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Sarcoma stratification by combined pH2AX and MAP17(PDZK1IP1)levels for a better outcome on doxorubicin plus olaparib treatment

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Signal Transduction and Targeted Therapy 2020年第1期5卷 697-709页

作者： Marco Perez JoséManuel García-Heredia Blanca Felipe-Abrio Sandra Muñoz-Galván Javier Martín-Broto Amancio Carnero Instituto de Biomedicina de Sevilla(IBIS) Hospital Universitario Virgen del RocíoUniversidad de SevillaConsejo Superior de Investigaciones CientíficasSevillaSpain Ciber de Cancer IS Carlos IIIMadridSpain departamento de Bioquímica Vegetal y Biología Molecular Universidad de SevillaSevillaSpain Departamento de Anatomía Patológica Hospital Universitario Virgen del RocíoSevillaSpain

Sarcomas constitute a rare heterogeneous group of tumors,including a wide variety of histological subtypes.despite advances in our understanding of the pathophysiology of the disease,first-line sarcoma treatment options are still limited and new treatment approaches are needed.Histone H2AX phosphorylation is a sensitive marker for double strand breaks and has recently emerged as biomarker of DNA damage for new drug development.In this study,we explored the role of H2AX phosphorylation at Ser139 alone or in combination with MAP17 protein,an inducer of DNA damage through ROS increase,as prognostic biomarkers in sarcoma tumors.Next,we proposed doxorubicin and olaparib combination as potential therapeutic strategies against sarcomas displaying high level of both markers.We evaluate retrospectively the levels of pH2AX(Ser139)and MAP17 in a cohort of 69 patients with different sarcoma types and its relationship with clinical and pathological features.We found that the levels of pH2AX and MAP17 were related to clinical features and poor survival.Next,we pursued PARP1 inhibition with olaparib to potentiate the antitumor effect of DNA damaging effect of the DNA damaging agent doxorubicin to achieve an optimal synergy in sarcoma.We demonstrated that the combination of olaparib and doxorubicin was synergistic in vitro,inhibiting cell proliferation and enhancing pH2AX intranuclear accumulation,as a result of DNA damage.The synergism was corroborated in patient-derived xenografts(PDX)where the combination was effective in tumors with high levels of pH2AX and MAP17,suggesting that both biomarkers might potentially identify patients who better benefit from this combined therapy.

关键词： H2AX doxorubicin treatment

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Taurine: a promising nutraceutic in the prevention of retinal degeneration

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Neural Regeneration Research 2024年第3期19卷 606-610页

作者： Diego García-Ayuso Johnny Di Pierdomenico Ana Martínez-Vacas Manuel Vidal-Sanz Serge Picaud María PVillegas-Pérez Grupo de Investigación Oftalmología Experimental Departamento de OftalmologíaOptometríaOtorrinolaringología y Anatomía PatológicaFacultad de MedicinaUniversidad de MurciaInstituto Murciano de Investigación Biosanitaria(IMIB)Campus de Ciencias de la SaludMurciaEspaña Sorbonne Université INSERMCNRSInstitut de la VisionParisFrance

Taurine is considered a non-essential amino acid because it is synthesized by most mammals.However,dietary intake of taurine may be necessary to achieve the physiological levels required for the development,maintenance,and function of certain tissues.Taurine may be especially important for the retina.The concentration of taurine in the retina is higher than that in any other tissue in the body and taurine deficiency causes retinal oxidative stress,apoptosis,and degeneration of photoreceptors and retinal ganglion cells.Low plasma taurine levels may also underlie retinal degeneration in humans and therefore,taurine administration could exert retinal neuroprotective effects.Taurine has antioxidant,anti-apoptotic,immunomodulatory,and calcium homeostasis-regulatory properties.This review summarizes the role of taurine in retinal health and disease,where it appears that taurine may be a promising nutraceutical.

