IFC (editorial board)

Publication date: March 2017
Source:Peptides, Volume 89





http://ift.tt/2mnNdXT

The International Neuropeptide society pages

Publication date: March 2017
Source:Peptides, Volume 89





http://ift.tt/2ma9QTw

Gayle & Richard Olson prize pages

Publication date: March 2017
Source:Peptides, Volume 89





http://ift.tt/2mnJFoC

Glucagon-like peptide-1 (GLP-1) increases in plasma and colon tissue prior to estrus and circulating levels change with increasing age in reproductively competent Wistar rats

Publication date: Available online 22 February 2017
Source:Peptides
Author(s): Michelle L. Johnson, M. Jill Saffrey, Victoria J. Taylor
There is a well-documented association between cyclic changes to food intake and the changing ovarian hormone levels of the reproductive cycle in female mammals. Limited research on appetite-controlling gastrointestinal peptides has taken place in females, simply because regular reproductive changes in steroid hormones present additional experimental factors to account for. This study focussed directly on the roles that gastrointestinal-secreted peptides may have in these reported, naturally occurring, changes to food intake during the rodent estrous cycle and aimed to determine whether peripheral changes occurred in the anorexigenic (appetite-reducing) hormones peptide-YY (PYY) and glucagon-like peptide-1 (GLP-1) in female Wistar rats (32-44 weeks of age). Total forms of each peptide were measured in matched fed and fasted plasma and descending colon tissue samples for each animal during the dark (feeding) phase. PYY concentrations did not significantly change between defined cycle stages, in either plasma or tissue samples. GLP-1 concentrations in fed plasma and descending colon tissue were significantly increased during proestrus, just prior to a significant reduction in fasted stomach contents at estrus, suggesting increased satiety and reduced food intake at this stage of the cycle. Increased proestrus GLP-1 concentrations could contribute to the reported reduction in food intake during estrus and may also have biological importance in providing the optimal nutritional and metabolic environment for gametes at the potential point of conception. Additional analysis of the findings demonstrated significant interactions of ovarian cycle stage and fed/fasted status with age on GLP-1, but not PYY plasma concentrations. Slightly older females had reduced fed plasma GLP-1 suggesting that a relaxation of regulatory control of this incretin hormone may also take place with increasing age in reproductively competent females.



http://ift.tt/2kOVrfi

Long Time No See: Enduring Behavioral and Neuronal Changes in Perceptual Learning of Motion Trajectories 3 Years After Training

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Here, we report on the long-term stability of changes in behavior and brain activity following perceptual learning of conjunctions of simple motion features. Participants were trained for 3 weeks on a visual search task involving the detection of a dot moving in a "v"-shaped target trajectory among inverted "v"-shaped distractor trajectories. The first and last training sessions were carried out during functional magnetic resonance imaging (fMRI). Learning stability was again examined behaviorally and using fMRI 3 years after the end of training. Results show that acquired behavioral improvements were remarkably stable over time and that these changes were specific to trained target and distractor trajectories. A similar pattern was observed on the neuronal level, when the representation of target and distractor stimuli was examined in early retinotopic visual cortex (V1–V3): training enhanced activity for the target relative to the surrounding distractors in the search array and this enhancement persisted after 3 years. However, exchanging target and distractor trajectories abolished both neuronal and behavioral effects, suggesting that training-induced changes in stimulus representation are specific to trained stimulus identities.</span>

http://ift.tt/2kP4Sez

Gβ2 Regulates the Multipolar-Bipolar Transition of Newborn Neurons in the Developing Neocortex

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Proper neuronal migration is critical for the formation of the six-layered neocortex in the mammalian brain. However, the precise control of neuronal migration is not well understood. Heterotrimeric guanine nucleotide binding proteins (G proteins), composed of Gα and Gβγ, transduce signals from G protein-coupled receptors to downstream effectors and play crucial roles in brain development. However, the functions of individual subunits of G proteins in prenatal brain development remain unclear. Here, we report that Gβ2 is expressed in the embryonic neocortex, with abundant expression in the intermediate zone, and is significantly upregulated in differentiated neurons. Perturbation of Gβ2 expression impairs the morphogenetic transformation of migrating neurons from multipolar to bipolar and subsequently delays neuronal migration. Moreover, Gβ2 acts as a scaffold protein to organize the MP1-MEK1-ERK1/2 complex and mediates the phosphorylation of ERK1/2. Importantly, expression of a constitutively active variant of MEK1 rescues the migration defects that are caused by the loss of Gβ2. In conclusion, our findings reveal that Gβ2 regulates proper neuronal migration during neocortex development by activating the ERK1/2 signaling pathway.</span>

http://ift.tt/2meN3Th

Higher Striatal Iron Concentration is Linked to Frontostriatal Underactivation and Poorer Memory in Normal Aging

