Endovascular Technique for Ascending Aorta Repair Based on TEVAR and TAVI Procedures.

PURPOSE: Ascending aorta (AAo) acute pathology still has an open-surgery indication with a high mortality rate associated to cardiopulmonary bypass and circulatory arrest. In these cases, the endovascular aortic approach could be an excellent option. The aim of the present study is to detail an optimized technique for the endovascular treatment of AAo diseases, based on thoracic endovascular aortic repair (TEVAR) and transcatheter aortic valve implantation (TAVI) procedures. TECHNIQUE: The procedure implies the usual preparation for TEVAR and TAVI implants. A transient pacemaker lead is necessary to deliver the prosthesis under "rapid pacing." As in the TAVI technique, a final high-support guidewire is placed at the left ventricle. The proximal landing zone is the sinotubular junction (zone 0B). Transesophageal echocardiography is essential to ensure aortic valve function and patency in coronary arteries during the delivery. To assess a potential occlusion of the brachiocephalic artery, a guidewire is positioned in the descending aorta from the axillary artery. Finally, a noncovered stent is implanted to stabilize the AAo prosthesis. CONCLUSION: The technique presented here can standardize a safe and reproducible procedure to endovascular repair of AAo diseases. However, new devices specifically designed for the AAo could facilitate the transcatheter approach. CLINICAL IMPACT: Ascending aorta acute pathology still has an open-surgery indication with high mortality rate associated to cardiopulmonary bypass and circulatory arrest. Moreover, near 30% of patients are not considered suitable for surgery because of age, critical situation or the presence of severe comorbidities. The present study provides a detailed and optimized technique for the endovascular treatment of ascending aorta disease, based on TEVAR and TAVI procedures.

Intermuscular S-ICD Implantation in Pediatric Patients.

The use of conventional implantable cardioverter-defibrillators (ICDs) in children presents important technical challenges. We present the surgical technique necessary to adapt the subcutaneous ICD (S-ICD) implantation designed for adults, to children, including patients weighing less than 20 kg. The implant procedure implies a two-incision technique and interfascial serratus anterior-latissimus dorsi dissection to accommodate the device. S-ICD implantation was successfully performed in three patients of 19, 28, and 24 kg, respectively, two of them suffered cardiorespiratory arrest. Intermuscular thoracic implantation of S-ICD might represent an effective strategy for primary or secondary prevention of sudden cardiac death in pediatric patients.

Immunophenotypic Conversion between Primary and Relapse Breast Cancer and its Effects on Survival.

BACKGROUND: The differential expression of oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2 (HER2) or Ki-67 between primary tumour and the recurrence has been described. We aimed to determine these changes and their prognostic implications. PATIENTS AND METHODS: We retrospectively reviewed 45 breast cancer patients with relapsed biopsy that were classified into local relapse (LR) or metastatic disease (MD) groups. We analyzed the conversion rate and the value of the immunophenotype of the primary tumour and the relapse as a prognostic factor for relapse-free survival (RFS), progression-free survival (PFS) and overall survival (OS). RESULTS: The conversion rate was 34.8% for Ki-67, 20% for ER, 20% for PR, and 15.6% for HER2. For the LR group, the RFS was 71.9 months and the OS was 141.6 months, without statistical differences according to the immunophenotype of the primary or the relapsed biopsy. For the MD group, the PFS was 20.8 months. According to immunophenotype of the relapse, the PFS were ER+ 24.7 months vs. ER- 9.3 months; PR+ 25.1 months vs. PR- 12.7 months without statistical differences according to HER2 or Ki67. The OS for MD group was 54.4 months without statistical differences according to immunophenotype. CONCLUSION: The characteristics of breast cancer can change over the time. Variations of the ER or PR status in MD group have prognostic value for PFS. To perform a biopsy of relapses is warranted in order to establish the prognostic of the current disease, and probably a more accurate treatment.

The role of exosomes on colorectal cancer: A review.

Exosomes are extracellular microvesicles released from cells, which are involved in many biological and pathological processes, mainly because of their role in intercellular communication. Exosomes derived from colorectal cancer (CRC) cells are related to oncogenesis, tumor cell survival, chemo-resistance, and metastasis. The role of the exosomes in these processes involves the transfer of proteins, RNAs, or mutant versions of proto-oncogenes to the target cells. In recent years, great efforts have been made to identify useful biomarkers in CRC exosomes for diagnosis, prediction of prognosis, and treatment response. This review focuses on recent studies on CRC exosomes, considering isolation, cargo, biomarkers, and the effects of exosomes on the development and progression of CRC, including resistance to antitumor therapy.

