXL‑1) were also found in the placental villi of women with CVD. To the best of our knowledge, the results from the present study showed for the first time that CVD during pregnancy was associated with changes in the mRNA and protein expression level in essential components of the EGFL7‑modulated elastogenesis process in placental villi.

Introduction: Chronic venous disorder (CVeD) has a high prevalence, being commonly diagnosed by the presence of varicose veins. In fact, the development of varicose veins in lower extremities and/or pelvic venous insufficiency (LEPVI) is frequent. However, its potential impact on fetal health has not been investigated. This study aimed to examine whether the presence of varicose veins in women's LEPVI is related to an intrapartum fetal compromise event. Materials: A cross-sectional, national study was conducted using medical administrative records (CMBD) of all vaginal births ( n = 256,531) recorded in 2015 in Spain. The independent variable was defined as the presence of varicose veins in the legs, vulva, and perineum or hemorrhoids. A logistic regression model was used to assess the association of interest. Results: Among women with vaginal deliveries, those with varicose veins in their LEPVI have a significantly greater odds of intrapartum fetal compromise (OR = 1.30, 99.55%CI = 1.08-1.54) than their counterparts without varicose veins. After adjustment, this association remained significant (OR = 1.25, 99.5%CI = 1.05-1.50). Conclusions: Our findings of an association between varicose veins in women's lower extremities and/or pelvis and intrapartum fetal compromise suggest that varicose veins may be a novel and important clinical risk factor for fetal well-being and health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Asúnsolo, Chaowen, Ortega, Coca, Borrell, De León-Luis, García-Honduvilla, Álvarez-Mon and Buján.)

Lower limbs venous insufficiency refers to a wide variety of venous disorders grouped by the term of chronic venous disease (CVD). Hemodynamic and hormonal changes related to pregnancy period, may promote the development of CVD affecting approximately 1 in 3 women. It has been shown that the presence of this condition is associated with damage and placental suffering. Thus, taking IGF-1/PAPP-A/STC-2, inflammatory cytokines production, PI3K/Akt and Wnt/ β-catenin pathways as a part of the alterations that occurs in the placenta due to CVD, the aim of this study will be to examine the main components of these pathways. Genic and protein expression of PAPP-A, STC-2, IGF-1, IRS-4 Wnt-1, β-catenin, c-myc, Cyclin D1, IL-4/IL-6 and PI3K/Akt/mTOR pathway will be analysed through RT-qPCR and immunohistochemical techniques in women with CVD (n=62) and pregnant women without this condition (HC) (n=52). PAPP-A, IGF-1, IL-4, IL-6, IRS-4, PI3K, Akt, mTOR, Wnt-1, β-catenin, c-myc and Cyclin D1 expression were found to be increased in women with CVD, whereas STC-2 were decreased in this group, compared to non-affected women. Our study has demonstrated that IGF-1/PAPP-A/STC-2 axis, PI3K/Akt and Wnt/β-catenin pathways, along with c-myc, Cyclin D1 and inflammatory cytokines are altered in placenta women with CVD. These results extent the knowledge that CVD is associated to a placenta damage with abnormal tissue environment and cellular regulation., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The pathogenesis of chronic venous disorder (CVeD) remains partially understood. A marked wall remodeling has been shown with potential accelerated tissue senescence. We have investigated the expression of peroxisome proliferator-activated receptor (PPAR) isoforms transcription factor EB (TFEB) as regulatory molecules of cellular homeostasis and makers of peroxisomal and lysosomal biogenesis. We have also quantified p16 expression as a cellular senescence marker. In specimens of maior safena vein from 35 CVeD and 27 healthy venous controls (HV), we studied the expression of PPAR-α, PPAR-β/δ, PPAR-γ, TFEB and p16 by RT-qPCR and immunohistochemical techniques. We have demonstrated a reduced gene and protein expression of the PPAR-α and PPAR-β/δ isoform as well as that of TFEB in the venous wall of CVeD patients, suggesting an altered peroxisomal and lysosomal biogenesis associated with an increased cellular senescence shown by increased p16 expression.

