T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Ilaria Marigo, Serena Zilio, Giacomo Desantis, Bernhard Mlecnik, Andrielly H.R. Agnellini, Stefano Ugel, Maria Stella Sasso, Joseph E. Qualls, Franz Kratochvill, Paola Zanovello, Barbara Molon, Carola H. Ries, Valeria Runza, Sabine Hoves, Amélie M. Bilocq, Gabriela Bindea, Emilia M.C. Mazza, Silvio Bicciato, Jérôme Galon, Peter J. Murray, Vincenzo Bronte
Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8⁺ cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1⁺ myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies.

Graphical abstract

Teaser

Marigo et al. show that nitric oxide produced by Tip-DCs, a subset of tumor-infiltrating myeloid cells, is important for tumor control by adoptive cell therapy (ACT). Tip-DCs require the CD40-CD40L pathway but not CSF-1R; CSF-1R blockade reduces immunosuppressive macrophages and improves tumor control by ACT.


http://ift.tt/2chRk8j

Co-inhibition of CD73 and A2AR Adenosine Signaling Improves Anti-tumor Immune Responses

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Arabella Young, Shin Foong Ngiow, Deborah S. Barkauskas, Erin Sult, Carl Hay, Stephen J. Blake, Qihui Huang, Jing Liu, Kazuyoshi Takeda, Michele W.L. Teng, Kris Sachsenmeier, Mark J. Smyth
Preclinical studies targeting the adenosinergic pathway have gained much attention for their clinical potential in overcoming tumor-induced immunosuppression. Here, we have identified that co-blockade of the ectonucleotidase that generates adenosine CD73 and the A2A adenosine receptor (A2AR) that mediates adenosine signaling in leuokocytes, by using compound gene-targeted mice or therapeutics that target these molecules, limits tumor initiation, growth, and metastasis. This tumor control requires effector lymphocytes and interferon-γ, while antibodies targeting CD73 promote an optimal therapeutic response in vivo when engaging activating Fc receptors. In a two-way mixed leukocyte reaction using a fully human anti-CD73, we demonstrated that Fc receptor binding augmented the production of proinflammatory cytokines.

Graphical abstract

Teaser

Young et al. show that blockade of CD73 and A2AR, two components of the adenosinergic pathway, has more potent anti-tumor activity than blockade of either, partly due to increased CD73 expression in the absence of A2AR. Moreover, anti-CD73 antibodies require the FcR binding domain for optimal anti-tumor activity.


http://ift.tt/2chSIb7

Tipping the Balancing ACT

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Shari Pilon-Thomas, Brian Ruffell
Adoptive cell transfer therapy has emerged as a powerful treatment for metastatic melanoma, but efficacy is limited by an inhospitable tumor microenvironment. In this issue of Cancer Cell, Marigo et al. demonstrate that therapy requires induced expression of nitric oxide synthase 2 in monocyte-derived dendritic cells.

Teaser

Adoptive cell transfer therapy has emerged as a powerful treatment for metastatic melanoma, but efficacy is limited by an inhospitable tumor microenvironment. In this issue of Cancer Cell, Marigo et al. demonstrate that therapy requires induced expression of nitric oxide synthase 2 in monocyte-derived dendritic cells.


http://ift.tt/2cJr7ea

Physiologic Expression of Sf3b1K700E Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome Modulation

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Esther A. Obeng, Ryan J. Chappell, Michael Seiler, Michelle C. Chen, Dean R. Campagna, Paul J. Schmidt, Rebekka K. Schneider, Allegra M. Lord, Lili Wang, Rutendo G. Gambe, Marie E. McConkey, Abdullah M. Ali, Azra Raza, Lihua Yu, Silvia Buonamici, Peter G. Smith, Ann Mullally, Catherine J. Wu, Mark D. Fleming, Benjamin L. Ebert
More than 80% of patients with the refractory anemia with ring sideroblasts subtype of myelodysplastic syndrome (MDS) have mutations in Splicing Factor 3B, Subunit 1 (SF3B1). We generated a conditional knockin mouse model of the most common SF3B1 mutation, Sf3b1^K700E. Sf3b1^K700E mice develop macrocytic anemia due to a terminal erythroid maturation defect, erythroid dysplasia, and long-term hematopoietic stem cell (LT-HSC) expansion. Sf3b1^K700E myeloid progenitors and SF3B1-mutant MDS patient samples demonstrate aberrant 3′ splice-site selection associated with increased nonsense-mediated decay. Tet2 loss cooperates with Sf3b1^K700E to cause a more severe erythroid and LT-HSC phenotype. Furthermore, the spliceosome modulator, E7017, selectively kills SF3B1^K700E-expressing cells. Thus, SF3B1^K700E expression reflects the phenotype of the mutation in MDS and may be a therapeutic target in MDS.