Antiproliferative Activity of Natural Taiwaniaquinoids and Related Compounds.

The in vitro antiproliferative activities of some taiwaniaquinoids and related compounds with functionalized A, B, or C rings against human breast (MCF-7), colon (T-84), and lung (A-549) tumor cell lines were assayed. The most potent compounds, 16, 27, and 36, were more effective than the naturally occurring taiwaniaquinones A (4) and F (5) in all three cell lines. The structure-activity relationship study of these new taiwaniaquinoids highlighted the correlation between the bromo substituent and the antiproliferative activity, especially in MCF-7 cells. These findings indicate that some of the taiwaniaquinoids might be useful as cytostatic agents against breast, colon, and lung cancer cell lines.

First enantiospecific syntheses of marine merosesquiterpenes neopetrosiquinones a and B: evaluation of biological activity.

The first enantiospecific syntheses of neopetrosiquinones A (6) and B (7), two merosesquiterpenes isolated from the deep-water sponge Neopetrosia cf. proxima, from the labdane diterpene trans-communic acid (10) have been achieved. A key step of the synthetic sequence is the simultaneous aromatization of the C ring and the benzylic oxidation on C-7 of an advanced intermediate, mediated by the oxygen-DDQ system. The in vitro antiproliferative activities of neopetrosiquinone B (7) and of the synthetic intermediates 8 and 9 against human breast (MCF-7), lung (A-549), and colon (T-84) tumor cell lines have been assayed. The most potent was compound 9 (IC50 = 4.1 µM), which was twice as active as natural compound 7 (IC50 = 8.3 µM) against A-549 cells. In addition, the treatment with these compounds resulted in an induction of apoptosis. These findings indicate that the terpene benzoquinones reported here might be potentially useful as anticancer agents.

Exosomes Derived from Breast Cancer Cells, Small Trojan Horses?

Exosomes are small extracellular vesicles secreted to the extracellular environment by several cell types, including tumor cells. It has been demonstrated that exosomes have an important role in intercellular communication, but they have recently been implicated in various tumor processes, including the oncogenic transformation of cells in the tumor microenvironment, tumor drug resistance, and the transport of tumor factors. Tumors appear to use exosomes to dialogue with and transform neighboring cells to create an ideal environment for their growth and expansion. On the other hand, the structure and function of exosomes may make them useful in cancer diagnosis and prognosis, because they contain molecules that could serve as biomarkers, including oncogenes, miRNAs, and certain proteins. They have the ability to travel via body fluids, from which they could be isolated and used to transport drugs to specific targets. This review aims to provide an update on the role of exosomes derived from breast cancer cells.

Cancer stem cells and their implication in breast cancer.

BACKGROUND: The cancer stem cell (CSC) hypothesis on the origin of cancer has recently gained considerable support. CSCs are tumour cells with the capacity for self-renewal and differentiation that direct the origin and progression of the disease and may be responsible for relapse, metastasis and treatment failures. DESIGN: This article reviews breast CSCs (BCSCs) phenotyping, clinical implications and clinical trials focused on BCSCs in breast cancer. Relevant studies were found through PubMed and Clinicaltrials.gov databases. RESULTS: Cancer stem cells are identified and isolated using membrane and cell activity markers; in the case of BCSCs, these are CD44(+) /CD24(low/-) and show aldehyde dehydrogenase activity, alongside their capacity to grow and form mammospheres. The presence of stem cell properties is associated with a worse outcome. Hence, these cells have important clinical implications, and elucidation of the mechanisms underlying their activity will allow the development of novel effective therapies and diagnostic instruments, improving the prognosis of these patients. CONCLUSIONS: Standard treatments are directed against the tumour mass and do not eliminate CSCs. There is therefore a need for specific anti-CSC therapies, and numerous authors are investigating new targets to this end, as reported in this review. It is also necessary for clinical trials to be undertaken to allow this new knowledge to be applied in the clinical setting. However, there have been few trials on anti-BCSCs therapies to date.

