GALNT2 as a novel modulator of adipogenesis and adipocyte insulin signaling

Background/objectives: A better understanding of adipose tissue biology is crucial to tackle insulin resistance and eventually coronary heart disease and diabetes, leading causes of morbidity and mortality worldwide. GALNT2, a GalNAc-transferase, positively modulates insulin signaling in human liver cells by down-regulating ENPP1, an insulin signaling inhibitor. GALNT2 expression is increased in adipose tissue of obese as compared to that of non-obese individuals. Whether this association is secondary to a GALNT2-insulin sensitizing effect exerted also in adipocytes is unknown. We then investigated in mouse 3T3-L1 adipocytes the GALNT2 effect on adipogenesis, insulin signaling and expression levels of both Enpp1 and 72 adipogenesis-related genes. Methods: Stable over-expressing GALNT2 and GFP preadipocytes (T 0 ) were generated. Adipogenesis was induced with (R+) or without (R−) rosiglitazone and investigated after 15 days (T 15 ). Lipid accumulation (by Oil Red-O staining) and intracellular triglycerides (by fluorimetric assay) were measured. Lipid droplets (LD) measures were analyzed at confocal microscope. Gene expression was assessed by RT-PCR and insulin-induced insulin receptor (IR), IRS1, JNK and AKT phosphorylation by Western blot. Results: Lipid accumulation, triglycerides and LD measures progressively increased from T 0 to T 15 R- and furthermore to T 15 R+. Such increases were significantly higher in GALNT2 than in GFP cells so that, as compared to T 15 R+GFP, T 15 R- GALNT2 cells showed similar (intracellular lipid and triglycerides accumulation) or even higher (LD measures, p < 0.01) values. In GALNT2 preadipocytes, insulin-induced IR, IRS1 and AKT activation was higher than that in GFP cells. GALNT2 effect was totally abolished during adipocyte maturation and completely reversed at late stage maturation. Such GALNT2 effect trajectory was paralleled by coordinated changes in the expression of Enpp1 and adipocyte-maturation key genes. Conclusions: GALNT2 is a novel modulator of adipogenesis and related cellular phenotypes, thus becoming a potential target for tackling the obesity epidemics and its devastating sequelae

The first 3500 years of aspirin history from its roots - A concise summary

none3Aspirin is currently the most widely used drug worldwide, and has been clearly one of the most important pharmacological achievements of the twentieth century. Historians of medicine have traced its birth in 1897, but the fascinating history of aspirin actually dates back >3500 years, when willow bark was used as a painkiller and antipyretic by Sumerians and Egyptians, and then by great physicians from ancient Greece and Rome. The modern history of aspirin precursors, salicylates, began in 1763 with Reverend Stone - who first described their antipyretic effects - and continued in the 19th century with many researchers involved in their extraction and chemical synthesis. Bayer chemist Felix Hoffmann synthesized aspirin in 1897, and 70 years later the pharmacologist John Vane elucidated its mechanism of action in inhibiting prostaglandin production. Originally used as an antipyretic and anti-inflammatory drug, aspirin then became, for its antiplatelet properties, a milestone in preventing cardiovascular and cerebrovascular diseases. The aspirin story continues today with the growing evidence of its chemopreventive effect against colorectal and other types of cancer, now awaiting the results of ongoing primary prevention trials in this setting. This concise review revisits the history of aspirin with a focus on its most remote origins.Montinari, Maria Rosa; Minelli, Sergio; De Caterina, RaffaeleMontinari, Maria Rosa; Minelli, Sergio; De Caterina, Raffael

Aspirin Therapy for Primary Prevention: The Case for Continuing Prescribing to Patients at High Cardiovascular Risk-A Review

