Depósito Académico
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- The role of the adenylate kinase 5 gene in various diseases and cancer(Cambridge University Press, 2024) Sarim-Siddiqui, M. (M.); Saez-Castresana, J. (Javier); Shahi, M.H. (Mehdi Hayat)Adenylate kinases (AKs) are important enzymes involved in cellular energy metabolism. Among AKs, AK5 (adenylate kinase 5), a cytosolic protein, is emerging as a significant contributor to various diseases and cellular processes. This comprehensive review integrates findings from various research groups on AK5 since its discovery, shedding light on its multifaceted roles in nucleotide metabolism, energy regulation, and cellular differentiation. We investigate its implications in a spectrum of diseases, including autoimmune encephalitis, epilepsy, neurodegenerative disorders such as Alzheimer’s and Parkinson’s, diabetes, lower extremity arterial disease, celiac disease, and various cancers. Notably, AK5’s expression levels and methylation status have been associated with cancer progression and patient outcomes, indicating its potential as a prognostic indicator. Furthermore, AK5 is implicated in regulating cellular processes in breast cancer, gastric cancer, colorectal carcinoma, prostate cancer, and colon adenocarcinoma, suggesting its relevance across different cancer types. However, a limitation lies in the need for more robust clinical validation and a deeper understanding of AK5’s precise mechanisms in disease pathogenesis, despite its association with various pathophysiological conditions. Nonetheless, AK5 holds promise as a therapeutic target, with emerging evidence suggesting its potential in therapy development.
- From natural sources to synthetic derivatives: the allyl motif as a powerful tool for fragment-based design in cancer treatment(American Chemical Society, 2023) Sanmartin-Grijalba, C. (Carmen); Plano-Amatriain, D. (Daniel); Sharma, A.K. (Arun K.); Astráin-Redín, N. (Nora)Since the beginning of history, natural products have been an abundant source of bioactive molecules for the treatment of different diseases, including cancer. Many allyl derivatives, which have shown anticancer activity both in vitro and in vivo in a large number of cancers, are bioactive molecules found in garlic, cinnamon, nutmeg, or mustard. In addition, synthetic products containing allyl fragments have been developed showing potent anticancer properties. Of particular note is the allyl derivative 17-AAG, which has been evaluated in Phase I and Phase II/III clinical trials for the treatment of multiple myeloma, metastatic melanoma, renal cancer, and breast cancer. In this Perspective, we compile extensive literature evidence with descriptions and discussions of the most recent advances in different natural and synthetic allyl derivatives that could generate cancer drug candidates in the near future.
- Long-term results of intraoperative multicatheter breast implant (IOMBI) for accelerated partial breast irradiation (APBI) on early breast cancer patients(Elsevier, 2024) Martinez-Monge, R. (Rafael); Blanco, J. (Javier); Martinez-Regueira, F. (Fernando); Rodriguez-Spiteri, N. (Natalia); Jablonska, P.A. (Paola Anna); Elizalde, A. (Arlette); Pina-Insausti, L. (Luis); Abengozar-Muela, M. (Marta); Cambeiro, M. (Mauricio); Olartecoechea, B. (Begoña); Gimeno-Morales, M. (Marta); Ramos, L. (Luis); Martínez-Lage, A. (Adriana)Background and purpose: Multicatheter breast brachytherapy is a standard technique for accelerated partial breast irradiation (APBI) in early breast cancer patients. Intraoperative multicatheter breast implant (IOMBI) followed by perioperative high-dose-rate brachytherapy (PHDRBT) offers a novel and advantageous approach. We present long-term oncological, toxicity, and cosmesis outcomes for a well-experienced single institution. Materials and methods: Eligible women aged ≥ 40 years with clinically and radiologically confirmed unifocal invasive or in situ ≤ 3 cm breast tumors underwent IOMBI during breast-conserving surgery. Patients meeting APBI criteria by definitive pathologic results received 3.4 Gy × 10fx with PHDRBT. Patients not suitable for APBI received PHDRBT-boost followed by WBRT. Results: A total of 171 patients underwent IOMBI during BCS, 120 patients (70.1 %) were suitable for APBI and 51 (29.8 %) for anticipated PHDRBT-boost. The median age was 61 years (range: 40-78), the median tumor size was 1.1 cm (range: 0.2-3.5), with a histological diagnosis of invasive ductal carcinoma in 78.9 % and ductal in situ in 21.1 %. A median of 9 catheters (range: 4-14) were used. For APBI, the median CTV and V100 were 40.8 cc (range: 8.6-99) and 35.4 cc (range: 7.2-94). The median of healthy breast tissue irradiated represents 7.2 % (range: 2.3-28 %) and the median local treatment duration was 10 days (range: 7-16). With a median follow-up of 8.8 years (range: 0.3-16.25), the 8-year local, locoregional, and distant control rates were 99 %, 98.1 %, and 100 %. G1-G2 late-toxicity rate was 53.4 %. Long-term cosmetic evaluation was excellent-good in 90.8 %. Conclusion: IOMBI&PHDRBT program reports excellent long-term oncological outcomes, with a reduction from unnecessary irradiation exposure which translates into low long-term toxicity and good cosmesis outcomes, especially on well-selected APBI patients.
