Dynamic regulation of neutrophil immunometabolism by platelet-derived metabolites

Platelets, traditionally known for their roles in hemostasis and thrombosis, have emerged as key regulators of immune responses, particularly through their dynamic interactions with neutrophils. This review explores how platelets influence neutrophil functions by forming platelet-neutrophil aggregates, releasing extracellular vesicles, and secreting metabolites. These processes govern critical immune activities, including cell recruitment, activation, endothelium interactions and the resolution or exacerbation of inflammation. Additionally, platelets induce metabolic reprogramming in neutrophils, affecting glycolysis and mitochondrial pathways, while also shaping the immune microenvironment by modulating other immune cells, such as T and B cells. Understanding this complex crosstalk between platelets and neutrophils—two of the most abundant cell types in the bloodstream—might reveal new therapeutic opportunities to regulate immune responses in inflammatory and immune-mediated diseases

ITALIAN CANCER FIGURES - REPORT 2015: The burden of rare cancers in Italy = I TUMORI IN ITALIA - RAPPORTO 2015: I tumori rari in Italia

OBJECTIVES: This collaborative study, based on data collected by the network of Italian Cancer Registries (AIRTUM), describes the burden of rare cancers in Italy. Estimated number of new rare cancer cases yearly diagnosed (incidence), proportion of patients alive after diagnosis (survival), and estimated number of people still alive after a new cancer diagnosis (prevalence) are provided for about 200 different cancer entities. MATERIALS AND METHODS: Data herein presented were provided by AIRTUM population- based cancer registries (CRs), covering nowadays 52% of the Italian population. This monograph uses the AIRTUM database (January 2015), which includes all malignant cancer cases diagnosed between 1976 and 2010. All cases are coded according to the International Classification of Diseases for Oncology (ICD-O-3). Data underwent standard quality checks (described in the AIRTUM data management protocol) and were checked against rare-cancer specific quality indicators proposed and published by RARECARE and HAEMACARE (www.rarecarenet.eu; www.haemacare.eu). The definition and list of rare cancers proposed by the RARECAREnet "Information Network on Rare Cancers" project were adopted: rare cancers are entities (defined as a combination of topographical and morphological codes of the ICD-O-3) having an incidence rate of less than 6 per 100,000 per year in the European population. This monograph presents 198 rare cancers grouped in 14 major groups. Crude incidence rates were estimated as the number of all new cancers occurring in 2000-2010 divided by the overall population at risk, for males and females (also for gender-specific tumours).The proportion of rare cancers out of the total cancers (rare and common) by site was also calculated. Incidence rates by sex and age are reported. The expected number of new cases in 2015 in Italy was estimated assuming the incidence in Italy to be the same as in the AIRTUM area. One- and 5-year relative survival estimates of cases aged 0-99 years diagnosed between 2000 and 2008 in the AIRTUM database, and followed up to 31 December 2009, were calculated using complete cohort survival analysis. To estimate the observed prevalence in Italy, incidence and follow-up data from 11 CRs for the period 1992-2006 were used, with a prevalence index date of 1 January 2007. Observed prevalence in the general population was disentangled by time prior to the reference date (≤2 years, 2-5 years, ≤15 years). To calculate the complete prevalence proportion at 1 January 2007 in Italy, the 15-year observed prevalence was corrected by the completeness index, in order to account for those cancer survivors diagnosed before the cancer registry activity started. The completeness index by cancer and age was obtained by means of statistical regression models, using incidence and survival data available in the European RARECAREnet data. RESULTS: In total, 339,403 tumours were included in the incidence analysis. The annual incidence rate (IR) of all 198 rare cancers in the period 2000-2010 was 147 per 100,000 per year, corresponding to about 89,000 new diagnoses in Italy each year, accounting for 25% of all cancer. Five cancers, rare at European level, were not rare in Italy because their IR was higher than 6 per 100,000; these tumours were: diffuse large B-cell lymphoma and squamous cell carcinoma of larynx (whose IRs in Italy were 7 per 100,000), multiple myeloma (IR: 8 per 100,000), hepatocellular carcinoma (IR: 9 per 100,000) and carcinoma of thyroid gland (IR: 14 per 100,000). Among the remaining 193 rare cancers, more than two thirds (No. 139) had an annual IR <0.5 per 100,000, accounting for about 7,100 new cancers cases; for 25 cancer types, the IR ranged between 0.5 and 1 per 100,000, accounting for about 10,000 new diagnoses; while for 29 cancer types the IR was between 1 and 6 per 100,000, accounting for about 41,000 new cancer cases. Among all rare cancers diagnosed in Italy, 7% were rare haematological diseases (IR: 41 per 100,000), 18% were solid