Expanding a precision medicine platform for malignant peripheral nerve sheath tumors: New patient-derived orthotopic xenografts, cell lines and tumor entities.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas with a poor survival rate, presenting either sporadically or in the context of neurofibromatosis type 1 (NF1). The histological diagnosis of MPNSTs can be challenging, with different tumors exhibiting great histological and marker expression overlap. This heterogeneity could be partly responsible for the observed disparity in treatment response due to the inherent diversity of the preclinical models used. For several years, our group has been generating a large patient-derived orthotopic xenograft (PDOX) MPNST platform for identifying new precision medicine treatments. Herein, we describe the expansion of this platform using six primary tumors clinically diagnosed as MPNSTs, from which we obtained six additional PDOX mouse models and three cell lines, thus generating three pairs of in vitro-in vivo models. We extensively characterized these tumors and derived preclinical models, including genomic, epigenomic, and histological analyses. Tumors were reclassified after these analyses: three remained as MPNSTs (two being classic MPNSTs), one was a melanoma, another was a neurotrophic tyrosine receptor kinase (NTRK)-rearranged spindle cell neoplasm, and, finally, the last was an unclassifiable tumor bearing neurofibromin-2 (NF2) inactivation, a neuroblastoma RAS viral oncogene homolog (NRAS) oncogenic mutation, and a SWI/SNF-related matrix-associated actin-dependent regulator of chromatin (SMARCA4) heterozygous truncated variant. New cell lines and PDOXs faithfully recapitulated histology, marker expression, and genomic characteristics of the primary tumors. The diversity in tumor identity and their specific associated genomic alterations impacted treatment responses obtained when we used the new cell lines for testing compounds against known altered pathways in MPNSTs. In summary, we present here an extension of our MPNST precision medicine platform, with new PDOXs and cell lines, including tumor entities confounded as MPNSTs in a real clinical scenario. This platform may constitute a useful tool for obtaining correct preclinical information to guide MPNST clinical trials.

Effects of ultrasonic vibration on the micro-molding processing of polylactide.

A new ultrasonic micro-molding system was used to process polylactide (PLA) and fabricate reduced dimension specimens. Plasticization and molding of PLA were achieved by applying ultrasonic waves after feeding the polymer into a plasticizing chamber. Chemical and physical characteristics of processed PLA varied depending on the processing window (i.e. changes in ultrasonic wave amplitude between 14.2 and 48.1 µm and molding pressure between 0.5 in 6 bars). In terms of chemical effects, the application of ultrasound can lead to lower molecular weights (e.g. decreases of more than 45% in the weight average molecular weight), revealing partial degradation of the material. Also, the processed materials exhibited slightly higher thermal degradability than pure PLA because ultrasonic vibrations break molecular linkages and worsen the polymer structure. Finally, the processing conditions for the preparation of PLA specimens could be optimized without causing degradation and preserving structural characteristics and mechanical properties. Specifically, the use of an amplitude of 48.1 µm and a pressure of 3 bars gave samples with the same molecular weight as the raw material (i.e. 117,500 g/mol as opposed to 117,300 g/mol for Mw).

Phosphorylation at Ser-181 of oncogenic KRAS is required for tumor growth.

KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein in vitro. In this study, we defined S181 as a specific phosphorylation site required to license the oncogenic function of mutant KRAS in vivo. The phosphomutant S181A failed to induce tumors in mice, whereas the phosphomimetic mutant S181D exhibited an enhanced tumor formation capacity, compared with the wild-type KRAS protein. Reduced growth of tumors composed of cells expressing the nonphosphorylatable KRAS S181A mutant was correlated with increased apoptosis. Conversely, increased growth of tumors composed of cells expressing the phosphomimetic KRAS S181D mutant was correlated with increased activation of AKT and ERK, two major downstream effectors of KRAS. Pharmacologic treatment with PKC inhibitors impaired tumor growth associated with reduced levels of phosphorylated KRAS and reduced effector activation. In a panel of human tumor cell lines expressing various KRAS isoforms, we showed that KRAS phosphorylation was essential for survival and tumorigenic activity. Furthermore, we identified phosphorylated KRAS in a panel of primary human pancreatic tumors. Taken together, our findings establish that KRAS requires S181 phosphorylation to manifest its oncogenic properties, implying that its inhibition represents a relevant target to attack KRAS-driven tumors.

Alletament matern en la unitat neonatal. Donem tots la mateixa informació? / No disponible

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Noves i velles infeccions en nadons / No disponible

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Síndrome de celulitis-adenitis inguinal por Streptococcus agalactiae / Cellulitis-adenitis syndrome inguinal Streptococcus agalactiae

Las infecciones de tejidos blandos en la infancia son producidas habitualmente por el Staphylococcus aureus pero, en los primeros meses de vida, el Streptococcus agalactiae (SGB) puede ser responsable de celulitis con afectación sistémica. El síndrome de celulitis-adenitis por SGB constituye una presentación infrecuente de la infección tardía causada por este germen. Las manifestaciones clínicas consisten en fiebre, mal estado general y signos inflamatorios locales. La localización más frecuente es la submaxilar, siendo excepcional la inguinal. Aportamos el caso de un paciente de 30 días de vida con fiebre, con una placa eritematosa y adenopatías en la zona inguinal derecha. En el hemocultivo se aisló SGB. El tratamiento inicial fue cloxacilina y cefotaxima parenterales cambiándose a las 48 horas, tras la recepción del hemocultivo, por cefotaxima y ampicilina. La evolución fue favorable. En niños menores de 3 meses, ante la presencia de celulitis y adenitis regional, debemos considerar al SGB como posible agente etiológico y contemplar la posibilidad de bacteriemia y afectación del sistema nervioso central para no diferir el tratamiento adecuado.

Soft-tissue infections in children are most often caused by Staphylococcus aureus but, in the first months of life, group B streptococcus (GBS) can be the etiologic agent of cellulitis with systemic involvement. Group B streptococcus cellulitis-adenitis syndrome is a rare form of late-onset disease for this germen. Clinical manifestations include fever and local inflammatory signs. Typical localization is submandibular but the inguinal form is exceptional. We present a case of a 30-day-old infant with fever, an erythematous plaque and lymphadenopathy in the right inguinal area. Blood culture was positive for GBS. Evolution was good with initial parenteral therapy with oxacylin and cefotaxime that was changed at 48 hours of treatment, after the blood culture reception, to ampicilin and cefotaxime. In cases of cellulitis and adenitis in infants during the first 3 months of life, GBS has to be considered the probable etiologic agent, and severe invasive disease has to be ruled-out in order to establish the appropriate antimicrobial therapy.