Concurrent paclitaxel, capecitabine, mitomycin C and pelvic radiation therapy for patients with squamous cell anal carcinoma

Abstract

Purpose

The goals of this study were to assess safety and efficacy of triplet chemoradiotherapy (CRT) with paclitaxel for squamous cell anal carcinoma (SCAC).

Methods

Patients with stage I–IIIB SCAC were enrolled and received 52–58 Gy intensity-modulated radiotherapy (IMRT) (with dose based on the T stage) in consecutive daily 1.8–2.2 Gy fractions. The concurrent chemotherapy consisted of paclitaxel 45 mg/m² days 3, 10, 17, 24, 31, capecitabine 625 mg/m² bid on treatment days and mitomycin C 10 g/m² on day 1. Primary endpoints were complete clinical response at 26 weeks and protocol compliance; secondary endpoints included toxicity, overall survival (OS) and progression-free survival (PFS).

Results

Thirty-eight patients were enrolled. The percentage of patients with stage I, II, IIIA, and IIIB disease were 1 (2.6%), 5 (13.2%), 15 (39.5%), and 17 (44.7%), respectively. 32 patients (84.2%) completed CRT without significant alterations. Grade 3–4 toxicity occurred in 23 (60.5%) patients. 33 (86.8%) patients had complete clinical response at 26 weeks. Median follow-up was 25.6 months. Seven (18.4%) patients experienced disease progression: four patients had residual tumor after CRT, 2 patients developed distant metastases and 1 patient developed a local recurrence 12 months after CRT. Two-year OS was 93.6%, 2-year PFS was 83.9%.

Conclusions

Investigated treatment scheme is feasible despite high toxicity profile, and may be beneficial for patients with advanced SCAC. Further research is warranted.

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Vaccines, Vol. 5, Pages 20: Maternal Immunization: New Perspectives on Its Application Against Non-Infectious Related Diseases in Newborns

Vaccines, Vol. 5, Pages 20: Maternal Immunization: New Perspectives on Its Application Against Non-Infectious Related Diseases in Newborns

Vaccines doi: 10.3390/vaccines5030020

Authors: Federica Riccardo Aline Réal Claudia Voena Roberto Chiarle Federica Cavallo Giuseppina Barutello

The continuous evolution in preventive medicine has anointed vaccination a versatile, human-health improving tool, which has led to a steady decline in deaths in the developing world. Maternal immunization represents an incisive step forward for the field of vaccination as it provides protection against various life-threatening diseases in pregnant women and their children. A number of studies to improve prevention rates and expand protection against the largest possible number of infections are still in progress. The complex unicity of the mother-infant interaction, both during and after pregnancy and which involves immune system cells and molecules, is an able partner in the success of maternal immunization, as intended thus far. Interestingly, new studies have shed light on the versatility of maternal immunization in protecting infants from non-infectious related diseases, such as allergy, asthma and congenital metabolic disorders. However, barely any attempt at applying maternal immunization to the prevention of childhood cancer has been made. The most promising study reported in this new field is a recent proof of concept on the efficacy of maternal immunization in protecting cancer-prone offspring against mammary tumor progression. New investigations into the possibility of exploiting maternal immunization to prevent the onset and/or progression of neuroblastoma, one of the most common childhood malignancies, are therefore justified. Maternal immunization is presented in a new guise in this review. Attention will be focused on its versatility and potential applications in preventing tumor progression in neuroblastoma-prone offspring.

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Immunotherapy in ovarian, endometrial and cervical cancer: state of the art and future perspectives

The tumors of the female genital tract represent a huge health problem in Europe, Endometrial Cancer, EC, with 6.1% of cases estimated in 2012 [1] is the most common, followed by Epithelial Ovarian Cancer, EOC, and Cervical Cancer, CC; those malignancies have distinct biology and molecular features and differ from each other based on clinical behavior, nevertheless all them are associated with high mortality. Important goals have been achieved in CC prevention and treatment: the worldwide spreading of the Papanicolaou test, PAP test, has dramatically increased the rate of diagnosis for precancerous conditions/early stage tumors and the extensive HPV (Human Papillomavirus) vaccination programs are expected to produce a massive decrease in the incidence of CC in the next few years.

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Outcome of patients with lung adenocarcinoma with transformation to small-cell lung cancer following tyrosine kinase inhibitors treatment: A Systematic Review and Pooled Analysis

Lung cancer is the leading cause of cancer-related death. It accounts for 353,000 deaths in the European Union and about 160,000 deaths in the United States[1].

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Concurrent paclitaxel, capecitabine, mitomycin C and pelvic radiation therapy for patients with squamous cell anal carcinoma

Abstract

Purpose

The goals of this study were to assess safety and efficacy of triplet chemoradiotherapy (CRT) with paclitaxel for squamous cell anal carcinoma (SCAC).

Methods

Patients with stage I–IIIB SCAC were enrolled and received 52–58 Gy intensity-modulated radiotherapy (IMRT) (with dose based on the T stage) in consecutive daily 1.8–2.2 Gy fractions. The concurrent chemotherapy consisted of paclitaxel 45 mg/m² days 3, 10, 17, 24, 31, capecitabine 625 mg/m² bid on treatment days and mitomycin C 10 g/m² on day 1. Primary endpoints were complete clinical response at 26 weeks and protocol compliance; secondary endpoints included toxicity, overall survival (OS) and progression-free survival (PFS).

Results

Thirty-eight patients were enrolled. The percentage of patients with stage I, II, IIIA, and IIIB disease were 1 (2.6%), 5 (13.2%), 15 (39.5%), and 17 (44.7%), respectively. 32 patients (84.2%) completed CRT without significant alterations. Grade 3–4 toxicity occurred in 23 (60.5%) patients. 33 (86.8%) patients had complete clinical response at 26 weeks. Median follow-up was 25.6 months. Seven (18.4%) patients experienced disease progression: four patients had residual tumor after CRT, 2 patients developed distant metastases and 1 patient developed a local recurrence 12 months after CRT. Two-year OS was 93.6%, 2-year PFS was 83.9%.

Conclusions

Investigated treatment scheme is feasible despite high toxicity profile, and may be beneficial for patients with advanced SCAC. Further research is warranted.

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RIPped for neuroinflammation

RIPped for neuroinflammation

Cell Research advance online publication, May 19 2017. doi:10.1038/cr.2017.75

Authors: Bart Tummers & Douglas R Green

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Non-central peripherally inserted central catheters in neonatal intensive care: complication rates and longevity of catheters relative to tip position

Abstract

Background

Peripherally inserted central catheters (PICCs) represent a mainstay of intravascular access in the neonatal intensive care setting when long-term vascular access is needed. Ideally, PICCs should be inserted and maintained in a central position with the tip ending in the superior or inferior vena cava. This is not always achievable, and sometimes the tip remains in a peripheral location. Higher complication rates have been reported with non-central PICCs; however these findings have not been confirmed in a solely neonatal series and PICCs with tips in peripheral veins have not been studied.

Objective

To compare complication rates and length of catheter duration related to PICC position in neonates.

Materials and methods

We conducted a retrospective analysis of all PICCs inserted in term and preterm infants in a tertiary neonatal intensive care unit between May 2007 and December 2009. A single pediatric radiologist reinterpreted the catheter tip site on initial anteroposterior (AP) chest radiographs and categorized sites as central (superior vena cava, inferior vena cava, brachiocephalic vein), intermediate (subclavian, axillary, common or external iliac veins), or peripheral (veins peripheral to axillary or external iliac veins). We analyzed complication rates and length of catheter duration among the three categories.

Results

We collected data on a total of 176 PICCs. Infants with PICCs in a central location had a significantly lower complication rate (18/97, 19%) than those with the PICC tip in an intermediate (24/64, 38%) or peripheral (9/15, 60%) locations (P=0.0003). Length of catheter duration was noted to be longest with central, intermediate with intermediate, and shortest with peripheral PICC tip locations (17.7±14.8 days for central vs. 11.4±10.7 days for intermediate vs. 5.4±2.5 days for peripheral, P=0.0003).

Conclusion

A central location is ideal for the tip of a PICC. When this is not achievable, an intermediate location is preferable to a more peripheral position.

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Changes in femoral head size and growth rate in young children with severe developmental dysplasia of the hip

Abstract

Background

Developmental dysplasia of the hip (DDH) is known to result in smaller femoral head size in toddlers; however, alterations in femoral head size and growth have not been documented in infants.

Objective

To determine with ultrasound (US) whether femoral head size and growth are altered in infants (younger than 1 year of age) with severe DDH.

Materials and methods

We identified all patients at our tertiary care children's hospital from 2002 to 2014 who underwent US for DDH. We included studies with at least one hip with severe DDH, defined as <25% coverage of the femoral head, and excluded teratological DDH. We constructed a control group of randomized patients with normal US studies. Two pediatric radiologists blinded to diagnosis measured bilateral femoral head diameter. Inter-reader variability and femoral head diameter difference between dislocated and contralateral normal femoral heads were evaluated. Mean femoral head diameters were compared across types of hip joint; femoral head growth rates per month were calculated.

Results

Thirty-seven children with DDH (28 female) were identified (median age: 33 days). The control group contained 75 children (47 female) with a median age of 47 days. Fifty-three of the 74 hips in the study group had severe DDH. Twenty-four children with DDH had completely dislocated hips (nine bilateral, five with contralateral severe subluxations). Thirteen other children had severe subluxation, two bilaterally. There was good inter-reader agreement in the normal femoral head group and moderate agreement in the severe DDH group. In the study group, severe DDH femoral head diameter was significantly smaller than their contralateral normal hip. Severe DDH femoral head diameter was significantly smaller than normal femoral head diameter in the control group. The severe DDH femoral head growth rate was slightly less but not significantly slower than normal femoral head growth rate in the study group.