Graphical abstract

Teaser

Obeng et al. generate knockin mice with Sf3b1^K700E, a prevalent mutation in myelodysplastic syndrome (MDS). Sf3b1^+/K700E mice display characteristics of MDS. Mouse and human MDS cells expressing SF3B1^K700E exhibit aberrant 3′ splice-site selection, and SF3B1^K700E sensitizes cells to a spliceosome modulator.


http://ift.tt/2ckunw0

Lactate Dehydrogenase B Controls Lysosome Activity and Autophagy in Cancer

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Lucie Brisson, Piotr Bański, Martina Sboarina, Coralie Dethier, Pierre Danhier, Marie-Joséphine Fontenille, Vincent F. Van Hée, Thibaut Vazeille, Morgane Tardy, Jorge Falces, Caroline Bouzin, Paolo E. Porporato, Raphaël Frédérick, Carine Michiels, Tamara Copetti, Pierre Sonveaux
Metabolic adaptability is essential for tumor progression and includes cooperation between cancer cells with different metabolic phenotypes. Optimal glucose supply to glycolytic cancer cells occurs when oxidative cancer cells use lactate preferentially to glucose. However, using lactate instead of glucose mimics glucose deprivation, and glucose starvation induces autophagy. We report that lactate sustains autophagy in cancer. In cancer cells preferentially to normal cells, lactate dehydrogenase B (LDHB), catalyzing the conversion of lactate and NAD⁺ to pyruvate, NADH and H⁺, controls lysosomal acidification, vesicle maturation, and intracellular proteolysis. LDHB activity is necessary for basal autophagy and cancer cell proliferation not only in oxidative cancer cells but also in glycolytic cancer cells.

Graphical abstract

Teaser

Brisson et al. show that lactate dehydrogenase B (LDHB) is critical for lysosomal activity and autophagy in cancer cells. Silencing LDHB selectively inhibits the proliferation of both oxidative and glycolytic cancer cells over normal cells, suggesting inhibition of LDHB as a promising anticancer approach.


http://ift.tt/2ckulo5

Feedback Activation of Leukemia Inhibitory Factor Receptor Limits Response to Histone Deacetylase Inhibitors in Breast Cancer

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Hanlin Zeng, Jia Qu, Nan Jin, Jun Xu, Chenchu Lin, Yi Chen, Xinying Yang, Xiang He, Shuai Tang, Xiaojing Lan, Xiaotong Yang, Ziqi Chen, Min Huang, Jian Ding, Meiyu Geng
Histone deacetylase (HDAC) inhibitors have demonstrated clinical benefits in subtypes of hematological malignancies. However, the efficacy of HDAC inhibitors in solid tumors remains uncertain. This study takes breast cancer as a model to understand mechanisms accounting for limited response of HDAC inhibitors in solid tumors and to seek combination solutions. We discover that feedback activation of leukemia inhibitory factor receptor (LIFR) signaling in breast cancer limits the response to HDAC inhibition. Mechanistically, HDAC inhibition increases histone acetylation at the LIFR gene promoter, which recruits bromodomain protein BRD4, upregulates LIFR expression, and activates JAK1-STAT3 signaling. Importantly, JAK1 or BRD4 inhibition sensitizes breast cancer to HDAC inhibitors, implicating combination inhibition of HDAC with JAK1 or BRD4 as potential therapies for breast cancer.

Graphical abstract

Teaser

Zeng et al. show that HDAC inhibitors (HDACi) promote BRD4-mediated activation of LIFR, which in turn activates JAK1-STAT3 signaling and restrains the efficacy of HDACi in breast cancer. Concurrent inhibition of BRD4 or JAK sensitizes breast cancer, in particular the triple-negative subset, to HDACi.


http://ift.tt/2ckujfW

Small-Molecule Targeting of E3 Ligase Adaptor SPOP in Kidney Cancer

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Zhong-Qiang Guo, Tong Zheng, Baoen Chen, Cheng Luo, Sisheng Ouyang, Shouzhe Gong, Jiafei Li, Liu-Liang Mao, Fulin Lian, Yong Yang, Yue Huang, Li Li, Jing Lu, Bidong Zhang, Luming Zhou, Hong Ding, Zhiwei Gao, Liqun Zhou, Guoqiang Li, Ran Zhou, Ke Chen, Jingqiu Liu, Yi Wen, Likun Gong, Yuwen Ke, Shang-Dong Yang, Xiao-Bo Qiu, Naixia Zhang, Jin Ren, Dafang Zhong, Cai-Guang Yang, Jiang Liu, Hualiang Jiang
In the cytoplasm of virtually all clear-cell renal cell carcinoma (ccRCC), speckle-type POZ protein (SPOP) is overexpressed and misallocated, which may induce proliferation and promote kidney tumorigenesis. In normal cells, however, SPOP is located in the nucleus and induces apoptosis. Here we show that a structure-based design and subsequent hit optimization yield small molecules that can inhibit the SPOP-substrate protein interaction and can suppress oncogenic SPOP-signaling pathways. These inhibitors kill human ccRCC cells that are dependent on oncogenic cytoplasmic SPOP. Notably, these inhibitors minimally affect the viability of other cells in which SPOP is not accumulated in the cytoplasm. Our findings validate the SPOP-substrate protein interaction as an attractive target specific to ccRCC that may yield novel drug discovery efforts.