Objective: To compare pelvic floor disorders between vaginal delivery (VD) and cesarean delivery (CD)., Methods: For this study, a PUBMED database search was used, utilizing a combination of relevant medical subjects' headings (MeSH) terms, with the following keywords: "Pelvic floor disorders" or "Pelvic floor morbidity" and "Delivery". Search limits were articles in English or Spanish, about women, published from December 2009 to December 2019. The STATA 16 package was used for meta-analysis and data heterogeneity assessment., Results: Thirteen studies meeting eligibility criteria were identified comprising 1,597,303 participants. Abstract: Pelvic floor morbidity prevalence was Urinary Incontinence (UI) 27.9% (5411 patients in 7 studies with reported cases), Pelvic Organ Prolapse (POP) 14.2% (6019 patients in 8 studies with reported cases), and Anal Incontinence (AI) 0.4% (1,589,740 patients in 5 studies with reported cases). Our meta-analyses revealed significantly higher rates of all three morbidities and overall morbidity in the VD versus CD group: UI OR = 2.17, 95% CI 1.64-2.87, p for heterogeneity ≤ 0.0001, I 2 = 84%; POP OR = 3.28, 95% CI 1.91-5.63, p for heterogenicity ≤ 0.043, I 2 = 63%; AI OR = 1.53, 95% CI 1.32-1.77; p for heterogeneity ≤ 0.291, I 2 = 20%; and overall morbidity (OR = 2.17, 95% CI 1.64-2.87; p for heterogeneity ≤ 0.0001, I 2 = 84%)., Conclusion: Vaginal delivery is directly related to the appearance of pelvic floor disorders, mainly UI, POP, and AI. The risk of POP should be taken into higher consideration after vaginal delivery and postpartum follow-up should be performed, to identify and/or treat it at the earliest stages.

Chronic venous insufficiency (CVI) is one of the most common vascular pathologies worldwide. One of the risk factors for the development of CVI is aging, which is why it is related to senile changes. The main trigger of the changes that occur in the venous walls in CVI is blood flow reflux, which produces increased hydrostatic pressure, leading to valve incompetence. The cellular response is one of the fundamental processes in vascular diseases, causing the activation of cell signalling pathways such as c-Jun N-terminal kinase (JNK). Metabolic changes and calcifications occur in vascular pathology as a result of pathophysiological processes. The aim of this study was to determine the expression of JNK in venous disease and its relationship with the role played by the molecules involved in the osteogenic processes in venous tissue calcification. This was a cross-sectional study that analyzed the greater saphenous vein wall in 110 patients with (R) and without venous reflux (NR), classified according to age. Histopathological techniques were used and protein expression was analysed using immunohistochemistry techniques for JNK and markers of osteogenesis (RUNX2, osteocalcin (OCN), osteopontin (OPN)). Significantly increased JNK, RUNX2, OCN, OPN and pigment epithelium-derived factor (PEDF) protein expression and the presence of osseous metaplasia and amorphous calcification were observed in younger patients (<50 years) with venous reflux. This study shows for the first time the existence of an osteogenesis process related to the expression of JNK in the venous wall., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

SARS‑CoV‑2 is a newly discovered member of the betacoronaviruses and the etiological agent of the disease COVID‑19. SARS‑CoV‑2 is responsible for the worldwide pandemic which has been taking place in 2020, and is causing a markedly higher number of infections and deaths compared to previous coronaviruses, such as SARS‑CoV or MERS‑CoV. Based on updated scientific literature, the present review compiles the most relevant knowledge of SARS‑CoV‑2, COVID‑19 and the clinical and typical responses that patients have exhibited against this virus, discussing current and future therapies, and proposing strategies with which to combat the disease and prevent a further global threat. The aggressiveness of SARS‑CoV‑2 arises from its capacity to infect, and spread easily and rapidly through its tight interaction with the human angiotensin‑converting enzyme 2 (ACE‑2) receptor. While not all patients respond in a similar manner and may even be asymptomatic, a wide range of manifestations associated with COVID‑19 have been described, particularly in vulnerable population groups, such as the elderly or individuals with other underlying conditions. The proper function of the immune system plays a key role in an individual's favorable response to SARS‑CoV‑2 infection. A hyperactivated response, on the contrary, could account for the more severe cases of COVID‑19, and this may finally lead to respiratory insufficiency and other complications, such as thrombotic or thromboembolic events. The development of novel therapies and vaccines designed to control and regulate a proper immune system response will be key to clinical management, prevention measures and effective population screening to attenuate the transmission of this novel RNA virus.