Conclusion

On US during infancy, femoral head size is significantly reduced in severe cases of DDH.

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Multiphase Calcite Cementation and Fluids Evolution of a Deeply Buried Carbonate Reservoir in the Upper Ordovician Lianglitag Formation, Tahe Oilfield, Tarim Basin, NW China

Oil and gas have been found in the Upper Ordovician Lianglitag Formation carbonates in the Tahe Oilfield, Tarim Basin, NW China. This study documents the origin of diagenetic fluids by using a combination of petrology, SIMS, fluid inclusion, and radiogenic isotope analysis. Six stages of calcite cements were revealed. C1-C2 formed in marine to early burial environments. C3 has relatively low δ18 values (−8.45 to −6.50) and likely has a meteoric origin. Meteoric water probably fluxed into aquifers during the Early Paleozoic and Late Paleozoic uplift. C4 has δ18 values typically 3 higher than those of C3, and probably formed during shallow burial. C5 displays relatively negative δ18 values (−8.26 to −5.12), and the moderate-to-high fluid-inclusion temperatures imply that it precipitated in burial environments. C6 shows homogenization temperatures (up to 200°C) higher than the maximum burial and much lower salinities (

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Several Indicators of Critical Transitions for Complex Diseases Based on Stochastic Analysis

Many complex diseases (chronic disease onset, development and differentiation, self-assembly, etc.) are reminiscent of phase transitions in a dynamical system: quantitative changes accumulate largely unnoticed until a critical threshold is reached, which causes abrupt qualitative changes of the system. Understanding such nonlinear behaviors is critical to dissect the multiple genetic/environmental factors that together shape the genetic and physiological landscape underlying basic biological functions and to identify the key driving molecules. Based on stochastic differential equation (SDE) model, we theoretically derive three statistical indicators, that is, coefficient of variation (CV), transformed Pearson's correlation coefficient (TPC), and transformed probability distribution (TPD), to identify critical transitions and detect the early-warning signals of the phase transition in complex diseases. To verify the effectiveness of these early-warning indexes, we use high-throughput data for three complex diseases, including influenza caused by either H3N2 or H1N1 and acute lung injury, to extract the dynamical network biomarkers (DNBs) responsible for catastrophic transition into the disease state from predisease state. The numerical results indicate that the derived indicators provide a data-based quantitative analysis for early-warning signals for critical transitions in complex diseases or other dynamical systems.

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Acute Hypocalcemia and Metabolic Alkalosis in Children on Cation-Exchange Resin Therapy

Background. Sodium polystyrene sulfonate (SPS) is a chelating agent used for the treatment of hyperkalemia. SPS has a wide range of exchange capacity requiring close monitoring of serum electrolytes. We observed two patients who developed acute hypocalcemia and increased metabolic alkalosis after initiating SPS therapy. We report these cases to draw attention to the potential risk of this medication in pediatric patients. Case Diagnosis/Treatment. Two children with chronic kidney disease on dialysis were started on SPS for hyperkalemia. Within a week after initiation of the medication, both patients developed hypocalcemia on routine labs without overt clinical manifestations. The hypocalcemia was rapidly corrected with oral supplementation and discontinuation of SPS. Conclusions. Severe hypocalcemia can develop after SPS therapy. The metabolic alkalosis in these patients associated with the hypocalcemia put them at increased risk for complications. Hence, careful attention must be paid to the state of calcium metabolism in all patients receiving SPS. Often calcium supplementation is required to maintain normal calcium levels.

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Multihopping Multilevel Clustering Heterogeneity-Sensitive Optimized Routing Protocol for Wireless Sensor Networks

Effective utilization of energy resources in Wireless Sensor Networks (WSNs) has become challenging under uncertain distributed cluster-formation and single-hop intercluster communication capabilities. So, sensor nodes are forced to operate at expensive full rate transmission power level continuously during whole network operation. These challenging network environments experience unwanted phenomena of drastic energy consumption and packet drop. In this paper, we propose an adaptive immune Multihopping Multilevel Clustering (MHMLC) protocol that executes a Hybrid Clustering Algorithm (HCA) to perform optimal centralized selection of Cluster-Heads (CHs) within radius of centrally located Base Station (BS) and distributed CHs selection in the rest of network area. HCA of MHMLC also produces optimal intermediate CHs for intercluster multihop communications that develop heterogeneity-aware economical links. This hybrid cluster-formation facilitates the sensors to function at short range transmission power level that enhances link quality and avoids packet drop. The simulation environments produce fair comparison among proposed MHMLC and existing state-of-the-art routing protocols. Experimental results give significant evidence of better performance of the proposed model in terms of network lifetime, stability period, and data delivery ratio.

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Jordan -Derivations on Operator Algebras

Let be a CSL subalgebra of a von Neumann algebra acting on a Hilbert space . It is shown that any Jordan -derivation on is an -derivation, where are any automorphisms on . Moreover, the th power -maps on are investigated.

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A Truncated Singular Value Decomposition Enhanced Nested Complex Source Beam Method

This work presents a novel matrix compression algorithm to improve the computational efficiency of the nested complex source beam (NCSB) method. The algorithm is based on the application of the truncated singular value decomposition (TSVD) to the multilevel aggregation, translation, and disaggregation operations in NCSB. In our implementation, the aggregation/disaggregation matrices are solved by the truncated far-field matching, which is based on the directional far-field radiation property of the complex source beams (CSBs). Furthermore, the translation matrices are obtained according to the beam width of CSBs. Due to the high directivity of the radiation patterns of CSBs, all the far-field related interaction matrices are low-ranked. Therefore, TSVD can be employed and a new set of equivalent sources can be constructed by a linear combination of the original CSBs. It is proved that the radiation power of the new sources is proportional to the square of the corresponding singular values. This provides a theoretical guideline to drop the insignificant singular vectors in the calculation. In doing so, the efficiency of the original NCSB method can be much improved while a reasonably good accuracy is maintained. Several numerical tests are conducted to validate the proposed method.

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An Efficient Code-Based Threshold Ring Signature Scheme with a Leader-Participant Model

Digital signature schemes with additional properties have broad applications, such as in protecting the identity of signers allowing a signer to anonymously sign a message in a group of signers (also known as a ring). While these number-theoretic problems are still secure at the time of this research, the situation could change with advances in quantum computing. There is a pressing need to design PKC schemes that are secure against quantum attacks. In this paper, we propose a novel code-based threshold ring signature scheme with a leader-participant model. A leader is appointed, who chooses some shared parameters for other signers to participate in the signing process. This leader-participant model enhances the performance because every participant including the leader could execute the decoding algorithm (as a part of signing process) upon receiving the shared parameters from the leader. The time complexity of our scheme is close to Courtois et al.'s (2001) scheme. The latter is often used as a basis to construct other types of code-based signature schemes. Moreover, as a threshold ring signature scheme, our scheme is as efficient as the normal code-based ring signature.

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An Attempt to Establish a Common Animal Model for Hepatorenal Fibrosis in Rats

It is already a proven fact that there exists a relationship between CLD (chronic liver disease) and kidney disease but still there is no available combined animal model of liver and kidney fibrosis on the same animal. An animal model is one of the important research tools in the field of medical science because it is important to build a model that can simulate the disease condition so that the particular disease can be studied. Therefore, the aim of this study is to build a less expensive, less time consuming, and reproducible model of hepatorenal fibrosis on rats. We administered combined intraperitoneal injection of CCl4 (Carbon Tetrachloride) and BSA (Bovine Serum Albumin) on a female Wistar rats. At the end, the liver and kidney tissues were examined under microscope to see whether we were successful in establishing the model or not. The results show that liver fibrosis was marked but the changes on the kidneys were mild. In this study, we were able to induce significant fibrosis in the liver and early stages of fibrosis in the kidneys. The result also demonstrated that the addition of BSA conferred a liver protective effect against CCl4 induced hepatotoxicity, whereas combination of CCl4 and BSA proved to be detrimental for kidneys.

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The Ser/Thr Protein Kinase Protein-Protein Interaction Map of M. tuberculosis [Research]

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, the leading cause of death among all infectious diseases. There are 11 eukaryotic-like serine/threonine protein kinases (STPKs) in Mtb, which are thought to play pivotal roles in cell growth, signal transduction and pathogenesis. However, their underlying mechanisms of action remain largely uncharacterized. In this study, using a Mtb proteome microarray, we have globally identified the binding proteins in Mtb for all of the STPKs, and constructed the first STPK protein interaction (KPI) map that includes 492 binding proteins and 1,027 interactions. Bioinformatics analysis showed that the interacting proteins reflect diverse functions, including roles in two-component system, transcription, protein degradation, and cell wall integrity. Functional investigations confirmed that PknG regulates cell wall integrity through key components of peptidoglycan (PG) biosynthesis, e.g. MurC. The global STPK-KPIs network constructed here is expected to serve as a rich resource for understanding the key signaling pathways in Mtb, thus facilitating drug development and effective control of Mtb.

