Papers by Alberto J. Schuhmacher
Journal of Clinical Medicine
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The measurement of CO2 has positioned itself as a low-cost and straightforward technique to indir... more The measurement of CO2 has positioned itself as a low-cost and straightforward technique to indirectly control indoor air quality, allowing the reduction of the concentration of potentially pathogen-loaded aerosols to which we are exposed. However, on numerous occasions, bad practice limits the technique for CO2 level interpreting and does not apply methodologies that guarantee air renewal. This work proposes a new methodology for measuring and controlling CO2 levels for indoor air in shared spaces. The proposed methodology is based on three stages: diagnosis, correction protocols, and monitoring/control/surveillance (MCS). The procedure is explained using a cultural center as an actual base case study. Additionally, the procedure was validated by implementing 40 voluntary commercial spaces in Zaragoza (Spain). Standardization of methods is suggested so that the measurement of CO2 becomes an effective strategy to control the airborne transmission of pathogens and thus prevent future...
Science of The Total Environment
Journal of Clinical Medicine
The spread dynamics of the SARS-CoV-2 virus have not yet been fully understood after two years of... more The spread dynamics of the SARS-CoV-2 virus have not yet been fully understood after two years of the pandemic. The virus’s global spread represented a unique scenario for advancing infectious disease research. Consequently, mechanistic epidemiological theories were quickly dismissed, and more attention was paid to other approaches that considered heterogeneity in the spread. One of the most critical advances in aerial pathogens transmission was the global acceptance of the airborne model, where the airway is presented as the epicenter of the spread of the disease. Although the aerodynamics and persistence of the SARS-CoV-2 virus in the air have been extensively studied, the actual probability of contagion is still unknown. In this work, the individual heterogeneity in the transmission of 22 patients infected with COVID-19 was analyzed by close contact (cough samples) and air (environmental samples). Viral RNA was detected in 2/19 cough samples from patient subgroups, with a mean Ct...
Cancers, 2021
Neuroimaging has transformed neuro-oncology and the way that glioblastoma is diagnosed and treate... more Neuroimaging has transformed neuro-oncology and the way that glioblastoma is diagnosed and treated. Magnetic Resonance Imaging (MRI) is the most widely used non-invasive technique in the primary diagnosis of glioblastoma. Although MRI provides very powerful anatomical information, it has proven to be of limited value for diagnosing glioblastomas in some situations. The final diagnosis requires a brain biopsy that may not depict the high intratumoral heterogeneity present in this tumor type. The revolution in “cancer-omics” is transforming the molecular classification of gliomas. However, many of the clinically relevant alterations revealed by these studies have not yet been integrated into the clinical management of patients, in part due to the lack of non-invasive biomarker-based imaging tools. An innovative option for biomarker identification in vivo is termed “immunotargeted imaging”. By merging the high target specificity of antibodies with the high spatial resolution, sensitivi...
Methods in Molecular Biology, 2018
Flow cytometry analysis and fluorescence-activated cell sorting (FACS) allow the determination an... more Flow cytometry analysis and fluorescence-activated cell sorting (FACS) allow the determination and isolation of different cell types from a given tumor sample. Here we describe and comment a method consisting of the preparation of a single cell suspension from a freshly dissected mouse brain tumor mass, staining with a combination of fluorescently labeled antibodies and analysis by flow cytometry to determine, characterize, and isolate different immune populations.
Molecular Cancer Therapeutics, 2021
Glioblastoma (GBM) is the most frequent and aggressive primary tumor type in the central nervous ... more Glioblastoma (GBM) is the most frequent and aggressive primary tumor type in the central nervous system in adults. Resistance to chemotherapy remains one of the major obstacles in GBM treatment. Identifying and overcoming the mechanisms of therapy resistance is instrumental to develop novel therapeutic approaches for patients with GBM. To determine the major drivers of temozolomide (TMZ) sensitivity, we performed shRNA screenings in GBM lines with different O6-methylguanine-DNA methyl-transferase (MGMT) status. We then evaluated dianhydrogalactitol (Val-083), a small alkylating molecule that induces interstrand DNA crosslinking, as a potential treatment to bypass TMZ-resistance mechanisms. We found that loss of mismatch repair (MMR) components and MGMT expression are mutually exclusive mechanisms driving TMZ resistance in vitro. Treatment of established GBM cells and tumorsphere lines with Val-083 induces DNA damage and cell-cycle arrest in G2–M phase, independently of MGMT or MMR s...