Graphical abstract

Teaser

Using a structure-based design followed by hit optimization, Guo et al. report small-molecule inhibitors that disrupt oncogenic SPOP-mediated pathways by blocking SPOP-substrate interactions and suppress human clear-cell renal cell carcinoma in vitro and in vivo, suggesting the potential of SPOP-targeted therapy.


http://ift.tt/2cFuKTE

Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Najoua Lalaoui, Kay Hänggi, Gabriela Brumatti, Diep Chau, Nhu-Y.N. Nguyen, Lazaros Vasilikos, Lisanne M. Spilgies, Denise A. Heckmann, Chunyan Ma, Margherita Ghisi, Jessica M. Salmon, Geoffrey M. Matthews, Elisha de Valle, Donia M. Moujalled, Manoj B. Menon, Sukhdeep Kaur Spall, Stefan P. Glaser, Jennifer Richmond, Richard B. Lock, Stephen M. Condon, Raffi Gugasyan, Matthias Gaestel, Mark Guthridge, Ricky W. Johnstone, Lenka Munoz, Andrew Wei, Paul G. Ekert, David L. Vaux, W. Wei-Lynn Wong, John Silke




http://ift.tt/2cFtXSU

Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Haidong Tang, Yang Wang, Lukasz K. Chlewicki, Yuan Zhang, Jingya Guo, Wei Liang, Jieyi Wang, Xiaoxiao Wang, Yang-Xin Fu




http://ift.tt/2cVYL3X

IDH1, Histone Methylation, and So Forth

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Virginie Penard-Lacronique, Olivier A. Bernard




http://ift.tt/2cFtKiv

An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Zoi Karoulia, Yang Wu, Tamer A. Ahmed, Qisheng Xin, Julien Bollard, Clemens Krepler, Xuewei Wu, Chao Zhang, Gideon Bollag, Meenhard Herlyn, James A. Fagin, Amaia Lujambio, Evripidis Gavathiotis, Poulikos I. Poulikakos




http://ift.tt/2cswwJ8

Clustered double-strand breaks in heterochromatin perturb DNA repair after high linear energy transfer irradiation

Publication date: Available online 13 September 2016
Source:Radiotherapy and Oncology
Author(s): Yvonne Lorat, Sara Timm, Burkhard Jakob, Gisela Taucher-Scholz, Claudia E. Rübe
Background and purposeHigh linear energy transfer (LET) radiotherapy offers superior dose conformity and biological effectiveness compared with low-LET radiotherapy, representing a promising alternative for radioresistant tumours. A prevailing hypothesis is that energy deposition along the high-LET particle trajectories induces DNA lesions that are more complex and clustered and therefore more challenging to repair. The precise molecular mechanisms underlying the differences in radiobiological effects between high-LET and low-LET radiotherapies remain unclear.Material and MethodsHuman fibroblasts were irradiated with high-LET carbon ions or low-LET photons. At 0.5h and 5h post exposure, the DNA-damage pattern in the chromatin ultrastructure was visualised using gold-labelled DNA-repair factors. The induction and repair of single-strand breaks, double-strand breaks (DSBs), and clustered lesions were analysed in combination with terminal dUTP nick-end labelling of DNA breaks.ResultsHigh-LET irradiation induced clustered lesions with multiple DSBs along ion trajectories predominantly in heterochromatic regions. The cluster size increased over time, suggesting inefficient DSB repair. Low-LET irradiation induced many isolated DSBs throughout the nucleus, most of which were efficiently rejoined.ConclusionsThe clustering of DSBs in heterochromatin following high-LET irradiation perturbs efficient DNA repair, leading to greater biological effectiveness of high-LET irradiation versus that of low-LET irradiation.



http://ift.tt/2csgFae

Prospective swallowing outcomes after IMRT for oropharyngeal cancer: Dosimetric correlations in a population-based cohort