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RhoA Inhibitor Treatment At Acute Phase of Spinal Cord Injury May Induce Neurite Outgrowth and Synaptogenesis [Research]

The therapeutic use of RhoA inhibitors (RhoAi) has been experimentally tested in spinal cord injury (SCI). In order to decipher the underlying molecular mechanisms involved in such a process, an in vitro neuroproteomic-systems biology platform was developed in which the pan-proteomic profile of the dorsal root ganglia (DRG) cell line ND7/23 DRG was assessed in a large array of culture conditions using RhoAi and/or conditioned media obtained from SCI ex vivo derived spinal cord slices. A fine mapping of the spatio-temporal molecular events of the RhoAi treatment in SCI was performed. The data obtained allow a better understanding of regeneration/degeneration induced above and below the lesion site. Results notably showed a time-dependent alteration of the transcription factors profile along with the synthesis of growth cone-related factors (receptors, ligands, and signaling pathways) in RhoAi treated DRG cells. Furthermore, we assessed in a rat SCI model the in vivo impact of RhoAi treatment administered in situ via alginate scaffold that was combined with FK506 delivery. The improved recovery of locomotion was detected only at the early postinjury time points, whereas after overall survival a dramatic increase of synaptic contacts on outgrowing neurites in affected segments was observed. We validate these results by in vivo proteomic studies along the spinal cord segments from tissue and secreted media analyses, confirming the increase of the synaptogenesis expression factors under RhoAi treatment. Taken together, we demonstrate that RhoAi treatment seems to be useful to stimulate neurite outgrowth in both in vitro as well in vivo environments. However, for in vivo experiments there is a need for sustained delivery regiment to facilitate axon regeneration and promote synaptic reconnections with appropriate target neurons also at chronic phase, which in turn may lead to higher assumption for functional improvement.

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Proteomic Analysis of Regulatory T Cells Reveals the Importance of Themis1 in the Control of Their Suppressive Function [Research]

Regulatory T cells (Treg) represent a minor subpopulation of T lymphocytes that is crucial for the maintenance of immune homeostasis. Here, we present a large-scale quantitative mass spectrometry study that defines a specific proteomic "signature" of Treg. Treg and conventional T lymphocyte (Tconv) subpopulations were sorted by flow cytometry and subjected to global proteomic analysis by single-run nanoLC-MS/MS on a fast-sequencing Q-Exactive mass spectrometer. Besides "historical" proteins that characterize Treg, our study identified numerous new proteins that are up- or downregulated in Treg versus Tconv. We focused on Themis1, a protein particularly under-represented in Treg, and recently described as being involved in the pathogenesis of immune diseases. Using a transgenic mouse model overexpressing Themis1, we provided in vivo and in vitro evidence of its importance for Treg suppressive functions, in an animal model of inflammatory bowel disease and in coculture assays. We showed that this enhanced suppressive activity in vitro is associated with an accumulation of Tregs. Thus, our study highlights the usefulness of label free quantitative methods to better characterize the Treg cell lineage and demonstrates the potential role of Themis1 in the suppressive functions of these cells.

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Proteome-wide Identification of Glycosylation-dependent Interactors of Galectin-1 and Galectin-3 on Mesenchymal Retinal Pigment Epithelial (RPE) Cells [Research]

Identification of interactors is a major goal in cell biology. Not only protein-protein but also protein-carbohydrate interactions are of high relevance for signal transduction in biological systems. Here, we aim to identify novel interacting binding partners for the β-galactoside-binding proteins galectin-1 (Gal-1) and galectin-3 (Gal-3) relevant in the context of the eye disease proliferative vitreoretinopathy (PVR). PVR is one of the most common failures after retinal detachment surgeries and is characterized by the migration, adhesion, and epithelial-to-mesenchymal transition of retinal pigment epithelial cells (RPE) and the subsequent formation of sub- and epiretinal fibrocellular membranes. Gal-1 and Gal-3 bind in a dose- and carbohydrate-dependent manner to mesenchymal RPE cells and inhibit cellular processes like attachment and spreading. Yet knowledge about glycan-dependent interactors of Gal-1 and Gal-3 on RPE cells is very limited, although this is a prerequisite for unraveling the influence of galectins on distinct cellular processes in RPE cells. We identify here 131 Gal-3 and 15 Gal-1 interactors by galectin pulldown experiments combined with quantitative proteomics. They mainly play a role in multiple binding processes and are mostly membrane proteins. We focused on two novel identified interactors of Gal-1 and Gal-3 in the context of PVR: the low-density lipoprotein receptor LRP1 and the platelet-derived growth factor receptor β PDGFRB. Addition of exogenous Gal-1 and Gal-3 induced cross-linking with LRP1/PDGFRB and integrin-β1 (ITGB1) on the cell surface of human RPE cells and induced ERK/MAPK and Akt signaling. Treatment with kifunensine, an inhibitor of complex-type N-glycosylation, weakened the binding of Gal-1 and Gal-3 to these interactors and prevented lattice formation. In conclusion, the identified specific glycoprotein ligands shed light into the highly specific binding of galectins to dedifferentiated RPE cells and the resulting prevention of PVR-associated cellular events.

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Differential Proteomic Analysis of Gender-dependent Hepatic Tumorigenesis in Hras12V Transgenic Mice [Research]

Male prevalence is an outstanding characteristic of hepatocellular carcinoma (HCC), and the underlying mechanisms for this have remained largely unknown. In the present study, Hras12V transgenic mice, in which hepatocyte-specific expression of the ras oncogene induces male-biased hepatic tumorigenesis, were studied, and altered proteins were detected by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Protein samples from hepatic tumor tissues (T) and peritumor tissues (P) of transgenic males and females and the corresponding normal liver tissues (Wt) of nontransgenic males and females were subjected to pairwise comparisons based on proteomic analysis. Among 2381 autodetected protein spots, more than 1600 were differentially expressed based on a pairwise comparison (|ratio| > = 1.5, p < = 0.05). Of these, 180 spots were randomly selected for matrix-assisted laser desorption ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF MS) identification; finally, 89 distinct proteins were obtained. Among these 89 proteins, 7 and 50 proteins were further validated by Western blotting and literature investigation, respectively. Intriguingly, compared with Wt, the altered proteins were relatively concentrated in T in transgenic females but in P in transgenic males. Consistently, the levels of p-ERK and p-mTOR were significantly higher in the T of females compared with that of males. The pathway enrichment assay showed that 5 pathways in males but only 1 in females were significantly altered in terms of the upregulated proteins in T compared with Wt. These data indicate that female hepatocytes are disturbed by oncogenes with great difficulty, whereas male hepatocytes readily do so. In addition, 33 proteins were gender-dependently altered in hepatic tumorigenesis. Moreover, 4% DNA packaging and 4% homeostasis-related functional proteins were found in females but not in males, and more nucleus proteins were found in females (8%) than in males (3%). In conclusion, the proteomic data and comparative analysis presented here offer crucial clues for elucidating the mechanisms that underlie the male prevalence in HCC.

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Quantitative Temporal Viromics of an Inducible HIV-1 Model Yields Insight to Global Host Targets and Phospho-Dynamics Associated with Protein Vpr [Research]

The mechanisms by which human immunodeficiency virus (HIV) circumvents and coopts cellular machinery to replicate and persist in cells are not fully understood. HIV accessory proteins play key roles in the HIV life cycle by altering host pathways that are often dependent on post-translational modifications (PTMs). Thus, the identification of HIV accessory protein host targets and their PTM status is critical to fully understand how HIV invades, avoids detection and replicates to spread infection. To date, a comprehensive characterization of HIV accessory protein host targets and modulation of their PTM status does not exist. The significant gap in knowledge regarding the identity and PTMs of HIV host targets is due, in part, to technological limitations. Here, we applied current mass spectrometry techniques to define mechanisms of viral protein action by identifying host proteins whose abundance is affected by the accessory protein Vpr and the corresponding modulation of down-stream signaling pathways, specifically those regulated by phosphorylation. By utilizing a novel, inducible HIV-1 CD4+ T-cell model system expressing either the wild type or a vpr-negative viral genome, we overcame challenges associated with synchronization and infection-levels present in other models. We report identification and abundance dynamics of over 7000 proteins and 28,000 phospho-peptides. Consistent with Vpr's ability to impair cell-cycle progression, we observed Vpr-mediated modulation of spindle and centromere proteins, as well as Aurora kinase A and cyclin-dependent kinase 4 (CDK4). Unexpectedly, we observed evidence of Vpr-mediated modulation of the activity of serine/arginine-rich protein-specific kinases (SRPKs), suggesting a possible role for Vpr in the regulation of RNA splicing. This study presents a new experimental system and provides a data-resource that lays the foundation for validating host proteins and phosphorylation-pathways affected by HIV-1 and its accessory protein Vpr.

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Agonist-specific Protein Interactomes of Glucocorticoid and Androgen Receptor as Revealed by Proximity Mapping [Research]

Glucocorticoid receptor (GR) and androgen receptor (AR) are steroid-inducible transcription factors (TFs). The GR and the AR are central regulators of various metabolic, homeostatic and differentiation processes and hence important therapeutic targets, especially in inflammation and prostate cancer, respectively. Hormone binding to these steroid receptors (SRs) leads to DNA binding and activation or repression of their target genes with the aid of interacting proteins, coregulators. However, protein interactomes of these important drug targets have remained poorly defined. We used proximity-dependent biotin identification to map the protein interaction landscapes of GR and AR in the presence and absence of their cognate agonist (dexamethasone, 5α-dihydrotestosterone) and antagonist (RU486, enzalutamide) in intact human cells. We reproducibly identified more than 30 proteins that interacted with the GR in an agonist-specific manner and whose interactions were significantly influenced by the DNA-binding function of the receptor. Interestingly, the agonist-dependent interactome of the GR overlapped considerably with that of the AR. In addition to known coactivators, corepressors and components of BAF (SWI/SNF) chromatin-remodeling complex, we identified a number of proteins, including lysine methyltransferases and demethylases that have not been previously linked to glucocorticoid or androgen signaling. A substantial number of these novel agonist-dependent GR/AR-interacting proteins, e.g. BCOR, IRF2BP2, RCOR1, and TLE3, have previously been implicated in transcription repression. This together with our data on the effect of BCOR, IRF2BP2, and RCOR1 on GR target gene expression suggests multifaceted functions and roles for SR coregulators. These first high confidence SR interactomes will aid in therapeutic targeting of the GR and the AR.