rare cancers. Among the latter, the rare epithelial tumours of the digestive system were the most common (23%, IR: 26 per 100,000), followed by epithelial tumours of head and neck (17%, IR: 19) and rare cancers of the female genital system (17%, IR: 17), endocrine tumours (13% including thyroid carcinomas and less than 1% with an IR of 0.4 excluding thyroid carcinomas), sarcomas (8%, IR: 9 per 100,000), central nervous system tumours and rare epithelial tumours of the thoracic cavity (5%with an IR equal to 6 and 5 per 100,000, respectively). The remaining (rare male genital tumours, IR: 4 per 100,000; tumours of eye, IR: 0.7 per 100,000; neuroendocrine tumours, IR: 4 per 100,000; embryonal tumours, IR: 0.4 per 100,000; rare skin tumours and malignant melanoma of mucosae, IR: 0.8 per 100,000) each constituted <4% of all solid rare cancers. Patients with rare cancers were on average younger than those with common cancers. Essentially, all childhood cancers were rare, while after age 40 years, the common cancers (breast, prostate, colon, rectum, and lung) became increasingly more frequent. For 254,821 rare cancers diagnosed in 2000-2008, 5-year RS was on average 55%, lower than the corresponding figures for patients with common cancers (68%). RS was lower for rare cancers than for common cancers at 1 year and continued to diverge up to 3 years, while the gap remained constant from 3 to 5 years after diagnosis. For rare and common cancers, survival decreased with increasing age. Five-year RS was similar and high for both rare and common cancers up to 54 years; it decreased with age, especially after 54 years, with the elderly (75+ years) having a 37% and 20% lower survival than those aged 55-64 years for rare and common cancers, respectively. We estimated that about 900,000 people were alive in Italy with a previous diagnosis of a rare cancer in 2010 (prevalence). The highest prevalence was observed for rare haematological diseases (278 per 100,000) and rare tumours of the female genital system (265 per 100,000). Very low prevalence (<10 prt 100,000) was observed for rare epithelial skin cancers, for rare epithelial tumours of the digestive system and rare epithelial tumours of the thoracic cavity. COMMENTS: One in four cancers cases diagnosed in Italy is a rare cancer, in agreement with estimates of 24% calculated in Europe overall. In Italy, the group of all rare cancers combined, include 5 cancer types with an IR>6 per 100,000 in Italy, in particular thyroid cancer (IR: 14 per 100,000).The exclusion of thyroid carcinoma from rare cancers reduces the proportion of them in Italy in 2010 to 22%. Differences in incidence across population can be due to the different distribution of risk factors (whether environmental, lifestyle, occupational, or genetic), heterogeneous diagnostic intensity activity, as well as different diagnostic capacity; moreover heterogeneity in accuracy of registration may determine some minor differences in the account of rare cancers. Rare cancers had worse prognosis than common cancers at 1, 3, and 5 years from diagnosis. Differences between rare and common cancers were small 1 year after diagnosis, but survival for rare cancers declined more markedly thereafter, consistent with the idea that treatments for rare cancers are less effective than those for common cancers. However, differences in stage at diagnosis could not be excluded, as 1- and 3-year RS for rare cancers was lower than the corresponding figures for common cancers. Moreover, rare cancers include many cancer entities with a bad prognosis (5-year RS <50%): cancer of head and neck, oesophagus, small intestine, ovary, brain, biliary tract, liver, pleura, multiple myeloma, acute myeloid and lymphatic leukaemia; in contrast, most common cancer cases are breast, prostate, and colorectal cancers, which have a good prognosis. The high prevalence observed for rare haematological diseases and rare tumours of the female genital system is due to their high incidence (the majority of haematological diseases are rare and gynaecological cancers added up to fairly high incidence rates) and relatively good prognosis. The low prevalence of rare epithelial tumours of the digestive system was due to the low survival rates of the majority of tumours included in this group (oesophagus, stomach, small intestine, pancreas, and liver), regardless of the high incidence rate of rare epithelial cancers of these sites. This AIRTUM study confirms that rare cancers are a major public health problem in Italy and provides quantitative estimations, for the first time in Italy, to a problem long known to exist. This monograph provides detailed epidemiologic indicators for almost 200 rare cancers, the majority of which (72%) are very rare (IR<0.5 per 100,000). These data are of major interest for different stakeholders. Health care planners can find useful information herein to properly plan and think of how to reorganise health care services. Researchers now have numbers to design clinical trials considering alternative study designs and statistical approaches. Population-based cancer registries with good quality data are the best source of information to describe the rare cancer burden in a population

