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1.
Br J Cancer ; 125(9): 1261-1269, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34493820

RESUMEN

INTRODUCTION: Molecular-matched therapies have revolutionized cancer treatment. We evaluated the improvement in clinical outcomes of applying an in-house customized Next Generation Sequencing panel in a single institution. METHODS: Patients with advanced solid tumors were molecularly selected to receive a molecular-matched treatment into early phase clinical trials versus best investigators choice, according to the evaluation of a multidisciplinary molecular tumor board. The primary endpoint was progression-free survival (PFS) assessed by the ratio of patients presenting 1.3-fold longer PFS on matched therapy (PFS2) than with prior therapy (PFS1). RESULTS: Of a total of 231 molecularly screened patients, 87 were eligible for analysis. Patients who received matched therapy had a higher median PFS2 (6.47 months; 95% CI, 2.24-14.43) compared to those who received standard therapy (2.76 months; 95% CI, 2.14-3.91, Log-rank p = 0.022). The proportion of patients with a PFS2/PFS1 ratio over 1.3 was significantly higher in the experimental arm (0.33 vs 0.08; p = 0.008). DISCUSSION: We demonstrate the pivotal role of the institutional molecular tumor board in evaluating the results of a customized NGS panel. This process optimizes the selection of available therapies, improving disease control. Prospective randomized trials are needed to confirm this approach and open the door to expanded drug access.


Asunto(s)
Terapia Molecular Dirigida/métodos , Neoplasias/genética , Análisis de Secuencia de ADN/métodos , Adulto , Anciano , Anciano de 80 o más Años , Teorema de Bayes , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Medicina de Precisión , Estudios Prospectivos , Nivel de Atención
2.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-34298873

RESUMEN

Solid tumors are complex systems characterized by dynamic interactions between neoplastic cells, non-tumoral cells, and extracellular components. Among all the stromal cells that populate tumor microenvironment, fibroblasts are the most abundant elements and are critically involved in disease progression. Cancer-associated fibroblasts (CAFs) have pleiotropic functions in tumor growth and extracellular matrix remodeling implicated in local invasion and distant metastasis. CAFs additionally participate in the inflammatory response of the tumor site by releasing a variety of chemokines and cytokines. It is becoming clear that understanding the dynamic, mutual melanoma-fibroblast relationship would enable treatment options to be amplified. To better characterize melanoma-associated fibroblasts, here we analyzed low-passage primary CAFs derived from advanced-stage primary skin melanomas, focusing on the immuno-phenotype. Furthermore, we assessed the expression of several CAF markers and the production of growth factors. To deepen the study of CAF-melanoma cell crosstalk, we employed CAF-derived supernatants and trans-well co-culture systems to evaluate the influences of CAFs on (i) the motogenic ability of melanoma cells, (ii) the chemotherapy-induced cytotoxicity, and (iii) the release of mediators active in modulating tumor growth and spread.


Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Melanoma/genética , Neoplasias Cutáneas/genética , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Técnicas de Cocultivo , Citocinas/genética , Matriz Extracelular/genética , Perfilación de la Expresión Génica/métodos , Humanos , Inflamación/genética , Células del Estroma/metabolismo , Melanoma Cutáneo Maligno
3.
Int J Mol Sci ; 21(3)2020 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-31979112

RESUMEN

Nevoid basal cell carcinoma syndrome (NBCCS), also named Gorlin syndrome, is a rare multisystem genetic disorder characterized by marked predisposition to basal cell carcinomas (BCCs), childhood medulloblastomas, maxillary keratocysts, celebral calcifications, in addition to various skeletal and soft tissue developmental abnormalities. Mutations in the tumor suppressor gene PATCHED1 (PTCH1) have been found to be associated in the majority of NBCCS cases. PATCH1 somatic mutations and loss of heterozygosity are also very frequent in sporadic BCCs. Unlike non-syndromic patients, NBCCS patients develop multiple BCCs in sun-protected skin area starting from early adulthood. Recent studies suggest that dermo/epidermal interaction could be implicated in BCC predisposition. According to this idea, NBCCS fibroblasts, sharing with keratinocytes the same PTCH1 germline mutation and consequent constitutive activation of the Hh pathway, display features of carcinoma-associated fibroblasts (CAF). This phenotypic traits include the overexpression of growth factors, specific microRNAs profile, modification of extracellular matrix and basement membrane composition, increased cytokines and pro-angiogenic factors secretion, and a complex alteration of the Wnt/-catenin pathway. Here, we review studies about the involvement of dermal fibroblasts in BCC predisposition of Gorlin syndrome patients. Further, we matched the emerged NBCCS fibroblast profile to those of CAF to compare the impact of cell autonomous "pre-activated state" due to PTCH1 mutations to those of skin tumor stroma.


