Fas/Fas ligand regulation mediates cell death in human Ewing's sarcoma cells treated with melatonin.

BACKGROUND: Despite recent advances in cancer therapy, the 5-year survival rate for Ewing's sarcoma is still very low, and new therapeutic approaches are necessary. It was found previously that melatonin induces cell death in the Ewing's sarcoma cell line, SK-N-MC, by activating the extrinsic apoptotic pathway. METHODS: Melatonin actions were analysed by metabolic viability/survival cell assays, flow cytometry, quantitative PCR for mRNA expression, western blot for protein activation/expression and electrophoretic mobility shift assay for transcription factor activation. RESULTS: Melatonin increases the expression of Fas and its ligand Fas L, this increase being responsible for cell death induced by the indolamine. Melatonin also produces a transient increase in intracellular oxidants and activation of the redox-regulated transcription factor Nuclear factor-kappaB. Inhibition of such activation prevents cell death and Fas/Fas L upregulation. Cytotoxic effect and Fas/Fas L regulation occur in all Ewing's cell lines studied, and do not occur in the other tumour cell lines studied where melatonin does not induce cell death. CONCLUSION: Our data offers new insights in the study of alternative therapeutic strategies in the treatment of Ewing's sarcoma. Further attention deserves to be given to the differences in the cellular biology of sensitive tumours that could explain the cytotoxic effect of melatonin and the increase in the level of free radicals caused by this molecule, in particular cancer types.

Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma.

The SMOOTHENED inhibitor vismodegib is FDA approved for advanced basal cell carcinoma (BCC), and shows promise in clinical trials for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma (MB) patients. Clinical experience with BCC patients shows that continuous exposure to vismodegib is necessary to prevent tumor recurrence, suggesting the existence of a vismodegib-resistant reservoir of tumor-propagating cells. We isolated such tumor-propagating cells from a mouse model of SHH-subgroup MB and grew them as sphere cultures. These cultures were enriched for the MB progenitor marker SOX2 and formed tumors in vivo. Moreover, while their ability to self-renew was resistant to SHH inhibitors, as has been previously suggested, this self-renewal was instead WNT-dependent. We show here that loss of Trp53 activates canonical WNT signaling in these SOX2-enriched cultures. Importantly, a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup MB in vivo, in an on-target manner, leading to increased survival. Our results imply that the tumor-propagating cells driving the growth of bulk SHH-dependent MB are themselves WNT dependent. Further, our data suggest combination therapy with WNT and SHH inhibitors as a therapeutic strategy in patients with SHH-subgroup MB, in order to decrease the tumor recurrence commonly observed in patients treated with vismodegib.

Síndrome de Hamman como complicación inusual de COVID-19 / Hamman syndrome as an unusual complication of covid-19

La enfermedad por SARS-CoV-2 ha sido bien conocida por su capacidad de infección y afectación multiórgano con cierta preferencia y gravedad a los pulmones incluyendo lesiones parenquimatosas, alveolares e intersticiales. En esta oportunidad se presenta un caso infrecuente como lo es el síndrome de Hamman en un paciente masculino de 35 años con neumonía viral por COVID-19, Entidad que podría ser un indicador potencial de progresión y agravante de la enfermedad como de los síntomas asociados al patrón usual de la infección. Su tratamiento lo definirá la estabilidad clínica y el tamaño del neumomediastino (AU)

SARS-CoV-2 disease has been well known for its capacity for infection and multi-organ involvement with some preference and severity to the lungs including parenchymal, alveolar and interstitial lesions. On this occasion, an infrequent case such as Hamman syndrome is presented in a 35-year-old male patient with viral pneumonia due to COVID-19. Entity that could be a potential indicator of progression and aggravation of the disease as well as the symptoms associated with the pattern usual infection. His treatment will define the clinical stability and size of the pneumomediastinum (AU)

The hedgehog processing pathway is required for NSCLC growth and survival.