Increasing incidence of childhood tumours of the central nervous system in Denmark, 1980–1996

The registered incidence rate of childhood central nervous system (CNS) tumours has increased in several countries. It is uncertain whether these increases are biologically real or owing to improved diagnostic methods. We explored the medical records of 626 CNS tumours diagnosed in Danish children between 1980 and 1996. Population-based registers were used to extract data on mortality and background population. Temporal patterns were analysed by regression techniques. Most tumours were verified by computed tomography (78%) or magnetic resonance imaging (14%). Overall, the incidence rate increased by 2.9% per year (95% confidence interval (CI): 1.3;4.5) and the mortality rate increased by 1.4% per year (95% CI: −0.4;3.3). Among children aged 0–4 years, the survival rate after diagnosis remained almost unchanged, whereas among children aged 5–14 years, the 10-year survival rate improved from 59 to 74%. These data suggest that the incidence rate of CNS tumours among Danish children has truly increased, although alternative explanations cannot be excluded

Relationship of metabolic syndrome and its components with -844 G/A and HindIII C/G PAI-1 gene polymorphisms in Mexican children

<p>Abstract</p> <p>Background</p> <p>Several association studies have shown that -844 G/A and <it>HindIII </it>C/G <it>PAI-1 </it>polymorphisms are related with increase of PAI-1 levels, obesity, insulin resistance, glucose intolerance, hypertension and dyslipidemia, which are components of metabolic syndrome. The aim of this study was to analyze the allele and genotype frequencies of these polymorphisms in <it>PAI-1 </it>gene and its association with metabolic syndrome and its components in a sample of Mexican mestizo children.</p> <p>Methods</p> <p>This study included 100 children with an age range between 6-11 years divided in two groups: a) 48 children diagnosed with metabolic syndrome and b) 52 children metabolically healthy without any clinical and biochemical alteration. Metabolic syndrome was defined as the presence of three or more of the following criteria: fasting glucose levels ≥ 100 mg/dL, triglycerides ≥ 150 mg/dL, HDL-cholesterol < 40 mg/dL, obesity BMI ≥ 95^thpercentile, systolic blood pressure (SBP) and diastolic blood pressure (DBP) ≥ 95^thpercentile and insulin resistance HOMA-IR ≥ 2.4. The -844 G/A and <it>HindIII </it>C/G <it>PAI-1 </it>polymorphisms were analyzed by PCR-RFLP.</p> <p>Results</p> <p>For the -844 G/A polymorphism, the G/A genotype (OR = 2.79; 95% CI, 1.11-7.08; <it>p </it>= 0.015) and the A allele (OR = 2.2; 95% CI, 1.10-4.43; <it>p </it>= 0.015) were associated with metabolic syndrome. The -844 G/A and A/A genotypes were associated with increase in plasma triglycerides levels (OR = 2.6; 95% CI, 1.16 to 6.04; <it>p </it>= 0.02), decrease in plasma HDL-cholesterol levels (OR = 2.4; 95% CI, 1.06 to 5.42; <it>p </it>= 0.03) and obesity (OR = 2.6; 95% CI, 1.17-5.92; <it>p </it>= 0.01). The C/G and G/G genotypes of the <it>HindIII </it>C/G polymorphism contributed to a significant increase in plasma total cholesterol levels (179 vs. 165 mg/dL; <it>p </it>= 0.02) in comparison with C/C genotype.</p> <p>Conclusions</p> <p>The -844 G/A <it>PAI-1 </it>polymorphism is related with the risk of developing metabolic syndrome, obesity and atherogenic dyslipidemia, and the <it>HindIII </it>C/G <it>PAI-1 </it>polymorphism was associated with the increase of total cholesterol levels in Mexican children.</p