Asunto(s)
Síndrome del Nevo Basocelular/patología , Carcinoma Basocelular/patología , Fibroblastos/patología , Neoplasias Cutáneas/patología , Animales , Síndrome del Nevo Basocelular/metabolismo , Carcinoma Basocelular/metabolismo , Fibroblastos/metabolismo , Humanos , Receptor Patched-1/metabolismo , Transducción de Señal/fisiología , Neoplasias Cutáneas/metabolismo
4.
Exp Dermatol ; 28(6): 695-703, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31066942

RESUMEN

Vitiligo is a common, disfiguring autoimmune disease that negatively affects patients' self-esteem and quality of life. Current treatments are moderately effective in reversing disease and promoting melanocyte regeneration. Thus, therapeutic advanced strategies are emerging from regenerative medicine. It has recently emerged that adipose tissue secretome may be used as a cell-free therapy in skin regeneration since paracrine functions of adipose-derived stem cells alone are responsible for most of the therapeutic effect of stem cells in several animal disease models. In this study, we tested the effect of adipose tissue extracellular fraction (AT-Ex) isolated from lipoaspirates on dermal and epidermal vitiligo cells in vitro. Using this experimental model, we demonstrated that molecules secreted by adipose tissue ameliorate the capability to counteract oxidative stress by a physiological stimulation of intracellular antioxidant enzymes and positively impact on cell proliferation. Due to the presence of Wnt-secreted factors, AT-Ex treatment promotes glycogen synthase kinase 3ß inactivation and consequently Wnt/ß-catenin pathway activation. Collectively, our findings show that AT-Ex could be useful as a natural approach to improve treatment of vitiligo.


Asunto(s)
Tejido Adiposo/fisiología , Medicina Regenerativa/métodos , Vitíligo/terapia , Adolescente , Adulto , Anciano , Antioxidantes/metabolismo , Proliferación Celular , Femenino , Fibroblastos/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Masculino , Melanocitos/citología , Persona de Mediana Edad , Estrés Oxidativo , Calidad de Vida , Especies Reactivas de Oxígeno/metabolismo , Regeneración , Piel/patología , Proteínas Wnt/metabolismo , Adulto Joven
5.
Int J Mol Sci ; 19(11)2018 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-30441809

RESUMEN

An overactivation of hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (MET) axis promotes tumorigenesis and tumor progression in various cancer types. Research data recently evidenced that HGF/MET signaling is also involved also in the immune response, mainly modulating dendritic cells functions. In general, the pathway seems to play an immunosuppressive role, thus hypothesizing that it could constitute a mechanism of primary and acquired resistance to cancer immunotherapy. Recently, some approaches are being developed, including drug design and cell therapy to combine MET and programmed cell death receptor-1 (PD-1)/programmed cell death receptor-ligand 1 (PD-L1) inhibition. This approach could represent a new weapon in cancer therapy in the future.


Asunto(s)
Factor de Crecimiento de Hepatocito/metabolismo , Inmunoterapia/métodos , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Animales , Humanos , Neoplasias/terapia
6.
FASEB J ; 27(1): 13-24, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23024375

RESUMEN

Primary tumors are responsible for 10% of cancer deaths. In most cases, the main cause of mortality is the formation of metastases. Accumulating evidence suggests that a subpopulation of tumor cells with distinct stem-like properties is responsible for tumor initiation, invasive growth, and metastasis formation. This population is defined as cancer stem cells (CSCs). Existing therapies have enhanced the length of survival after diagnosis of cancer but have completely failed in terms of recovery. CSCs appear to be resistant to chemotherapy, may remain quiescent for extended periods, and have affinity for hypoxic environments. The CSCs can be identified and isolated by different methodologies, including isolation by CSC-specific cell surface marker expression, detection of side population phenotype by Hoechst 33342 exclusion, assessment of their ability to grow as floating spheres, and aldehyde dehydrogenase (ALDH) activity assay. None of the methods mentioned are exclusively used to isolate the solid tumor CSCs, highlighting the imperative to delineate more specific markers or to use combinatorial markers and methodologies. This review provides an overview of the main characteristics and approaches used to identify, isolate, and characterize CSCs from solid tumors.