Publication date: October 2016
Source:Oral Oncology, Volume 61
Author(s): Gordon Z. Guo, Keith R. Sutherland, Candace Myers, Pascal Lambert, Shaun K. Loewen, Harvey C. Quon
ObjectivesTo identify dose constraints to preserve swallowing after head and neck (H&N) radiotherapy using prospectively collected functional outcomes.Materials and methodsStage III–IV oropharyngeal cancer patients were prospectively evaluated using the Royal Brisbane Hospital Outcome Measure for Swallowing and Performance Status Scale for H&N Cancer Patients at pre-treatment and 3, 6, 12, and 24months after intensity-modulated radiotherapy. Dosimetric parameters were correlated with swallowing function.ResultsNinety-six patients were evaluated with median follow-up of 14.1months (interquartile range 9.9–26.3). Six patients (8.3%) remained feeding tube (FT) dependent at 12months. At 2years, 32.6% tolerated a normal diet without restrictions. Mean doses of 55Gy to supraglottic larynx, 44Gy to glottic larynx, 48Gy to cricopharyngeus, and 44Gy to esophageal inlet were associated with >25% risk of FT dependence at 6months.ConclusionHigher mean doses to the larynx and pharyngo-esophageal junction were associated with longer duration of FT dependence and dietary restrictions.



http://ift.tt/2csupEX

Construct validity and responsiveness of Movakic: An instrument for the evaluation of motor abilities in children with severe multiple disabilities

Publication date: December 2016
Source:Research in Developmental Disabilities, Volume 59
Author(s): Sonja M. Mensch, Michael A. Echteld, Heleen M. Evenhuis, Eugène A.A. Rameckers
Movakic is a newly developed instrument for measurement of motor abilities in children with severe multiple disabilities, with a satisfactory feasibility and content validity and good inter-observer and test-retest reliability.The objective of this study was to investigate its construct validity and responsiveness to change.Sixty children with severe multiple disabilities (mean age 7.7 years, range 2–16) were measured using Movakic six times during 18 months. Construct validity was assessed by correlating Movakic scores with expert judgment. In order to assess responsiveness, scores during 3-months intervals were compared (mean score-changes and intraclass correlations) during which some children experienced meaningful events influencing motor abilities and during which others experienced no such event.Forty-five percent of children had a lower cognitive development level than 6-month, 52% had Gross Motor Function Classification System level V and 37% had level IV. For 27 children all measurements were completed, six children dropped out. Construct validity was good (r=0.50–0.71). Responsiveness was demonstrated by significantly larger score changes after events than when such events did not occur.Movakic is a valid instrument for measuring motor abilities in children with severe multiple disabilities. Results suggest responsiveness to change in motor abilities after meaningful events.



http://ift.tt/2cTIwBu

Serum Procalcitonin: An Independent Predictor of Clinical Outcome in Health Care-Associated Pneumonia

Background: Early prediction of the clinical outcomes for health care-associated pneumonia (HCAP) patients is challenging. Objectives: This is the first study to evaluate procalcitonin (PCT) as a predictor of outcomes in HCAP patients. Methods: We conducted an observational study based on data for HCAP patients prospectively collected between 2011 and 2014. Outcome variables were intensive care unit (ICU) admission and 30-day mortality. PCT was categorized into three groups: 2.0 ng/ml. We analysed multiple variables including age, sex, comorbidities, clinical findings, and PCT group to assess their association with outcomes. Results: Of 245 HCAP patients, 99 (40.4%) were admitted to an ICU and 44 (18.0%) died within 30 days. The median PCT level was significantly higher in the ICU admission (1.19 vs. 0.4 ng/ml; p 2.0 ng/ml) was strongly associated with ICU admission [odds ratio 3.734, 95% confidence interval (CI) 1.753-7.951; p = 0.001] and 30-day mortality (hazard ratio 2.254, 95% CI 1.250-5.340; p = 0.035). In receiver operating characteristic analysis, PCT had a poor discrimination power regarding ICU admission [0.695 of the area under the curve (AUC)] and a fair discrimination power regarding 30-day mortality in HCAP patients (0.768 of the AUC). Conclusions: High PCT on admission was strongly associated with ICU admission and 30-day mortality in HCAP patients. However, application of PCT alone seems to be limited to predicting outcomes.
Respiration

http://ift.tt/2cksIq9

Im Gedenken an Professor Dr. Dr. Michael Wannenmacher

http://ift.tt/2cA0Baa

Glycated albumin: from biochemistry and laboratory medicine to clinical practice

Abstract

This review summarizes current knowledge about glycated albumin. We review the changes induced by glycation on the properties of albumin, the pathological implications of high glycated albumin levels, glycated albumin quantification methods, and the use of glycated albumin as a complementary biomarker for diabetes mellitus diagnosis and monitoring and for dealing with long-term complications. The advantages and limits of this biomarker in different clinical settings are also discussed.

http://ift.tt/2c5Fqsa

Obesity treatment by very low-calorie-ketogenic diet at two years: reduction in visceral fat and on the burden of disease