<span class="paragraphSection"><div class="boxTitle">Abstract</div>In the brain, intracellular iron is essential for cellular metabolism. However, an overload of free iron is toxic, inducing oxidative stress and cell death. Although an increase of striatal iron has been related to atrophy and impaired cognitive performance, the link between elevated iron and altered brain activity in aging remains unexplored. In a sample of 37 younger and older adults, we examined whether higher striatal iron concentration could underlie age-related differences in frontostriatal activity induced by mental imagery of motor and non-motor scenes, and poorer recall of the scenes. Higher striatal iron concentration was linked to underrecruitment of frontostriatal regions regardless of age and striatal volume, the iron-activity association in right putamen being primarily driven by the older adults. In older age, higher striatal iron was related to poorer memory. Altered astrocytic functions could account for the link between brain iron and brain activity, as astrocytes are involved in iron buffering, neurovascular coupling, and synaptic activity. Our preliminary findings, which need to be replicated in a larger sample, suggest a potential frontostriatal target for intervention to counteract negative effects of iron accumulation on brain function and cognition.</span>

http://ift.tt/2kP190D

Neuronal and Peripheral Pentraxins Modify Glutamate Release and may Interact in Blood–Brain Barrier Failure

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Neuronal pentraxin 1 (NPTX1) has been implicated in Alzheimer's disease, being present in and around dystrophic neurons in plaques, affecting glutamatergic transmission postsynaptically and mediating effects of amyloidβ. Here, we confirm the presence of NPTX1 around plaques in postmortem Alzheimer's disease brain and report that acutely applied human NPTX1 increases paired-pulse ratio at mouse CA3-CA1 hippocampal synapses, indicating a decrease in glutamate release. In contrast, chronic exposure to NPTX1, NPTX2, or NPTX receptor decreases paired-pulse ratio, mimicking some of the earliest changes in mice expressing familial Alzheimer's disease genes. The peripheral pentraxin, serum amyloid P component (SAP), causes similar synaptic effects to NPTX1. The presence of SAP on amyloid plaques in Alzheimer's disease confirms that it can enter the brain. We show that SAP and neuronal pentraxins can interact and that SAP can enter the brain if the blood–brain barrier is compromised, suggesting that peripheral pentraxins could affect central synaptic transmission via this interaction, especially in the event of blood–brain barrier breakdown.</span>

http://ift.tt/2meIGrs

Low-Rank and Sparse Decomposition Based Shape Model and Probabilistic Atlas for Automatic Pathological Organ Segmentation

Publication date: Available online 22 February 2017
Source:Medical Image Analysis
Author(s): Changfa Shi, Yuanzhi Cheng, Jinke Wang, Yadong Wang, Kensaku Mori, Shinichi Tamura
One major limiting factor that prevents the accurate delineation of human organs has been the presence of severe pathology and pathology affecting organ borders. Overcoming these limitations is exactly what we are concerned in this study. We propose an automatic method for accurate and robust pathological organ segmentation from CT images. The method is grounded in the active shape model (ASM) framework. It leverages techniques from low-rank and sparse decomposition (LRSD) theory to robustly recover a subspace from grossly corrupted data. We first present a population-specific LRSD-based shape prior model, called LRSD-SM, to handle non-Gaussian gross errors caused by weak and misleading appearance cues of large lesions, complex shape variations, and poor adaptation to the finer local details in a unified framework. For the shape model initialization, we introduce a method based on patient-specific LRSD-based probabilistic atlas (PA), called LRSD-PA, to deal with large errors in atlas-to-target registration and low likelihood of the target organ. Furthermore, to make our segmentation framework more efficient and robust against local minima, we develop a hierarchical ASM search strategy. Our method is tested on the SLIVER07 database for liver segmentation competition, and ranks 3rd in all the published state-of-the-art automatic methods. Our method is also evaluated on some pathological organs (pathological liver and right lung) from 95 clinical CT scans and its results are compared with the three closely related methods. The applicability of the proposed method to segmentation of the various pathological organs (including some highly severe cases) is demonstrated with good results on both quantitative and qualitative experimentation; our segmentation algorithm can delineate organ boundaries that reach a level of accuracy comparable with those of human raters.