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Tracing Cellular Origin of Human Exosomes Using Multiplex Proximity Extension Assays [Additions and Corrections]

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Pediatric tracheotomy: A comparison of outcomes and lengths of hospitalization between different indications

Publication date: October 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 101
Author(s): Che-Yi Lin, Te-Tien Ting, Tzu-Yu Hsiao, Wei-Chung Hsu
ObjectivesTo assess outcomes of pediatric tracheotomy and duration of associated hospital stay according to indications.Subjects and methodsIn this retrospective study, subjects were 142 consecutive pediatric patients (<18 years old) who underwent tracheotomy at a tertiary referral medical center, National Taiwan University Hospital, in 1997–2012. Age, sex, indications, pre-operative status (oxygen demand, number of repeated intubations), and post-operative status (duration of weaning, length of hospital stay, mortality) were analyzed.ResultsThe indications included craniofacial anomalies (n = 19, 13.4%), upper airway obstruction (n = 41, 28.9%), neurological deficit (n = 58, 40.8%), prolonged ventilation (n = 15, 10.6%), and trauma (n = 9, 6.3%). Ninety-one patients (64.1%) were successfully weaned off ventilation after tracheotomy (40% in the prolonged ventilation group). Total hospital stay and duration of ventilation before tracheotomy were longest in patients with craniofacial anomalies (150.9 ± 98.8 days, p = 0.004; 108.8 ± 88.2, p < 0.001). The early tracheotomy group had a shorter duration of post-tracheotomy mechanical ventilation support than the late tracheotomy group (14.4 ± 19.0, n = 49 vs. 34.9 ± 58.6, n = 80, p = 0.004). Decannulation was successful in 20 patients (14.1%), with the highest rate in the upper airway obstruction group (n = 14, 34.1%) and lowest in the prolonged ventilation group (none). Thirteen patients (9.2%) died during admission from causes unrelated to tracheotomy.ConclusionOutcomes of pediatric tracheotomy and duration of hospitalization depend on indications. Children with craniofacial anomalies had earlier tracheotomy age and longer mechanical ventilation before tracheotomy resulted in longer hospitalization. Earlier tracheotomy can shorten the duration of post-tracheotomy mechanical ventilation in several conditions.



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Speech processor data logging helps in predicting early linguistic outcomes in implanted children

Publication date: October 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 101
Author(s): Letizia Guerzoni, Domenico Cuda
ObjectiveTo analyse the value of listening-data logged in the speech processor on the prediction of the early auditory and linguistic skills in children who received a cochlear implant in their first 2 years of life.Study designProspective observational non-randomized study.MethodsTen children with profound congenital sensorineural hearing loss were included in the study. The mean age at CI activation was 16.9 months (SD ± 7.2; range 10–24). The auditory skills were evaluated with the Infant Toddler Meaningful Inventory Scale and the Category of Auditory Performance. Lexical level was assessed with the MacArthur-Bates Communicative Development Inventory.The overall data of average daily use and acoustic scene-analyses were extracted from Data Logging system.The effect of the one-year cumulative listening time to speech (in quiet) and speech-in-noise on the auditory and lexical scores was analysed.ResultsA significant positive correlation was found between speech in quiet exposure time at low loudness level (<70 dB) and lexical quotient after one year of CI use. Infant Toddler Meaningful Inventory Scale was negatively correlated with the highest speech-in-noise loudness levels (>80 dB). The Category of Auditory Performance was not related to the logged data.ConclusionThe listening environment can influence the early functional outcomes in younger implanted children. In this perspective, the data logging system is a promising tool in predicting early linguistic and auditory outcomes.



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Pediatric tracheotomy: A comparison of outcomes and lengths of hospitalization between different indications

Publication date: October 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 101
Author(s): Che-Yi Lin, Te-Tien Ting, Tzu-Yu Hsiao, Wei-Chung Hsu
ObjectivesTo assess outcomes of pediatric tracheotomy and duration of associated hospital stay according to indications.Subjects and methodsIn this retrospective study, subjects were 142 consecutive pediatric patients (<18 years old) who underwent tracheotomy at a tertiary referral medical center, National Taiwan University Hospital, in 1997–2012. Age, sex, indications, pre-operative status (oxygen demand, number of repeated intubations), and post-operative status (duration of weaning, length of hospital stay, mortality) were analyzed.ResultsThe indications included craniofacial anomalies (n = 19, 13.4%), upper airway obstruction (n = 41, 28.9%), neurological deficit (n = 58, 40.8%), prolonged ventilation (n = 15, 10.6%), and trauma (n = 9, 6.3%). Ninety-one patients (64.1%) were successfully weaned off ventilation after tracheotomy (40% in the prolonged ventilation group). Total hospital stay and duration of ventilation before tracheotomy were longest in patients with craniofacial anomalies (150.9 ± 98.8 days, p = 0.004; 108.8 ± 88.2, p < 0.001). The early tracheotomy group had a shorter duration of post-tracheotomy mechanical ventilation support than the late tracheotomy group (14.4 ± 19.0, n = 49 vs. 34.9 ± 58.6, n = 80, p = 0.004). Decannulation was successful in 20 patients (14.1%), with the highest rate in the upper airway obstruction group (n = 14, 34.1%) and lowest in the prolonged ventilation group (none). Thirteen patients (9.2%) died during admission from causes unrelated to tracheotomy.ConclusionOutcomes of pediatric tracheotomy and duration of hospitalization depend on indications. Children with craniofacial anomalies had earlier tracheotomy age and longer mechanical ventilation before tracheotomy resulted in longer hospitalization. Earlier tracheotomy can shorten the duration of post-tracheotomy mechanical ventilation in several conditions.



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Evaluation of tracheobronchial branching abnormalities in patients with microtia using chest computed tomography

The objective of this study was to identify the characteristics and incidence of Tracheobronchial branching abnormalities in patients with microtia and to evaluate the risk of anesthesia.

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Stabilizing air dampers for hovering aerial robotics: design, insect-scale flight tests, and scaling

Abstract

Most hovering aircraft such as helicopters and animal-inspired flapping-wing flyers are dynamically unstable in flight, quickly tumbling in the absence of feedback control. The addition of feedback loops can stabilize, but at the cost of additional sensing and actuation components. This can add expense, weight, and complexity. An alternative to feedback is the use of passive mechanisms such as aerodynamic drag to stabilize attitude. Previous work has suggested that small aircraft can be stabilized by adding air dampers above and below the center of mass. We present flight tests of an insect-scale robot operating under this principle. When controlled to a constant altitude, it remains stably upright while undergoing cyclic attitude oscillations. To characterize these oscillations, we present a nonlinear analytic model derived from first principles that reproduces the observed behavior. Using numerical simulation, we analyze how changing damper size, position, mass, and midpoint offset affect these oscillations, building on previous work that considered only a single configuration. Our results indicate that only by increasing damper size can lateral oscillation amplitude be significantly reduced, at the cost of increased damper mass. Additionally, we show that as scale diminishes, the damper size must get relatively larger. This suggests that smaller damper-equipped robots must operate in low-wind areas or in boundary-layer flow near surfaces.

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Cable-suspended load lifting by a quadrotor UAV: hybrid model, trajectory generation, and control

Abstract

In the last years, autonomous aerial vehicles have become promising mobile robotic platforms capable of manipulating external objects. In particular, quadrotors, rotorcrafts with four propellers, have been used for aerial transportation of cable-suspended loads. A critical step before transporting a payload is the lift maneuver. However, the analysis and planning of this maneuver have received a little attention in the literature so far. In this work, we decompose the cable-suspended load lifting into three simpler discrete states or modes: Setup, Pull, and Raise. Each of these states represents the dynamics of the quadrotor-load system at particular regimes during the maneuver. Furthermore, we define a hybrid system based on these states and show that it is a differentially-flat hybrid system. Exploiting this property, we generate a trajectory by using a series of waypoints associated with each mode. We design a nonlinear hybrid controller to track this trajectory and therefore execute the lift maneuver. We verify the proposed approach by carrying out experiments on an actual quadrotor with a cable-suspended load.

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Planning using hierarchical constrained Markov decision processes

Abstract

Constrained Markov decision processes offer a principled method to determine policies for sequential stochastic decision problems where multiple costs are concurrently considered. Although they could be very valuable in numerous robotic applications, to date their use has been quite limited. Among the reasons for their limited adoption is their computational complexity, since policy computation requires the solution of constrained linear programs with an extremely large number of variables. To overcome this limitation, we propose a hierarchical method to solve large problem instances. States are clustered into macro states and the parameters defining the dynamic behavior and the costs of the clustered model are determined using a Monte Carlo approach. We show that the algorithm we propose to create clustered states maintains valuable properties of the original model, like the existence of a solution for the problem. Our algorithm is validated in various planning problems in simulation and on a mobile robot platform, and we experimentally show that the clustered approach significantly outperforms the non-hierarchical solution while experiencing only moderate losses in terms of objective functions.

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Simultaneous area partitioning and allocation for complete coverage by multiple autonomous industrial robots

Abstract

For tasks that require complete coverage of surfaces by multiple autonomous industrial robots, it is important that the robots collaborate to appropriately partition and allocate the surface areas amongst themselves such that the robot team's objectives are optimized. An approach to this problem is presented, which takes into account unstructured and complex 3D environments, and robots with different capabilities. The proposed area partitioning and allocation approach utilizes Voronoi partitioning to partition objects' surfaces, and multi-objective optimization to allocate the partitioned areas to the robots whilst optimizing robot team's objectives. In addition to minimizing the overall completion time and achieving complete coverage, which are objectives particularly useful for applications such as surface cleaning, manipulability measure and joint's torque are also optimized so as to help autonomous industrial robots to operate better in applications such as spray painting and grit-blasting. The approach is validated using six case studies that consist of comparative studies, complex simulated scenarios as well as real scenarios using data obtained from real objects and applications.