Asunto(s)
Neoplasias/patología , Células Madre Neoplásicas/patología , Separación Celular , Humanos
7.
Cells ; 13(5)2024 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-38474338

RESUMEN

BACKGROUND: Cutaneous melanoma arises from skin melanocytes and has a high risk of metastatic spread. Despite better prevention, earlier detection, and the development of innovative therapies, melanoma incidence and mortality increase annually. Major clinical risk factors for melanoma include fair skin, an increased number of nevi, the presence of dysplastic nevi, and a family history of melanoma. However, several external inducers seem to be associated with melanoma susceptibility such as environmental exposure, primarily unprotected sun experience, alcohol consumption, and heavy metals. In recent years, epidemiological studies have highlighted a potential risk of ß-hexachlorocyclohexane (ß-HCH), the most studied organochlorine pesticide, causing cancer induction including melanoma. METHODS: We evaluated in vitro the impact of this pollutant on epidermal and dermal cells, attempting to describe mechanisms that could render cutaneous cells more prone to oncogenic transformation. RESULTS: We demonstrated that ß-HCH impacts melanocyte biology with a highly cell-type specific signature that involves perturbation of AKT/mTOR and Wnt/ß-catenin signaling, and AMPK activation, resulting in lowering energy reserve, cell proliferation, and pigment production. CONCLUSIONS: In conclusion, long-term exposure to persistent organic pollutants damages melanocyte metabolism in its function of melanin production with a consequent reduction of melanogenesis indicating a potential augmented skin cancer risk.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/patología , Neoplasias Cutáneas/patología , Melanocitos/metabolismo , Hexaclorociclohexano/metabolismo
8.
Sci Rep ; 14(1): 500, 2024 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-38177190

RESUMEN

Osimertinib is a third-generation tyrosine kinase inhibitor clinically approved for first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC) patients. Although an impressive drug response is initially observed, in most of tumors, resistance occurs after different time and an alternative therapeutic strategy to induce regression disease is currently lacking. The hyperactivation of MEK/MAPKs, is one the most common event identified in osimertinib-resistant (OR) NSCLC cells. However, in response to selective drug pressure, the occurrence of multiple mechanisms of resistance may contribute to treatment failure. In particular, the epithelial-to-mesenchymal transition (EMT) and the impaired DNA damage repair (DDR) pathways are recognized as additional cause of resistance in NSCLC thus promoting tumor progression. Here we showed that concurrent upregulation of ITGB1 and DDR family proteins may be associated with an increase of EMT pathways and linked to both osimertinib and MEK inhibitor resistance to cell death. Furthermore, this study demonstrated the existence of an interplay between ITGB1 and DDR and highlighted, for the first time, that combined treatment of MEK inhibitor with DDRi may be relevant to downregulate ITGB1 levels and increase cell death in OR NSCLC cells.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Receptores ErbB/metabolismo , Resistencia a Antineoplásicos/genética , Mutación , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Línea Celular Tumoral
9.
Biomedicines ; 12(4)2024 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-38672164