Considerable interest has been generated from the results of recent clinical trials using smoothened (SMO) antagonists to inhibit the growth of hedgehog (HH) signaling-dependent tumors. This interest is tempered by the discovery of SMO mutations mediating resistance, underscoring the rationale for developing therapeutic strategies that interrupt HH signaling at levels distinct from those inhibiting SMO function. Here, we demonstrate that HH-dependent non-small cell lung carcinoma (NSCLC) growth is sensitive to blockade of the HH pathway upstream of SMO, at the level of HH ligand processing. Individually, the use of different lentivirally delivered shRNA constructs targeting two functionally distinct HH-processing proteins, skinny hedgehog (SKN) or dispatched-1 (DISP-1), in NSCLC cell lines produced similar decreases in cell proliferation and increased cell death. Further, providing either an exogenous source of processed HH or a SMO agonist reverses these effects. The attenuation of HH processing, by knocking down either of these gene products, also abrogated tumor growth in mouse xenografts. Finally, we extended these findings to primary clinical specimens, showing that SKN is frequently overexpressed in NSCLC and that higher DISP-1 expression is associated with an unfavorable clinical outcome. Our results show a critical role for HH processing in HH-dependent tumors, identifies two potential druggable targets in the HH pathway, and suggest that similar therapeutic strategies could be explored to treat patients harboring HH ligand-dependent cancers.

The role and implications of bassanite as a stable precursor phase to gypsum precipitation.

Calcium sulfate minerals such as gypsum play important roles in natural and industrial processes, but their precipitation mechanisms remain largely unexplored. We used time-resolved sample quenching and high-resolution microscopy to demonstrate that gypsum forms via a three-stage process: (i) homogeneous precipitation of nanocrystalline hemihydrate bassanite below its predicted solubility, (ii) self-assembly of bassanite into elongated aggregates co-oriented along their c axis, and (iii) transformation into dihydrate gypsum. These findings indicate that a stable nanocrystalline precursor phase can form below its bulk solubility and that in the CaSO(4) system, the self-assembly of nanoparticles plays a crucial role. Understanding why bassanite forms prior to gypsum can lead to more efficient anti-scaling strategies for water desalination and may help to explain the persistence of CaSO(4) phases in regions of low water activity on Mars.

Relación entre estrés oxidativo y ciclo celular en la etiología de la muerte neuronal en la enfermedad de Parkinson. Efectos de los antioxidantes / Oxidative stress and cell cycle in the ethiology of neuronal cell death in Parkinson disease

La enfermedad de Parkinson es un trastorno neurodegenerativo caracterizado por la pérdida progresiva de las neuronas dopaminérgicas de la Sustancia Negra. Recientes trabajos relacionan al estrés oxidativo, implicado en la etiología de esta patología, con una sobreexpresión en las neuronas de proteínas reguladoras del ciclo celular. Las células postmitóticas, en respuesta a esta sobreexpresión, mueren por apoptosis en lugar de progresar a través de un ciclo celular descoordinado y por ello fatal. En este trabajo hemos comprobado el efecto neuroprotector de la melatonina frente a la muerte inducida por las neurotoxinas catecolinérgicas, MPP+ y 6-0HDA, en dos líneas celulares dopaminérgicas diferenciadas (UR61 y PC12), observando una prevención de entre el 10-20% (p<0.05). Un efecto similar fue observado con el empleo de antioxidantes y de inhibidores del ciclo celular, por lo que la neuroprotección mostrada por la melatonina podría estar mediada tanto por su actividad antioxidante, como su capacidad para impedir la reentrada en el ciclo celular

Parkinson's disease is a neurodegenerative disorder that leads to a progressive death of dopaminergic neurons in the Substantia Nigra. The generation of reactive oxygen species is considered to be implicated in its etiology. Recent works connect oxidative stress with the overexpresion of cell cycle proteins in neurons. Postmitotic neurons, because of said overexpresion, undergo apoptosis instead of going through a deregulated, therefore fatal, cell cycle. Our work shows the neuroprotector etTect of melatonin against neuronal death induced by the catecolinergic toxins MPP+ and 6-0HDA on two ditTerentiated dopaminergic celllines (UR61 and PC12). Melatonin was able to reduce cell death over a 10-20% (p<0.05). Other antioxidants, as well as other cell cycle inhibitors tested, produced a similar effect. Thus, it appears that either melatonin antioxidant properties or cell cycle reentry inhibiting properties may mediate its neuroprotector effect