Macrophages are myeloid cells that play an essential role in inflammation and host defense, regulating immune responses and maintaining tissue homeostasis. Depending on the microenvironment, ...macrophages can polarize to two distinct phenotypes. The M1 phenotype is activated by IFN-γ and bacterial products, and displays an inflammatory profile, while M2 macrophages are activated by IL-4 and tend to be anti-inflammatory or immunosupressive. It was observed that DnaK from Mycobacterium tuberculosis has immunosuppressive properties, inducing a tolerogenic phenotype in dendritic cells and MDSCs, contributing to graft acceptance and tumor growth. However, its role in macrophage polarization remains to be elucidated. We asked whether DnaK was able to modulate macrophage phenotype. Murine macrophages, derived from bone marrow, or from the peritoneum, were incubated with DnaK and their phenotype compared to M1 or M2 polarized macrophages. Treatment with DnaK leads macrophages to present higher arginase I activity, IL-10 production and FIZZ1 and Ym1 expression. Furthermore, DnaK increased surface levels of CD206. Importantly, DnaK-treated macrophages were able to promote tumor growth in an allogeneic melanoma model. Our results suggest that DnaK polarizes macrophages to the M2-like phenotype and could constitute a virulence factor and is an important immunomodulator of macrophage responses.
The nutrition of broodstock is one of the least studied areas because biological mechanisms, such as gonadal maturation, are extremely complex processes and are affected by several nutrients, ...especially in continuous spawning fish with short vitellogenic periods as
Rhamdia quelen. For the present experiment, 66, 14-month-old female
R. quelen were randomly distributed in six cages and fed for 90
days with three isocaloric diets containing either 28%, 34%, or 40% crude protein. Data were collected at the beginning of the experiment (day zero) and after 45 and 90
days, for evaluation of several parameters as final weight, length, condition factor, hepatosomatic, gonadosomatic and visceral fat indexes, amino acids in the ovaries, plasma enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT), total plasma protein, testosterone, 17β-estradiol, free amino acids (AAL), and triglycerides (TG). From these females, the reproductive cycle, egg characteristics and larval size were evaluated. The results showed that the different protein levels in diets had no effect on the main physiological and reproductive parameters. In conclusion, the 28% crude protein dietary level was sufficient for maintenance of the broodstock and the reproductive indexes of
R. quelen females.
Glioblastoma multiforme (GBM) is a deadly cancer characterized by a pro-tumoral immune response. T-regulatory (Treg) lymphocytes suppress effector immune cells through cytokine secretion and the ...adenosinergic system. Ecto-5′-nucleotidase/CD73 plays a crucial role in Treg-mediated immunosuppression in the GBM microenvironment (GME). Methotrexate (MTX) is an immunosuppressive drug that can increase the extracellular concentration of adenosine. In this manuscript, C6 GBM cells were treated with 1.0 μM MTX, and ecto-5′-nucleotidase/CD73 expression and extracellular AMP metabolism were analyzed in vitro. For in vivo studies, rats with implanted GBM were treated for 10 days with MTX-loaded lipid-core nanocapsules (MTX-LNCs, 1 mg/kg/day). The activity of ectonucleotidase and the expression of NTPDase1/CD39 and ecto-5′-nucleotidase/CD73 were measured. The frequencies of T lymphocytes (CD3
+
CD4
+
, CD3
+
CD8
+
, and CD4
+
CD25
high
CD39
+
) were quantified. In vitro, treatment with MTX increased CD73 expression and activity in C6 cells, which is in agreement with higher levels of extracellular adenosine. In vivo, MTX-LNC treatment increased CD39 expression on CD3
+
CD8
+
lymphocytes. In addition, MTX-LNC treatment up-regulated CD73 expression in tissue isolated from GBM, a finding that is in agreement with the higher activity of this enzyme. More specifically, the treatment increased CD73 expression on CD3
+
CD4
+
and CD3
+
CD8
+
lymphocytes. Treatment with MTX-LNCs decreased the frequencies of T-cytotoxic, T-helper, and Treg lymphocytes in the GME. Although more studies are necessary to better understand the complex cross-talk mediated by supra-physiological concentrations of adenosine in the GME, these studies demonstrate that MTX treatment increases CD73 enzyme expression and AMP hydrolysis, leading to an increase in adenosine production and immunosuppressive capability.
Ductal adenocarcinoma is a rare variant of prostate cancer, and as such clinical outcomes and best management are not well defined. This series demonstrates the atypical presentation and unusual ...clinical behaviour of ductal adenocarcinoma and proposes management guidelines to assist clinicians.
A retrospective review of pure (nine patients) and mixed (18 patients) ductal adenocarcinoma of the prostate referred to the Departments of Radiation Oncology of the Sydney Cancer Centre, Royal Prince Alfred Hospital and Northern Sydney Cancer Centre, Royal North Shore Hospital, between 2000 and 2015.
Twenty-seven patients were treated with definitive radiotherapy, nine patients (33%) with pure ductal and 18 (67%) with mixed ductal-acinar adenocarcinoma. The median follow-up was 38 months. Four patients (15%) failed locally, all of whom received less than 80 Gy, or no brachytherapy boost. Five patients (19%) failed distantly, four with biopsy-proven lung metastases. All distant failures occurred with a prostate-specific antigen (PSA) < 3 ng/ml.
This series shows the atypical clinical presentation of this entity, as well as its propensity to metastasise to unusual sites. Relapse may occur at low absolute PSA values and is often asymptomatic. Ductal cancer should not simply be regarded as a high Gleason grade cancer. We propose management guidelines, including regular computed tomography examinations (rather than relying solely on PSA levels) as part of the follow-up for patients with any component of ductal adenocarcinoma.
•Prostate ductal adenocarcinoma commonly presents with haematuria and lower urinary tract symptoms.•Radiotherapy is a suitable treatment option for the management of ductal adenocarcinoma.•Ductal adenocarcinoma recurs at unusual sites such as the lung.•Prostate-specific antigen is not a reliable marker for recurrence.
Mutations in mitofusin 2 (MFN2) are the most common cause of axonal Charcot-Marie-Tooth disease (CMT2). Over 50 mutations have been reported, mainly causing autosomal dominant disease, though ...families with homozygous or compound heterozygous mutations have been described. We present 3 families with early-onset CMT2 associated with compound heterozygous MFN2 mutations. Transcriptional analysis was performed to investigate the effects of the mutations.
Patients were examined clinically and electrophysiologically; parents were also examined where available. Genetic investigations included MFN2 DNA sequencing and dosage analysis by multiplex ligation-dependent probe amplification. MFN2 mRNA transcripts from blood lymphocytes were analyzed in 2 families.
Compound heterozygosity for MFN2 mutations was associated with early-onset CMT2 of varying severity between pedigrees. Parents, where examined, were unaffected and were heterozygous for the expected mutations. Four novel mutations were detected (one missense, one nonsense, an intragenic deletion of exons 7 + 8, and a 3-base pair deletion), as well as 2 previously reported missense mutations. Transcriptional analysis demonstrated aberrant splicing of the exonic deletion and indicated nonsense-mediated decay of mutant alleles with premature truncating mutations.
Our findings confirm that MFN2 mutations can cause early-onset CMT2 with apparent recessive inheritance. Novel genetic findings include an intragenic MFN2 deletion and nonsense-mediated decay. Carrier parents were asymptomatic, suggesting that MFN2 null alleles can be nonpathogenic unless coinherited with another mutation.
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