Advances in Biology and Treatment of Glioblastoma, 2017
The gliomas are a large group of brain tumors and Glioblastoma Multiforme (GBM) is the most commo... more The gliomas are a large group of brain tumors and Glioblastoma Multiforme (GBM) is the most common and lethal primary central nervous system tumor in adults. Despite the recent advances in treatment modalities, GBM patients generally respond poorly to all therapeutic approaches and prognosis remain dismal. Gaining insights into the pathways that determine this poor treatment response and the generation of more relevant animal models that recapitulate a patient’s tumor will be instrumental for the elaboration of new therapeutic modalities.
Tesis doctoral inedita leida en la Universidad Autonoma de Madrid, Departamento de Biologia Molec... more Tesis doctoral inedita leida en la Universidad Autonoma de Madrid, Departamento de Biologia Molecular. Fecha de lectura: 19-11-2008
Biomolecules, 2021
Single-domain antibodies derive from the heavy-chain-only antibodies of Camelidae (camel, dromeda... more Single-domain antibodies derive from the heavy-chain-only antibodies of Camelidae (camel, dromedary, llama, alpaca, vicuñas, and guananos; i.e., nanobodies) and cartilaginous fishes (i.e., VNARs). Their small size, antigen specificity, plasticity, and potential to recognize unique conformational epitopes represent a diagnostic and therapeutic opportunity for many central nervous system (CNS) pathologies. However, the blood–brain barrier (BBB) poses a challenge for their delivery into the brain parenchyma. Nevertheless, numerous neurological diseases and brain pathologies, including cancer, result in BBB leakiness favoring single-domain antibodies uptake into the CNS. Some single-domain antibodies have been reported to naturally cross the BBB. In addition, different strategies and methods to deliver both nanobodies and VNARs into the brain parenchyma can be exploited when the BBB is intact. These include device-based and physicochemical disruption of the BBB, receptor and adsorptive-...
BMC Biotechnology, 2018
This year the Spanish Federation of Biotechnologists (https://febiotec.es/) held the 12 th editio... more This year the Spanish Federation of Biotechnologists (https://febiotec.es/) held the 12 th edition of the Annual Biotechnology Congress (BAC) in Girona from 11 th to 13 th of July 2018. What is more, this entity with more than 1700 members, celebrated the 10 th anniversary of its foundation. One of the main goals of the event was to develop the appropriate atmosphere to allow the meeting and results sharing of young students and professionals with the audience and senior professionals. BAC Girona 2018 gathered biotechnologists from all over Spain to learn and enjoy the last trends in the field. This year's conferences included speeches from academia researchers, business biotechnology and oral communications of our assistants. As a recognition to the work of our participants, we are proud of sharing a sample of the abstracts presented in Girona. We hope to see you in the following edition of our Congress which will take place in Madrid in July 2019. O1 Virtual biopsy: development of non-invasive immunotargeted imaging agents for the diagnosis of glioblastoma
The Journal of Pathology, 2019
Glioblastoma (GBM) is a highly invasive brain neoplasia with an elevated recurrence rate after su... more Glioblastoma (GBM) is a highly invasive brain neoplasia with an elevated recurrence rate after surgical resection. The CyclinD1 (Ccnd1)/Cdk4-RB1 axis is frequently altered in GBM, leading to over-proliferation by RB1 deletion or by Ccnd1/Cdk4 over-activation. By not so well understood mechanisms, high levels of Ccnd1-Cdk4 also promote GBM cell invasion. The purpose of this work is to elucidate the in vivo role of the cytoplasmic Ccnd1-Cdk4 activity in the dissemination of GBM. We show that Ccnd1 activates invasion of primary human GBM cells through cytoplasmic RB1-independent mechanisms. By using GBM mouse models, we have observed that evaded GBM cells showed cytoplasmic Ccnd1 co-localizing with regulators of cell invasion such as RalA and Paxillin. Our genetic data strongly suggest that, in GBM cells, the Ccnd1/Cdk4 complex is acting upstream of those regulators. Accordingly, expression of Ccnd1 induces FAK, RalA and Rac1 activities. Finally, in vivo experiments demonstrated that the expression of a membrane-targeted Ccnd1 form expanded the GBM dissemination. We conclude that Ccnd1-Cdk4 activity promotes GBM dissemination through cytoplasmic and RB1-independent mechanisms. Therefore, the inhibition of Ccnd1-Cdk4 activity may be useful to hinder dissemination of recurrent GBM.