Abstract

The long-term effect of therapeutic diets in obesity treatment is a challenge at present. The current study aimed to evaluate the long-term effect of a very low-calorie-ketogenic (VLCK) diet on excess adiposity. Especial focus was set on visceral fat mass, and the impact on the individual burden of disease. A group of obese patients (n = 45) were randomly allocated in two groups: either the very low-calorie-ketogenic diet group (n = 22), or a standard low-calorie diet group; (n = 23). Both groups received external support. Adiposity parameters and the cumulative number of months of successful weight loss (5 or 10 %) over a 24-month period were quantified. The very low-calorie-ketogenic diet induced less than 2 months of mild ketosis and significant effects on body weight at 6, 12, and 24 months. At 24 months, a trend to regress to baseline levels was observed; however, the very low-calorie-ketogenic diet induced a greater reduction in body weight (−12.5 kg), waist circumference (−11.6 cm), and body fat mass (−8.8 kg) than the low-calorie diet (−4.4 kg, −4.1 cm, and −3.8 kg, respectively; p < 0.001). Interestingly, a selective reduction in visceral fat measured by a specific software of dual-energy x-ray absorptiometry (DEXA)-scan (−600 g vs. −202 g; p < 0.001) was observed. Moreover, the very low-calorie-ketogenic diet group experienced a reduction in the individual burden of obesity because reduction in disease duration. Very low-calorie-ketogenic diet patients were 500 months with 5 % weight lost vs. the low-calorie diet group (350 months; p < 0.001). In conclusion, a very low-calorie-ketogenic diet was effective 24 months later, with a decrease in visceral adipose tissue and a reduction in the individual burden of disease.

http://ift.tt/2cbBOIb

Evaluation of a New Brain Tissue Probe for Cerebral Blood Flow Monitoring in an Experimental Pig Model.

BACKGROUND: Bedside monitoring of cerebral blood flow (CBF) may provide new insights into the pathophysiology of brain injury, allow early detection of secondary ischemia, and help guide therapy. OBJECTIVE: To evaluate a new brain tissue probe for serial CBF monitoring using near-infrared spectroscopy and indocyanine green dye dilution (NeMo Probe) compared with the existing thermal diffusion probe (QFlow 500 Probe). METHODS: In 7 pigs, the NeMo Probe and QFlow 500 Probe were inserted into the subcortical white matter. Parallel measurements were recorded during (1) baseline, (2) hypotension, (3) hypertension, and (4) hyperventilation. Thereafter, protocol points 1 through 4 were repeated once. The Spearman correlation (rs), Bland-Altman plot, concordance rate, and coefficient of variation were used for statistical analysis. RESULTS: There was poor agreement between 56 pairs of absolute CBF values (rs = 0.52, P

http://ift.tt/2c5EP9H

Consumer product ingestion and aspiration in children: A 15-year review

Objectives/Hypothesis

Our objectives were to identify consumer product (CP) ingestion and aspiration trends. Our hope is that evaluation of contemporary trends may be useful to physicians and policy makers and further guide preventative measures.

Methods

The Consumer Product Safety Commission's National Electronic Injury Surveillance System was queried for pediatric CP aspiration and ingestion data for the years 2000 to 2014. Data from 2000 to 2004 were compared to 2010 to 2014 data and analyzed for CP and injury occurrence. Injury trends over the past 15 years were identified; patient demographics were analyzed; and patient disposition was reported.

Results

Emergency department visits for pediatric CP ingestion increased 41.4% over the 15-year period analyzed and remained relatively stable for aspiration events. In all, an estimated 1.1 million visits occurred during this time frame. Jewelry overtook coins as the most common CP aspirated (29.3%). Coins remained the most frequent ingestion but comprised a smaller proportion of ingestions in recent years than years past. From 2010 through 2014, children under 5 years of age accounted for 89.4% and 77.8% of CP aspiration and ingestion cases, respectively.

Conclusion

Pediatric aspiration/ingestion remains a frequent occurrence with potentially significant ramifications. Injury demographics and CPs most likely to be involved may represent valuable information to the otolaryngologist who wishes to provide appropriate counseling to patients and parents and continued investigation on injury prevention.

Level of Evidence

4. Laryngoscope, 2016

http://ift.tt/2cnvht3

Development and validation of a high-fidelity phonomicrosurgical trainer

Objectives

To validate the use of a high-fidelity phonomicrosurgical trainer.

Study Design

A high-fidelity phonomicrosurgical trainer, based on a previously validated model by Contag et al.,¹ was designed with multilayered vocal folds that more closely mimic the consistency of true vocal folds, containing intracordal lesions to practice phonomicrosurgical removal. A training module was developed to simulate the true phonomicrosurgical experience. A validation study with novice and expert surgeons was conducted.