Cumulative live birth rate after two single frozen embryo transfers (eSFET) versus a double frozen embryo transfer (DFET) with cleavage stage embryos: a retrospective cohort study.

PURPOSE: According to the latest ART report for Europe, about 13% of pregnancies after frozen embryo transfer are multiple. Our objective was to analyse the impact on the multiple pregnancy rate of two eSFET (elective single frozen embryo transfers) versus a DFET (double frozen embryo transfer) in women aged under 38 years, who had not achieved pregnancy in their fresh transfer and who had at least two vitrified embryos of A/B quality. METHODS: This study was conducted from January 2010 to June 2013 at a public hospital. The couples were divided into three groups. Group DFET: the first cryotransfer of two embryos (105 women); cSFET group: the only cryotransfer of a single vitrified embryo (60 women); eSFET group, individually vitrified embryos: 20 patients included in a clinical trial of single-embryo fresh and frozen transfer and 21 patients who chose to receive eSFET. RESULTS: The clinical pregnancy rate was 38.1% in the DET group and the cumulative clinical pregnancy rate was 43.3% in the eSFET group. There were no significant differences between the DFET and eSFET groups (30.0 vs 34.1%) in cumulative live birth delivery rate. The rate of multiple pregnancies varied significantly between the DFET and eSFET groups (32.5 vs 0%, p < 0.05). CONCLUSIONS: For good-prognosis women aged under 38 years, taking embryo quality as a criterion for inclusion, an eSFET policy can be applied, achieving acceptable cumulative clinical pregnancy and live birth rates and reducing multiple pregnancy rates.

The Predictive Value of Blood-Derived Exosomal miRNAs as Biomarkers in Breast Cancer: A Systematic Review.

Breast cancer (BC) remains a widespread disease worldwide, despite advances in its detection and treatment. microRNAs (miRNAs) play a significant role in cancer, and their presence within exosomes may confer several advantages in terms of tumor initiation, propagation, immune evasion, and drug resistance compared to freely circulating miRNAs in the blood. The objective of this study was to conduct a systematic review to analyze the role of exosomal miRNAs present in serum or plasma as biomarkers in BC. Bibliographic sources were collected from various databases with no starting date limit until March 2023. The search terms used were related to "breast cancer," "microRNAs," and "exosomes." Following the search, inclusion and exclusion criteria were applied, resulting in a total of 46 articles. Data were extracted from the selected studies and summarized to indicate the miRNAs, type of dysregulation, sample source, number of patients and controls, and clinical relevance of the miRNAs. We carried out an enrichment study of the microRNAs that appeared in at least 3 studies, those that were suitable for selection were miR-16, miR-21 and miR-155. Exosomal miRNAs isolated from blood samples of patients diagnosed with BC could be valuable in the clinical setting. They could provide information about early diagnosis, disease progression, recurrence, treatment response, and metastases. It is crucial to reach a consensus on the specific exosomal miRNAs to detect and the most appropriate type of sample for comprehensive utilization of miRNAs as biomarkers for BC.

HER2/neu 655 polymorphism, trastuzumab-induced cardiotoxicity, and survival in HER2-positive breast cancer patients.

PURPOSE: HER2 overexpression in breast cancer correlates with poor outcomes. The incorporation of Trastuzumab into the treatment regimen has notably improved patient prognoses. However, cardiotoxicity emerges in approximately 20% of patients treated with the drug. This study aims to investigate the association between the HER2 655 A > G polymorphism, Trastuzumab-induced cardiotoxicity, and patient survival. METHODS: The study involved 88 patients treated with Trastuzumab. Cardiotoxicity, defined as a reduction in left ventricular ejection fraction (LVEF) from baseline or the emergence of clinical signs of congestive heart failure, was identified during treatment follow-up. Genotyping of HER2 655 A > G employed TaqMan SNP technology. RESULTS: Genotype frequencies of HER2/neu 655 (53 AA, 32 AG, and 3 GG) were consistent with Hardy-Weinberg equilibrium. No significant differences were observed in mean baseline LVEF between patients who developed cardiotoxicity and those who did not. Within these groups, neither AA nor AG genotypes showed an association with changes in mean baseline or reduced LVEF levels. Logistic regression analysis, adjusted for hormonal status and anthracycline treatment, revealed that AG genotype carriers face a significantly higher risk of cardiotoxicity compared to AA carriers (OR = 4.42; p = 0.037). No association was found between the HER2/neu 655 A > G polymorphism and disease-free or overall survival, regardless of whether the data was adjusted for stage or not. CONCLUSION: HER2 655 A > G polymorphism is significantly linked to an increased risk of Trastuzumab-induced cardiotoxicity but does not correlate with variations in disease-free survival or overall survival rates.