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Tracking attracting manifolds in flows

Abstract

This paper presents a collaborative control strategy designed to enable a team of robots to track attracting Lagrangian coherent structures (LCS) and unstable manifolds in two-dimensional flows. Tracking LCS in flows is important for many applications such as planning energy optimal paths in the ocean and for predicting the evolution of various physical and biological processes in the ocean. The proposed strategy which tracks attracting LCS and unstable manifolds in real-time through direct computation of the local finite time Lyapunov exponent field, does not require global information about the dynamics of the surrounding flow, and is based on local sensing, prediction, and correction. The collaborative control strategy is implemented on a team of robots and theoretical guarantees for the tracking and formation keeping strategies are presented. We demonstrate the performance of the tracking strategy in simulation using actual ocean flow data and experimental flow data generated in a tank. The strategy is validated experimentally using a team of micro autonomous surface vehicles in an actual fluid environment.

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Synergistic antibacterial effect of silver and ebselen against multidrug-resistant Gram-negative bacterial infections

Multidrug-resistant (MDR) Gram-negative bacteria account for a majority of fatal infections, and development of new antibiotic principles and drugs is therefore of outstanding importance. Here, we report that five most clinically difficult-to-treat MDR Gram-negative bacteria are highly sensitive to a synergistic combination of silver and ebselen. In contrast, silver has no synergistic toxicity with ebselen on mammalian cells. The silver and ebselen combination causes a rapid depletion of glutathione and inhibition of the thioredoxin system in bacteria. Silver ions were identified as strong inhibitors of Escherichia coli thioredoxin and thioredoxin reductase, which are required for ribonucleotide reductase and DNA synthesis and defense against oxidative stress. The bactericidal efficacy of silver and ebselen was further verified in the treatment of mild and acute MDR E. coli peritonitis in mice. These results demonstrate that thiol-dependent redox systems in bacteria can be targeted in the design of new antibacterial drugs. The silver and ebselen combination offers a proof of concept in targeting essential bacterial systems and might be developed for novel efficient treatments against MDR Gram-negative bacterial infections.

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GDF15 is a heart-derived hormone that regulates body growth

The endocrine system is crucial for maintaining whole-body homeostasis. Little is known regarding endocrine hormones secreted by the heart other than atrial/brain natriuretic peptides discovered over 30 years ago. Here, we identify growth differentiation factor 15 (GDF15) as a heart-derived hormone that regulates body growth. We show that pediatric heart disease induces GDF15 synthesis and secretion by cardiomyocytes. Circulating GDF15 in turn acts on the liver to inhibit growth hormone (GH) signaling and body growth. We demonstrate that blocking cardiomyocyte production of GDF15 normalizes circulating GDF15 level and restores liver GH signaling, establishing GDF15 as a bona fide heart-derived hormone that regulates pediatric body growth. Importantly, plasma GDF15 is further increased in children with concomitant heart disease and failure to thrive (FTT). Together these studies reveal a new endocrine mechanism by which the heart coordinates cardiac function and body growth. Our results also provide a potential mechanism for the well-established clinical observation that children with heart diseases often develop FTT.

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SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes

Azoospermia, characterized by the absence of spermatozoa in the ejaculate, is a common cause of male infertility with a poorly characterized etiology. Exome sequencing analysis of two azoospermic brothers allowed the identification of a homozygous splice mutation in SPINK2, encoding a serine protease inhibitor believed to target acrosin, the main sperm acrosomal protease. In accord with these findings, we observed that homozygous Spink2 KO male mice had azoospermia. Moreover, despite normal fertility, heterozygous male mice had a high rate of morphologically abnormal spermatozoa and a reduced sperm motility. Further analysis demonstrated that in the absence of Spink2, protease-induced stress initiates Golgi fragmentation and prevents acrosome biogenesis leading to spermatid differentiation arrest. We also observed a deleterious effect of acrosin overexpression in HEK cells, effect that was alleviated by SPINK2 coexpression confirming its role as acrosin inhibitor. These results demonstrate that SPINK2 is necessary to neutralize proteases during their cellular transit toward the acrosome and that its deficiency induces a pathological continuum ranging from oligoasthenoteratozoospermia in heterozygotes to azoospermia in homozygotes.

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A normal genetic variation modulates synaptic MMP-9 protein levels and the severity of schizophrenia symptoms

Matrix metalloproteinase 9 (MMP-9) has recently emerged as a molecule that contributes to pathological synaptic plasticity in schizophrenia, but explanation of the underlying mechanisms has been missing. In the present study, we performed a phenotype-based genetic association study (PGAS) in > 1,000 schizophrenia patients from the Göttingen Research Association for Schizophrenia (GRAS) data collection and found an association between the MMP-9 rs20544 C/T single-nucleotide polymorphism (SNP) located in the 3'untranslated region (UTR) and the severity of a chronic delusional syndrome. In cultured neurons, the rs20544 SNP influenced synaptic MMP-9 activity and the morphology of dendritic spines. We demonstrated that Fragile X mental retardation protein (FMRP) bound the MMP-9 3'UTR. We also found dramatic changes in RNA structure folding and alterations in the affinity of FMRP for MMP-9 RNA, depending on the SNP variant. Finally, we observed greater sensitivity to psychosis-related locomotor hyperactivity in Mmp-9 heterozygous mice. We propose a novel mechanism that involves MMP-9-dependent changes in dendritic spine morphology and the pathophysiology of schizophrenia, providing the first mechanistic insights into the way in which the single base change in the MMP-9 gene (rs20544) influences gene function and results in phenotypic changes observed in schizophrenia patients.

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HPV/E7 induces chemotherapy-mediated tumor suppression by ceramide-dependent mitophagy

Human papillomavirus (HPV) infection is linked to improved survival in response to chemo-radiotherapy for patients with oropharynx head and neck squamous cell carcinoma (HNSCC). However, mechanisms involved in increased HNSCC cell death by HPV signaling in response to therapy are largely unknown. Here, using molecular, pharmacologic and genetic tools, we show that HPV early protein 7 (E7) enhances ceramide-mediated lethal mitophagy in response to chemotherapy-induced cellular stress in HPV-positive HNSCC cells by selectively targeting retinoblastoma protein (RB). Inhibition of RB by HPV-E7 relieves E2F5, which then associates with DRP1, providing a scaffolding platform for Drp1 activation and mitochondrial translocation, leading to mitochondrial fission and increased lethal mitophagy. Ectopic expression of a constitutively active mutant RB, which is not inhibited by HPV-E7, attenuated ceramide-dependent mitophagy and cell death in HPV(+) HNSCC cells. Moreover, mutation of E2F5 to prevent Drp1 activation inhibited mitophagy in HPV(+) cells. Activation of Drp1 with E2F5-mimetic peptide for inducing Drp1 mitochondrial localization enhanced ceramide-mediated mitophagy and led to tumor suppression in HPV-negative HNSCC-derived xenograft tumors in response to cisplatin in SCID mice.

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Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure

Approaches to prolong responses to BRAF targeting drugs in melanoma patients are challenged by phenotype heterogeneity. Melanomas of a "MITF-high" phenotype usually respond well to BRAF inhibitor therapy, but these melanomas also contain subpopulations of the de novo resistance "AXL-high" phenotype. > 50% of melanomas progress with enriched "AXL-high" populations, and because AXL is linked to de-differentiation and invasiveness avoiding an "AXL-high relapse" is desirable. We discovered that phenotype heterogeneity is supported during the response phase of BRAF inhibitor therapy due to MITF-induced expression of endothelin 1 (EDN1). EDN1 expression is enhanced in tumours of patients on treatment and confers drug resistance through ERK re-activation in a paracrine manner. Most importantly, EDN1 not only supports MITF-high populations through the endothelin receptor B (EDNRB), but also AXL-high populations through EDNRA, making it a master regulator of phenotype heterogeneity. Endothelin receptor antagonists suppress AXL-high-expressing cells and sensitize to BRAF inhibition, suggesting that targeting EDN1 signalling could improve BRAF inhibitor responses without selecting for AXL-high cells.

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Inactivation of {gamma}-secretases leads to accumulation of substrates and non-Alzheimer neurodegeneration

-Secretases are a family of intramembrane cleaving aspartyl proteases and important drug targets in Alzheimer's disease. Here, we generated mice deficient for all -secretases in the pyramidal neurons of the postnatal forebrain by deleting the three anterior pharynx defective 1 (Aph1) subunits (Aph1abc cKO Cre⁺). The mice show progressive cortical atrophy, neuronal loss, and gliosis. Interestingly, this is associated with more than 10-fold accumulation of membrane-bound fragments of App, Aplp1, Nrg1, and Dcc, while other known substrates of -secretase such as Aplp2, Lrp1, and Sdc3 accumulate to lesser extents. Despite numerous reports linking neurodegeneration to accumulation of membrane-bound App fragments, deletion of App expression in the combined Aph1 knockout does not rescue this phenotype. Importantly, knockout of only Aph1a- or Aph1bc-secretases causes limited and differential accumulation of substrates. This was not associated with neurodegeneration. Further development of selective Aph1--secretase inhibitors should be considered for treatment of Alzheimer's disease.