关键词： amino acid anti-inflammatory antioxidant gamma-aminobutyric acid nutraceutical photoreceptor degeneration retina retinitis pigmentosa taurine

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A new treatment for sarcoma extracted from combination of miRNA deregulation and gene association rules

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Signal Transduction and Targeted Therapy 2023年第7期8卷 3221-3224页

作者： JoséManuel García-Heredia Marco Pérez Eva M.Verdugo-Sivianes María M.Martínez-Ballesteros Sara M.Ortega-Campos Amancio Carnero Instituto de Biomedicina de Sevilla(IBIS)/HUVR/Universidad de Sevilla/CSIC SevillaSpain departamento de Bioquímica Vegetal y Biología Molecular Universidad de SevillaSevillaSpain CIBERONC IS Carlos IIIMadridSpain Departamento de Anatomía Patológica HUVRSevillaSpain departamento de Lenguajes y Sistemas Informáticos Escuela Superior de Ingeniería InformáticaUniversidad de SevillaSevillaSpain

dear Editor Sarcomas are a group of heterogeneous mesodermic rare tumors with high incidence in children,reaching up to 20%of neoplasms.Standard treatment for sarcomas is surgical resection,and only some patients are treated with chemotherapy and/or radiation therapy.The 5-year relative survival rate for patients with metastatic sarcoma is only 15%.

关键词： neoplasms chemotherapy treatment

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Oligodendroctyes:the forgotten players of diabetes pathophysiology

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Neural Regeneration Research 2024年第11期19卷 2349-2350页

作者： Juan Antonio López-Villodres Beatriz García-Díaz departamento Fisiología Humana Histología HumanaAnatomía Patológica y Educación Física y DeportivaFacultad de MedicinaUniversidad de MálagaMálagaSpain UGC Neurociencia.Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina(IBIMA Plataforma Bionand) MálagaSpain

Oligodendrocytes(OLs),glial cells that provide myelin sheaths to axons in the central nervous system(CNS),have a dual role.First,this myelin fatty cover around the axons protects the nerves and is crucial for the saltatory propagation of action potentials.Second and not less important,OLs provide trophic support to neurons and axons.Thus,OL metabolism is important for OL well-being and the proper accomplishment of their functions,and OL metabolism energetics directly affect the energy metabolism of neighboring neurons.

关键词： metabolism nerves myelin

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Myxoid and Lipomatous Solitary Fibrous Tumor of Soft Tissue: A Case description

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Open Journal of Pathology 2017年第1期7卷 20-24页

作者： Javier Ortiz Rodríguez-Parets Cristina González Velasco Elisa Mu&ntilde oz Torres María Dolores Lude&ntilde a de la Cruz Departamento de Anatomía Patológica Hospital Universitario de Salamanca Salamanca Spain

We present a case of a myxoid and lipomatous solitary fibrous tumor that was observed in a 67-year-old man. The tumor, which had a maximum diameter of 10 cm, was located in the soft tissues of the dorsal region and appeared macroscopically well delimited and encapsulated. Upon cutting, a markedly gelatinous internal surface was observed. A microscopic study revealed an intense and diffusely myxoid neoplasia, with small areas of adipose aspect, in which histological (staghorn vessels, perivascular hyalinization, fusiform cells of benign aspect) and immunohistochemical (intensive positivity for CD34, Bcl-2 and Cd99 and negativity for muscle markers) data were consistent with a solitary fibrous tumor were observed. To conclude, the main characteristics of this lesion are discussed, and a differential diagnosis is established with other entities.

关键词： Solitary Fibrous Tumor Myxoid and Lipomatous Differentiation Histopathology Immunohistochemistry

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Blockade of Rho-associated kinase prevents inhibition of axon regeneration of peripheral nerves induced by anti-ganglioside antibodies

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Neural Regeneration Research 2024年第4期19卷 895-899页

作者： Andrés Berardo Cristian R.Bacaglio Bárbara B.Báez Rubén Sambuelli Kazim A.Sheikh Pablo H.H.Lopez Laboratorio de Neurobiología Instituto de Investigación Médica Mercedes y Martin Ferreyra(INIMEC)-Consejo Nacional de Investigaciones Cientificas y Técnicas(CONICET)Universidad Nacional de Córdoba departamento de Química Biológica-Centro de Investigaciones en Química Biológica de Córdoba(CIQUIBIC)-Consejo Nacional de Investigaciones Cientificas y Técnicas(CONICET) Facultad de Cs.QuímicasUniversidad Nacional de Córdoba Servicio de anatomía patológica Clínica Universitaria Reina FabiolaUniversidad Católica de Córdoba department of Neurology University of Texas Medical School at Houston

