Euglycemic Ketoacidosis in Spinal Muscular Atrophy

Euglycemic ketoacidosis is defined by the triad of high anion gap acidosis, increased plasma ketones, and the absence of hyperglycemia. Apart from diabetes mellitus, the disorder may occur in prolonged fasting, excessive alcohol consumption, pregnancy, and inborn errors of metabolism. Here, we highlight the diagnosis of euglycemic ketoacidosis in a pediatric nondiabetic patient with spinal muscular atrophy (SMA) type 1 (Werdnig–Hoffmann disease), who, subsequently to her postoperative admission to the intensive care unit following a spinal surgery, developed high anion gap metabolic acidosis. We discuss the pathophysiology of acid-base disorders in SMA, along with the glucose and fatty acids metabolism, the necessary knowledge for medical practitioners.

http://bit.ly/2RSzkVT

Handling Big Data Scalability in Biological Domain Using Parallel and Distributed Processing: A Case of Three Biological Semantic Similarity Measures

In the field of biology, researchers need to compare genes or gene products using semantic similarity measures (SSM). Continuous data growth and diversity in data characteristics comprise what is called big data; current biological SSMs cannot handle big data. Therefore, these measures need the ability to control the size of big data. We used parallel and distributed processing by splitting data into multiple partitions and applied SSM measures to each partition; this approach helped manage big data scalability and computational problems. Our solution involves three steps: split gene ontology (GO), data clustering, and semantic similarity calculation. To test this method, split GO and data clustering algorithms were defined and assessed for performance in the first two steps. Three of the best SSMs in biology [Resnik, Shortest Semantic Differentiation Distance (SSDD), and SORA] are enhanced by introducing threaded parallel processing, which is used in the third step. Our results demonstrate that introducing threads in SSMs reduced the time of calculating semantic similarity between gene pairs and improved performance of the three SSMs. Average time was reduced by 24.51% for Resnik, 22.93%, for SSDD, and 33.68% for SORA. Total time was reduced by 8.88% for Resnik, 23.14% for SSDD, and 39.27% for SORA. Using these threaded measures in the distributed system, combined with using split GO and data clustering algorithms to split input data based on their similarity, reduced the average time more than did the approach of equally dividing input data. Time reduction increased with increasing number of splits. Time reduction percentage was 24.1%, 39.2%, and 66.6% for Threaded SSDD; 33.0%, 78.2%, and 93.1% for Threaded SORA in the case of 2, 3, and 4 slaves, respectively; and 92.04% for Threaded Resnik in the case of four slaves.

http://bit.ly/2RVVeaz

Levels of CEACAM6 in Peripheral Blood Are Elevated in Patients with Plasma Cell Disorders: A Potential New Diagnostic Marker and a New Therapeutic Target?

Introduction. The prognosis of multiple myeloma is still unfavorable due to inherent characteristics of the disease and the often-delayed diagnosis due to widespread and unspecific symptoms such as back pain and fatigue. Therefore, a simple diagnostic blood test would be helpful to speed up the diagnostic procedure in such patients (pts.). Here, we evaluated the diagnostic value of plasma levels of carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) in the peripheral blood and bone marrow of pts. with plasma cell disorders and in healthy controls. Materials and Methods. Immunoreactive CEACAM6 was determined in the peripheral blood and bone marrow () of pts. with monoclonal gammopathy of unknown significance (MGUS: 28/37), newly diagnosed multiple myeloma (NDMM: 42/40), and relapsed/refractory multiple myeloma (RRMM: 25/23) by sandwich ELISA. Results. Median CEACAM6 levels in the peripheral blood of pts. with plasma cell disorders were significantly higher than those of healthy controls (healthy controls: 15.2 pg/ml (12.1-17.1); MGUS: 19.0 pg/ml (16.4-22.5); NDMM: 18.0 pg/ml (13.4-21.2); and RRMM: 18.9 pg/ml (15.2-21.5); ). Plasma levels of CEACAM6 discriminated healthy subjects from MGUS/NDMM pts. (, 95% CI: 0.6-0.8); i.e., a CEACAM6  pg/ml has an 82% (95% CI: 70-90) predictive probability for the identification of MGUS or NDMM. Moreover, CEACAM6 levels in the bone marrow were significantly higher in RRMM pts. than in NDMM pts. (), suggesting a role of this molecule in disease progression. Conclusion. CEACAM6 plasma levels can noninvasively identify pts. with a plasma cell disorder and should be evaluated prospectively as a potential diagnostic marker. Moreover, due to high CEACAM6 levels in the bone marrow in RRMM pts., this adhesion molecule might be a therapeutic target in multiple myeloma pts.

http://bit.ly/2sRFgza

Proinflammatory Role of Angiotensin II in the Aorta of Normotensive Mice

Angiotensin II plays important functions in cardiovascular system mediating actions leading to inflammatory responses such as activation of VSMC in order to produce ROS, inflammatory cytokines, chemokines, and adhesion molecules. Changes in angiotensin II production could stimulate the recruitment and activation of myeloid cells initiating local inflammatory response without effect on BP. We aimed to verify if angiotensin II induces an inflammatory response in the aorta and if it correlates with variations in BP. C57Bl/6 mice treated with saline solution (0.9%, control group) or angiotensin II (30ng/kg, Ang II group) were used. BP and HR levels were measured. Immunohistochemistry for IL1-β, TGF-β, iNOS, CD45, and α-actin was performed in the aorta. BP and HR do not change. A biphasic response was observed both for IL1-β and TGF-β expression and also for the presence of CD45 positive cells, with an acute increase (between 30 and 60 minutes) and a second increase, between 24 and 48 hours. Positive staining for iNOS increased in the earlier period (30 minutes) in perivascular adipose tissue and in a longer period (48 hours) in tunica adventitia. Immunoblotting to α-actin showed no alterations, suggesting that the applied dose of angiotensin II does not alter the aortic VSMCs phenotype. The results suggest that angiotensin II, even at doses that do not alter BP, induces the expression of inflammatory markers and migration of inflammatory cells into the aorta of normotensive mice. Thus, angiotensin II may increase the propensity to develop a cardiovascular injury, even in normotensive individuals.