Immunodeficient mouse models with human skin xenografts have been developed in the past decades to study different conditions of the skin. Features such as follow-up period and size of the graft are of different relevance depending on the purpose of an investigation. The aim of this study is to analyze the different mouse models grafted with human skin. A systematic review of the literature was performed in line with the PRISMA statement using MEDLINE/PubMed databases from January 1970 to June 2020. Articles describing human skin grafted onto mice were included. Animal models other than mice, skin substitutes, bioengineered skin, postmortem or fetal skin, and duplicated studies were excluded. The mouse strain, origin of human skin, graft dimensions, follow-up of the skin graft, and goals of the study were analyzed. Ninety-one models were included in the final review. Five different applications were found: physiology of the skin (25 models, mean human skin graft size 1.43 cm2 and follow-up 72.92 days), immunology and graft rejection (17 models, mean human skin graft size 1.34 cm2 and follow-up 86 days), carcinogenesis (9 models, mean human skin graft size 1.98 cm2 and follow-up 253 days), skin diseases (25 models, mean human skin graft size 1.55 cm2 and follow-up 86.48 days), and would healing/scars (15 models, mean human skin graft size 2.54 cm2 and follow-up 129 days). The follow-up period was longer in carcinogenesis models (253 ± 233.73 days), and the skin graft size was bigger in wound healing applications (2.54 ± 3.08 cm2). Depending on the research application, different models are suggested. Careful consideration regarding graft size, follow-up, immunosuppression, and costs should be analyzed and compared before choosing any of these mouse models. To our knowledge, this is the first systematic review of mouse models with human skin transplantation., (© 2021 S. Karger AG, Basel.)

Chronic venous disease (CVeD) has a remarkable prevalence, with an estimated annual incidence of 2%. It has been demonstrated how the loss of homeostatic mechanisms in the vein wall can take part in the physiopathology of CVeD. In this regard, it has been described how different axis, such as IGF-1/PAPP-A/STC-2 axis, may play an essential role in tissue homeostasis. The aim of this research is to study both genetic and protein expressions of the IGF-1/PAPP-A/STC-2 axis in CVeD patients. It is a cross-sectional study in which genetic (RT-qPCR) and protein (immunohistochemistry) expression analysis techniques were accomplished in saphenous veins from CVeD patients ( n = 35) in comparison to individuals without vascular pathology (HV). Results show a significant increase in both genetic and protein expressions of PAPP-A and IGF-1, and a decrement STC-2 expression at the same time in CVeD patients. Our study is a pioneer for demonstrating that the expression of the different components of the IGF-1/PAPP-A/STC-2 axis is altered in CVeD patients. This fact can be a part of the loss of homeostatic mechanisms of the venous tissue. Further research should be destined to deepen into alterations of this axis, as well as to evaluate the usage of these components as therapeutic targets for CVeD., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Miguel A. Ortega et al.)

Postpartum depression (PPD) affects 13% of mothers and can have a major impact on their lives and those of their children. However, most cases go undiagnosed, and the risk factors for this underdiagnosis are not yet fully known. We intended to analyze the influence of different sociodemographic and health factors associated with symptoms of postpartum depression. Data from the New York City Pregnancy Risk Assessment Monitoring System (PRAMS) for 2016-2017 were analyzed. 618 women met the inclusion criterion of recurring depressive symptoms. Most women who experienced PPD symptoms did not seek help. Seeking help was a much better predictor of the diagnosis of PPD when compared to questions regarding symptoms. The most important factors related to a decreased risk of not asking for help were having a previous mental health history and having doctor visits for a chronic illness. The racial group most at risk of not asking for help were Asian/Pacific Islander (API) women. Interventions aimed at reducing the stigma and increasing knowledge of PPD should be incorporated into the antenatal education of expectant mothers, particularly among women who may not have previously sought care for mental or chronic illnesses.

This study was designed to examine maternal-perinatal outcomes in pregnant women with suspected coronavirus disease 2019 (COVID-19) according to the result of a real-time reverse transcription polymerase chain reaction (RT-PCR) test and to investigate possible variables that could be useful for predicting a negative RT-PCR result. Participants of this retrospective cohort study were obstetrics patients with suspected COVID-19 who underwent an RT-PCR test in a tertiary hospital in Madrid, Spain. Maternal-perinatal features were analysed according to the results of this test. Clinical, radiological and analytical characteristics that could be associated with a negative result were also explored. In a final subgroup analysis, patients were included if they had pneumonia and a negative test result for the virus. Out of the 111 obstetric patients with suspected COVID-19 that were enrolled, 38.7% returned a negative result. In this RT-PCR-negative group, we recorded lower rates of pneumonia (21.4% vs. 45.6%, p = 0.009), severe or critical clinical features (4.7% vs. 11.8% and 0.0% vs. 5.9%, p = 0.02, respectively), lower lactate dehydrogenase (LDH) levels (168 UI/L vs. 224.5 UI/L, p = 0.003), a greater need for maternal treatment (60.3% vs 24.4%, p < 0.001), a reduced need for oxygen therapy (2.4% vs 28.8%, p < 0.001) and a lower rate of intensive care unit admission (0.0% vs. 3.7%, p = 0.046) than the RT-PCR-positive group. While no differences were found in other variables, the monocyte count was higher (946.2/μL vs. 518.8/μL, p = 0.022) in this group. The predictive model for a negative test result included the monocyte count, LDH level and no need for oxygen therapy. This model was able to identify 73.5% of patients with a negative RT-PCR result. Only 11% of the patients with pneumonia testing negative for the virus had IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The proportion of pregnant women with suspected COVID-19 and a negative RT-PCR result was nearly 39%. In these patients, the symptoms were mild and the systemic severity of the disease was lower. The monocyte count, LDH level and no need for oxygen therapy were the factors that were more related to a negative test result in this group. These variables could be used to guide the management of patients with suspected COVID-19, mainly while waiting for RT-PCR results or in settings where this test is not available.