- Biosafety evaluation of etoposide lipid nanomedicines in C. elegans(Springer Nature, 2024) Blanco-Prieto, M.J. (María José); El-Moukhtari, S.H. (Souhaila H.); Campo, R. (Ruben) del; Laromaine, A. (Anna); Muñoz‑Juan, A. (Amanda)Neuroblastoma is a pediatric tumor that originates during embryonic development and progresses into aggressive tumors, primarily affecting children under two years old. Many patients are diagnosed as high-risk and undergo chemotherapy, often leading to short- and long-term toxicities. Nanomedicine offers a promising solution to enhance drug efficacy and improve physical properties. In this study, lipid-based nanomedicines were developed with an average size of 140 nm, achieving a high encapsulation efficiency of over 90% for the anticancer drug etoposide. Then, cytotoxicity and apoptosis-inducing effects of these etoposide nanomedicines were assessed in vitro using human cell lines, both cancerous and non-cancerous. The results demonstrated that etoposide nanomedicines exhibited high toxicity and selectively induced apoptosis only in cancerous cells.Next, the biosafety of these nanomedicines in C. elegans, a model organism, was evaluated by measuring survival, body size, and the effect on dividing cells. The findings showed that the nanomedicines had a safer profile than the free etoposide in this model. Notably, nanomedicines exerted etoposide's antiproliferative effect only in highly proliferative germline cells. Therefore, the developed nanomedicines hold promise as safe drug delivery systems for etoposide, potentially leading to an improved therapeutic index for neuroblastoma treatment.
- Unlocking the potential of 1,4-naphthoquinones: A comprehensive review of their anticancer properties(Elsevier, 2024) Sanmartin-Grijalba, C. (Carmen); Morán-Serradilla, C. (Cristina); Angulo-Elizari, E. (Eduardo); Plano-Amatriain, D. (Daniel); Henriquez-Figuereo, A. (Andreina)Cancer encompasses a group of pathologies with common characteristics, high incidence, and prevalence in all countries. Although there are treatments available for this disease, they are not always effective or safe, often failing to achieve the desired results. This is why it is necessary to continue the search for new therapies. One of the strategies for obtaining new antitumor drugs is the use of 1,4-naphthoquinone as a scaffold in synthetic or natural products with antitumor activity. This review focuses on compiling studies related to the antitumor activity of 1,4-naphthoquinone and its natural and synthetic derivatives over the last 10 years. The work describes the main natural naphthoquinones with antitumor activity and classifies the synthetic naphthoquinones based on the structural modifications made to the scaffold. Additionally, the formation of metal complexes using naphthoquinones as a ligand is considered. After a thorough review, 197 synthetic compounds with potent biological activity against cancer have been classified according to their chemical structures and their mechanisms of action have been described.