Microbiología de las aguas mineromedicinales de los balnearios de Jaraba

Se han estudiado cinco manantiales bicarbonatados termales situados en la localidad de Jaraba (Zaragoza), utilizados en los tratamientos terapéuticos de los Balnearios: Sicilia (San Vicente), Serón (San Luis y La Peña) y La Virgen (San José y Pilas). Las muestras se tomaron en tres épocas del año. El número de microorganismos totales es bajo (1,9 x 104 a 2,1 x 105) estando en su mayoría vivos (75 al85%). El número de bacterias heterótrofas viables ha sido inferior a 10 ufc/ml, predominando los bacilos Gram negativos (65%) y en menor proporción cocos Gram positivos (17,3%) y bacilos Gram positivos no esporulados (13,8%). Los manantiales San Vicente, Pilas y San José han presentado una gran diversidad microbiana mientras que en el manantial La Peña predomina el género Enterobacter. Los principales géneros de bacilos Gram negativos identificados han sido: Pseudomonas, Enterobacter, Burkholderia, Ochrobactrum y Brevundimonas. Los cocos Gram positivos han sido, principalmente, Staphylococcus y los bacilos Gram positivos: Cellulomonas, Corynebacterium y Rhodococcus. No se han encontrado indicadores fecales ni microorganismos patógenos. Se han detectado microorganismos proteolíticos, amilolíticos y amonificantes en número inferior a 103/100 ml, y celulolíticos, halófilos y hongos en número menor de 50/100 ml. No se han detectado bacterias sulfato-reductoras, actinomicetos, cianobacterias ni algas.Microbiology of the mineral water of Jaraba Spas Five carbonated hot springs from the town of Jaraba (Zaragoza, Spain) have been studied. Water from all of them are used with therapeutic purposes at the following Spas: Sicilia (San Vicente), Serón (San Luis and La Peña) and La Virgen (San José and Pilas). Samples were collected at three different seasons of the year. There was a low total number of microorganisms (1.9 x 104 to 2.1 x 105) most of which were alive (75% to 85%). The number of heterotrophic viable bacteria was lower than 10 cfu/ mL, with a predominance of Gram-negative bacilli (65%); meanwhile Gram-positive cocci (17.3%) and Gram-positive non sporulated bacilli (13.8%) were founded in lower percentage. The San Vicente, Pilas and San José mineral hot springs have shown a great microbial diversity, whereas in La Peña hot spring the genus mainly detected was Enterobacter. The main identified genera of Gram-negative bacilli have been: Pseudomonas, Enterobacter, Burkholderia, Ochrobactrum and Brevundimonas. On the other hand, most of the Gram-positive cocci identified belong to the genus Staphylococcus, and the Gram-positive bacilli belong to the genera Cellulomonas, Corynebacterium and Rhodococcus. No faecal indicators were detected neither pathogenic microorganisms. The number of proteolytic, amylolytic and ammonifiers microorganisms was lower than 103/ 100 mL; and cellulolytic and halophylic microorganisms and fungi were detected in reduced number (lower than 50/100 mL). Neither sulphate reducing bacteria, actinomycetes, cyanobacteria nor algi were detected

Thrombin-Induced Oxidative Phosphorylation in Platelets Is Repressed By Dengue Virus through Inhibition of the PI3K/Akt Signaling Pathway