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CXCL12{alpha}/SDF-1 from perisynaptic Schwann cells promotes regeneration of injured motor axon terminals

The neuromuscular junction has retained through evolution the capacity to regenerate after damage, but little is known on the inter-cellular signals involved in its functional recovery from trauma, autoimmune attacks, or neurotoxins. We report here that CXCL12α, also abbreviated as stromal-derived factor-1 (SDF-1), is produced specifically by perisynaptic Schwann cells following motor axon terminal degeneration induced by α-latrotoxin. CXCL12α acts via binding to the neuronal CXCR4 receptor. A CXCL12α-neutralizing antibody or a specific CXCR4 inhibitor strongly delays recovery from motor neuron degeneration in vivo. Recombinant CXCL12α in vivo accelerates neurotransmission rescue upon damage and very effectively stimulates the axon growth of spinal cord motor neurons in vitro. These findings indicate that the CXCL12α-CXCR4 axis plays an important role in the regeneration of the neuromuscular junction after motor axon injury. The present results have important implications in the effort to find therapeutics and protocols to improve recovery of function after different forms of motor axon terminal damage.

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Calcineurin-NFAT signalling in myeloid leucocytes: new prospects and pitfalls in immunosuppressive therapy

Myeloid leucocytes mediate host protection against infection and critically regulate inflammatory responses in body tissues. Pattern recognition receptor signalling is crucial for myeloid cell responses to pathogens, but growing evidence suggests an equally potent role for Calcineurin–NFAT signalling in control of myeloid cell function. All major subsets of myeloid leucocytes employ Calcineurin–NFAT signalling during immune responses to pathogens and/or tissue damage, but the influence this pathway exerts on pathogen clearance and host susceptibility to infection is not fully understood. Recent data from experimental models indicate that Calcineurin-NFAT signalling is essential for infection control, and calcineurin inhibitors used in transplantation medicine (including cyclosporine A and tacrolimus) are now being tested for efficacy in a diverse range of inflammatory conditions and autoimmune pathologies. Efforts to repurpose calcineurin inhibitor drugs for new therapeutic applications may yield rapid improvements in clinical outcomes, but the potential impact of these compounds on myeloid cell function in treated patients is largely unknown. Here we discuss Calcineurin–NFAT control of myeloid leucocyte function in the context of recent therapeutic developments and ongoing clinical studies.

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Phenotypic diversity drives paracrine drug tolerance

Considerable clinical successes have been achieved in cancer treatment since the introduction of targeted therapies. However, almost inevitably tumors develop therapy resistance, which limits durable clinical responses. Tumors are often heterogeneous, and as a result, therapy-resistant cells are present even before the start of treatment. Resistance is commonly mediated via genetic changes. However, in this issue of EMBO Molecular Medicine, Smith et al (2017) report that phenotypic heterogeneity can contribute to resistance as well.

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CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib

Cyclin D-CDK4/6 are the first CDK complexes to be activated in the G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (palbociclib) was recently approved by the FDA and EMA for treatment of advanced ER-positive breast tumors. Unfortunately, no reliable predictive tools are available for identifying potentially responsive or insensitive tumors. We had shown that the activating T172 phosphorylation of CDK4 is the central rate-limiting event that initiates the cell cycle decision and signals the presence of active CDK4. Here, we report that the profile of post-translational modification including T172 phosphorylation of CDK4 differs among breast tumors and associates with their subtypes and risk. A gene expression signature faithfully predicted CDK4 modification profiles in tumors and cell lines. Moreover, in breast cancer cell lines, the CDK4 T172 phosphorylation best correlated with sensitivity to PD0332991. This gene expression signature identifies tumors that are unlikely to respond to CDK4/6 inhibitors and could help to select a subset of patients with HER2-positive and basal-like tumors for clinical studies on this class of drugs.

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Letter to editor regarding “improvement of psychiatric symptoms in youth following resolution of sinusitis”

We read with a great interest the recent paper by Mahoni T et al., regarding the potential relationship between the occurrence of sinusitis and the development of neuropsychiatric symptoms in children. In this retrospective study, the authors reviewed 150 patients (aged 6–17 years) referred to the multidisciplinary Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) clinic in a 5-year period and, interestingly, they noticed that 47% (n = 70) had presented sinus diseases in their medical records.

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Evaluation of tracheobronchial branching abnormalities in patients with microtia using chest computed tomography

The objective of this study was to identify the characteristics and incidence of Tracheobronchial branching abnormalities in patients with microtia and to evaluate the risk of anesthesia.

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Diet-induced obesity causes visceral, but not subcutaneous, lymph node hyperplasia via increases in specific immune cell populations

Abstract

Objectives

The spatial proximity of adipose depots to secondary lymph nodes allows a unique relation between the two systems. Obesity, predominately visceral adiposity, links to numerous diseases; hence, we postulate that secondary lymphatics within this region contributes to disease risk.

Material and methods

Male C57BL/6 mice were fed standard CHOW (18% kcal fat) or Western diet (45% kcal fat) for 7 weeks. Visceral and subcutaneous lymph nodes and associated adipose depots they occupy were excised. Lymph node morphology and resident immune cell populations were characterized via histopathology, immunofluorescence and flow cytometry. Adipose tissue immune cell populations were also characterized.

Results

Obesity caused lymph node expansion, increased viable cell number and deviations in immune cell populations. These alterations were exclusive to visceral lymph nodes. Notably, pro-inflammatory antigen presenting cells and regulatory T cells increased in number in the visceral lymph node. Obesity, however, reduced T regulatory cells in visceral lymph nodes. The visceral adipose depot also had greater reactivity towards HFD than subcutaneous, with a greater percent of macrophages, dendritic and CD8⁺ T cells. Immune cell number, in both the visceral and subcutaneous, however decreased as adipose depots enlarged.

Conclusion

Overall, HFD has a greater influence on visceral cavity than the subcutaneous. In the visceral lymph node, but not subcutaneous, HFD-induced obesity decreased cell populations that suppressed immune function while increasing those that regulate/activate immune response.

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Visfatin mediates doxorubicin resistance in human non–small-cell lung cancer via Akt-mediated up-regulation of ABCC1

Abstract

Objectives

Non–small-cell lung cancer (NSCLC) is one of the leading causes of cancer deaths worldwide. Increasing levels of visfatin are correlated with worse clinical prognosis of NSCLC. However, the effects of visfatin on drug resistant are still not well illustrated.

Materials and methods

Effects of visfatin on drug resistant cells were checked by CCK-8 kit. Gene and protein variations were measured by real-time PCR and western blot analysis, respectively.

Results

Our present data confirmed that expression of visfatin was significantly increased in NSCLC cells and tissues. In addition, protein and mRNA expression of visfatin were significantly elevated in doxorubicin (Dox) resistance of NSCLC cells when compared with their corresponding sensitivity parental cells. Overexpression of visfatin can down-regulate the Dox sensitivity of NSCLC cells and up-regulate the mRNA and protein expression of ABCC1, while has no effect on ABCB1. Knockdown of visfatin can down-regulate the expression of ABCC1 in Dox-resistant NSCLC cells. Visfatin can increase the phosphorylation and nuclear localization of Akt in NSCLC cells. LY294002 can decrease the expression of multidrug resistance protein-1 (MRP1) in NSCLC Dox-resistant cells. Chromatin immunoprecipitation assays showed that overexpression of visfatin can significantly increase the binding of Akt with the promoter of ABCC1 in both A549 and H1793 cells.

Conclusions

These data showed that visfatin can decrease Dox sensitivity of NSCLC cells via activation of Akt/MRP1. It indicated that inhibition of visfatin signals might be a promising therapeutic strategy for the management of chemoresistance of NSCLC patients.

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Vertebral Artery Caught in the Fracture Gap after Traumatic C2/3 Spondylolisthesis

Background Context. Patient with a C2 fracture and entrapment of the right vertebral artery in the fracture gap. Purpose. Presentation of a case with follow-up until end of treatment. Study Design. Case report. Methods. A 25-year-old woman was brought into our emergency room after falling while riding a horse. She complained of pain in the cervical spine. Clinical examinations showed local tenderness at the upper cervical spine and painful impairment of the mobility of the neck, with no signs of neurological impairment. Radiological diagnostics revealed a traumatic C2/3 spondylolisthesis. A computer tomography (CT) angiographic scan showed a dislocation of the right vertebral artery into the fracture gap without injury to the artery. Open reduction and osteosynthesis were considered of too high risk. Therefore, we conducted fracture treatment with closed reduction and halo fixation. After removal of the halo fixator, the patient was given a soft cervical collar and was advised to rest for additional 6 weeks before beginning gradual activity. Results. Conventional follow-up revealed osseous consolidation and a CT angiographic scan showed consistent blood flow to the artery. Conclusion. Halo fixation was a safe and effective therapy strategy in the case of vertebral artery entrapment after traumatic C2 spondylolisthesis.

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Creativity as a Stepping Stone towards Developing Other Competencies in Classrooms

Creativity, as a 21st-century skill, has gained more interest these past years and has become one of the key competencies to be implemented in classrooms. However, some studies highlight teachers' difficulties to integrate it in a classroom context. For instance, introducing creativity in overloaded school curricula may be a hindrance to developing it. Teachers have to implement other 21st-century competencies (the 4Cs) at the same time as well. These educational objectives can be considerable in terms of time and means for teachers and thus do not encourage them to develop these competencies. The purpose of this article is to present links, essentially theoretical, made by researchers between creativity and other 21st-century skills (e.g., critical thinking, metacognition, and collaboration). We considered that if creativity shares some characteristics with other competencies, it can be possible that, by applying only a teaching-for-creativity approach in classroom, we can also contribute to developing the other "C" as well. So choosing only creativity can be a way for teachers to develop their pupils' skills without falling behind in their curriculum. In this article, we will also discuss our hypothesis taking into account limits from teachers' classroom practices. Teachers' training, evaluation, and everyday practices will be considered.