- Survival and safety after neoadjuvant chemotherapy or upfront surgery for locally advanced colon cancer: meta-analysis(Oxford University Press, 2024) Pastor, C. (Carlos); Rotellar, F. (Fernando); Matos, I. (Ignacio); Baixauli-Fons, J. (Jorge); Rodriguez, J. (Javier); Sanchez-Justicia, C. (C.); Arredondo, J. (Jorge); Aliseda, D. (Daniel); Alvarellos, A. (A.)Background: Neoadjuvant chemotherapy is increasingly used to treat locally advanced (T3-4 Nx-2 M0) colon cancer due to its potential advantages over the standard approach of upfront surgery. The primary objective of this systematic review and meta-analysis was to analyse data from comparative studies to assess the impact of neoadjuvant chemotherapy on oncological outcomes. Methods: A systematic review was conducted by searching the MEDLINE and Scopus databases. The search encompassed RCTs, propensity score-matched studies, and controlled prospective studies published up to 1 April 2023. As a primary objective, overall survival and disease-free survival were compared. As a secondary objective, perioperative morbidity, mortality, and complete resection were compared using the DerSimonian and Laird models. Results: A total of seven studies comprising a total of 2120 patients were included. Neoadjuvant chemotherapy was associated with a reduction in the hazard of recurrence (HR 0.73, 95% c.i. 0.59 to 0.90; P = 0.003) and death (HR 0.67, 95% c.i. 0.54 to 0.83; P < 0.001) compared with upfront surgery. Additionally, neoadjuvant chemotherapy was significantly associated with higher 5-year overall survival (79.9% versus 72.6%; P < 0.001) and disease-free survival (73.1% versus 64.5%; P = 0.028) rates. No significant differences were observed in perioperative mortality (OR 0.97, 95% c.i. 0.28 to 3.33), overall complications (OR 0.95, 95% c.i. 0.77 to 1.16), or anastomotic leakage/intra-abdominal abscess (OR 0.88, 95% c.i. 0.60 to 1.29). However, neoadjuvant chemotherapy was associated with a lower risk of incomplete resection (OR 0.70, 95% c.i. 0.49 to 0.99). Conclusion: Neoadjuvant chemotherapy is associated with a reduced hazard of recurrence and death, as well as improved overall survival and disease-free survival rates, compared with upfront surgery in patients with locally advanced colon cancer.
- Practice-oriented solutions integrating intraoperative electron irradiation and personalized proton therapy for recurrent or unresectable cancers: Proof of concept and potential for dual FLASH effect(Frontiers, 2022) Aguilar, B. (Borja); Pedrero, D. (Diego); Aristu-Mendioroz, J.J. (José Javier); Ayestaran, A. (Adriana); Alonso, A. (Alberto); Meiriño, R. (Rosa); Palma, J. (Jacobo); Calvo, F.A. (Felipe A.); Lapuente, F. (Fernando); Chiva, L. (Luis); Pascau, J. (Javier); Cambeiro, M. (Mauricio); Morcillo, M.A. (Miguel Ángel); Prezado, Y. (Yolanda); Serrano-Andreu, J. (Javier); Azcona, J.D. (Juan Diego); Delgado, J.M. (José Miguel)Background: Oligo-recurrent disease has a consolidated evidence of long-term surviving patients due to the use of intense local cancer therapy. The latter combines real-time surgical exploration/resection with high-energy electron beam single dose of irradiation. This results in a very precise radiation dose deposit, which is an essential element of contemporary multidisciplinary individualized oncology. Methods: Patient candidates to proton therapy were evaluated in Multidisciplinary Tumor Board to consider improved treatment options based on the institutional resources and expertise. Proton therapy was delivered by a synchrotron-based pencil beam scanning technology with energy levels from 70.2 to 228.7 MeV, whereas intraoperative electrons were generated in a miniaturized linear accelerator with dose rates ranging from 22 to 36 Gy/min (at Dmax) and energies from 6 to 12 MeV. Results: In a period of 24 months, 327 patients were treated with proton therapy: 218 were adults, 97 had recurrent cancer, and 54 required re-irradiation. The specific radiation modalities selected in five cases included an integral strategy to optimize the local disease management by the combination of surgery, intraoperative electron boost, and external pencil beam proton therapy as components of the radiotherapy management. Recurrent cancer was present in four cases (cervix, sarcoma, melanoma, and rectum), and one patient had a primary unresectable locally advanced pancreatic adenocarcinoma. In re-irradiated patients (cervix and rectum), a tentative radical total dose was achieved by integrating beams of electrons (ranging from 10- to 20-Gy single dose) and protons (30 to 54-Gy Relative Biological Effectiveness (RBE), in 10–25 fractions). Conclusions: Individual case solution strategies combining intraoperative electron radiation therapy and proton therapy for patients with oligo-recurrent or unresectable localized cancer are feasible. The potential of this combination can be clinically explored with electron and proton FLASH beams.