RESUMEN

BACKGROUND: Lung cancer (LC), including both non-small (NSCLC) and small (SCLC) subtypes, is currently treated with a combination of chemo- and immunotherapy. However, predictive biomarkers to identify high-risk patients are needed. Here, we explore the role of peripheral blood mononuclear cells (PBMCs) as a tool for novel biomarkers searching. METHODS: We analyzed the expression of the cGAS-STING pathway, a key DNA sensor that activates during chemotherapy, in PBMCs from LC patients divided into best responders (BR), responders (R) and non-responders (NR). The PBMCs were whole exome sequenced (WES). RESULTS: PBMCs from BR and R patients of LC cohorts showed the highest levels of STING (p < 0.0001) and CXCL10 (p < 0.0001). From WES, each subject had at least 1 germline/somatic alteration in a DDR gene and the presence of more DDR gene mutations correlated with clinical responses, suggesting novel biomarker implications. Thus, we tested the effect of the pharmacological DDR inhibitor (DDRi) in PBMCs and in three-dimensional spheroid co-culture of PBMCs and LC cell lines; we found that DDRi strongly increased cGAS-STING expression and tumor infiltration ability of immune cells in NR and R patients. Furthermore, we performed FACS analysis of PBMCs derived from LC patients from the BR, R and NR cohorts and we found that cytotoxic T cell subpopulations displayed the highest STING expression. CONCLUSIONS: cGAS-STING signaling activation in PBMCs may be a novel potential predictive biomarker for the response to immunotherapy and high levels are correlated with a better response to treatment along with an overall increased antitumor immune injury.

10.
J Exp Clin Cancer Res ; 43(1): 166, 2024 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-38877575

RESUMEN

BACKGROUND: Breast cancer (BC) is a complex disease, showing heterogeneity in the genetic background, molecular subtype, and treatment algorithm. Historically, treatment strategies have been directed towards cancer cells, but these are not the unique components of the tumor bulk, where a key role is played by the tumor microenvironment (TME), whose better understanding could be crucial to obtain better outcomes. METHODS: We evaluated mitochondrial transfer (MT) by co-culturing Adipose stem cells with different Breast cancer cells (BCCs), through MitoTracker assay, Mitoception, confocal and immunofluorescence analyses. MT inhibitors were used to confirm the MT by Tunneling Nano Tubes (TNTs). MT effect on multi-drug resistance (MDR) was assessed using Doxorubicin assay and ABC transporter evaluation. In addition, ATP production was measured by Oxygen Consumption rates (OCR) and Immunoblot analysis. RESULTS: We found that MT occurs via Tunneling Nano Tubes (TNTs) and can be blocked by actin polymerization inhibitors. Furthermore, in hybrid co-cultures between ASCs and patient-derived organoids we found a massive MT. Breast Cancer cells (BCCs) with ASCs derived mitochondria (ADM) showed a reduced HIF-1α expression in hypoxic conditions, with an increased ATP production driving ABC transporters-mediated multi-drug resistance (MDR), linked to oxidative phosphorylation metabolism rewiring. CONCLUSIONS: We provide a proof-of-concept of the occurrence of Mitochondrial Transfer (MT) from Adipose Stem Cells (ASCs) to BC models. Blocking MT from ASCs to BCCs could be a new effective therapeutic strategy for BC treatment.


Asunto(s)
Neoplasias de la Mama , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Mitocondrias , Humanos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Mitocondrias/metabolismo , Células Madre/metabolismo , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Línea Celular Tumoral , Microambiente Tumoral
11.
Front Physiol ; 14: 1284410, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38046945

RESUMEN

Aging of human skin is a complex process leading to a decline in homeostasis and regenerative potential of this tissue. Mitochondria are important cell organelles that have a crucial role in several cellular mechanisms such as energy production and free radical maintenance. However, mitochondrial metabolism as well as processes of mitochondrial dynamics, biogenesis, and degradation varies considerably among the different types of cells that populate the skin. Disturbed mitochondrial function is known to promote aging and inflammation of the skin, leading to impairment of physiological skin function and the onset of skin pathologies. In this review, we discuss the essential role of mitochondria in different skin cell types and how impairment of mitochondrial morphology, physiology, and metabolism in each of these cellular compartments of the skin contributes to the process of skin aging.

12.
Curr Opin Pharmacol ; 69: 102348, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36842387

RESUMEN

Gastro-esophageal tumors constitute a big health problem. Treatment options still mainly rely on chemotherapy, and apart from human epidermal growth factor receptor 2 positive and microsatellite instable/Epstein-Barr Virus disease, there are no molecularly guided options. Therefore, despite the large number of identified molecular alterations, precision medicine is still far from the clinic. In this context, the recently developed technology of patient-derived organoids (PDOs) could offer the chance to accelerate drug development and biomarker discovery. Indeed, PDOs are 3D primary cultures that were shown to reproduce patient's tumor characteristics. Moreover, several reports indicated that PDOs can replicate patient's response to a given drug; therefore, they are one of the most promising tools for functional precision medicine.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Neoplasias Esofágicas , Humanos , Medicina de Precisión , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/patología , Herpesvirus Humano 4 , Neoplasias Esofágicas/patología , Organoides/metabolismo
13.
Nucl Med Commun ; 44(5): 345-350, 2023 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-36826418