http://bit.ly/2MyzSKn

“Crack, Reduce, and Implant”: A Safe Phaco Technique in a Case with Hard Brown Cataract

This report describes two maneuvers in different steps of phaco surgery in a case with hard cataract, which provide debulking of the central dense nucleus and prevents posterior capsule rupture (PCR). In the current case, clear corneal incisions were created, and anterior chamber was filled with ophthalmic viscosurgical device (OVD). Anterior capsule was punctured, and capsulorhexis was completed. Nucleus was cracked into two halves following vertical groove formation. Core nucleus was hollowed sideward bilaterally in the capsular bag. Nuclear halves were removed from capsular bag, and each one was pushed to one side on the iris plane. Capsular bag was inflated with OVD, and intraocular lens (IOL) was implanted. Nuclear halves were removed in confidence. The presented maneuvers initially reduce dense nucleus load in the safe zone and allow surgeon to use IOL as a barrier to protect floppy posterior capsule from early steps of the surgery.

http://bit.ly/2sMQJQH

Cancers, Vol. 11, Pages 147: A Simplified Genomic Profiling Approach Predicts Outcome in Metastatic Colorectal Cancer

Cancers, Vol. 11, Pages 147: A Simplified Genomic Profiling Approach Predicts Outcome in Metastatic Colorectal Cancer

Cancers doi: 10.3390/cancers11020147

Authors: Carlo Capalbo Francesca Belardinilli Domenico Raimondo Edoardo Milanetti Umberto Malapelle Pasquale Pisapia Valentina Magri Alessandra Prete Silvia Pecorari Mariarosaria Colella Anna Coppa Caterina Bonfiglio Arianna Nicolussi Virginia Valentini Alessandra Tessitore Beatrice Cardinali Marialaura Petroni Paola Infante Matteo Santoni Marco Filetti Valeria Colicchia Paola Paci Silvia Mezi Flavia Longo Enrico Cortesi Paolo Marchetti Giancarlo Troncone Diana Bellavia Gianluca Canettieri Giuseppe Giannini

The response of metastatic colorectal cancer (mCRC) to the first-line conventional combination therapy is highly variable, reflecting the elevated heterogeneity of the disease. The genetic alterations underlying this heterogeneity have been thoroughly characterized through omic approaches requiring elevated efforts and costs. In order to translate the knowledge of CRC molecular heterogeneity into a practical clinical approach, we utilized a simplified Next Generation Sequencing (NGS) based platform to screen a cohort of 77 patients treated with first-line conventional therapy. Samples were sequenced using a panel of hotspots and targeted regions of 22 genes commonly involved in CRC. This revealed 51 patients carrying actionable gene mutations, 22 of which carried druggable alterations. These mutations were frequently associated with additional genetic alterations. To take into account this molecular complexity and assisted by an unbiased bioinformatic analysis, we defined three subgroups of patients carrying distinct molecular patterns. We demonstrated these three molecular subgroups are associated with a different response to first-line conventional combination therapies. The best outcome was achieved in patients exclusively carrying mutations on TP53 and/or RAS genes. By contrast, in patients carrying mutations in any of the other genes, alone or associated with mutations of TP53/RAS, the expected response is much worse compared to patients with exclusive TP53/RAS mutations. Additionally, our data indicate that the standard approach has limited efficacy in patients without any mutations in the genes included in the panel. In conclusion, we identified a reliable and easy-to-use approach for a simplified molecular-based stratification of mCRC patients that predicts the efficacy of the first-line conventional combination therapy.

http://bit.ly/2TlgBPu

Cancers, Vol. 11, Pages 148: Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells

Cancers, Vol. 11, Pages 148: Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells

Cancers doi: 10.3390/cancers11020148

Authors: Anna Wawruszak Joanna Kalafut Estera Okon Jakub Czapinski Marta Halasa Alicja Przybyszewska Paulina Miziak Karolina Okla Adolfo Rivero-Muller Andrzej Stepulak

Histone deacetylase inhibitors (HDIs) are a group of potent epigenetic drugs which have been investigated for their therapeutic potential in various clinical disorders, including hematological malignancies and solid tumors. Currently, several HDIs are already in clinical use and many more are on clinical trials. HDIs have shown efficacy to inhibit initiation and progression of cancer cells. Nevertheless, both pro-invasive and anti-invasive activities of HDIs have been reported, questioning their impact in carcinogenesis. The aim of this review is to compile and discuss the most recent findings on the effect of HDIs on the epithelial-mesenchymal transition (EMT) process in human cancers. We have summarized the impact of HDIs on epithelial (E-cadherin, β-catenin) and mesenchymal (N-cadherin, vimentin) markers, EMT activators (TWIST, SNAIL, SLUG, SMAD, ZEB), as well as morphology, migration and invasion potential of cancer cells. We further discuss the use of HDIs as monotherapy or in combination with existing or novel anti-neoplastic drugs in relation to changes in EMT.

http://bit.ly/2B6RCZ7