Anti-ganglioside antibodies are associated with delayed/poor clinical recovery in Guillain-Barrèsyndrome,mostly related to halted axon regeneration.Cross-linking of cell surface gangliosides by anti-ganglioside antibodies triggers inhibition of nerve repair in in vitro and in vivo paradigms of axon regeneration.These effects involve the activation of the small GTPase Rho A/ROCK signaling pathways,which negatively modulate growth cone cytoskeleton,similarly to well stablished inhibitors of axon regeneration described so far.The aim of this work was to perform a proof of concept study to demonstrate the effectiveness of Y-27632,a selective pharmacological inhibitor of ROCK,in a mouse model of axon regeneration of peripheral nerves,where the passive immunization with a monoclonal antibody targeting gangliosides GD1a and GT1b was previously reported to exert a potent inhibitory effect on regeneration of both myelinated and unmyelinated fibers.Our results demonstrate a differential sensitivity of myelinated and unmyelinated axons to the pro-regenerative effect of Y-27632.Treatment with a total dosage of 9 mg/kg of Y-27632 resulted in a complete prevention of anti-GD1a/GT1b monoclonal antibody-mediated inhibition of axon regeneration of unmyelinated fibers to skin and the functional recovery of mechanical cutaneous sensitivity.In contrast,the same dose showed toxic effects on the regeneration of myelinated fibers.Interestingly,scale down of the dosage of Y-27632 to 5 mg/kg resulted in a significant although not complete recovery of regenerated myelinated axons exposed to anti-GD1a/GT1b monoclonal antibody in the absence of toxicity in animals exposed to only Y-27632.Overall,these findings confirm the in vivo participation of Rho A/ROCK signaling pathways in the molecular mechanisms associated with the inhibition of axon regeneration induced by anti-GD1a/GT1b monoclonal antibody.Our findings open the possibility of therapeutic pharmacological intervention targeting Rho A/Rock pathway in immune neuropathies associated wi

关键词： anti-ganglioside antibodies anti-glycan antibodies axon regeneration ganglioside Guillain-Barrésyndrome nerve repair ROCK Y-27632

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Interplay between mesenchymal stromal cells and the immune system after transplantation: implications for advanced cell therapy in the retina

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Neural Regeneration Research 2024年第3期19卷 542-547页

作者： María Norte-Muñoz David García-Bernal Diego García-Ayuso Manuel Vidal-Sanz Marta Agudo-Barriuso Grupo de Investigación Oftalmología Experimental Departamento de OftalmologíaOptometríaOtorrinolaringología y Anatomía PatológicaFacultad de MedicinaUniversidad de MurciaInstituto Murciano de Investigación Biosanitaria(IMIB)Campus de Ciencias de la Salud30120 MurciaSpain Grupo de Investigación Trasplante Hematopoyético y Terapia celular Departamento de Bioquímica e Inmunología.Facultad de MedicinaUniversidad de MurciaInstituto Murciano de Investigación Biosanitaria(IMIB)Campus de Ciencias de la Salud30120 MurciaSpain

Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.

关键词： adaptive immunity cell therapy central nervous system immune system innate immunity mesenchymal stromal cells neuroregeneration preclinical studies retina transplantation

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Helicobacter pylori vacA s1a and s1b alleles from clinical isolates from different regions of Chile show a distinct geographic distribution

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World Journal of Gastroenterology 2005年第40期11卷 6366-6372页

作者： MI Díaz A Valdivia P Martínez JL Palacios P Harris J Novales E Garrido D Valderrama C Shilling A Kirberg E Hebel J Fierro R Bravo F Siegel G Leon G Klapp A Venegas departamento de Genética Molecular y Microbiología. Pontificia Universidad Católica de Chile. Santiago departamento de Pediatría Centro de Diagnóstico Terapéutico Los Angeles Unidad de Gastroenterología anatomía patológica Centro de Endoscopía Quirúrgica Hospital Base de Linares Hospital Regional de Valdivia Instituto de Bioquímica Hospital Regional de Punta Arenas