RESUMEN

BACKGROUND: Sentinel lymph node (SLN) biopsy in cutaneous melanoma patients evaluates the regional draining basin for occult micrometastatic disease. Occasionally, nonidentification of SLN impairs the acquisition of this important prognostic factor. OBJECTIVES: To investigate the outcomes of melanoma patients with negative lymphoscintigraphic findings and patients who underwent SLN biopsy from 2004 to 2015 ( n = 1200) were retrospectively reviewed for tumor characteristics and clinical outcomes. METHODS: Patients with nonvisualized lymph nodes (NV group) who underwent only preoperative lymphoscintigraphy were separated and compared with a cohort drawn from all melanoma patients who completed the surgical procedure within the same period (V group). RESULTS: A negative lymphoscintigraphic scan was observed in 38 cases (3.2% of all patients). The NV group showed a significantly older age (median 66.0 vs. 48.3 years; P < 0.0001). Head and neck melanomas were more frequent in the NV group compared to the control group (25.1 vs. 7.8%; P = 0.009). Tumor characteristics such as ulceration and Breslow thickness do not influence the lymphoscintigraphy result. No differences were found in overall survival (OS) and disease-free survival (DFS) between the groups. CONCLUSIONS: The nonvisualization of regional lymph nodes by lymphoscintigraphy is more frequent in older patients with head and neck melanomas. From the clinical point of view, no specific recommendation emerged for patients' management because the nonvisualization of the SLN did not show a significant influence on DFS and OS rates. However, lack of knowledge of lymph node status suggests performing a tighter follow-up eventually by ultrasound evaluation of all potential lymph node drainage basins.


Asunto(s)
Melanoma , Ganglio Linfático Centinela , Neoplasias Cutáneas , Humanos , Anciano , Melanoma/diagnóstico por imagen , Melanoma/cirugía , Melanoma/patología , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/patología , Ganglio Linfático Centinela/patología , Estudios Retrospectivos , Linfocintigrafia , Metástasis Linfática/patología , Biopsia del Ganglio Linfático Centinela , Ganglios Linfáticos/patología , Melanoma Cutáneo Maligno
14.
J Exp Clin Cancer Res ; 42(1): 8, 2023 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-36604765

RESUMEN

BACKGROUND: Patient-derived organoids (PDOs) from advanced colorectal cancer (CRC) patients could be a key platform to predict drug response and discover new biomarkers. We aimed to integrate PDO drug response with multi-omics characterization beyond genomics. METHODS: We generated 29 PDO lines from 22 advanced CRC patients and provided a morphologic, genomic, and transcriptomic characterization. We performed drug sensitivity assays with a panel of both standard and non-standard agents in five long-term cultures, and integrated drug response with a baseline proteomic and transcriptomic characterization by SWATH-MS and RNA-seq analysis, respectively. RESULTS: PDOs were successfully generated from heavily pre-treated patients, including a paired model of advanced MSI high CRC deriving from pre- and post-chemotherapy liver metastasis. Our PDOs faithfully reproduced genomic and phenotypic features of original tissue. Drug panel testing identified differential response among PDOs, particularly to oxaliplatin and palbociclib. Proteotranscriptomic analyses revealed that oxaliplatin non-responder PDOs present enrichment of the t-RNA aminoacylation process and showed a shift towards oxidative phosphorylation pathway dependence, while an exceptional response to palbociclib was detected in a PDO with activation of MYC and enrichment of chaperonin T-complex protein Ring Complex (TRiC), involved in proteome integrity. Proteotranscriptomic data fusion confirmed these results within a highly integrated network of functional processes involved in differential response to drugs. CONCLUSIONS: Our strategy of integrating PDOs drug sensitivity with SWATH-mass spectrometry and RNA-seq allowed us to identify different baseline proteins and gene expression profiles with the potential to predict treatment response/resistance and to help in the development of effective and personalized cancer therapeutics.