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Some Generalized Pythagorean Fuzzy Bonferroni Mean Aggregation Operators with Their Application to Multiattribute Group Decision-Making

The Pythagorean fuzzy set as an extension of the intuitionistic fuzzy set characterized by membership and nonmembership degrees has been introduced recently. Accordingly, the square sum of the membership and nonmembership degrees is a maximum of one. The Pythagorean fuzzy set has been previously applied to multiattribute group decision-making. This study develops a few aggregation operators for fusing the Pythagorean fuzzy information, and a novel approach to decision-making is introduced based on the proposed operators. First, we extend the generalized Bonferroni mean to the Pythagorean fuzzy environment and introduce the generalized Pythagorean fuzzy Bonferroni mean and the generalized Pythagorean fuzzy Bonferroni geometric mean. Second, a new generalization of the Bonferroni mean, namely, the dual generalized Bonferroni mean, is proposed by considering the shortcomings of the generalized Bonferroni mean. Furthermore, we investigate the dual generalized Bonferroni mean in the Pythagorean fuzzy sets and introduce the dual generalized Pythagorean fuzzy Bonferroni mean and dual generalized Pythagorean fuzzy Bonferroni geometric mean. Third, a novel approach to multiattribute group decision-making based on proposed operators is proposed. Lastly, a numerical instance is provided to illustrate the validity of the new approach.

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-Adaptive Refinement Based on Stress Recovery Technique Considering Ordinary Kriging Interpolation in L-Shaped Domain

The primary objectives of this study are twofold. Firstly, the original SPR method of stress recovery has been modified by incorporating the kriging interpolation technique to fit a polynomial to the derivatives recovered at the Gauss points. For this purpose, the -version of finite element analysis is performed to produce the stresses at the fixed Gauss points where the integrals of Legendre polynomials are used as a basis function. In contrast to the conventional least square method for stress recovery, the weight factor is determined by experimental and theoretical variograms for interpolation of stress data, unlike the conventional interpolation methods that use an equal weight factor. Secondly, an adaptive procedure for hierarchical -refinement in conjunction with a posteriori error based on the modified SPR (superconvergent patch recovery) method is proposed. Thirdly, a new error estimator based on the limit value approach is proposed by predicting the exact strain energy to verify the kriging-based SPR method. The validity of the proposed approach has been tested by analyzing two-dimensional plates with a rectangular cutout in the presence of stress singularity.

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Adjuvant Second-Dose Chemotherapy before Surgery for Patients with Locally Advanced Rectal Malignancy Is Not Beneficial: A Systematic Review and Meta-Analysis

Background. Preoperative chemoradiotherapy is the standard treatment for patients with locally advanced rectal cancer, although tumor responses vary widely; some patients may achieve a pathologic complete response rate (pCR) after chemoradiotherapy. Controversy exists with regard to the efficacy of different preoperative combination chemotherapy regimens and neoadjuvant chemoradiotherapy, compared with chemoradiotherapy alone. Methods. PubMed, the Cochrane Library, and Embase databases were searched for comparative studies of patients with locally advanced rectal cancer that were published between January 1991 and January 2016. Efficacies of different preoperative combination chemotherapy regimens and neoadjuvant chemoradiotherapy (group A) were compared with chemoradiotherapy alone (group B) in a meta-analysis using Review Manager v5.2. Results. Three prospective randomized controlled trials and two prospective nonrandomized controlled trials comprising 444 cases were eligible for analysis. No significant difference was detected in the rate of pCR (50/223, 22.4% versus 35/223, 15.7%; relative risk, RR: 1.42 [95% confidence interval, CI: 0.97–2.09], ) between the two groups. The rate of tumor regression was similar for both groups (122/203, 60.1% versus 111/203, 54.7%; RR: 1.11 [95% CI: 0.94–1.29], ). Conclusions. Adjuvant chemotherapy with preoperative chemoradiotherapy did not significantly improve the rate of pCR nor the rate of T and N downstaging.

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Radiofrequency Ablation for Treatment of Refractory Gastric Antral Vascular Ectasia: A Systematic Review of the Literature

Background and Study Aims. GAVE is an uncommon cause of upper nonvariceal bleeding and often manifests itself as occult bleeding with chronic anemia. To date, the standard of care for GAVE is endoscopic treatment with thermoablative techniques. Despite good technical results, approximately two thirds of patients remain dependent on transfusions after the therapy. One of the emerging and more promising endoscopic treatments for GAVE is radiofrequency ablation (RFA). The aim of this study is to perform a systematic review of literature in order to assess current evidence supporting the effectiveness of this technique for treatment of refractory GAVE. Materials and Methods. Through electronic search, we identified 14 records, and after removal of duplicates and irrelevant studies, we selected 10 studies on radiofrequency ablation of GAVE: 4 prospective open-label single-center studies, 1 retrospective multicentric study, and 5 case reports. Results. Among all 72 treated patients reported in literature, 74.3% achieved a clinical response, while nonfatal AEs have been reported in 4.2% of cases. Conclusions. Despite some qualitative limitations, all literature data support effectiveness of RFA for treatment of refractory GAVE. In the future, large prospective controlled trials with adequate follow-up are needed to better assess the effectiveness and safety of this procedure.

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3D printing prepares to enter clinical arena

The U.K. National Health Service has appointed its first biomedical 3D technician,...

Read more on AuntMinnieEurope.com

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Prehistoric creatures dazzle in recreated art nouveau murals

Ichthyosaurs soaring over the waves like dolphins may not be scientifically accurate, but these painstakingly repaired murals from Berlin Aquarium are history in their own right

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Medication adherence among psoriasis patients on traditional systemic and biologic treatment

Abstract

The World Health Organisation defines medication adherence as "the extent to which a patients' behaviour in taking their medication corresponds to agreed recommendations by their healthcare provider". Up to 25% of patients, across all medical conditions, do not take their medication. Patients with poor adherence have worse outcomes and higher health care costs.

This article is protected by copyright. All rights reserved.

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Re: Comparison of different hypotensive anaesthesia techniques in orthognathic surgery with regard to intraoperative blood loss, quality of the surgical field, and postoperative nausea and vomiting

Publication date: Available online 31 July 2017
Source:International Journal of Oral and Maxillofacial Surgery
Author(s): S. Lin, C. Chen, Y.-R. Chen




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Double whammy: a tale of two malignancies

Description

A 61-year-old woman was referred to the dermatology clinic with multiple skin lesions on her scalp and central back. They were relatively asymptomatic but had increased in size over the previous few months. Her medical history was significant as she had a cerebellar medulloblastoma when she was 19 years old that was treated with a 6-month course of radiotherapy on her scalp and along the spinal cord.

On examination, she had multiple erythematous scaly plaques on the right occipital scalp and lower back, consistent with superficial basal cell carcinomas (BCC) and a nodular BCC in the left occipital scalp. They were present within the areas previously treated with radiotherapy, arising from the skin that showed poikilodermatous (atrophic) changes (figures 1 and 2). Scarring alopecia from the previous radiotherapy was also prominent in the occipital scalp. A diagnosis of postradiotherapy BCCs was made. In...

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Acquired capillary haemangioma of the eyelid in a 10-year-old boy

A 10-year-old boy presented with painless, gradually increasing mass in right upper lid without preceding trauma for the past 2 months. On examination, the mass was bluish red, soft to firm in consistency which bleeds on touch. Contrast-enhanced CT showed a well-defined heterogeneously enhancing mass lesion without any continuity with the underlying bone or the orbital cavity. Complete excision of the mass was performed under general anaesthesia, subsequent histopathological examination showed findings consistent with an acquired variant of capillary haemangioma. At the end of 1 year, patient is cosmetically fine without any recurrence/morbidity.

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Large chordoma of the sacrum

Description

A 53-year-old man presented to our service with a 1-month history of subacute bowel obstruction. Clinical examination was unremarkable with normal power and sensation in the lower limbs. This patient had no medical or surgical history. MRI of the pelvis identified a well-defined presacral midline lesion of 9.9 cm diameter, which appeared to arise from the S2 nerve root and below (figure 1A,B). These nerve roots control anal sphincter tone and prohibit faecal incontinence. Whole spine MRI and CT-thorax abdomen pelvis CT-TAP) out ruled metastasis. A biopsy confirmed diagnosis of chordoma. This patient was discussed by a multidisciplinary team consisting of orthopaedics, colorectal, vascular and plastic surgeons. Anterior mobilisation of the lesion, with ileostomy due to expected loss of anal tone and supporting vessel ligation, was undertaken. A wide sacral en-masse resection at the level of S1 disc and inferior nerve roots, incorporating partial gluteus...

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Carotid dissection presenting as a prolonged cluster-like headache in a patient with episodic cluster headache

We present a patient with known episodic cluster headache, who presented with cluster-like headache in the course of internal carotid artery dissection (ICAD) and discuss possible pathophysiological links between the two diseases. It is well known that cluster-like headache could be the presenting symptom of ICAD. However, ICAD occurring in a patient with a known episodic cluster headache was only once previously described. In the end of the manuscript, we propose red flags to help clinicians differentiate between primary cluster headache and cluster-like attacks masking underlying ICAD. Finally, we raise the question whether at least some proportion of those patients with cluster headache and Horner syndrome previously classified as a primary headache disorder might have been secondary cases to ICAD.

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Early intracardiac thrombus and pulmonary embolus after trauma

Here, we present the case of a patient with the findings of an early intracardiac thrombus and a pulmonary embolus after major trauma. A large clot was identified extending from the inferior vena cava into the right atrium and ventricle in the setting of preserved right ventricular function. Post-traumatic intracardiac thrombus is extremely rare and no comparable cases have previously been described in the absence of a congenital heart defect and obvious myocardial injury. Best practice afterpost-traumatic intracardiac thrombus is not well established but we found that early inferior vena cava filter placement and treatment with therapeutic coagulation resulted in clinical improvement, resolution of the thrombus and no further emboli. The successful use of rivaroxaban, a direct-acting oral anticoagulant, to treat a right heart thrombus has, to our knowledge, not previously been reported. Early acute traumatic coagulopathy has received much attention but the hypercoagulable state that often follows is less well appreciated.