- A simple immunoassay for extracellular vesicle liquid biopsy in microliters of non‑processed plasma(2022) Beneitez, A. (Alexandra); Sánchez-Herrero, E. (Estela); Valés-Gómez, M. (Mar); Gonzalez-Hernandez, A. (Alvaro); Romero, A. (A.); Provencio, M. (Mariano); Jara-Acevedo, R. (Ricardo); Yáñez-Mó, M. (María); Campos-Silva, C. (Carmen)Background: Extracellular vesicles (EVs), released by most cell types, provide an excellent source of biomarkers in biological fluids. However, in order to perform validation studies and screenings of patient samples, it is still necessary to develop general techniques permitting rapid handling of small amounts of biological samples from large numbers of donors. Results: Here we describe a method that, using just a few microliters of patient’s plasma, identifies tumour markers exposed on EVs. Studying physico-chemical properties of EVs in solution, we demonstrate that they behave as stable colloidal suspensions and therefore, in immunocapture assays, many of them are unable to interact with a stationary functionalised surface. Using flocculation methods, like those used to destabilize colloids, we demonstrate that cationic polymers increase EV ζ-potential, diameter, and sedimentation coefficient and thus, allow a more efficient capture on antibody-coated surfaces by both ELISA and bead-assisted flow cytometry. These findings led to optimization of a protocol in microtiter plates allowing effective immunocapture of EVs, directly in plasma without previous ultracentrifugation or other EV enrichment. The method, easily adaptable to any laboratory, has been validated using plasma from lung cancer patients in which the epithelial cell marker EpCAM has been detected on EVs. Conclusions: This optimized high throughput, easy to automate, technology allows screening of large numbers of patients to phenotype tumour markers in circulating EVs, breaking barriers for the validation of proposed EV biomarkers and the discovery of new ones.
- Increased risk of local recurrence in cutaneous squamous cell carcinoma arising in sun-exposed skin: a retrospective cohort study(2023) Espejo-Marín, M. (Marta); Morelló-Vicente, A. (Ana); Salido-Vallejo, R. (Rafael); Antoñanzas-Perez, J. (Javier); Vélez, A. (Antonio); Oteiza-Rius, I. (Inés)The aim of this study is to compare the risk of local recurrence and metastases in patients with cSCC based on the presence or absence of prior sun exposure in the region of tumor development. A retrospective observational epidemiological study including 558 patients from January 2017 to December 2020 was conducted. Among the 463 patients with cSCC in highly sun-exposed areas, 73 (15.8%) were diagnosed with local recurrence versus only 7 of 95 patients (7.4%) in less sun-exposed areas. No differences were found in terms of metastasis between both groups. In regions with low sun exposure, the variables linked to a heightened risk of recurrence include tumor depth and the involvement of surgical margins. Our results suggest that highly sun-exposed areas could have a greater risk of developing local recurrence, conferring a worse prognosis for the patients. Background: The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing over the years. Risk factors for local recurrence and metastasis have been widely studied in highly sun-exposed areas of the body but less data exist about less sun-exposed ones. The main objective of this study is to compare the risk of local recurrence and metastases in patients with cSCC in highly sun-exposed areas compared to cSCC in less sun-exposed areas. Material and methods: A retrospective observational study was carried out, including 558 patients with histopathologically confirmed cSCC at the Reina Sofia University Hospital (HURS), Cordoba, during the period from 1 January 2017 to 31 December 2020. Demographic, clinical and anatomopathological data were collected. Results: Local recurrence occurs more often in highly sun-exposed areas (15.8%) compared to less sun-exposed ones (7.4%) (p < 0.05). However, no differences in the rate of metastases in both groups were found. The presence of affected surgical margins and tumor thickness were identified as independent risk factors for cSCC in low sun-exposure areas. Conclusions: cSCC located in anatomical areas of high sun exposure presented a greater risk of developing local recurrence in our population, which could suggest that these tumors have worse prognosis than those that lie in areas that do not receive chronic sun exposure.
- Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer(2023) Gil-Bazo, I. (Ignacio); Drosten, M. (Mathias); Barbacid, M. (Mariano); Kovalski, J. (Joanna); Pineda-Lucena, A. (Antonio); Román, M. (Marta); Jantus-Lewintre, E. (Eloisa); Calabuig-Fariñas, S. (Silvia); Vicent, S. (Silvestre); Ludwig, I.A. (Iziar Amaia); Entrialgo-Cadierno, R. (Rodrigo); Palomino-Echeverría, S. (Sara); Salmon, M. (Marina); Fernandez-Irigoyen, J. (Joaquín); Ruggero, D. (Davide); Lara-Astiaso, D. (David); Santos, A. (Alba); Ponz-Sarvise, M. (Mariano); Macaya, I. (Irati); Feliu, I. (Iker); Rodríguez-Remírez, M. (M.); Guruceaga, E. (Elizabeth); Paz-Ares, L. (Luis); Ferrer, I. (Irene); Narayanan, S. (Shruthi); Ferrero, M. (Macarena); Lecanda, F. (Fernando); Welch, C. (Connor); Lopez, I. (Inés); Lonfgren, S.M. (Shane M.); Santamaria, E. (Enrique); Khatri, P. (Purvesh)Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.