Asunto(s)
Antineoplásicos , Neoplasias Colorrectales , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Oxaliplatino/farmacología , Oxaliplatino/uso terapéutico , Proteómica , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Organoides
15.
FASEB J ; 25(6): 2022-30, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21385990

RESUMEN

This study aimed to identify, isolate, and characterize cancer stem cells from human primary sarcomas. We performed cytometric analyses for stemness and differentiation antigens, including CD29, CD34, CD44, CD90, CD117, and CD133, on 21 human primary sarcomas on the day of surgery. From sarcoma biopsies, we obtained 2 chondrosarcoma-stabilized cell lines and 2 osteosarcoma stabilized cell lines, on which sphere formation, side population profile, stemness gene expression, and in vivo and in vitro assays were performed. All samples expressed the CD133, CD44, and CD29 markers. Therefore, we selected a CD133(+) subpopulation from stabilized cell lines that displayed the capacity to grow as sarcospheres able to initiate and sustain tumor growth in nonobese diabetic/severe combined (NOD/SCID) mice, to express stemness genes, including OCT3/4, Nanog, Sox2, and Nestin, and to differentiate into mesenchymal lineages, such as osteoblasts and adipocytes. Our findings show the existence of cancer stem cells in human primary bone sarcomas and highlight CD133 as a pivotal marker for identification of these cells. This may be of primary importance in the development of new therapeutic strategies and new prognostic procedures against these highly aggressive and metastatic tumors.


Asunto(s)
Antígenos CD/metabolismo , Neoplasias Óseas/metabolismo , Condrosarcoma/metabolismo , Glicoproteínas/metabolismo , Células Madre Neoplásicas/metabolismo , Osteosarcoma/metabolismo , Péptidos/metabolismo , Antígeno AC133 , Adolescente , Adulto , Anciano , Animales , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Trasplante de Neoplasias , Neoplasias Experimentales , Adulto Joven
16.
Antioxidants (Basel) ; 11(6)2022 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-35740018

RESUMEN

Skin aging is one of the most evident signs of human aging. Modification of the skin during the life span is characterized by fine lines and wrinkling, loss of elasticity and volume, laxity, rough-textured appearance, and pallor. In contrast, photoaged skin is associated with uneven pigmentation (age spot) and is markedly wrinkled. At the cellular and molecular level, it consists of multiple interconnected processes based on biochemical reactions, genetic programs, and occurrence of external stimulation. The principal cellular perturbation in the skin driving senescence is the alteration of oxidative balance. In chronological aging, reactive oxygen species (ROS) are produced mainly through cellular oxidative metabolism during adenosine triphosphate (ATP) generation from glucose and mitochondrial dysfunction, whereas in extrinsic aging, loss of redox equilibrium is caused by environmental factors, such as ultraviolet radiation, pollution, cigarette smoking, and inadequate nutrition. During the aging process, oxidative stress is attributed to both augmented ROS production and reduced levels of enzymatic and non-enzymatic protectors. Apart from the evident appearance of structural change, throughout aging, the skin gradually loses its natural functional characteristics and regenerative potential. With aging, the skin immune system also undergoes functional senescence manifested as a reduced ability to counteract infections and augmented frequency of autoimmune and neoplastic diseases. This review proposes an update on the role of oxidative stress in the appearance of the clinical manifestation of skin aging, as well as of the molecular mechanisms that underline this natural phenomenon sometimes accelerated by external factors.

17.
Biomedicines ; 10(11)2022 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-36359263

RESUMEN

Vitiligo is a complex disorder with an important effect on the self-esteem and social life of patients. It is the commonest acquired depigmentation disorder characterized by the development of white macules resulting from the selective loss of epidermal melanocytes. The pathophysiology is complex and involves genetic predisposition, environmental factors, oxidative stress, intrinsic metabolic dysfunctions, and abnormal inflammatory/immune responses. Although several therapeutic options have been proposed to stabilize the disease by stopping the depigmentation process and inducing durable repigmentation, no specific cure has yet been defined, and the long-term persistence of repigmentation is unpredictable. Recently, due to the progressive loss of functional melanocytes associated with failure to spontaneously recover pigmentation, several different cell-based and cell-free regenerative approaches have been suggested to treat vitiligo. This review gives an overview of clinical and preclinical evidence for innovative regenerative approaches for vitiligo patients.