Background: Chronic venous disease (CVD) is a prevalent lower limb venous pathology that especially affects women, who also show an increased risk of this disease during pregnancy. Studies have shown significant structural changes in the placentas of women with CVD and several markers of tissue damage have been also described. Patients and Methods: To try to understand the different placental pathologies, research efforts have focused on examining metabolomic profiles as indicators of the repercussions of these vascular disorders. This study examines changes produced in the metabolomic profiles of chorionic villi in the placentas of women with CVD. In a study population of 12 pregnant women, 6 with and 6 without CVD, we compared through mass spectroscopy coupled to ultra-high performance liquid chromatography (UHPLC-MS), 240 metabolites in chorionic villus samples. Results: This study is the first to detect in the placental villi of pregnant women with CVD, modifications in lysophosphatidylcholines and amino acids along with diminished levels of other lipids such as triglycerides, sphingomyelins, and non-esterified omega 9 fatty acids, suggesting a role of these abnormalities in the pathogenesis of CVD. Conclusions: Our findings are a starting point for future studies designed to examine the impacts of CVD on maternal and fetal well-being., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Obesity is a condition of rising prevalence worldwide, with important socioeconomic implications, being considered as a growing public health concern. Frequently, obesity brings other complications in addition to itself-like Type 2 Diabetes Mellitus (T2DM)-sharing origin, risk factors and pathophysiological mechanisms. In this context, some authors have decided to include both conditions as a unique entity known as "diabesity". In fact, understanding diabesity as a single disease is possible to maximise the benefits from therapies received in these patients. Gut microbiota plays a key role in individual's health, and their alterations, either in its composition or derived products are related to a wide range of metabolic disorders like T2DM and obesity. The present work aims to collect the different changes reported in gut microbiota in patients with T2DM associated with obesity and their possible role in the onset, development, and establishment of the disease. Moreover, current research lines to modulate gut microbiota and the potential clinical translation derived from the knowledge of this system will also be reviewed, which may provide support for a better clinical management of such a complex condition.

Breast cancer is the most prevalent and incident female neoplasm worldwide. Although survival rates have considerably improved, it is still the leading cause of cancer-related mortality in women. MicroRNAs are small non-coding RNA molecules that regulate the posttranscriptional expression of a wide variety of genes. Although it is usually located in the cytoplasm, several studies have detected a regulatory role of microRNAs in other cell compartments such as the nucleus or mitochondrion, known as "mitomiRs". MitomiRs are essential modulators of mitochondrion tasks and their abnormal expression has been linked to the aetiology of several human diseases related to mitochondrial dysfunction, including breast cancer. This review aims to examine basic knowledge of the role of mitomiRs in breast cancer and discusses their prospects as biomarkers or therapeutic targets.

Pregnancy is a period in a woman's life associated with an increased risk of developing lower extremity chronic venous disease (CVD). Pregnancy-associated CVD is associated with changes in placental villi. We investigated angiogenesis and lymphangiogenesis in the placental villi of women with CVD during pregnancy compared with healthy controls with no history of CVD (HC). An observational, analytical, and prospective cohort study was conducted on 114 women in their third trimester of pregnancy (32 weeks). Sixty-two participants were clinically diagnosed with CVD. In parallel, 52 controls with no history of CVD (HC) were studied. Gene and protein expression of CD31, podoplanin (D2-40), Flt-1, and placental growth factor (PIGF) was analysed by real-time polymerase chain reaction (RT-qPCR) and immunohistochemistry. CD31 and D2-40 gene expression was significantly greater in the placental villi of women with CVD, as were the numbers of vessels positive for CD31 and D2-40. Significantly higher gene and protein expression of Flt-1 and PIGF was observed in the placental villi of women with CVD. Histological analysis showed more placental villi with periodic acid of Schiff (PAS)-positive material in women with CVD. Our results show a connection between pregnancy-associated CVD and leading to higher proangiogenic and lymphangiogenic activity in placental villi.