Current evidence supports the use of low-dose aspirin for secondary cardiovascular prevention. By contrast, the benefit-to-risk ratio of aspirin use in primary prevention is debated: Three contemporary randomized control trials have been conflicting, and meta-analyses have concluded for an unclear clinical benefit, based on the consideration that the reduction in thromboembolic events is counterbalanced by increased bleeding. The primary prevention setting is, however, a heterogeneous mix of subjects at highly variable cardiovascular risk. One possible explanation for the uncertainty of data interpretation is the progressive reduction in risk of major adverse cardiovascular events (MACEs) in primary prevention that has accompanied global education programs, leading patients to smoke less, exercise more, and increasingly take lipid-lowering therapies. Based on a meta-regression of the benefits and harm of aspirin therapy in primary prevention as a function of the 10-year risk of MACE, we favor a nuanced approach still, however, based on the evaluation of cardiovascular risk, acknowledging differences between patients and emphasizing an individualized assessment of both benefits and harm. After optimal control of cardiovascular risk factors, and when patients are less than 70 years of age, clinicians should assess the risk of MACE and base decision on such stratification, considering the risk of bleeding and patient preferences. Clinicians would then advise the use of aspirin in primary prevention patients at the highest risk of MACE who do not have a prohibitive risk of bleeding, and in the majority of cases after initiation of properly titrated statin therapy

Análise da expansão de áreas agrícolas no sul do Estado do Maranhão.

O estudo da dinâmica de expansão das áreas agrícolas por meio da classificação de imagens de sensoriamento remoto tem significativa importância, pois possibilita o acompanhamento contínuo da utilização do território e o monitoramento das áreas com cobertura vegetal, nativa ou manejada. Neste trabalho, foi realizada a análise da cobertura vegetal na região sul do Maranhão, local que vem apresentando aumento nas áreas agrícolas na última década. Foram utilizadas imagens do sensor TM, a bordo do satélite Landsat 5, de três anos (2001, 2005 e 2010). Nestas imagens, foram realizadas classificações supervisionadas com o objetivo de identificar as áreas agrícolas. O mapeamento mostrou aumento das áreas agrícolas de 144 mil ha em 2001 para 374 mil ha em 2010 na região. A verificação do mapa gerado foi realizada por meio da comparação da área agrícola mapeada com a área plantada de soja nos municípios da área de estudo, de acordo com os dados do IBGE. Foi constatada boa concordância entre a área agrícola mapeada e os dados oficiais de área plantada. Desta forma, a classificação supervisionada mostrou ser uma ferramenta adequada para o mapeamento e monitoramento da expansão agrícola no Maranhão

Pre-treatment high-sensitivity troponin T for the short-term prediction of cardiac outcomes in patients on immune checkpoint inhibitors

Background: Immune checkpoint inhibitors (ICIs) are an emerging option for several advanced metastatic cancers, but may have cardiotoxic effects. The prognostic value of high-sensitivity troponin T (hs-TnT) before treatment start has never been investigated. Materials and methods: Thirty consecutive patients underwent measurement of hs-TnT before starting ICI therapy (pembrolizumab, 23%; nivolumab, 12%; atezolizumab, 6%; durvalumab, 5%). The primary endpoint of cardiovascular death, stroke or transient ischaemic attack, pulmonary embolism and new-onset heart failure, and the secondary endpoint of progression of cardiac involvement according to the CARDIOTOX classification were evaluated after 3 months from the first cycle. Results: Patients (median age 68 years, 77% men, 13% with coronary artery disease, 90% current or former smokers, 67% overweight or obese and 43% hypertensive) had a median hs-TnT of 12 ng/L (interquartile interval 8-23). The primary endpoint occurred only in patients with hs-TnT ≥ 14 ng/L at baseline. Therefore, only patients who had hs-TnT ≥ 14 ng/L before the first cycle died had a stroke/TIA or new-onset HF. Furthermore, nine out of 13 patients with the secondary endpoint (progression of cardiac disease) had hs-TnT ≥ 14 ng/L before the first cycle (P =.012). AUC values were 0.909 for the primary endpoint and 0.757 for the secondary endpoint. The best cut-off was 14 ng/L for both the primary (100% sensitivity, 73% specificity) and secondary endpoints (sensitivity 75%, specificity 77%). Conclusions: In patients on ICIs, baseline hs-TnT predicts a composite cardiovascular endpoint and the progression of cardiac involvement at 3 months, with 14 ng/L as the best cut-off