Cancer cell, Jan 13, 2017
Glioblastoma multiforme (GBM) is a deadly and common brain tumor. Poor prognosis is linked to hig... more Glioblastoma multiforme (GBM) is a deadly and common brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity, including glioma stem cells (GSCs). Telomere genes are frequently mutated. The telomere binding protein TRF1 is essential for telomere protection, and for adult and pluripotent stem cells. Here, we find TRF1 upregulation in mouse and human GBM. Brain-specific Trf1 genetic deletion in GBM mouse models inhibited GBM initiation and progression, increasing survival. Trf1 deletion increased telomeric DNA damage and reduced proliferation and stemness. TRF1 chemical inhibitors mimicked these effects in human GBM cells and also blocked tumor sphere formation and tumor growth in xenografts from patient-derived primary GSCs. Thus, targeting telomeres throughout TRF1 inhibition is an effective therapeutic strategy for GBM.
Expert Review of Endocrinology & Metabolism, 2017
ABSTRACT Introduction: Noonan syndrome is a RASopathy that results from activating mutations in d... more ABSTRACT Introduction: Noonan syndrome is a RASopathy that results from activating mutations in different members of the RAS/MAPK signaling pathway. At least eleven members of this pathway have been found mutated, PTPN11 being the most frequently mutated gene affecting about 50% of the patients, followed by SOS1 (10%), RAF1 (10%) and KRAS (5%). Recently, even more infrequent mutations have been newly identified by next generation sequencing. This spectrum of mutations leads to a broad variety of clinical symptoms such as cardiopathies, short stature, facial dysmorphia and neurocognitive impairment. The genetic variability of this syndrome makes it difficult to establish a genotype-phenotype correlation, which will greatly help in the clinical management of the patients. Areas covered: Studies performed with different genetically engineered mouse models (GEMMs) developed up to date. Expert commentary: GEMMs have helped us understand the role of some genes and the effect of the different mutations in the development of the syndrome. However, few models have been developed and more characterization of the existing ones should be performed to learn about the impact of the different modifiers in the phenotypes, the potential cancer risk in patients, as well as preventative and therapeutic strategies.
Scientific reports, Apr 28, 2017
RASopathies, characterized by germline mutations in genes encoding proteins of the RAS-ERK signal... more RASopathies, characterized by germline mutations in genes encoding proteins of the RAS-ERK signaling pathway, show overlapping phenotypes, which manifest themselves with a varying severity of intellectual disability. However, it is unclear to what extent they share the same downstream pathophysiology that underlies the cognitive deficits. Costello syndrome (CS) is a rare RASopathy caused by activating mutations in the HRAS gene. Here we investigated the mechanisms underlying the cognitive deficits of HRas (G12V/G12V) mice. HRas (G12V/G12V) mice showed robust upregulation of ERK signaling, neuronal hypertrophy, increased brain volume, spatial learning deficits, and impaired mGluR-dependent long-term depression (LTD). In contrast, long-term potentiation (LTP), which is affected in other RASopathy mouse models was unaffected. Treatment with lovastatin, a HMG-CoA-Reductase inhibitor which has been shown to rescue the behavioral phenotypes of mouse models of NF1 and Noonan syndrome, was ...