The development of lower extremity venous insufficiency (VI) during pregnancy has been associated with placental damage. VI is associated with increased oxidative stress in venous wall. We have investigated potential disturbance/dysregulation of the production of reactive oxygen species (ROS) in placenta and its eventual systemic effects through the measurement of malondialdehyde (MDA) plasma levels in women with VI. A total of 62 women with VI and 52 healthy controls (HCs) were studied. Levels of nicotinamide adenine dinucleotide phosphate-oxidase 1 (NOX1), 2 (NOX2), inducible nitric oxide synthase (iNOS), endothelial (eNOS), poly(ADP-ribose) polymerase PARP (PARP) and ERK were measured in placental tissue with immunohistochemistry and RT-qPCR. Plasma and placental levels of MDA were determined by colorimetry at the two study times of 32 weeks of gestation and post-partum. Protein and gene expression levels of NOX1, NOX2, iNOS, PARP and ERK were significantly increased in placentas of VI. eNOS activity was low in both study groups, and there were no significant differences in gene or protein expression levels. Women with VI showed a significant elevation of plasma MDA levels at 32 weeks of gestation, and these levels remained elevated at 32 weeks post-partum. The MDA levels were significantly higher in placentas of women with VI. Placental damage that was found in the women with VI was characterized by overexpression of oxidative stress markers NOX1, NOX2, and iNOS, as well as PARP and ERK. Pregnant women with VI showed systemic increases in oxidative stress markers such as plasma MDA levels. The foetuses of women with VI had a significant decrease in their venous pH as compared to those from HC women. The situation of oxidative stress and cellular damage created in the placenta is in coexpression with the production of a pH acidification., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Breast cancer is the cancer with the highest prevalence in women and is the number-one cause of cancer mortality worldwide. Cell transduction is a fundamental process in the development and progression of cancer. Modifications in various cell signalling pathways promote tumour cell proliferation, progression, and survival. The PI3K/Akt/mTOR pathway is an example of that, and it is involved in growth, proliferation, survival, motility, metabolism, and immune response regulation. Activation of this pathway is one of the main causes of cancer cell resistance to antitumour therapies. This makes PI3K/Akt/mTOR signalling a crucial object of study for understanding the development and progression of this disease. Thus, this pathway may have a role as a potential therapeutic target, as well as prognostic and diagnostic value, in patients with breast cancer. Despite the existence of selective PI3K/Akt/mTOR pathway inhibitors and current clinical trials, the cellular mechanisms are not yet known. The present review aims to understand the current state of this important disease and the paths that must be forged., Competing Interests: The authors declare that they have no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Miguel A. Ortega et al.)

Pregnancy is a period in a woman's life in which changes can occur that affect different physiological processes. Common conditions during this period include vascular changes, such as lower extremity venous insufficiency (VI). This is an observational, analytical, and prospective cohort study in which 114 pregnant women were analyzed, of which 62 were clinically diagnosed with VI. In parallel, 52 control patients without VI (HC) were studied. The aim of this study was to observe changes in angiogenesis and inflammation markers as well as the presence of calcium deposits. The expression of vascular endothelial growth factor (VEGF), transforming growth factor- β (TGF- β ), and pigment epithelium-derived factor (PEDF) was analyzed by immunohistochemistry and RT-qPCR. The presence of calcium deposits was revealed using the von Kossa method. In the placentas of mothers with VI, gene expression of VEGF (34.575 [32.380-36.720] VI vs 32.965 [30.580-36.320] HC) and PEDF (25.417 [24.459-27.675] VI vs 24.400 [23.102-30.223] HC) significantly increased, as was protein expression in the placental villi. An increase in calcium deposits was observed in the placentas of women with VI (72.58% VI/53.84% HC). This study revealed the existence of cellular damage in the placental villi of mothers with VI with tissue implications such as increased calcification., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Miguel A Ortega et al.)

Joint prostheses are an essential element to improve quality of life. However, prostheses may fail due to several factors, including the most frequent cause, Staphylococcus aureus infection. The identification of new fixing bone cements with less reactivity on bone tissue and an adequate response to infection remains a primary challenge. The aim of this study is to evaluate the response of bone tissue in rabbits after introduction of a hydroxyapatite-coated titanium rod with a commercial fixative cement (Palacos®) compared to a modified experimental cement (EC) containing polylactic-co-glycolic acid (PLGA) microspheres in the presence or absence of contaminating germs. This study used 20 New Zealand rabbits which were divided into four groups (n = 5) depending on the presence or absence of S. aureus and the use of commercial (Palacos®) or EC. A histological method, based on bone architecture damage, was proposed to evaluate from 1 to 9 the histological results and the response of the infected tissue. The macrophage response was also evaluated using monoclonal antibody RAM-11. The study showed better bone conservation with the use of EC with PLGA microspheres against the Palacos® commercial cement, including the noncontaminated and contaminated groups. © 2019 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2517-2526, 2019., (© 2019 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals, Inc.)