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Turbulent tackle: a novel surgical approach to a rugby-related jejunal perforation

Viscus perforation in the context of blunt-force abdominal trauma is a rarity. Within a sporting context, it is especially rare. However, the increasing physicality observed in rugby union, both in the amateur and professional setting, has resulted in a higher rate of serious injury. We report a novel laparoscopic surgical approach to the management of a traumatic jejunal perforation sustained on the playing field in a previously fit and healthy 28-year-old.

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Valacyclovir-associated neurotoxicity treated with intensification of peritoneal dialysis

We report a 57-year-old woman with end-stage renal disease (ESRD) on maintenance peritoneal dialysis (PD), who presented to the emergency room (ER) by ambulance with complaints of confusion and altered sensorium for 48 hours. She had been reviewed in a walk-in clinic 72 hours earlier and had been prescribed the standard 1000 mg three times per day of valacyclovir for an acute attack of shingles instead of 500 mg once a day on ESRD. In the ER, she received further 500 mg of intravenous acyclovir as herpes encephalitis was clinically suspected. CT of the brain and lumbar puncture were non-contributory to the diagnosis. Valacyclovir and acyclovir were discontinued when the diagnosis of valacyclovir-associated neurotoxicity became clinically evident. As the patient's Glasgow Coma Scale declined, we intensified her PD regimen from one to six exchanges per day and 24 hours later there was a significant neurological improvement.

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Huge cardiac myxoma in pregnancy

A 28-year-old pregnant woman presented at 28 weeks of gestation. She was diagnosed to have a left atrial myxoma 2 years earlier, but was lost to follow-up. During this pregnancy, the transthoracic echocardiography showed a 9 cm mass in the left atrium obstructing mitral valve inflow, interfering with mitral valve closure, causing severe mitral regurgitation and severe pulmonary hypertension. However, there were no clinical signs of pulmonary and systemic congestion or obstruction. Based on the clinical symptoms of the patient, the echocardiographic findings and the term of her pregnancy, the patient decided to schedule for a vaginal delivery with surgical correction after delivery. She gave birth at 32 weeks of gestation. During labour, pulmonary oedema developed but was detected early and it responded to therapy. Two weeks after delivery, a right anterior thoracotomy was performed to facilitate the removal of the left atrial myxoma and repair of the mitral valve.

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Peripheral hepatojejunostomy: a last resort palliative solution in Greece during the economic crisis

The geographical distribution of Greece and the growing proportion of uninsured patients make imperative the need for effective and efficient palliative solutions regarding obstructive jaundice due to hepatic malignancy, while repeated endoscopic interventions and all associated materials are either not accessible to the whole population or not even available on a daily basis due to the economic crisis and the difficulties on the hospital supply. On this basis, palliative hepatojejunostomy, introduced more than 50 years ago, could be revisited in the Greek reality in very selected cases and under these special circumstances. We report on two patients with locally advanced hilar cholangiocarcinoma and intrahepatic cholangiocarcinoma, respectively, who were treated with a combination of double hepaticojejunostomy with peripheral hepatojejunostomy or peripheral hepatoejunostomy alone, respectively. Both patients experienced an adequate decompression of the biliary tract over more than a year. Palliative hepatojejunostomy could be an ultimate solution for selected patients and circumstances in Greece during the economic crisis.

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Embryonal carcinoma presenting as a calcified solitary testicular mass on ultrasound

A 24-year-old man presented with a 2-week history of a painless right testicular mass; ultrasound demonstrated a dense, solitary calcified mass. The patient elected observation after further workup showed no evidence of metastasis.

A repeat ultrasound 3 months later showed interval growth and the patient underwent right radical orchiectomy. Pathology was consistent with pure embryonal carcinoma of the testis. Calcified testicular masses are typically benign but do carry a differential of spermatic granuloma, large-cell calcifying Sertoli cell tumour, trauma, tuberculosis, filariasis, calcified Leydig cell tumour and burned-out testicular tumour.

To our knowledge, this is the first case report of pure embryonal carcinoma presenting as a solitary calcified testicular mass.

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Wernickea{euro}™s encephalopathy associated with liver abscess

Wernicke's encephalopathy is a rare neurological disorder caused by thiamine deficiency, characterised by ocular motor dysfunction, ataxia and impairment in consciousness. It predominantly affects brain regions with a high metabolic rate such as mammillary bodies, medial thalamic nuclei, the tectal region and the cerebellum. Although chronic alcoholism is the most common cause of Wernicke's encephalopathy, various other conditions not related to alcohol consumption such as bariatric surgery, acute pancreatitis, hyperemesis gravidarum, prolonged fasting and gastrointestinal surgery have been implicated in its aetiology. We report the case of a patient who underwent surgery for liver abscess and subsequently developed Wernicke's encephalopathy; he showed a positive response to thiamine supplementation. This is the first report describing liver abscess as the cause of Wernicke's encephalopathy.

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Pseudo retinitis pigmentosa in a case of missed intraocular foreign body

A 35-year-old man presented with history of painless, progressive loss of vision in the left eye for the past 7 years. There was history of trauma to the same eye with an iron object 7 years prior. Fundus examination revealed pigmentary retinopathy (unilateral advanced retinitis pigmentosa (RP)-like picture). X-ray orbits were suspicious of retained intraocular foreign body (IOFB). CT orbits confirmed the presence of IOFB. Electroretinogram revealed depressed responses. Right eye examination was within normal limits. A diagnosis of siderosis bulbi with unilateral pseudo RP-like fundus was made. No surgical intervention was planned for IOFB in view of poor visual prognosis.

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Triggering of the abductor pollicis longus in association with deQuervain's tenosynovitis

DeQuervain's tenosynovitis is a common cause of radial-sided wrist pain. Symptoms result from a narrow first dorsal compartment and associated tendinosis of the enclosed extensor pollicis brevis and/or abductor pollicis longus (APL). Surgical intervention, offered when conservative measures fail to adequately relieve symptoms, requires a detailed understanding of potentially aberrant anatomy in order to avoid persistence or recurrence of symptoms. We describe a case whereby the patient presented with complaints of thumb triggering in extension and associated disabling first dorsal compartment tendinosis. Intraoperatively, after supernumerary tendons were identified and addressed, the APL was at risk for subluxation over a prominent fibroosseous ridge. Routine first dorsal compartment release alone may have failed to address all of this patient's pathology.

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Tuberculosis presenting as broncho-oesophageal fistula in a young healthy man

A 21-year-old Saudi man presented with a history of dysphagia and choking. CT scan of the chest showed clear evidence of chronic recurrent aspiration pneumonia in the left lung. It also showed a fistula connecting the left main bronchus to the oesophagus. Endoscopy showed clear opening on the oesophageal side. Bronchoscopy also confirmed the presence of a broncho-oesophageal fistula on the left bronchial side with the presence of secretions on swallowing. Bronchoalveolar lavage (BAL) was done and sent for mycobacterial tuberculosis culture. The fistula was closed with clips under endoscopic guidance, which alleviated his symptoms of dysphagia and choking. The BAL culture grew mycobacterial tubercle bacilli. The patient showed marked improvement after starting antitubercular therapy and was discharged to be followed up in the clinic.

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Are there any differences between antagonist administration on days

The aim of this study was to investigate the cost-effectiveness of antagonist administration on stimulation on days <6 and ≥6 of COH on assisted reproductive technique (ART) outcomes.

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IJMS, Vol. 18, Pages 1528: Conditioned Medium from Malignant Breast Cancer Cells Induces an EMT-Like Phenotype and an Altered N-Glycan Profile in Normal Epithelial MCF10A Cells

IJMS, Vol. 18, Pages 1528: Conditioned Medium from Malignant Breast Cancer Cells Induces an EMT-Like Phenotype and an Altered N-Glycan Profile in Normal Epithelial MCF10A Cells

International Journal of Molecular Sciences doi: 10.3390/ijms18081528

Authors: Jia Guo Changmei Liu Xiaoman Zhou Xiaoqiang Xu Linhong Deng Xiang Li Feng Guan

Epithelial-mesenchymal transition (EMT) is a key process in cancer development and progression. Communication (crosstalk) between cancer cells and normal (nonmalignant) cells may facilitate cancer progression. Conditioned medium (CM) obtained from cultured cancer cells contains secreted factors capable of affecting phenotypes and the behaviors of normal cells. In this study, a culture of normal breast epithelial MCF10A cells with CM from malignant breast cancer cells (termed 231-CM and 453-CM) resulted in an alteration of morphology. CM-treated MCF10A, in comparison with control cells, showed a reduced expression of the epithelial marker E-cadherin, increased expression of the mesenchymal markers fibronectin, vimentin, N-cadherin, and TWIST1, meanwhile cell proliferation and migration were enhanced while cell apoptosis was decreased. N-glycan profiles of 231-CM-treated and control MCF10A cells were compared by MALDI-TOF/TOF-MS (Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry) and a lectin microarray analysis. The treated cells showed lower levels of high-mannose-type N-glycan structures, and higher levels of complex-type and hybrid-type structures. Altered N-glycan profiles were also detected in 453-CM-treated and non-treated MCF10A cells by MALDI-TOF/TOF-MS, and we found that the expression of five fucosylated N-glycan structures (m/z 1406.663, 1590.471, 1668.782, 2421.141, and 2988.342) and one high-mannose structure m/z 1743.722 have the same pattern as 231-CM-treated MCF10A cells. Our findings, taken together, show that CM derived from breast cancer cells induced an EMT-like process in normal epithelial cells and altered their N-glycan profile.

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