Anti-tumor activity of the MDM2-TP53 inhibitor BI-907828 in dedifferentiated liposarcoma patient-derived xenograft models harboring MDM2 amplification.

PURPOSE: Dedifferentiated liposarcoma (DDLPS) is a soft tissue malignancy characterized by amplification of the mouse double minute 2 homolog (MDM2) gene. MDM2 is a negative regulator of tumor protein 53 (TP53). We tested the in vivo efficacy of BI-907828, a small molecule inhibitor of the MDM2-TP53 interaction, in two DDLPS patient-derived xenografts (PDX). METHODS: Partially immunodeficient mice were bilaterally engrafted with UZLX-STS3 (n = 24) and UZLX-STS5 (n = 24) human DDLPS tissue harboring MDM2 amplifications. Mice were grouped as follows: (a) vehicle (0.5% hydroxyethylcellullose) 10 ml/kg daily per os (p.o.); (b) doxorubicin 5 mg/kg weekly intraperitoneally (i.p.); (c) BI-907828 2.5 mg/kg daily p.o. and (d) BI-907828 10 mg/kg daily p.o. The treatment lasted for 15 days, all mice treated with BI-907828 were followed for 37 days post-treatment. Efficacy was assessed by tumor volume and histopathological evaluation. RESULTS: The 15-day treatment with 2.5 mg/kg and 10 mg/kg BI-907828 significantly inhibited tumor growth in UZLX-STS5 and -STS3 (p < 0.0001 compared to control for both models). All UZLX-STS5 and -STS3 tumors treated with BI-907828 decreased in size during treatment, and BI-907828-treated UZLX-STS5 tumors even disappeared completely. During the follow-up period, no tumor regrowth was observed in the UZLX-STS5 model and both doses of BI-907828 led to a pathological complete response, whereas a dose-dependent regrowth was seen in the UZLX-STS3 model. CONCLUSION: BI-907828 showed significant anti-tumor activity in DDLPS PDX harboring MDM2 amplifications, providing a strong rationale for early clinical testing of BI-907828 in a DDLPS patient population.

Effect of Propionibacterium acnes (PA) injection on intervertebral disc degeneration in a rat model: Does it mimic modic changes?

INTRODUCTION: Multiple reports of bacterial isolates in human disc tissue have suggested a role of low-grade infection on intervertebral disc degeneration and modic changes (MC) generation. Animal models have been extensively used to study IDD; however, until recently, no consideration had been given to eventual infectious processes. To reproduce the phenomena by inoculating an infecting agent would support the infectious hypothesis. Therefore, we studied the effect of Propionibacterium acnes (PA) inoculation on rat-tails and determined whether it would produce MCs on the adjacent endplates. HYPOTHESIS: Disc infection with PA would accelerate IDD compared with the standard model and would also lead to MCs on the adjacent endplates. METHODS: Twelve Sprague-Dawley rats were randomized to receive a needle puncture in a caudal tail disc with either saline (control) or an inoculum of 5×107 CFU of strain 1a PA. Twelve weeks later, the rats were euthanized and the tails were analyzed. The main assessment criteria were obtained from the post-mortem MRI: T2 values of punctured discs and adjacent endplates, as well as disc volumes. A histological grading score for IDD was also used, measuring the morphology and cellularity of the nucleus and annulus, as well as endplate disruption. RESULTS: The median T2 value and disc volume were smaller in PA-punctured discs [T2 value: 30ms (23-44) vs. 61ms (38-132), respectively, P=0.01; 0.01mm3 (0.01-0.05) vs. 0.5mm3 (0.01-5.35), respectively; P=0.049]. There was no change in the adjacent endplates. There was no significant difference in histological grading between the test and control [13 (10-14) vs. 10.5 (6-13); P=0.05]. DISCUSSION: Inoculation of caudal discs with PA generated increased degeneration; however, no MCs were observed on the adjacent endplates. A better understanding of low-grade disc infections is still needed. LEVEL OF EVIDENCE: V (animal study).

M-protein gene-type distribution and hyaluronic acid capsule in group A Streptococcus clinical isolates in Chile: association of emm gene markers with csrR alleles.

Streptococcus pyogenes causes a variety of infections because of virulence factors such as capsular hyaluronic acid and M protein. The aim of this study was to determine emm types and capsule phenotype in 110 isolates of S. pyogenes from patients with invasive (sterile sites) and non-invasive (mainly pharyngitis) infections in Chile, and the relationship between both virulence factors. The most abundant types found were emm12, emm1, emm4 and emm28 and their distribution was similar to that seen in Latin America and developed countries, but very different from that in Asia and Pacific Island countries. Ten of 16 emm types identified in pharyngeal isolates were found in sterile-site isolates, and three of nine emm types of sterile-site isolates occurred in pharyngeal isolates; three emm subtypes were novel. The amount of hyaluronic acid was significantly higher in sterile-site isolates but did not differ substantially among emm types. Only three isolates were markedly capsulate and two of them had mutations in the csrR gene that codes for a repressor of capsule synthesis genes. We found a non-random association between emm types and csrR gene alleles suggesting that horizontal gene transfer is not freely occurring in the population.

Evasion of host immunity by virulent Salmonella: implications for vaccine design.