Chronic venous insufficiency (CVI) is a disease that impacts cellular homeostasis. CVI may occur with a valvular destruction process known as venous reflux or valvular incompetence. One of the cellular processes that may be triggered as a consequence of these events is the production of reactive oxygen species (ROS), which may trigger the production of different cellular markers and cell damage processes, such as lipid peroxidation. Therefore, the present study performed an observational, analytical, and prospective cohort study by reviewing 110 patients with CVI, and the activities and plasma levels of iNOS, eNOS, NOX1, and NOX2 were determined using immunohistochemistry and RT-qPCR. Lipid peroxidation (MDA) was also measured. Patients were distributed according to the presence or absence of valvular incompetence-venous reflux, which was diagnosed clinically as the absence of venous reflux (NR = 29) or presence of venous reflux (R = 81). Each group was divided according to age, with a cutoff point of fifty years (NR < 50 = 13, NR ≥ 50 = 16, R < 50 = 32, and R ≥ 50 = 49). The results showed that R patients exhibited significantly increased plasma MDA levels, and R < 50 patients exhibited the highest statistically significant increase. iNOS, NOX1, and NOX2 exhibited the highest gene and protein expression in R patients. The increased expression was maintained in the R < 50 patients. Our data suggest that young patients with valvular incompetence (venous reflux) show higher levels of lipid peroxidation and oxidative stress, which reflects the characteristics of an aged patient.

Varicose veins are a disease with high incidence and prevalence. In the venous wall, the smooth muscle cells (SMCs) act in the vascular homeostasis that secretes multiple substances in response to stimuli. Any alteration of these cells can modify the function and structure of the other venous layers such as the endothelium, resulting in increases in endothelial permeability and release of substances. Therefore, knowing the cellular and molecular mechanisms of varicose veins is imperative. The aims of this study are to understand how SMCs of patients with varicose veins subjected to saphenectomy of the great saphenous vein react under hypoxic cell conditions and to determine the role of vascular endothelial growth factor (VEGF) in this process. We obtained SMCs from human saphenous vein segments from patients with varicose veins (n=10) and from organ donors (n=6) undergoing surgery. Once expanded, the cells were subjected to hypoxic conditions in specific chambers, and expansion was examined through analyzing morphology and the expression of α -actin. Further gene expression studies of HIF-1 α , EGLN3, VEGF, TGF- β 1, eNOS, and Tie-2 were performed using RT-qPCR. This study reveals the reaction of venous cells to sustained hypoxia. As significant differential gene expression was observed, we were able to determine how venous cells are sensitive to hypoxia. We hypothesize that venous insufficiency leads to cellular hypoxia with homeostatic imbalance. VEGF plays a differential role that can be related to the cellular quiescence markers in varicose veins, which are possible therapeutic targets. Our results show how SMCs are sensitive to hypoxia with a different gene expression. Therefore, we can assume that the condition of venous insufficiency leads to a situation of sustained cellular hypoxia. This situation may explain the cellular response that occurs in the venous wall as a compensatory mechanism.

In chronic venous insufficiency of the lower limbs, data show that the clinical manifestation is varicose veins (VVs), and VV epidemiology suggests that sex hormones directly influence disease development through intracellular receptors. This study aimed to determine the presence and localization of oestrogen receptors (ERs), progesterone receptors (PRs), and androgen receptors (ARs) in both healthy and VV wall cells and their relationship with gender. In this study, samples from patients without a history of venous disease (CV) ( n = 18) and with VV ( n = 40) were used. The samples were divided by gender: CV women (CVw) = 6, CV men (CVm) = 12, VV women (VVw) = 25, and VV men (VVm) = 15. RT-qPCR and immunohistochemical techniques were performed, and increased ER and PR protein expression was found in VVw in all tunica layers. ARs were localized to the adventitial layer in the CV and were found in the neointima in VVs. mRNA expression was increased for ER and PR in VVw. AR gene expression was significantly decreased in VVm. The increase in the number of these receptors and their redistribution through the wall reinforces the role of sex hormones in varicose vein development.

