Measuring diffuse metabolic activity on FDG-PET/CT: new method for evaluating Langerhans cell histiocytosis activity in pulmonary parenchyma

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare cause of interstitial lung disease characterized by formation of nodules in the active phase of the disease that evolve into nonactive cystic lesions later on. To evaluate PLCH activity in patients, we developed a new method for measuring diffuse metabolic activity on fluorine-18-fluorodeoxyglucose positron emission tomography/ computed tomography (FDG-PET/CT) using a lung-to-liver activity ratio. Material and Methods: We retrospectively studied a series of 4 FDG-PET and 23 FDG-PET/CT scans from 7 patients with PLCH and analyzed a sample of 100 randomly chosen FDG-PET/CT studies free from any known lung or hepatic diseases. Maximum standardized uptake value (SUVmax) in a spherical volume (6–8 cm in diameter) in the right lung was put into relation with SUVmax in a spherical volume (9–10 cm in diameter) in the reference liver parenchyma to set up the SUVmaxPULMO/SUVmaxHEPAR index. The index values were compared to the disease course in each patient. Results: In patients with PLCH, a close correlation between the index value and the disease course was found in all seven subjects, where the increasing index values indicated disease activity, while decreasing index values were observed after therapy administration. In the group of 100 healthy control subjects, we found index values lower than 0.3 in 80% and lower than 0.4 in 96%. Conclusion: Measuring SUVmaxPULMO/SUVmaxHEPAR values and their time-trend monitoring represent simple, noninvasive screening tools allowing an early diagnosis and treatment response follow-up assessment in patients with PLCH

Altered adipocyte differentiation and unbalanced autophagy in type 2 Familial Partial Lipodystrophy: an in vitro and in vivo study of adipose tissue browning

Type-2 Familial Partial Lipodystrophy is caused by LMNA mutations. Patients gradually lose subcutaneous fat from the limbs, while they accumulate adipose tissue in the face and neck. Several studies have demonstrated that autophagy is involved in the regulation of adipocyte differentiation and the maintenance of the balance between white and brown adipose tissue. We identified deregulation of autophagy in laminopathic preadipocytes before induction of differentiation. Moreover, in differentiating white adipocyte precursors, we observed impairment of large lipid droplet formation, altered regulation of adipose tissue genes, and expression of the brown adipose tissue marker UCP1. Conversely, in lipodystrophic brown adipocyte precursors induced to differentiate, we noticed activation of autophagy, formation of enlarged lipid droplets typical of white adipocytes, and dysregulation of brown adipose tissue genes. In agreement with these in vitro results indicating conversion of FPLD2 brown preadipocytes toward the white lineage, adipose tissue from FPLD2 patient neck, an area of brown adipogenesis, showed a white phenotype reminiscent of its brown origin. Moreover, in vivo morpho-functional evaluation of fat depots in the neck area of three FPLD2 patients by PET/CT analysis with cold stimulation showed the absence of brown adipose tissue activity. These findings highlight a new pathogenetic mechanism leading to improper fat distribution in lamin A-linked lipodystrophies and show that both impaired white adipocyte turnover and failure of adipose tissue browning contribute to disease.We thank FPLD2 patients for donating biological samples. We thank the Italian Network for Laminopathies and the European Consortium of Lipodystrophies (ECLip) for support and helpful discussion. We thank Aurelio Valmori for the technical support. The studies were supported by Rizzoli Orthopedic Institute “5 per mille” 2014 project to MC, AIProSaB project 2016 and Fondazione Del Monte di Bologna e Ravenna grant 2015–2016 “New pharmacological approaches in bone laminopathies based on the use of antibodies neutralizing TGF beta 2” to GL. GL is also supported by PRIN MIUR project 2015FBNB5Y.S

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Lactate and tumor microenvironment: how prostate cancer and melanoma rely on this oncometabolite.

