Double inferior vena cava-an important anatomical variant in retroperitoneal surgery

University of Granada/CBU

O6-methylguanine-DNA Methyltransferase Promoter Methylation in Patients with Rectal Adenocarcinoma After Chemoradiotherapy Treatment: Clinical Implications

Brief Report 283Aims: To analyze the clinical relevance of O6-methylguanine-DNA methyltransferase in rectal adenocarcinoma treated with chemoradiotherapy followed by surgery. Methods: Tissue samples from 29 rectal adenocarcinoma patients were obtained after chemoradiotherapy. O6-methylguanine-DNA methyltransferase promoter methylation status was established by methylation-specific polymerase chain reaction. O6-methylguanine-DNA methyltransferase protein levels were determined by immunohistochemistry. Clinicopathologic variables, including treatment regression grade, recurrence, lymph node invasion, and stage and differentiation grade of the tumor, were determined. Results: The O6-methylguanine-DNA methyltransferase gene promoter was methylated in 81.5% of samples. Most patients (88.9%) showed low O6-methylguanine-DNA methyltransferase protein expression. O6-methylguanine-DNA methyltransferase methylation status was not correlated with any of the clinicopathological variables determined in rectal adenocarcinomas selected for chemoradiotherapy. Conclusion: O6-methylguanine-DNA methyltransferase methylation status is not correlated with clinicopathologic variables examined in rectal adenocarcinoma selected for chemoradiotherapy, although its role as a biomarker awaits further investigation

Active Biomolecules from Vegetable Extracts with Antitumoral Activity against Pancreas Cancer: A Systematic Review (2011–2021)

The emergence of resistance to pancreatic cancer (PC) current treatment requires the development of new therapeutic strategies. In this context, bioactive molecules from plant extracts have shown excellent properties to improve classical therapy against this type of tumor. This systematic review aims to collect all the in vitro studies related to the antiproliferative activity of isolated plant molecules that support their applicability in PC. A total of 620 articles published in the last 10 years were identified, although only 28 were finally included to meet the inclusion criteria. Our results reflect the most important biomolecules from natural compounds that induce cell death in PC and their essential mechanism of cell death, including apoptosis, pathways activated by the KRAS mutation and cycle cell arrest, among others. These in vitro studies provide an excellent molecule guide showing applications against PC and that should be tested in vivo and in clinical trials to determine their usefulness to reduce PC incidence and to improve the prognosis of these patients. However, natural compounds are isolated in small amounts, which prevents comprehensive drug screening, being necessary the role of organic synthesis for the total synthesis of natural compounds or for the synthesis of their simplified and bioactive analogs.GranadaUniversity INB-009Instituto de Salud Carlos IIIEuropean Commission DTS17/00081Spanish Government RTC2019-006870-1Junta de Andalucia P18-TP-1420 A-CTS-666-UGR20 B-CTS-122-UGR20Ministerio de Educacion, Ciencia y Deporte y Competitividad (Spain) FPU17/02977 Ibs. GRANAD

Antitumor Effect of Traditional Drugs for Neurological Disorders: Preliminary Studies in Neural Tumor Cell Lines

Glioblastoma multiforme is the most common malignant primary brain tumor in adults. Despite new treatments developed including immunomodulation using vaccines and cell therapies, mortality remains high due to the resistance mechanisms presented by these tumor cells and the function of the blood–brain barrier that prevents the entry of most drugs. In this context of searching for new glioblastoma therapies, the study of the existing drugs to treat neurological disorder is gaining great relevance. The aim of this study was to determine, through a preliminary in vitro study on human glioblastoma (A172, LN229), anaplastic glioma (SF268) and neuroblastoma (SK-N-SH) cell lines, the possible antitumor activity of the active principles of several drugs (levomepromazine, haloperidol, lacosamide, valproic acid, levetiracetam, glatiramer acetate, fingolimod, biperiden and dextromethorphan) with the ability to cross the blood–brain barrier and that are commonly used in neurological disorders. Results showed that levetiracetam, valproic acid, and haloperidol were able to induce a relevant synergistic antitumor effect when associated with the chemotherapy currently used in clinic (temozolomide). Regarding the mechanism of action, haloperidol, valproic acid and levomepromazine caused cell death by apoptosis, while biperiden and dextromethorphan induced autophagy. Fingolimod appeared to have anoikis-related cell death. Thus, the assayed drugs which are able to cross the blood–brain barrier could represent a possibility to improve the treatment of neural tumors, though future in vivo studies and clinical trials will be necessary to validate it.Funding for open access charge: Universidad de Granada / CBUA. This work was supported by the Project Innbio INB-009 (Granada University and ibs. GRANADA) and by the CTS-107 Group of the Junta de Andalucía (Spain)

Plant-Derived Bioactive Compounds for Rhabdomyosarcoma Therapy In Vitro: A Systematic Review