Discovery of a synthetic taiwaniaquinoid with potent in vitro and in vivo antitumor activity against breast cancer cells.

Taiwaniaquinoids are a unique family of diterpenoids predominantly isolated from Taiwania cryptomerioides Hayata. Previously, we evaluated the antiproliferative effect of several synthetic taiwaniaquinoids against human lung (A-549), colon (T-84), and breast (MCF-7) tumor cell lines. Herein, we report the in vitro and in vivo antitumor activity of the most potent compounds. Their cytotoxic activity against healthy peripheral blood mononuclear cells (PBMCs) has also been examined. We underscore the limited toxicity of compound C36 in PBMCs and demonstrate that it exerts its antitumor effect in MCF-7 cells (IC50 = 1.8 µM) by triggering an increase in reactive oxygen species, increasing the cell population in the sub-G1 phase of the cell cycle (90 %), and ultimately activating apoptotic (49.6 %) rather than autophagic processes. Western blot results suggested that the underlying mechanism of the C36 apoptotic effects was linked to caspase 9 activation and a rise in the Bax/Bcl-2 ratio. In vivo analyses showed normal behavior and hematological parameters in C57BL/6 mice post C36 treatment. Moreover, no significant impact was observed on the biochemical parameters of these animals, indicating that C36 did not induce liver toxicity. Furthermore, C36 demonstrated a significant reduction in tumor growth in immune-competent C57BL/6 mice implanted with E0771 mouse mammary tumor cells, effectively improving survival rates. These findings position taiwaniaquinoids, particularly compound C36, as promising therapeutic candidates for human breast cancer.

Early increase in tamoxifen dose in CYP2D6 poor metaboliser breast cancer patients and survival: A propensity score matching analysis.

PURPOSE: Tamoxifen is a drug used for hormone receptor-positive breast cancers, primarily metabolised by the CYP2D6 enzyme into active metabolites such as endoxifen. CYP2D6 displays varying degrees of activity depending on its genotype. This study aims to analyse the effect of an early increase in tamoxifen dose in poor metabolisers (PM) on survival. METHODS: We enrolled 220 patients diagnosed with breast cancer who were treated with tamoxifen. CYP2D6 polymorphisms were determined, and the phenotype was estimated according to the Clinical Pharmacogenetics Implementation Consortium. Disease-free survival (DFS) and overall survival (OS) were analysed considering the entire patient group, and a subgroup of 110 patients selected by Propensity Score Matching (PSM). All women were treated with 20 mg/day of tamoxifen for 5 years, except PM, who initially received 20 mg/day for 4 months, followed by 40 mg/day for 4 months and 60 mg/day for 4 months before returning to the standard dose of 20 mg/day until completing 5 years of treatment. RESULTS: The analysis of the influence of CYP2D6 polymorphisms in the complete group and in the PSM subgroup revealed no significant differences for DFS or OS. Furthermore, DFS and OS were analysed in relation to various covariates such as age, histological grade, nodal status, tumour size, HER-2, Ki-67, chemotherapy, and radiotherapy. Only age, histological grade, nodal status, and chemotherapy treatment demonstrated statistical significance. CONCLUSION: An early increase in tamoxifen dose in PM patients is not associated with survival differences among CYP2D6 phenotypes.

MGMT promoter methylation status and MGMT and CD133 immunohistochemical expression as prognostic markers in glioblastoma patients treated with temozolomide plus radiotherapy.