Epidemiology and Management of Acute Haematogenous Osteomyelitis in a Tertiary Paediatric Center

Background: Paediatric acute hematogenous osteomyelitis (AHOM) is a serious disease requiring early diagnosis and treatment. To review the clinical presentation, management and organisms responsible for AHOM, and to explore risk factors for complicated AHOM, a large cohort referring to a single center over a 6-year period was evaluated. Methods: Data from children with AHOM, hospitalized between 2010 and 2015, and aged > 1 month, were retrospectively collected and analyzed. Results: 121 children (median age 4.8 years; 55.4% males) were included. Fever at onset was present in 55/121 children (45.5%); the lower limb was most frequently affected (n = 68/121; 56.2%). Microbiological diagnosis (by culture and/or polymerase chain reaction (PCR)) was reached in 33.3% cases. Blood and pus/biopsy culture sensitivities were 32.4% and 46.4%, respectively. PCR sensitivity was 3.6% (2/55) on blood, and 66.6% (16/24) on pus/biopsy sample. Staphylococcus aureus was the most commonly identified pathogen (n = 20); no methicillin-resistant Staphylococcus aureus (MRSA) was isolated, 10.0% (n = 2) strains were Panton-Valentine-Leukocidin (PVL) producer; 48.8% (59/121) cases were complicated. At univariate analysis, factors associated with complicated AHOM were: recent fever episode, fever at onset, upper limb involvement, white blood count (WBC) ≥ 12,000/µL, C reactive protein (CRP) ≥ 10 mg/L, S. aureus infection. At multivariate analyses S. aureus infection remained the only risk factor for complicated AHOM (aOR = 3.388 (95%CI: 1.061–10.824); p-value = 0.039). Conclusions: In this study microbiological diagnosis was obtained in over one third of cases. Empiric treatment targeting methicillin-sensitive Staphylococcus aureus seems to be justified by available microbiological data

Deregulated expression of aurora kinases is not a prognostic biomarker in papillary thyroid cancer patients.

Abstract A number of reports indicated that Aurora-A or Aurora-B overexpression represented a negative prognostic factor in several human malignancies. In thyroid cancer tissues a deregulated expression of Aurora kinases has been also demonstrated, butno information regarding its possible prognostic role in differentiated thyroid cancer is available. Here, weevaluated Aurora-A and Aurora-B mRNA expression and its prognostic relevance in a series of 87 papillary thyroid cancers (PTC), with a median follow-up of 63 months. The analysis of Aurora-A and Aurora-B mRNA levels in PTC tissues, compared to normal matched tissues, revealed that their expression was either up-or down-regulatedin the majority of cancer tissues. In particular, Aurora-A and Aurora-B mRNA levels were altered, respectively, in 55 (63.2%) and 79 (90.8%) out of the 87 PTC analyzed. A significant positive correlation between Aurora-A and Aurora-B mRNAswas observed (p=0.001). The expression of both Aurora genes was not affected by the BRAF(V600E) mutation. Univariate, multivariate and Kaplan-Mayer analyses documented the lack of association between Aurora-A or Aurora-B expression and clinicopathological parameterssuch as gender, age, tumor size, histology, TNM stage, lymph node metastasis and BRAF status as well asdisease recurrences or disease-free interval. Only Aurora-B mRNA was significantly higher in T(3-4) tissues, with respect to T(1-2) PTC tissues. The data reported here demonstrate that the expression of Aurora kinases is deregulated in the majority of PTC tissues, likely contributing to PTC progression. However, differently from other human solid cancers, detection of Aurora-A or Aurora-B mRNAs is not a prognostic biomarker inPTC patients