Graphical abstract

http://ift.tt/2mnBcS0

Aims and Scope & Editorial Board

Publication date: January 2017
Source:Bioactive Carbohydrates and Dietary Fibre, Volume 9





http://ift.tt/2mnMjup

Naturally-occurring fatigue and cardiovascular response to a simple memory challenge

Publication date: Available online 22 February 2017
Source:International Journal of Psychophysiology
Author(s): Christopher Mlynski, Rex A. Wright, Stephanie D. Agtarap, Juan Rojas
Participants first completed a state affect checklist that included a fatigue (energy-tiredness) index and a measure of mental sharpness. They then were presented a simple memory challenge. In the first minute of the two-minute work period, heart rate responses (1) rose with values on the fatigue index, and (2) fell with values on the measure of mental sharpness. In the second minute of the work period, the responses were unrelated to fatigue index and mental sharpness values. Follow-up analysis indicated mental sharpness mediation of fatigue influence on heart rate in Minute 1. First minute findings add substantively to the body of evidence supporting recent suggestions that fatigue can lead people to try harder and experience stronger cardiovascular responses when confronted with simple challenges. They also support the suggestion that fatigue might exert its influence on cardiovascular responses to a mental challenge by diminishing cognitive clarity, that is, by obscuring thought. Second minute findings are contrary to the fatigue suggestions, but could indicate that memorization was accomplished in the first minute. A practical implication of the first minute results is that real-world fatigue could elevate health risk by enhancing CV responses to mundane daily tasks.



http://ift.tt/2l1ONO2

Event-related theta oscillatory substrates for facilitation and interference effects of negative emotion on children's cognition

Publication date: Available online 22 February 2017
Source:International Journal of Psychophysiology
Author(s): Zhongqing Jiang, Allison C. Waters, Ying Liu, Wenhui Li, Lizhu Yang
We investigated the brain oscillatory contribution to emotion-cognition interaction in young children. Five-year-old participants (n=27) underwent EEG recording while engaged in a color identification task. Each trial began with an emotional prime. Response times indicated whether emotional primes facilitated or interfered with performance. Related effects were detected in theta-band power over parietal-occipital cortex, early in the response epoch (<500ms). Children in the emotion facilitation group showed greater theta synchronization for negative stimuli. The opposite trend was observed in the interference group. Results suggest a role for theta oscillations in children's adaptive response to emotional content in cognitive performance.



http://ift.tt/2lsfbDZ

Over-expression of CircRNA_100876 in non-small cell lung cancer and its prognostic value

Publication date: Available online 22 February 2017
Source:Pathology - Research and Practice
Author(s): Jun-tao Yao, Qiu-ping Liu, Mo-qi Lv, Dang-xia Zhou, Zi-jun Liao, Ke-jun Nan
Circular RNAs (circRNAs) are a novel type of endogenous RNAs featuring stable structure and high tissue-specific expression. Recently, accumulating evidence has revealed that aberrant circRNAs expression plays important roles in carcinogenesis and tumor progression. However, the expression pattern and biological function of circRNAs in non small cell lung cancer (NSCLC) remain largely unknown. Therefore, the purpose of this study was to clarify the possible role of one of typical circRNAs, circRNA_100876 in NSCLC and to define its prognostic value in NSCLC. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of circRNA_100876 in tumor tissues and their adjacent nontumorous tissues in 101 patients with NSCLC. We found that the expression level of circRNA_100876 were significantly elevated in NSCLC tissues when compared with their adjacent nontumorous tissues (P=0.000). Moreover, there was a close correlation between the circRNA_100876 up-regulation expression and lymph node metastasis (P=0.001) and tumor staging (P=0.001) in NSCLC. In addition, Kaplan-Meier survival analysis demonstrated that the overall survival time of NSCLC patients with high circRNA_100876 expression was significantly shorter than those patients with low circRNA_100876 expression (P=0.000). In conclusion, our findings indicate that circRNA_100876 is closely related to the carcinogenesis of NSCLC and it might be served as a potential prognostic biomarker and therapeutic target for NSCLC.



http://ift.tt/2lb52JB

Dermal morphological changes following salicylic acid peeling and microdermabrasion

Summary

Background

Microdermabrasion and chemical peeling are popular, inexpensive, and safe methods for treatment of some skin disorders and to rejuvenate skin.

Objectives

To study the alterations of the dermal connective tissue following salicylic acid peeling and microdermabrasion.

Methods

Twenty patients were participated in our study. All participants underwent facial salicylic acid 30% peel or microdermabrasion (10 cases in each group) weekly for 6 weeks. Punch biopsies were obtained from the clinically normal skin of the right postauricular region 1 week before treatment (control group). Other punch skin biopsies were obtained 1 week after the end of the treatments from the left postauricular area. This region was treated in a similar way to the adjacent lesional skin (treated group). We used routine histological techniques (H&E stain), special stains (Masson trichrome and orcein stains), and image analyzer to study the alterations of the dermal connective tissues.