18.
Cells ; 11(23)2022 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-36497199

RESUMEN

Type 1 diabetes (T1D) is an autoimmune disease with immune cells' islet infiltration (called "insulitis"), which leads to beta cell loss. Despite being the critical element of T1D occurrence and pathogenesis, insulitis is often present in a limited percentage of islets, also at diagnosis. Therefore, it is needed to define reproducible methods to detect insulitis and beta-cell decline, to allow accurate and early diagnosis and to monitor therapy. However, this goal is still far due to the morphological aspect of islet microvasculature, which is rather dense and rich, and is considerably rearranged during insulitis. More studies on microvasculature are required to understand if contrast-enhanced ultrasound sonography measurements of pancreatic blood-flow dynamics may provide a clinically deployable predictive marker to predict disease progression and therapeutic reversal in pre-symptomatic T1D patients. Therefore, it is needed to clarify the relation between insulitis and the dynamics of ß cell loss and with coexisting mechanisms of dysfunction, according to clinical stage, as well as the micro vessels' dynamics and microvasculature reorganization. Moreover, the ideal cell-based therapy of T1D should start from an early diagnosis allowing a sufficient isolation of specific Procr+ progenitors, followed by the generation and expansion of islet organoids, which could be transplanted coupled to an immune-regulatory therapy which will permit the maintenance of pancreatic islets and an effective and long-lasting insulitis reversal.


Asunto(s)
Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Islotes Pancreáticos , Enfermedades Pancreáticas , Humanos , Diabetes Mellitus Tipo 1/metabolismo , Páncreas/patología , Islotes Pancreáticos/metabolismo , Células Secretoras de Insulina/metabolismo , Células Madre/metabolismo
19.
J Pers Med ; 12(11)2022 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-36422115

RESUMEN

Precision medicine approaches for solid tumors are mainly based on genomics. Its employment in clinical trials has led to somewhat underwhelming results, except for single responses. Moreover, several factors can influence the response, such as gene and protein expression, the coexistence of different genomic alterations or post-transcriptional/translational modifications, the impact of tumor microenvironment, etc., therefore making it insufficient to employ a genomics-only approach to predict response. Recently, the implementation of patient-derived organoids has shed light on the possibility to use them to predict patient response to drug treatment. This could offer for the first time the possibility to move precision medicine to a functional environment.

20.
Cells ; 11(22)2022 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-36429011

RESUMEN

Vitiligo is a complex disease wherein derangements in multiple pathways determine the loss of functional melanocytes. Since its pathogenesis is not yet completely understood, vitiligo lacks a definitive safe and efficacious treatment. At present, different therapies are available; however, each modality has its baggage of disadvantages and side effects. Recently we have described several metabolic abnormalities in cells from pigmented skin of vitiligo patients, including alterations of glucose metabolism. Therefore, we conducted a study to evaluate the effect of Pioglitazone (PGZ), a Peroxisome proliferator-activated receptor-γ (PPARγ) agonist, on cells from pigmented vitiligo skin. We treated vitiligo melanocytes and fibroblasts with low doses of PGZ and evaluated the effects on mitochondrial alterations, previously reported by our and other groups. Treatment with PGZ significantly increased mRNA and protein levels of several anaerobic glycolytic enzymes, without increasing glucose consumption. The PGZ administration fully restored the metabolic network, replacing mitochondrial membrane potential and mitochondrial DNA (mtDNA) copy number. These effects, together with a significant increase in ATP content and a decrease in reactive oxygen species (ROS) production, provide strong evidence of an overall improvement of mitochondria bioenergetics in vitiligo cells. Moreover, the expression of HMGB1, Hsp70, defined as a part of DAMPs, and PD-L1 were significantly reduced. In addition, PGZ likely reverts premature senescence phenotype. In summary, the results outline a novel mode of action of Pioglitazone, which may turn out to be relevant to the development of effective new vitiligo therapeutic strategies.


Asunto(s)
PPAR gamma , Vitíligo , Humanos , PPAR gamma/metabolismo , Vitíligo/tratamiento farmacológico , Vitíligo/genética , Vitíligo/metabolismo , Pioglitazona/farmacología , Pioglitazona/uso terapéutico , Hipoglucemiantes , Melanocitos/metabolismo
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