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, constitutes approximately 40% of all recorded soft tissue tumors and is associated with a poor prognosis, with survival rates of less than 20% at 3 years. The development of resistance to cytotoxic drugs is a primary contributor to therapeutic failure. Consequently, the exploration of new therapeutic strategies is of vital importance. The potential use of plant extracts and their bioactive compounds emerges as a complementary treatment for this type of cancer. This systematic review focuses on research related to plant extracts or isolated bioactive compounds exhibiting antitumor activity against RMS cells. Literature searches were conducted in PubMed, Scopus, Cochrane, and WOS. A total of 173 articles published to date were identified, although only 40 were finally included to meet the inclusion criteria. Furthermore, many of these compounds are readily available and have reduced cytotoxicity, showing an apoptosis-mediated mechanism of action to induce tumor cell death. Interestingly, their use combined with chemotherapy or loaded with nanoparticles achieves better results by reducing toxicity and/or facilitating entry into tumor cells. Future in vivo studies will be necessary to verify the utility of these natural compounds as a therapeutic tool for RMS.Spanish Ministry of Science and Innovation (FEDER) (CPP2022-009967 and CPP2022-010017)Spanish Ministry of Universities and Science (RTC2019-006870-1

Cancer Stem Cells in Sarcomas: In Vitro Isolation and Role as Prognostic Markers: A Systematic Review

Sarcomas are a diverse group of neoplasms with an incidence rate of 15% of childhood cancers. They exhibit a high tendency to develop early metastases and are often resistant to available treatments, resulting in poor prognosis and survival. In this context, cancer stem cells (CSCs) have been implicated in recurrence, metastasis, and drug resistance, making the search for diagnostic and prognostic biomarkers of the disease crucial. The objective of this systematic review was to analyze the expression of CSC biomarkers both after isolation from in vitro cell lines and from the complete cell population of patient tumor samples. A total of 228 publications from January 2011 to June 2021 was retrieved from different databases, of which 35 articles were included for analysis. The studies demonstrated significant heterogeneity in both the markers detected and the CSC isolation techniques used. ALDH was identified as a common marker in various types of sarcomas. In conclusion, the identification of CSC markers in sarcomas may facilitate the development of personalized medicine and improve treatment outcomes.CTS-107 (Andalusian Government

The challenge of drug resistance in pancreatic ductal adenocarcinoma: a current overview

Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates among all cancer types. Its delayed diagnosis precludes curative resection, thus most of the current therapies against PDAC are based on chemo- and radiotherapy. Unfortunately, these strategies are insufficient to improve its poor prognosis. Despite the advances made in chemotherapy (e.g. nab-Paclitaxel and Gemcitabine), many patients with PDAC are unable to benefit from them due to the rapid development of drug resistance. Currently, more than 165 genes have been found to be implicated in drug resistance of pancreatic tumors, including different integrins, mucins, NF-κβ, RAS and CXCR4. Moreover, drug resistance in PDAC is thought to be mediated by the modulation of miRNAs (e.g. miRNA-21, miRNA-145 and miRNA-155), which regulate genes that participate in cell proliferation, invasion and metastasis. Finally, cancer stem cells are intimately related to drug resistance in PDAC due to their ability to overexpress ABC genes -involved in drug transport-, and enzymes such as aldehyde dehydrogenases -implicated in cellular drug metabolism- and poly (ADP-ribose) polymerases -involved in drug-induced DNA damage repair-. Understanding the mechanisms involved in drug resistance will contribute to the development of efficient therapeutic strategies and to improve the prognosis of patients with PDAC.This work was funded by grants from Instituto de Salud Carlos III (Grant No. DTS15/00201 and DTS17/00081) and Junta de Andalucía (Grant No. PIN-0474-2016)

Differential chemotherapeutic regimen cytotoxicity against pancreatic cancer stem cells: a preliminary in vitro study

We are grateful to Scientific Instrumentation Center (CIC) from the Granada University.Introducción: El tratamiento del cáncer de páncreas en estadios avanzados se basa en diferentes regímenes de quimioterapia. Las células madre cancerosas son responsables de la quimiorresistencia tumoral y la recurrencia tras tratamientos en etapa adyuvante y metastásica. El objetivo de este artículo fue evaluar cómo estos regímenes quimioterapéuticos afectan a la proporción de células madre cancerosas y la expresión de sus marcadores. Método: Utilizamos la línea celular de adenocarcinoma pancreático PANC-1 como modelo para aplicar diferentes protocolos quimioterapéuticos (monoterapia y terapia combinada) utilizando 5-Fluorouracilo, Oxaliplatino, Irino tecán, Gemcitabina y Abraxane. Resultados: Tras analizar mediante RT-qPCR diferentes marcadores de células madre tumorales (SOX2, OCT4, CD133, CD44 y CD24) en células de cáncer de páncreas tratadas con diferentes protocolos quimioterapéuticos, el Oxaliplatino y la Gemcitabina en monoterapia fueron los quimioterápicos que seleccionaron en mayor medida las células madre cancerosas mientras que el protocolo FOLFIRI las disminuyó. Conclusiones: En cuanto a la selección de marcadores, ha sido mucho mayor en el caso de Gemcitabina en monoterapia. En conclusión, estos hallazgos podrían mejorar y personalizar la terapia del cáncer de páncreas.Introduction: Pancreatic cancer treatment in advanced stages is based on different chemotherapy regimens. Can cer stem cells are responsible for tumor chemoresistance and recurrence in adjuvant and metastatic settings. The objective of this article was to evaluate how these chemotherapeutic regimens affect the proportion of cancer stem cells and the expression of stemness markers. Method: We used the pancreatic adenocarcinoma cell line PANC-1 as a model to apply different chemotherapeu tic protocols (monotherapy and combined therapy) using 5-Fluorouracil, Oxaliplatin, Irinotecan, Gemcitabine and Abraxane. Results: After analyzing different tumor stem cell markers (SOX2, OCT4, CD133, CD44 and CD24) in pancreatic can cer cells treated with different chemotherapeutic protocols by means of RT-qPCR, Oxaliplatin and Gemcitabine in monotherapy were the chemotherapies that selected the most cancer stem cells while the FOLFIRI protocol de creased them. Conclusions: Regarding the selection of markers, it has been much higher in the case of Gemcitabine alone. In conclusion, these findings could improve and personalize pancreatic cancer therapy.This work was supported by funds from group CTS-107 (Andalusian Government). F. J. Q. acknowledges the FPU2019 grant from the Ministerio de Educacion Ciencia y Deporte y Competitividad (Spain)