The Journal of pathology, Jun 1, 2016
The Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature... more The Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, craniofacial dysmorphism, and congenital heart defects. A significant proportion of NS patients may also develop myeloproliferative disorders (MPDs), including juvenile myelomonocytic leukaemia (JMML). Surprisingly, scarce information is available in relation to other tumour types in these patients. We have previously developed and characterized a knock-in mouse model that carries one of the most frequent KRAS-NS-related mutations, the K-Ras(V14I) substitution, which recapitulates most of the alterations described in NS patients, including MPDs. The K-Ras(V14I) mutation is a mild activating K-Ras protein; thus, we have used this model to study tumour susceptibility in comparison with mice expressing the classical K-Ras(G12V) oncogene. Interestingly, our studies have shown that these mice display a generalized tumour predisposition and not just MPDs. In fact, we have observed that the K...
Science (New York, N.Y.), Jan 20, 2016
Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inh... more Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inhibition of colony-stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that although overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas reestablish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment-driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor-1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors.
Cancer Cell, 2015
In this issue of Cancer Cell, Giachino and colleagues, employing various approaches, describe a t... more In this issue of Cancer Cell, Giachino and colleagues, employing various approaches, describe a tumor suppressor function for Notch signaling in forebrain tumors and suggest that decreased Notch activity could be a key molecular event in supratentorial primitive neuroectodermal tumors (sPNET).
BMC Cancer, 2015
Background: Malignant melanoma is an aggressive tumor type that often develops drug resistance to... more Background: Malignant melanoma is an aggressive tumor type that often develops drug resistance to targeted therapeutics. The production of colony stimulating factor 1 (CSF-1) in tumors recruits myeloid cells such as M2-polarized macrophages and myeloid derived suppressor cells (MDSC), leading to an immune suppressive tumor milieu. Methods: We used the syngeneic mouse model of BRAF V600E-driven melanoma SM1, which secretes CSF-1, to evaluate the ability of the CSF-1 receptor (CSF-1R) inhibitor PLX3397 to improve the antitumor efficacy of the oncogenic BRAF inhibitor vemurafenib. Results: Combined BRAF and CSF-1R inhibition resulted in superior antitumor responses compared with either therapy alone. In mice receiving PLX3397 treatment, a dramatic reduction of tumor-infiltrating myeloid cells (TIM) was observed. In this model, we could not detect a direct effect of TIMs or pro-survival cytokines produced by TIMs that could confer resistance to PLX4032 (vemurafenib). However, the macrophage inhibitory effects of PLX3397 treatment in combination with the paradoxical activation of wild type BRAF-expressing immune cells mediated by PLX4032 resulted in more tumor-infiltrating lymphocytes (TIL). Depletion of CD8+ T-cells abrogated the antitumor response to the combination therapy. Furthermore, TILs isolated from SM1 tumors treated with PLX3397 and PLX4032 displayed higher immune potentiating activity. Conclusions: The combination of BRAF-targeted therapy with CSF-1R blockade resulted in increased CD8 T-cell responses in the SM1 melanoma model, supporting the ongoing evaluation of this therapeutic combination in patients with BRAF V600 mutant metastatic melanoma.
Rare Diseases, 2015
N oonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, c... more N oonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, craniofacial dysmorphism, and congenital heart defects. A significant fraction of NSpatients also develop myeloproliferative disorders. The penetrance of these defects varies considerably among patients. In this study, we have examined the effect of 2 genetic backgrounds (C57BL/6J. OlaHsd and 129S2/SvPasCrl) on the phenotypes displayed by a mouse model of NS induced by germline expression of the mutated K-Ras V14I allele, one of the most frequent NS-KRAS mutations. Our results suggest the presence of genetic modifiers associated to the genetic background that are essential for heart development and function at early stages of postnatal life as well as in the severity of the haematopoietic alterations.
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Papers by Alberto J. Schuhmacher