BACKGROUND: The CD133 antigen is a marker of radio- and chemo-resistant stem cell populations in glioblastoma (GBM). The O6-methylguanine DNA methyltransferase (MGMT) enzyme is related with temozolomide (TMZ) resistance. Our propose is to analyze the prognostic significance of the CD133 antigen and promoter methylation and protein expression of MGMT in a homogenous group of GBM patients uniformly treated with radiotherapy and TMZ. The possible connection between these GBM markers was also investigated. METHODS: Seventy-eight patients with GBM treated with radiotherapy combined with concomitant and adjuvant TMZ were analyzed for MGMT and CD133. MGMT gene promoter methylation was determined by methylation-specific polymerase chain reaction after bisulfite treatment. MGMT and CD133 expression was assessed immunohistochemically using an automatic quantification system. Overall and progression-free survival was calculated according to the Kaplan-Meier method. RESULTS: The MGMT gene promoter was found to be methylated in 34 patients (44.7%) and unmethylated in 42 patients (55.3%). A significant correlation was observed between MGMT promoter methylation and patients' survival. Among the unmethylated tumors, 52.4% showed low expression of MGMT and 47.6% showed high-expression. Among methylated tumors, 58.8% showed low-expression of MGMT and 41.2% showed high-expression. No correlation was found between MGMT promoter methylation and MGMT expression, or MGMT expression and survival. In contrast with recent results, CD133 expression was not a predictive marker in GBM patients. Analyses of possible correlation between CD133 expression and MGMT protein expression or MGMT promoter methylation were negative. CONCLUSIONS: Our results support the hypothesis that MGMT promoter methylation status but not MGMT expression may be a predictive biomarker in the treatment of patients with GBM. In addition, CD133 should not be used for prognostic evaluation of these patients. Future studies will be necessary to determine its clinical utility.

Ultrastructural and molecular analyzes of insulin-producing cells induced from human hepatoma cells.

BACKGROUND AIMS: Diabetes type I is an autoimmune disease characterized by the destruction of pancreatic insulin-producing (beta-) cells and resulting in external insulin dependence for life. Islet transplantation represents a potential treatment for diabetes but there is currently a shortage of suitable organs donors. To augment the supply of donors, different strategies are required to provide a potential source of beta-cells. These sources include embryonic and adult stem cells as well as differentiated cell types. The main goal of this study was to induce the transdifferentiation (or conversion of one type cell to another) of human hepatoma cells (HepG2 cells) to insulin-expressing cells based on the exposure of HepG2 cells to an extract of rat insulinoma cells (RIN). METHODS: HepG2 cells were first transiently permeabilized with Streptolysin O and then exposed to a cell extract obtained from RIN cells. Following transient exposure to the RIN extract, the HepG2 cells were cultured for 3 weeks. RESULTS: Acquisition of the insulin-producing cell phenotype was determined on the basis of (i) morphologic and (ii) ultrastructural observations, (iii) immunologic detection and (iv) reverse transcription (RT)-polymerase chain reaction (PCR) analysis. CONCLUSIONS: This study supports the use of cell extract as a feasible method for achieve transdifferentiation of hepatic cells to insulin-producing cells.

Transdifferentiation: why and how?

Cell therapy is based on the replacement of damaged cells in order to restore injured tissues. The first consideration is that an abundant source of cells is needed; second, these cells should be immunologically compatible with the guest and third, there should be no real threat of these cells undergoing malignant transformation in the future. Given these requirements, already differentiated adult cells or adult stem cells obtained from the body of the patient appear to be the ideal candidates to meet all of these demands. The utilization of somatic cells also avoids numerous ethical and political drawbacks and concerns. Transdifferentiation is the phenomenon by which an adult differentiated cell switches to another differentiated cell. This paper reviews the importance of transdifferentiation, discussing the cells that are suitable for this process and the methods currently employed to induce the change in cell type.

Nanomedicine: application areas and development prospects.

Nanotechnology, along with related concepts such as nanomaterials, nanostructures and nanoparticles, has become a priority area for scientific research and technological development. Nanotechnology, i.e., the creation and utilization of materials and devices at nanometer scale, already has multiple applications in electronics and other fields. However, the greatest expectations are for its application in biotechnology and health, with the direct impact these could have on the quality of health in future societies. The emerging discipline of nanomedicine brings nanotechnology and medicine together in order to develop novel therapies and improve existing treatments. In nanomedicine, atoms and molecules are manipulated to produce nanostructures of the same size as biomolecules for interaction with human cells. This procedure offers a range of new solutions for diagnoses and "smart" treatments by stimulating the body's own repair mechanisms. It will enhance the early diagnosis and treatment of diseases such as cancer, diabetes, Alzheimer's, Parkinson's and cardiovascular diseases. Preventive medicine may then become a reality.