The fetal profile line:a proposal for a sonographic reference line to classify forehead and mandible anomalies in the second and third trimester

Objectives To test the fetal profile (FP) line, defined as the line that passes through the anterior border of the mandible and the nasion, as a reference line for forehead and mandible anomalies. Methods Volumes of 248 normal and 24 pathological fetuses (1636 and 1937?weeks gestation, respectively) were analysed retrospectively. When the FP line passes anteriorly, across or posteriorly to the frontal bone, this was defined as negative, zero or positive, respectively. When the FP line was positive the distance (F distance) between the FP line and the frontal bone was measured. Results No cases with a negative FP line were found in the normal fetuses. Before 27?weeks gestation the FP line was always zero except in one case. After 27?weeks gestation the FP line was positive in up to 25% (F distance (mean, range): 2.8, 2.13.6?mm). The FP line correctly identified 13 cases with retrognathia, 5 cases with frontal bossing and 3 cases with a sloping forehead. Conclusion Although large prospective studies are needed, the FP line may be a useful tool to detect second trimester profile anomalies such as retrognathia, sloping forehead and frontal bossing with the possibility of quantifying the latter. (c) 2012 John Wiley & Sons, Ltd

Whole-exome analysis in osteosarcoma to identify a personalized therapy

Osteosarcoma is the most common pediatric primary non-hematopoietic bone tumor. Survival of these young patients is related to the response to chemotherapy and development of metastases. Despite many advances in cancer research, chemotherapy regimens for osteosarcoma are still based on non-selective cytotoxic drugs. It is essential to investigate new specific molecular therapies for osteosarcoma to increase the survival rate of these patients. We performed exomic sequence analyses of 8 diagnostic biopsies of patients with conventional high grade osteosarcoma to advance our understanding of their genetic underpinnings and to correlate the genetic alteration with the clinical and pathological features of each patient to identify a personalized therapy. We identified 18,275 somatic variations in 8,247 genes and we found three mutated genes in 7/8 (87%) samples (KIF1B, NEB and KMT2C). KMT2C showed the highest number of variations; it is an important component of a histone H3 lysine 4 methyltransferase complex and it is one of the histone modifiers previously implicated in carcinogenesis, never studied in osteosarcoma. Moreover, we found a group of 15 genes that showed variations only in patients that did not respond to therapy and developed metastasis and some of these genes are involved in carcinogenesis and tumor progression in other tumors. These data could offer the opportunity to get a key molecular target to identify possible new strategies for early diagnosis and new therapeutic approaches for osteosarcoma and to provide a tailored treatment for each patient based on their genetic profile

The impact of national prenatal screening on the time of diagnosis and outcome of pregnancies affected with common trisomies, a cohort study in the Northern Netherlands

Background: To evaluate the impact of the introduction of prenatal screening on time of detection and pregnancy outcome for trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13). Methods: We performed a retrospective, population-based cohort study in the Northern Netherlands including 503 trisomy cases born between 2005 and 2012. Screening tests and invasive procedures, timing of diagnosis and pregnancy outcome were compared between the period before (2005-2006) and after introduction (2007-2012) using chi(2) tests. Results: There was an increase in proportion of women who had a prenatal screening and/or invasive test, from 62% in 2005-2006 to 84% in 2010-2012 (p 35 years (p <0.01). More T13/T18 cases were diagnosed <24 weeks after introduction (62% vs 84%; p <0.01). In T13/T18 intra-uterine death decreased (26% vs 15%), while terminations increased: 55% vs 72%. Conclusion: The introduction of prenatal screening had limited impact on the time of detection and outcome of the most common trisomies. The introduction of the 20-week anomaly scan has resulted in more trisomy cases diagnosed <24 weeks and a shift from fetal death to terminations