Magnetic Nanoparticules in Cancer Diagnosis and Treatment

Los avances en el campo de la nanotecnología incluyen el desarrollo de nuevas nanopartículas que están siendo usadas en el en el campo de la oncología, no sólo como nuevos vehiculizadores de drogas capaces de dirigirlas a lugares específicos al mismo tiempo que disminuyen sus efectos sistémicos, sino como mediadores para generar calor localizado (hipertermia) como terapia antitumoral y para la localización y visualización de este tipo de patología. En este contexto, las nanopartículas que incorporan núcleos magnéticos confiriéndoles propiedades paramagnéticas están cobrando gran relevancia en el campo del diagnóstico tumoral y también en el del tratamiento ya sea sólo para aplicar la hipertermia o para combinarla con fenómenos de direccionamiento de drogas citotóxicas mediante la adición en la superficie de la nanopartícula de moléculas que reconocen algún tipo de biomarcador de cáncer (“targeting activo”). El principal objetivo de esta revisión es presentar los avances más relevantes en el desarrollo de nanoplataformas que incorporan núcleos magnéticos y que representan una nueva estrategia para el tratamiento y/o diagnóstico del cáncer (teragnosis) indicando los principales ensayos in vitro e in vivo y especialmente los ensayos clínicos más significativos que tiene como base esta nueva concepción terapéutica dentro del campo de la oncología.The advances in the field of nanotechnology include the development of new nanoparticles that are being used inside oncology, not only as new drugs transporters that are able to direct them to specific locations at the same time decreasing their systemic effects, furthermore, they generate localized heat (hyperthermia) as an antitumor therapy and for the localization and visualization of this type of pathology. In this context, nanoparticles with magnetic cores that have paramagnetic properties are gaining importance in the field of tumor diagnosis and also in the treatment, either only for applying hyperthermia phenomena or to combine them with targeting phenomenom of cytotoxic drugs by the addition of molecules onto the nanoparticle surface that recognize some kind of cancer biomarker (active targeting). The main objective of this review is to show the most relevant advances in the development of nanoplatforms that have magnetic cores and are a new strategy for the cancer treatment and/or diagnosis (theragnosis) by the mention of the main in vitro and in vivo assays, specially the clinical trials most important of this new therapeutic concept inside within the field of oncology

Antiproliferative, Antioxidant, Chemopreventive and Antiangiogenic Potential of Chromatographic Fractions from Anemonia sulcata with and without Its Symbiont Symbiodinium in Colorectal Cancer Therapy

Anemonia sulcata may be a source of marine natural products (MNPs) due to the antioxidant and antitumor activity of its crude homogenates shown in vitro in colon cancer cells. A bioguided chromatographic fractionation assay of crude Anemonia sulcata homogenates with and without its symbiont Symbiodinium was performed to characterize their bioactive composition and further determine their biological potential for the management of colorectal cancer (CRC). The 20% fractions retained the in vitro antioxidant activity previously reported for homogenates. As such, activation of antioxidant and detoxifying enzymes was also evaluated. The 40% fractions showed the greatest antiproliferative activity in T84 cells, synergistic effects with 5-fluoruracil and oxaliplatin, overexpression of apoptosis-related proteins, cytotoxicity on tumorspheres, and antiangiogenic activity. The predominantly polar lipids and toxins tentatively identified in the 20% and 40% fractions could be related to their biological activity in colon cancer cells although further characterizations of the active fractions are necessary to isolate and purify the bioactive compounds.Junta de Andalucía (project PYC20 RE 035 UGR)Junta de Andalucía (project P20_00540 and A-CTS-666-UGR20)Instituto Salud Carlos III (project PMPTA22/00136PI19/01478) (FEDER program)AGR145 and CTS-107 (Andalusian Government)FPU2019 (Ref. FPU19/06170) grant from the Ministerio de Universidades (Spain