Abstract Background: There are many very important events that condition the progression to severe dengue, these include cytokine storm and a profound thrombocytopenia. Still, the molecular mechanisms underlying these events are not fully understood. Increasing evidence supports the fact that platelet dysfunction, in patients with dengue, could be due to direct interaction between platelets and dengue virus. This event induces changes in platelet function and contributes to pathogenesis. Recent results from our laboratory have shown that thrombin induces oxygen consumption through activation of glycoprotein Ib and subsequent phosphorylation of PI3K and Akt enzymes. Here we want to evaluate changes in these signalling pathways as well as their impact on mitochondrial function. Aims: To evaluate DENV2 effects on platelet function, PI3K/Akt signaling, oxidative phosphorylation and GPIb expression. Methods: Blood samples from healthy volunteers were collected and platelet fraction was obtained. Purified DENV2 particles were incubated with platelets for 2 h at 37ºC. Then, morphological changes, activation and aggregation, mitochondrial function and surface markers expression were tested in platelets. Results: We found that DENV2 induces conspicuous morphological changes on platelets not induced by other arboviruses; increases CD41 (p&amp;lt;0.05), CD62P (8979 ± 1189 vs 1723 ± 160 MFI; p&amp;lt;0.05) and reduces CD42b (p&amp;lt;0.5) expressions on platelet surface; reduces agonist-induced platelet aggregation (30 ± 10 vs 71 ± 9%; p&amp;lt;0.05) through increases intracellular NO production (0.4 ± 0.2 vs 0.07 ± 0.01; p&amp;lt;0.05); inhibits thrombin-induced oxidative phosphorylation (45 ± 6.69 vs 348 ± 26.9 ngatomO/min/10 9 platelets; p&amp;lt;0.0001) through PI3K/Akt signaling pathways inhibition (p&amp;lt;0.001). Surprisingly, rDC-SIGN treatment reverts DENV2 effects on platelet activation (9693 ± 1033 vs 2379 ± 390 MFI; p&amp;lt;0.01). Conclusions: DENV2 inhibits thrombin-induced oxidative phosphorylation through PI3K/Akt signaling pathway inhibition. Dengue virus inhibits thrombin-induced phosphorylation at different levels in the platelet. First, by reducing the expression of the GPIb molecule on the platelet surface. This molecule is important for thrombin-induced intracellular signalling. Second, dengue virus inhibits the PI3K/Akat signalling pathway, which is important for the induction of oxidative phosphorylation in mitochondria. And third, dengue virus increases intracellular nitric oxide levels and promotes its excretion into the extracellular milieu, this mechanism could be involved in the inhibition of platelet aggregation processes.These changes induce by short-term interaction of platelets with DENV2 has a direct effect over platelet function and may be correlated with the clinical manifestations observed during severe dengue stage, such as thrombocytopenia and hemorrhages. The overall impact of these changes in signaling pathways related to immune activity remains to be determinate, as does the potential to develop new pharmacological treatments. Disclosures No relevant conflicts of interest to declare. </jats:sec

Dengue Virus Induces the Release of sCD40L and Changes in Levels of Membranal CD42b and CD40L Molecules in Human Platelets

Platelets are considered as significant players in innate and adaptive immune responses. The adhesion molecules they express, including P-selectin, CD40L, and CD42b, facilitate interactions with many cellular effectors. Upon interacting with a pathogen, platelets rapidly express and enhance their adhesion molecules, and secrete cytokines and chemokines. A similar phenomenon occurs after exposure of platelets to thrombin, an agonist extensively used for in vitro activation of these cells. It was recently reported that the dengue virus not only interacts with platelets but possibly infects them, which triggers an increased expression of adhesion molecule P-selectin as well as secretion of IL-1&beta;. In the present study, surface molecules of platelets like CD40L, CD42b, CD62P, and MHC class I were evaluated at 4 h of interaction with dengue virus serotype 2 (DENV-2), finding that DENV-2 induced a sharp rise in the membrane expression of all these molecules. At 2 and 4 h of DENV-2 stimulation of platelets, a significantly greater secretion of soluble CD40L (sCD40L) was found (versus basal levels) as well as cytokines such as GM-CSF, IL-6, IL-8, IL-10, and TNF-&alpha;. Compared to basal, DENV-2 elicited more than two-fold increase in these cytokines. Compared to the thrombin-induced response, the level generated by DENV-2 was much higher for GM-CSF, IL-6, and TNF-&alpha;. All these events induced by DENV end up in conspicuous morphological changes observed in platelets by confocal microscopy and transmission electron microscopy, very different from those elicited by thrombin in a more physiological scenery