Dendritic cells (DCs) are professional antigen presenting cells (APCs) capable of linking innate and adaptive immunity during infection. After recognition of pathogen-associated molecular patterns (PAMPs), DCs can engulf, process and present bacteria-derived antigens on MHC molecules to T cells. Because of the key role that DCs play on the initiation of innate and adaptive immunity, alterations in their function could render the host susceptible to bacterial dissemination. Consistent with this notion, is the observation that several pathogenic bacteria have evolved mechanisms to impair the DC capacity to prime naïve T cells. One of such bacteria is Salmonella enterica serovar Typhimurium, which causes a typhoid-like disease in mice and gastroenteritis in humans. Recent studies have shown that virulent Salmonella can use intestinal DCs to spread inside the host, evading T cell priming. The avoidance of T cell recognition by Salmonella is in large part achieved by the activity of gene products encoded on Salmonella Pathogenicity Islands -1 and - 2. The understanding of some of the remarkable molecular virulence mechanisms displayed by Salmonella has contributed to the design of new vaccines capable of inducing protective immunity against this pathogen in mouse models. Here we describe recent data underscoring the virulence mechanisms used by Salmonella to exploit DC function and discuss strategies based on this new knowledge aimed at the design of new efficient and safe vaccines against this pathogen.

Expression of the carotenoid biosynthesis genes in Xanthophyllomyces dendrorhous.

In the yeast Xanthophyllomyces dendrorhous the genes idi, crtE, crtYB, crtl and ast are involved in the biosynthesis of astaxanthin from isopentenyl pyrophosphate. The carotenoid production and the kinetics of mRNA expression of structural genes controlling the carotenogenesis in a wild-type ATCC 24230 and in carotenoid overproducer deregulated atxS2 strains were studied. The biosynthesis of carotenoid was induced at the late exponential growth phase in both strains. However, the cellular carotenoid concentration was four times higher in atxS2 than in the wild-type strain in the exponential growth phase, suggesting that carotenogenesis was deregulated in atxS2 at the beginning of growth. In addition, the maximum expression of the carotenogenesis genes at the mRNA level was observed during the induction period of carotenoid biosynthesis in the wild-type strain. The mRNA level of the crtYB, crtl, ast genes and to a lesser extent the idi gene, decayed at the end of the exponential growth phase. The mRNA levels of the crtE gene remained high along the whole growth curve of the yeast. In the atxS2 strain the mRNA levels of crtE gene were about two times higher than the wild-type strain in the early phase of the growth cycle.

Expression of the carotenoid biosynthesis genes in Xanthophyllomyces dendrorhous

In the yeast Xanthophyllomyces dendrorhous the genes idi, crtE, crtYB, crtl and ast are involved in the biosynthesis of astaxanthin from isopentenyl pyrophosphate. The carotenoid production and the kinetics of mRNA expression of structural genes controlling the carotenogenesis in a wild-type ATCC 24230 and in carotenoid overproducer deregulated atxS2 strains were studied. The biosynthesis of carotenoid was induced at the late exponential growth phase in both strains. However, the cellular carotenoid concentration was four times higher in atxS2 than in the wild-type strain in the exponential growth phase, suggesting that carotenogenesis was deregulated in atxS2 at the beginning of growth. In addition, the maximum expression of the carotenogenesis genes at the mRNA level was observed during the induction period of carotenoid biosynthesis in the wild-type strain. The mRNA level of the crtYB, crtl, ast genes and to a lesser extent the idi gene, decayed at the end of the exponential growth phase. The mRNA levels of the crtE gene remained high along the whole growth curve of the yeast. In the atxS2 strain the mRNA levels of crtE gene were about two times higher than the wild-type strain in the early phase of the growth cycle.

[Jugular chemodectoma with Garcin syndrome]. / Quemodectoma yugular con sindrome de Garcin.

The authors present an exceptional case of chemodectoma jugulare with important invasion of the skull base involving all the cranial nerves on one side and conforming Garcin's syndrome. Practically all the possible ways of spreading were followed by the tumor, with involvement of the posterior, middle and anterior fossas of the skull base and also orbit, middle ear and neck. The clinical and histopathological difficulties in the diagnosis, especially when the chemodectoma has only neurological signs, are stressed. The association of otologic symptoms makes the diagnosis easier. The patient had an early onset of the symptoms and a rapid evolution considering this type of tumors. The appearance of goitre in this patient is a sign of endocrine disturbance, which is occasionally associated with these tumors. Apparently this chemodectoma was not a secreting tumor, since the blood pressure values were normal. No signs of multicentricity or metastatic growths were detected. The radiological studies, and especially computerized tomography scanning, gave precise information about the spreading of the tumor. The authors consider that the knowledge of this entity is important in order to arrive at a correct diagnosis.

El estudio de la hidatidosis con tomografia computada. / Study of hydatidosis using computed tomography

La presentacion esta basada en 35 casos de quiste hidatico diagnosticados y corroborados quirurgicamente, que se estudiaron durante un periodo de 18 meses en el Centro de Tomografia Computada del Sanatorio Larghero.El quiste hidatico no complicado (hepatico o pulmonar) se presenta como una imagen hipodensa (0 a 10 uH) homogenea, de forma redondeada y limites netos. Las complicaciones vistas incluyen: 1) Infeccion que se traduce en un aumento de la densidad intraquistica en algunos casos aparicion de tabiques e irregularidad del contorno. En el pulmon se ven los fenomenos inflamatorios del parenquima circundante.2) Vesiculizacion, aparicion de vesiculas hijas y contorno polilobulados.3) Multiplicidad 4) Hidatidosis secundaria intraperitoneal. 5) Transito hepato-bronquico. 6) Hidatidosis pleural. En todos los casos se determino exatamente la cantidad de lesiones, el tamano y topografia de cada una de ellas