Despite advances in regenerative medicine and tissue engineering, human skin substitutes remain a clear goal to achieve. Autografts remain the principal clinical option. The long-term changes in dermis, as well as its response after injuries, are not well known. Research in this field has been hindered by a lack of experimental animal models. This study analyzes the architectural dermal scaffold (collagen and elastin fibers plus fibrillin-microfibrils) changes in a model of human skin pressure ulcers in mice. Immunosuppressed NOD/Scid mice (n=10) were engrafted with human skin of dimensions 4x3 cm. After 60 days as a permanent graft, a pressure ulcer (PU) was created in the human skin using a compression device. Three study groups were established: full-thickness skin graft before (hFTSG) and after applying mechanical pressure (hFTSG-PU). Native human skin was used as control group. Evaluations were conducted with visual and histological assessment. Scaffold components from each group were compared by immunohistochemical staining (tropoelastin, collagen I and III, metalloproteins (MMP), fibulins, and lysil oxidases (LOX) among others). The long-term engrafted skin showed a certain degradative state of dermis scaffold, as noticed by the active expression of MMPs and tropoelastin compared to native skin. However, a great reparative response after pressure ulcer onto the engrafted skin was observed. A significant increase of fibrillin microfibrils components (TGF-β, MAGP-1 and fibrillin-1), and matrix suprastructures of collagen I, III and LOX lead to an active restructuration of dermal tissue. Our human skin model in mice revealed the important role of the dermal scaffold component to reach skin stability and its capability to react to mechanical pressure injuries. These results showed the important role of dermal scaffold to support the histoarchitecture and mechanosensation of the human skin.

Chronic venous insufficiency (CVI) is a multifactorial disease, commonly caused by valvular incompetence (clinically diagnosed by venous reflux) and venous hypertension. The incidence of these factors clearly increases with patient age, and aging is one of the risk factors involved. The activity of the PI3K/Akt/mTOR pathway is considered fundamental in vascular pathologies, and understanding its involvement would help in the development of possible therapeutic targets. This is an observational, analytical, and prospective cohort study that reviewed 110 patients with CVI scheduled to undergo stratified saphenectomy. They were distributed according to the presence (R = 81) or absence (NR = 29) of valvular incompetence (venous reflux) diagnosed clinically. Each of the groups was further divided according to age, with a cutoff point of 50 years (NR < 50 = 13, NR ≥ 50 = 16, R < 50 = 32, and R ≥ 50 = 49). The involvement of the PI3K/Akt/mTOR pathway, as well as that of HIF-1 α and HIF-2 α and of CD4+, CD8+, and CD19+ cells and mastocytes, was assessed. Saphenous vein tissue samples obtained during surgery were processed for RT-qPCR and immunohistochemistry. Patients with venous reflux showed a significant increase in mRNA and protein expression levels for PI3K/mTOR and HIF-1 α /HIF-2 α . The number of mast cells was significantly elevated in the R group. In distribution by age, PI3K/Akt/mTOR and HIF-1 α were significantly higher in R < 50 patients. Furthermore, these patients had a significant increase in the number of CD4+, CD8+, and CD19+ cells and mastocytes in the saphenous vein wall. These findings provide a basis for the possible existence of changes in PI3K/Akt/mTOR pathway expression in young patients, with potential accelerated asynchronous aging that is enhanced by CVI.

Lower extremity venous insufficiency (VI) is a complication of pregnancy. The potential association of this venous disease with structural damage of the placenta has not been described. We analyzed the pattern of histopathologic lesions and the gene and protein expression of HIF1-α and apoptosis regulatory proteins. A prospective study was carried out on placenta samples from 43 women with pregnancy-associated VI and 24 age-matched pregnant healthy controls (HCs). Women with VI showed a significant increase in the number of villi (150.77 ± 42.55 VI versus 122.13 ± 27.74 HC) and in syncytial knots compared with those found in the placentas from HCs (67.15 ± 31.08 VI versus 42.49 ± 17.36 HC), and an increase in the number of bridges (32.40 ± 2.67 VI versus 22.73 ± 2.37 HC; P < .05). The mean number of syncytial nodes per villus is 1.37 ± 0.90 in the VI group and 0.49 ± 0.58 in the HC group (P < .001). Significant increases in the expression of Bax and caspase-3 and caspase-9 in the placentas from women with VI were observed compared with those found in HC. The expression of HIF-1α at both the messenger RNA and protein levels was also significantly increased in the placentas from women with VI. Our study demonstrates that placentas from women with pregnancy-associated VI show structural remodeling, with an increase in the number of villi and syncytial knots and enhanced apoptotic cellular death. Interestingly, this placental damage is associated with an increased expression of hypoxia-triggered molecular pathways, such as HIF-1α., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Haemodynamic changes produced during pregnancy lead to elevated venous pressure in the legs and an increased resting consumption of oxygen. These events can cause varicose veins, or venous insufficiency (VI), which by creating an environment of hypoxia could affect the structure and function of the placental barrier. This study assesses the remodelling state of the placental villi by examining differences in collagens with a known role in villus structure and in placental barrier permeability between patients with and without VI. Samples of 67 placentas from women with VI (n=24) and without VI (n=43) during their pregnancy were processed for gene and protein expression analysis of COL-I, COL-III, MMP-2 and MMP-9 by RT-qPCR and immunohistochemistry. While no differences in COL-I expression levels were detected in the samples from women with and without VI, significant differences did emerge in both gene and protein expression levels of COL-III. Importantly, COL-I/III ratios were reduced in the VI group compared to controls. MMP-2 activity was similar in the two groups while MMP-9 levels were significantly elevated in VI with greatest expression differences observed at the level of the decidual cells. Mothers who developed VI during pregnancy showed significantly higher COL-III and MMP-9 levels consistent with a state of remodelling of the placental villi.