Methods

Novices and experts were instructed to remove the lesion from the synthetic vocal folds, and novices were given four training trials. Performances were measured by the amount of time spent and tissue injury (microflap, superficial, deep) to the vocal fold. An independent Student t test and Fisher exact tests were used to compare subjects. A matched-paired t test and Wilcoxon signed rank tests were used to compare novice performance on the first and fourth trials and assess for improvement.

Results

Experts completed the excision with less total errors than novices (P = .004) and made less injury to the microflap (P = .05) and superficial tissue (P = .003). Novices improved their performance with training, making less total errors (P = .002) and superficial tissue injuries (P = .02) and spending less time for removal (P = .002) after several practice trials.

Conclusion

This high-fidelity phonomicrosurgical trainer has been validated for novice surgeons. It can distinguish between experts and novices; and after training, it helped to improve novice performance.

Level of Evidence

N/A. Laryngoscope, 2016

http://ift.tt/2cBn47M

Analysis of semen parameters in a young cohort of cancer patients

Abstract

Background

Infertility can be the result of some common cancer treatments and can significantly impact quality of life. Semen cryopreservation allows for fertility preservation. We analyzed the semen parameters of specimens collected from pubertal males from the Children's Hospital of Philadelphia (CHOP) in order to expand current knowledge on the quality of these specimens and inform a standard clinical practice.

Procedure

Males who were at least Tanner stage III and newly diagnosed with cancer at CHOP were approached regarding sperm banking. The success and quality of the samples collected were analyzed and compared in relation to prior treatment, age, and diagnosis.

Results

From 399 patients approached for semen collection, 339 (85%) attempted to bank sperm, of which 265 (78%) were successful and 60 (15%) refused to participate. Therapy prior to sperm banking significantly impacted a successful collection (P < 0.01). Only 16.9% of the untreated patients were azoospermic, whereas 84.0% of the treated subjects were azoospermic. Older patients were less likely to be azoospermic and have a greater quality collection when compared with younger patients (P < 0.01). However, 65% of our youngest patients still were able to cryopreserve semen. There was no difference in azoospermia across diagnostic groups (P = 0.35), though there were differences in quality of semen parameters across diagnoses.

Conclusion

Our data support that sperm banking pubertal males prior to the initiation of therapy is feasible. While there were differences in quality of semen parameters across age and diagnostic groups, most males, regardless of age or diagnosis, had adequate specimens for cryopreservation.

http://ift.tt/2cVOvZu

Cranial epidural hematomas: A case series and literature review of this rare complication associated with sickle cell disease

Abstract

Background

Patients with sickle cell disease (SCD) may experience many complications of the central nervous system (CNS) including stroke, silent cerebral infarcts, and neuropsychological deficits. Cranial epidural hematoma is a rare but potentially serious complication.

Procedure

Case series of cranial epidural hematomas in children with SCD from three different institutions is considered, along with a literature review of cranial epidural hematomas in this population.

Results

Seven children with SCD with cranial epidural hematomas were identified from three different institutions. All patients were male and the age at presentation ranged from 10 to 18 years. Two patients presented with headache (28.6%), while the rest had no neurologic symptoms at presentation. Four patients required urgent neurosurgical intervention (57.1%) and one patient died (14.3%). A literature review identified 18 additional cases of cranial epidural hematomas in children with SCD. Of these, treatment ranged from supportive care to neurosurgical intervention. Twelve patients completely recovered (66.7%), one patient had long-term cognitive impairment (5.6%), and four patients died (22.2%). Combined with our data, cranial epidural hematomas have a mortality rate of 20.0%.

Conclusions

Although rare, cranial epidural hematoma can be fatal and should be considered in patients with acute neurological symptoms.

http://ift.tt/2cFiBya

Transcriptome and digital gene expression analysis of herbaceous peony ( Paeonia lactiflora Pall.) to screen thermo-tolerant related differently expressed genes

Abstract

Herbaceous peony (Paeonia lactiflora Pall.) is easily injured by heat stress (HS), which greatly restricts its application and promotion. In this study, the thermo-tolerance of three representative P. lactiflora cultivars had been firstly assessed. 'Zifengyu' was identified as the thermo-tolerant cultivar with relatively lower values and smaller variations in malondialdehyde, hydrogen peroxide (H₂O₂) and proline contents under HS. Subsequently, their transcriptomes were sequenced by RNA sequencing (RNA-seq) technology to construct a complete database. 81,599 unigenes were obtained, and 34,940 unigenes had been annotated. Moreover, through digital gene expression analysis of thermo-tolerant 'Zifengyu' and moderately thermo-tolerant 'Hongyanzhenghui', 161 heat stress response genes had been screened involving heat shock protein genes, plant hormone signal transduction related genes, fatty acid synthesis genes, reactive oxygen species-scavenging genes and secondary metabolites related genes. And the effectively and timely response of these genes to HS could endow thermo-tolerance to 'Zifengyu'. Among these genes, 11 key thermo-tolerant related genes whose expressions were all significantly up-regulated in 'Zifengyu' and 'Hongyanzhenghui' during development and the former possessed higher levels could be regarded as the candidate genes, including isoprene synthase gene, 2 peroxidase genes, 3-oxoacyl-acyl carrier protein reductase gene (FabG), 3 transcription factor genes (bHLH, NAC and WRKY), HSP20 and 3 HSP70. These results could provide a better understanding of heat stress response in P. lactiflora, and pave for the breeding of thermo-tolerant cultivars.