Human cardiac tissue induces transdifferentiation of adult stem cells towards cardiomyocytes.

BACKGROUND AIMS: The goal was to induce the transdifferentiation (or conversion) of human adipose-derived stem cells to cardiomyocytes using an intracellular extract obtained from adult human heart tissue. METHODS: Human adult stem cells from lipoaspirates were transiently permeabilized, exposed to human atrial extracts and allowed to recover in culture. RESULTS: After 21 days, the cells acquired a cardiomyocyte phenotype, as demonstrated by morphologic changes (appearance of binucleate, striated cells and branching fibers), immunofluorescence detection of cardiac-specific markers (connexin-43, sarcomeric alpha-actinin, cardiac troponin I and T, and desmin) and the presence of cardiomyocyte-related genes analyzed by reverse transcription-polymerase chain reaction (cardiac myosin light chain 1, alpha-cardiac actin, cardiac troponin T and cardiac beta-myosin). CONCLUSIONS: We have demonstrated for the first time that adult cardiomyocytes obtained from human donors retain the capacity to induce cardiomyocyte differentiation of mesenchymal stromal cells. The use of autologous extracts for reprogramming adult stem cells may have potential therapeutic implications for treating heart disease.

Differentiation of intestinal epithelial cells mediated by cell confluence and/or exogenous nucleoside supplementation.

Nucleotides (NT) and nucleosides (NS) play a key role in gastrointestinal development and in enterocyte healing after tissue damage. Exogenous NT and NS may therefore represent a novel therapy for maintaining gastrointestinal tract integrity. An exogenous NS mixture of thymidine, cytidine, guanosine and inosine (T-CGI) increases the proliferation rate of rat intestinal epithelial cell line 6 (IEC-6) cells, while a mixture of uridine, cytidine, guanosine and inosine (U-CGI) reduces IEC-6 proliferation independently of necrosis or apoptosis. This study aimed to analyze the effects of exogenous NS on IEC-6 differentiation under proliferation and differentiation conditions. To this end, IEC-6 cells were treated with NS T-CGI and NS U-CGI mixtures under low- and high-density conditions. Enterocyte differentiation was also assessed by flow cytometry, Western blotting, and light, fluorescence and transmission electron microscopy. Under proliferative conditions, villin expression was reduced in all cases, but NS-treated cells showed twofold the expression observed in NS-free cultures (controls) and more frequently showed characteristics of mature enterocytes. When cells were grown after confluence, villin expression, total protein production and morphology of NS-treated cultures were more differentiated compared with the control group. Our results demonstrate that T-CGI and U-CGI mixtures promote IEC-6 cell differentiation, with no significant differences between them. Unlike previous authors, we obtained this effect in cultures without an exogenous extracellular matrix such as Matrigel, reducing the variability among independent assays.

Promotion of human adipose-derived stem cell proliferation mediated by exogenous nucleosides.

Adult stem cells are becoming the best option for regenerative medicine because they have low tumourigenic potential and permit autologous transplantation, even without in vitro culture. Our objectives were to evaluate the effects of exogenous nucleosides on the proliferation of hASCs (human adipose-derived stem cells), with or without co-treatment with 5-aza (5-azacytidine), and to analyse the expression of lamin A/C during cardiomyocyte differentiation of these cells. We isolated hASCs from human lipoaspirates that were positive for mesenchymal stem cell markers. We found that 5-aza induces a dose-dependent inhibition of hASC proliferation [IC50 (inhibitory concentration 50): 5.37 microM], whereas exogenous nucleosides significantly promote the proliferation of hASCs and partially revert the antiproliferative effect of the drug. Multipotentiality of isolated hASCs was confirmed by adipogenic, osteogenic and cardiomyogenic induction. 5-Aza-induced cells expressed cardiac troponins I and T and myosin light chain 2, myocardial markers that were directly correlated with lamin A/C expression. Our results support the importance of the nucleoside supplementation of media to improve conditions for the expansion and maintenance of hASCs in culture. In addition, the quantification of lamin A/C expression appears to be a good marker for the characterization of cardiomyocyte differentiation of stem cells that has rarely been used.