Chronic venous disorder (CVeD), is a disorder in which there is a modification in the conditions of blood return to the heart. The disorder may arise from incompetent valves and the resultant venous reflux (chronic venous insufficiency, CVI). The economic burden of CVeD on health systems is high, and research efforts have sought to elucidate the mechanisms involved as possible therapeutic targets. The mitogen-activated protein kinase (MAPK) enzymes mediate a wide array of physiopathological processes in human tissues. In this family of proteins, extracellular signal-regulated kinase (ERK)1/2 plays a direct role in the cell homeostasis that determines the viability of mammalian tissues. This study sought to examine whether ERK1/2 plays a role in venous reflux. This was a prospective study performed on 56 participants including 11 healthy controls. Of the CVeD patients, 23 had venous reflux with CVI (CVI-R) and 22 had no reflux (NR). Distribution by age was: controls <50 years (n = 4) and ≥50 years (n = 7); NR <50 years (n = 9) and ≥50 years (n = 13); CVI-R <50 years (n = 11) and ≥50 years (n = 12). Great saphenous vein specimens were subjected to gene (real-time polymerase chain reaction, RT-qPCR) and protein (immunohistochemistry, IHC) expression techniques to identify ERK1/2. Data was compared between groups using the Mann Whitney U test. Patients with CVI showed significant gene activation of ERK1/2 protein, and, in those with venous reflux, the expression of this gene was significantly greater. The CVI-R group <50 years showed significantly greater ERK1/2 gene expression than their age-matched controls. Expression patterns were consistent with IHC findings. Our studies suggest that ERK1/2 expression is involved in venous vascular disease., (© 2019 S. Karger AG, Basel.)

Purpose: We evaluated the expression of several extracellular matrix constituents implicated in the synthesis and reticulation of elastin in human pterygium, according to age and sex of the patients., Methods: Pterygia and normal conjunctiva samples were divided into groups according to age (<50/≥50 years) and sex. Tissue was subjected to immunohistochemical staining with anti-lysyl oxidase (LOX), lyxyl oxidase-like 1 (LOXL-1), fibulin (FBLN)-5 and FBLN4, and fibrillin-1 (FBN1) antibodies. Specific primers for the same constituents were used in a quantitative real-time PCR (qRT-PCR) analysis to determine gene expression., Results: The LOXL-1 (P = 0.0002), FBLN5 (P = 0.0035), and FBN1 (P < 0.0001) mRNAs were significantly higher in pterygium than conjunctiva. No differences were found for LOX and FBLN4 mRNA. The expression of LOXL-1 was not affected by age or sex; however, pterygium from men and patients over 50 years old exhibited significantly higher FBLN5/FBN1 expression than did controls. The LOX gene expression was higher in the pathologic samples from the over 50-year-olds compared to the conjunctiva (P = 0.0396) and in men's versus women's pterygium (P = 0.0173). In general, the levels of LOX, LOXL-1, and FBLN5 decreased with age in healthy samples, while the pathology seemed to have increased expression of the three proteins, and even more so in older patients. The FBLN4 and FBN1 immunostaining was slight in all samples, displaying no differences between groups., Conclusions: Several extracellular matrix constituents, LOXs, FBN1, and FBLN5, implicated in the development of elastin, are overexpressed in the subepithelial connective tissue extracellular matrix of human pterygium, supporting our hypothesis that elastic synthesis and reticulation is dysregulated in this type of pathology., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)