http://ift.tt/2cAwSh4

Bacteriological profile and antibiotic sensitivity patterns of blood cultures

2016-09-13T00-32-58Z
Source: International Journal of Contemporary Pediatrics
K. Ashwin Reddy, S. Uday Kanth.
ABSTRACT Background: Neonatal septicemia is a significant cause of morbidity and mortality worldwide especially so in developing countries. To reduce the mortality caused by neonatal septicemia, it became vital to diagnose it as soon as possible and treat with administration of appropriate antibiotics. The objective of the study was bacteriological spectrum in blood culture of neonates admitted in a hospital, and antibiotic susceptibility pattern of blood culture positive isolates. Methods: A total of 593 blood culture sample were received from NICU admissions for a period of 15 months were included for this study. Under aseptic precautions, 1 ml of blood was collected from a peripheral vein and inoculated into a bottle of Brain Heart Infusion broth and was incubated for 7 days. Repeated sub-culturing was done as per standard procedures. Inoculation on blood agar and Mac-Conkeys agar plates were made. Any growth was subjected for identification by appropriate biochemical tests. Antibiotic susceptibility testing was done by disc diffusion method. Results: Of the 593 cases studied 12.14 % were blood culture positive. Among the blood culture positive neonates 67% were male neonates. Late onset septicemia (87.5%) was more common than early onset septicemia (12.5%). Gram negative organisms 46 (63.88%) were predominant than Gram positive organisms 18 (25%). Klebsiella pneumonia 18 (25%), Citrobacter 10 (13.88%), and Pseudomonas auroginosa was found in 7 (9.72%). The other organisms isolated were Escherichia coli 06 (8.33%), Enterobacter 04 (5.55%), Gram positive organisms were obtained in 18 (25.00%) out of 72 cases. MSSA 06 (8.33%), Enterococci 06 (8.33%) was the commonest organisms isolated. Most of the isolates were more susceptible imipenem, meropenem, and ciprofloxacin to amikacin antibiotics. Conclusions: Blood culture remains the gold standard for the diagnosis of neonatal septicemia. Periodic surveillance of organisms and their antibiotic sensitivity patterns are essential to understand and to prevent emergence of resistant organisms. Effective/Correct selection of antibiotic is essential to decrease mortality and morbidity in the vulnerable group of neonatal population.


http://ift.tt/2cJi2Cf

Effect of porous layer engineered with acid vapor etching on optical properties of solid silicon nanowire arrays

Publication date: 5 December 2016
Source:Materials & Design, Volume 111
Author(s): Chohdi Amri, Rachid Ouertani, Abderrahmean Hamdi, Radhouane Chtourou, Hatem Ezzaouia
In this paper, we report, for the first time, an investigative study involving the engineering of lightly doped porous silicon nanowire arrays (pSiNWs) by exposing solid silicon nanowire arrays (SiNWs) to an acid vapor emanating from HF/HNO3 hot solution. SEM and TEM images exhibit vertically distributed SiNW arrays on the whole silicon (Si) surface with relatively smooth surface sidewalls. By submitting the SiNW arrays to Acid Vapor Etching (AVE), they become porous with a substantial decrease in their densities and lengths. Increasing etching duration leads to a higher porosity without affecting the wire diameter which remains almost constant nearly 100nm. Exceeding a critical etching duration, a porous structure is observed superseding the SiNW structure. The morphological characterizations have been correlated to the optical properties. We note a blue shift of the strong visible photoluminescence (PL) bands after AVE treatment due to the decrease of the silicon quantum dots diameter (Si-QDs). UV–Visible measurement shows a decrease of the total reflectivity by 5% after AVE treatment.