AIM: To establish the most common vacA alleles in Helicobacter pylori(H pylori) strains isolated from Chilean patients and its relationship with gastritis and gastroduodenal ulcers.METHODS: Two hundred and forty five H pylori clinical isolates were obtained from 79 biopsies from Chilean infected patients suffering from gastrointestinal diseases. An average of 2-3 strains per patient was isolated and the vacA genotype was analyzed by PCR and 3% agarose electrophoresis. Some genotypes were checked by DNA sequencing.RESULTS: The most prevalent vacA genotype inChilean patients was s1b m1 (76%), followed by s1a m1 (21%). In contrast, the s2 m2 genotype was scarcely represented (3%).The s1b m1 genotype was found most frequently linked to gastropathies (P＜0.05) rather than ulcers. Ulcers were found more commonly in male and older patients. Curiously, patients living in cities located North and far South of Santiago, the capital and largest Chilean city, carried almost exclusively strains with the s1b m1 genotype. In contrast, patients from Santiago and cities located South of Santiago carried strains with either one or both s1a m1 and s1b m1 genotypes.Regarding the s2 m2 genotype, comparison with GenBank sequences revealed that Chilean s2 sequence was identical to those of Australian, American, and Colombian strains but quite different from those of Alaska and India.CONCLUSION: Differences in geographic distribution of the s and m vaccA alleles in Chile and a relationship of s1b m1 genotype with gastritis were found. Sequence data in part support a hispanic origin for the vacA genotype.Asymmetric distribution of genotypes s1b m1 and s2 m2recedes H Pyloristrain distribution in Spain and Portugal.

关键词：地理分布智利幽门螺杆菌单离体

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Pontocerebellar Progressive Multifocal Leukoencephalopathy. Radiological, Clinical, Histological and Immunohistochemical Findings in a Hematological Patient

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Open Journal of Pathology 2023年第4期13卷 177-183页

作者： Javier Ortiz Juan Carlos Paniagua Isidro Cavaco Raquel Rivas Andrea Jimenez Luis Chinchilla Elisa Muñoz María Dolores Ludeña departamento de Biología Celular y patología Universidad de Salamanca (USAL) Salamanca Spain Servicio de anatomía patológica Hospital Universitario de Salamanca Salamanca Spain Servicio de Radiodiagnóstico Hospital Universitario de Salamanca Salamanca Spain

Objective: To describe the radiological, histological and immunohistochemical findings in a case of Progressive Multifocal Leukoencephalopathy (PML) affecting the cerebellar peduncles in a patient with chronic lymphocytic leukemia. Patient and Methods: Magnetic Resonance Imaging (MRI), histological picture (H.E., Kluver-Barrera) and immunohistochemical picture (GFAP, neurofilaments, CD68, JC virus) were obtained. Results: 1) Magnetic resonance imaging: Asymmetric and progressive lesions on middle cerebellar peduncles, that were hyperintense in T2/FLAIR, extended towards the pons, had no mass effect and were unmodified after intravenous contrast. 2) Histology: Marked reactive gliosis with cytopathic changes suggesting viral infection, plus demyelination areas with axonal preservation. 3) Immunohistochemistry: Marked positivity for viral (polyoma and JC virus) markers in glial cells showing cytopathic changes. Conclusions: The importance of histological and immunohistochemical diagnosis in everyday assistance;of the collaboration between clinicians, radiologists and pathologists;and the validity of postmortem studies as a key element for research and clinical quality assessment must be stressed.

关键词： Progressive Multifocal Leukoencephalopathy JC Virus Immunohistochemistry

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The best of both worlds:mastering nerve regeneration combining biological and nanotechnological tools

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Neural Regeneration Research 2023年第3期18卷 556-557页

作者： Paula A.Soto Marcela B.Fernández van Raap C.Patricia Setton-Avruj departamento de Química Biológica Cátedra de Química Biológica PatológicaUniversidad de Buenos AiresFacultad de Farmacia y BioquímicaInstituto de Química y Fisicoquímica Biológicas(IQUIFIB)Universidad de Buenos AiresBuenos AiresArgentina departamento de Física Universidad Nacional de La Plata(UNLP)Facultad de Ciencias ExactasLa PlataArgentinaLaboratorio de BiotecnologíaUniversidad ORT UruguayMontevideoUruguay

Over the last decade,remarkable developments in nanotechnology have powered medical research,unveiling new approaches for the solution of public health issues such as the treatment of traumatic peripheral neuropathies.

关键词： traumatic technological treatment

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