The implication of lactate in carcinogenesis has become increasingly important, including its role as a tumor-promoting metabolite. In cancer, the acidic environment produced by lactate drives not only tumor progression, invasive ability, and metastasis, but also processes such as angiogenesis and immunosuppression, all of which are associated with negative prognosis. Particularly, lactate secreted by cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) plays an essential role in the metabolic reprogramming of tumor cells. Lactate sustains different processes within TME, being exploited as a source of energy or acting as an oncometabolite with signaling properties. In prostate cancers (PCa), lactate is one of the major nutrients secreted by CAFs and it is exploited to improve mitochondrial metabolism in PCa cells and their pro-aggressive features. Lactate is also a crucial driver governing the balance between immune evasion and immune surveillance. Melanoma cells generally rely on Warburg metabolism, characterized by a high glycolytic flux and high lactate dehydrogenase A (LDH-A) expression, accompanied by the secretion of large amounts of lactic acid, that results in the acidification of the TME, thereby concurring to immune escape. Melanoma-bearing patients showed gender disparities that influenced the outcome and response to therapy. Therefore, it is important to clarify if different sexual-dependent microenvironmental factors can selectively shape the immune system, resulting in gender-specific immune composition. My Ph.D. thesis aimed to study how prostate cancer and melanoma rely on Lactate. To do this, we investigated the impact of the metabolic reprogramming of PCa cells exposed to stromal conditioning on their epigenetic profile and on the metabolic-dependent regulation of gene expression. Instead, regarding melanoma, the research focus consists in better investigating the gender dependence of the metabolic regulation on the immune component, mainly given by a different presence of immunosuppressive metabolites. We hypothesized that different concentrations of lactate with immunosuppressive effects in male and female melanoma microenvironment may elicit different sex-related immune responses. Results In PCa model we demonstrated that i) metabolic tumor-stroma crosstalk is driven by CAF-derived lactate that leads to lipid anabolism and LDs accumulation; ii) LDs are used to provide acetyl groups useful for epigenetic modifications (increase of H3K9Ac and H3K27Ac); iii) higher histone acetylation is linked to the lactate-dependent enhancement of PCa invasiveness. These data suggest the close relation between lipid metabolism and epigenetic reprogramming driven by lactate-mediated tumor-stroma crosstalk. iv) Moreover, we observed that interfering with the lactate-dependent increase in lipid anabolism and histone acetylation by BET inhibition impaired CAF-induced PCa cell metabolic rewiring and invasiveness. v) Interestingly, RNAseq analysis revealed that PLIN2 is a direct target of the lactate-dependent histone acetylation and that it is responsible for stromal-induced LDs formation and PCa cell invasiveness. vi) In vivo Bet inhibition impairs lactate-sustained lung metastatic burden in PCa cells. In conclusion, we can firmly sustain that lactate is a mandatory driver to promote metastatic spreading in prostate cancer. In melanoma our data showed that i) male melanoma cells exhibit a more glycolytic profile (overexpression of key glycolytic enzymes, in particular a higher LDH-A expression, and increase of lactate secretion) with respect to the female counterparts; ii) upon IHC analysis on human samples, male melanoma reveals a more pronounced LDH-A expression, accompanied by an enrichment in CD4+/Treg infiltration, compared to female tissues; iii) interfering with LDH-A expression by both genetic (siLDH-A) and pharmacological (FX-11) approaches, we observed a reduction in Treg polarization in male melanoma cells co-cultured with CD4+ cells. These data suggest a role for lactate in eliciting an immunosuppressive landscape in male melanoma cells/samples with high Treg infiltration. In conclusion, lactate is an oncometabolite able to increase the metastatic capacity and reshape the immune component, causing a potential impact also in a gender context

The Azurin Coding Gene: Origin and Phylogenetic Distribution

Azurin is a bacterial-derived cupredoxin, which is mainly involved in electron transport reactions. Interest in azurin protein has risen in recent years due to its anticancer activity and its possible applications in anticancer therapies. Nevertheless, the attention of the scientific community only focused on the azurin protein found in Pseudomonas aeruginosa (Proteobacteria, Gammaproteobacteria). In this work, we performed the first comprehensive screening of all the bacterial genomes available in online repositories to assess azurin distribution in the three domains of life. The Azurin coding gene was not detected in the domains Archaea and Eucarya, whereas it was detected in phyla other than Proteobacteria, such as Bacteroidetes, Verrucomicrobia and Chloroflexi, and a phylogenetic analysis of the retrieved sequences was performed. Observed patchy distribution and phylogenetic data suggest that once it appeared in the bacterial domain, the azurin coding gene was lost in several bacterial phyla and/or anciently horizontally transferred between different phyla, even though a vertical inheritance appeared to be the major force driving the transmission of this gene. Interestingly, a shared conserved domain has been found among azurin members of all the investigated phyla. This domain is already known in P. aeruginosa as p28 domain and its importance for azurin anticancer activity has been widely explored. These findings may open a new and intriguing perspective in deciphering the azurin anticancer mechanisms and to develop new tools for treating cancer diseases

Microbiome-metabolome signatures in mice genetically prone to develop dementia, fed a normal or fatty diet

Cognitive decline, obesity and gut dysfunction or microbial dysbiosis occur in association. Our aim was to identify gut microbiota-metabolomics signatures preceding dementia in genetically prone (3xtg) mice, with and without superimposed high-fat diet. We examined the composition and diversity of their gut microbiota, and serum and faecal metabolites. 3xtg mice showed brain hypometabolism typical of pre-demented stage, and lacked the physiological bacterial diversity between caecum and colon seen in controls. Cluster analyses revealed distinct profiles of microbiota, and serum and fecal metabolome across groups. Elevation in Firmicutes-to-Bacteroidetes abundance, and exclusive presence of Turicibacteraceae, Christensenellaceae, Anaeroplasmataceae and Ruminococcaceae, and lack of Bifidobacteriaceae, were also observed. Metabolome analysis revealed a deficiency in unsaturated fatty acids and choline, and an overabundance in ketone bodies, lactate, amino acids, TMA and TMAO in 3xtg mice, with additive effects of high-fat diet. These metabolic alterations were correlated with high prevalence of Enterococcaceae, Staphylococcus, Roseburia, Coprobacillus and Dorea, and low prevalence of S24.7, rc4.4 and Bifidobacterium, which in turn related to cognitive impairment and cerebral hypometabolism. Our results indicate an effect of transgenic background on gut microbiome-metabolome, enhanced by high-fat diet. The resulting profiles may precede overt cognitive impairment, suggesting their predictive or risk-stratifying potential.This work was supported by the Ministry of Economy, Industry and Competitiveness of Spain (MINECO-Spanish Government, grant numbers SAF2014–52875R to DM, and AGL2015–707487-P to MCC), Instituto de Salud Carlos III and co-funded by ‘FEDER’ (grant number PIE15/00013 to DM), and the European DORIAN-Health-FP7 project (GA 278603 to PI).Peer Reviewe