Graphical abstract

http://ift.tt/2cs8Otl

Bienzymatic nanoreactors composed of chloroperoxidase–glucose oxidase on Au@Fe3O4 nanoparticles: Dependence of catalytic performance on the bioarchitecture

Publication date: 5 December 2016
Source:Materials & Design, Volume 111
Author(s): Fengqin Gao, Yucheng Jiang, Mancheng Hu, Shuni Li, Quanguo Zhai
The operational stability of chloroperoxidase (CPO) was considerably enhanced by coupling with glucose oxidase (GOx) because H2O2 could be generated in situ from glucose and oxygen. In this paper, a CPO–GOx nanoreactor was fabricated on the surface of Au@Fe3O4 nanoparticles through layer-by-layer assembly using the specific avidin–biotin interaction. The X-ray diffraction data indicated the presence of both Fe and Au in the Au@Fe3O4 carrier. The Au@Fe3O4 displayed a uniform core/shell nanostructure, whereas the nanoparticles of the bienzymatic reactor were larger than the carrier. The catalytic activity of CPO was highly dependent on the structure of the enzymatic nanoreactor. The activity of Au@Fe3O4–GOx (inner)–CPO (outer) was 15.5% higher than that of Au@Fe3O4–CPO (inner)–GOx (outer). Moreover, Au@Fe3O4–GOx–CPO exhibited better thermostability. Au@Fe3O4–GOx–CPO retained 53.2% of its initial activity after incubation for 1.0h at 60°C and 30.4% of its initial activity after 18h at 50°C. Au@Fe3O4–GOx–CPO had good reusability. It retained more than 62.4% of its activity after the 12th cycle. This was attributed to the cage-like structure in Au@Fe3O4–GOx–CPO, which could effectively prevent the removal of the enzyme molecules from the carrier.

Graphical abstract

http://ift.tt/2cs94bK

LaPO4 as a toughening agent for rare earth zirconate ceramics

Publication date: 5 December 2016
Source:Materials & Design, Volume 111
Author(s): Caimei Wang, Lei Guo, Fuxing Ye
Gd2Zr2O7−x mol% LaPO4 (x=0, 10, 20, 30, 40, 50, 60, 100) composites were produced, and their phase constitution and toughness were investigated. XRD and Raman spectra results revealed that Gd2Zr2O7 pyrochlore and LaPO4 monazite phases were compatible in Gd2Zr2O7-LaPO4 composite, and no chemical reaction occurred. TEM analysis demonstrated the coexistence of Gd2Zr2O7 and LaPO4 phases. The toughness of Gd2Zr2O7-LaPO4 composite first increased with the increase of the LaPO4 content, followed by a downward trend. The layer-structure of LaPO4 phase and its weak bond with Gd2Zr2O7 matrix could cause the initial increase in the toughness, and the growth of LaPO4 grains might contribute to the reduced toughness. Considering the fact that rare earth zirconates have similar structure and properties, it could be expected that LaPO4 can be designed as a toughening agent for all the compounds, but there exists an optimal LaPO4 addition content for desirable toughness.

Graphical abstract

http://ift.tt/2cs84V0

Influence of intrinsic strain on irradiation induced damage: the role of threshold displacement and surface binding energies

Publication date: 5 December 2016
Source:Materials & Design, Volume 111
Author(s): J. Guénolé, A. Prakash, E. Bitzek
Focused ion beam (FIB) machining has become a standard tool for sample preparation and in combination with digital image correlation (DIC) for the evaluation of local intrinsic stresses by measuring strain relaxation. However, FIB milling always leads to irradiation damage of the material. Current models for the formation of irradiation damage and the sputter yield are based on two key parameters, the threshold displacement energy (TDE) and surface binding energy (SBE), which are usually determined from unstrained systems with idealized surfaces. Here we use atomistic simulations to determine the TDE and SBE for strained silicon and aluminum and compare the results to full cascade simulations. A clear, material class dependent influence of the strain state on the TDE is observed, and surface amorphisation is shown to significantly increase the SBE of {001} surfaces.

Graphical abstract

http://ift.tt/2cs8rPl

Influence of ω phase precipitation on mechanical performance and corrosion resistance of Ti–Nb–Zr alloy

Publication date: 5 December 2016
Source:Materials & Design, Volume 111
Author(s): Qiang Li, Junjie Li, Guanghao Ma, Xuyan Liu, Deng Pan
A recently investigated Ti–24at.% Nb–2at.% Zr alloy was cold-rolled with reductions of 75% and 95%, and the resulting materials were heat-treated under the same conditions. The two types of specimens obtained through this procedure show the same phase composition. Precipitation of an isothermal ω phase leads to some improvement in the properties of the 75%-rolled specimens. The 95%-rolled and subsequently heated specimens exhibit different performances compared to the 75%-rolled samples heated under the same processing conditions. The stress-induced martensitic transformation is inhibited in the 95%-rolled specimens, owing to the combined effects of the isothermal ω phase and texture. The Ti–24at.% Nb–2at.% Zr alloy shows open circuit potential and corrosion behavior similar to commercially pure Ti. The corrosion resistance of the alloy is reduced upon precipitation of the ω phase, owing to an unstable passive film.

Graphical abstract

http://ift.tt/2cs8j28