Results

Our study demonstrates variations in the morphological changes between the control and the treated groups, and between chemical peels and microdermabrasion. Both salicylic acid 30% and microdermabrasion were associated with thickened epidermal layer, shallow dermal papillae, dense collagen, and elastic fibers. There was a significant increase among those treated sites vs control regarding epidermal thickness and collagen thickness. Also, there was a highly statistically significant increase among those treated with salicylic acid vs microdermabrasion regarding the epidermal, collagen, and elastin thickness.

Conclusions

Both methods stimulate the repair process. The mechanisms underlying these variations are open for further investigations.

http://ift.tt/2laU3Q9

Wogonin, a plant derived small molecule, exerts potent anti-inflammatory and chondroprotective effects through the activation of ROS/ERK/Nrf2 signaling pathways in human Osteoarthritis chondrocytes

Publication date: Available online 22 February 2017
Source:Free Radical Biology and Medicine
Author(s): Nazir M. Khan, Abdul Haseeb, Mohammad Y. Ansari, Pratap Devarapalli, Sara Haynie, Tariq M. Haqqi
Osteoarthritis (OA), characterized by progressive destruction of articular cartilage, is the most common form of human arthritis. Here, we evaluated the potential chondroprotective and anti-inflammatory effects of Wogonin, a naturally occurring flavonoid, in IL-1β-stimulated human OA chondrocytes and cartilage explants. Wogonin completely suppressed the expression and production of inflammatory mediators including IL-6, COX-2, PGE2, iNOS and NO in IL-1β-stimulated OA chondrocytes. Further, Wogonin exhibits potent chondroprotective potential by switching the signaling axis of matrix degradation from catabolic towards anabolic ends and inhibited the expression, production and activities of matrix degrading proteases including MMP-13, MMP-3, MMP-9, and ADAMTS-4 in OA chondrocytes, and blocked the release of s-GAG and COL2A1 in IL-1β-stimulated OA cartilage explants. Wogonin also elevated the expression of cartilage anabolic factors COL2A1 and ACAN in chondrocytes and inhibited the IL-1β-mediated depletion of COL2A1 and proteoglycan content in the matrix of cartilage explants. The suppressive effect of Wogonin was not mediated through the inhibition of MAPKs or NF-κB activation. Instead, Wogonin induced mild oxidative stress through the generation of ROS and depletion of cellular GSH, thereby modulating the cellular redox leading to the induction of Nrf2/ARE pathways through activation of ROS/ERK/Nrf2/HO-1-SOD2-NQO1-GCLC signaling axis in OA chondrocytes. Molecular docking studies revealed that Wogonin can disrupt KEAP-1/Nrf-2 interaction by directly blocking the binding site of Nrf-2 in the KEAP-1 protein. Genetic ablation of Nrf2 using specific siRNA, significantly abrogated the anti-inflammatory and chondroprotective potential of Wogonin in IL-1β-stimulated OA chondrocytes. Our data indicates that Wogonin exerts chondroprotective effects through the suppression of molecular events involved in oxidative stress, inflammation and matrix degradation in OA chondrocytes and cartilage explants. The study provides novel insights into the development of Nrf2 as a promising candidate and Wogonin as a therapeutic agent for the management of OA.



http://ift.tt/2meGikD

Single-Beam Acoustic Trapping of Red Blood Cells and Polystyrene Microspheres in Flowing Red Blood Cell Saline and Plasma Suspensions

Publication date: Available online 22 February 2017
Source:Ultrasound in Medicine & Biology
Author(s): Hsiao-Chuan Liu, Ying Li, Ruimin Chen, Hayong Jung, K. Kirk Shung
Single-beam acoustic tweezers (SBATs) represent a new technology for particle and cell trapping. The advantages of SBATs are their deep penetration into tissues, reduction of tissue damage and ease of application to in vivo studies. The use of these tools for applications in drug delivery in vivo must meet the following conditions: large penetration depth, strong trapping force and tissue safety. A reasonable penetration depth for SBATs in the development of in vivo applications was established in a previous study conducted in water with zero velocity. However, capturing objects in flowing fluid can provide more meaningful results. In this study, we investigated the capability of SBATs to trap red blood cells (RBCs) and polystyrene microspheres in flowing RBC suspensions. Two different types of RBC suspension were prepared in this work: an RBC phosphate-buffered saline (PBS) suspension and an RBC plasma suspension. The results indicated that SBATs successfully trapped RBCs and polystyrene microspheres in a flowing RBC PBS suspension with an average steady velocity of 1.6 cm/s in a 2-mm-diameter polyimide. Furthermore, SBATs were found able to trap RBCs in a flowing RBC PBS suspension at speeds as high as 7.9 cm/s in a polyimide tube, which is higher than the velocity in capillaries (0.03 cm/s) and approaches the velocity in arterioles and venules. Moreover, the results also indicated that polystyrene microspheres can be trapped in an RBC plasma suspension, where aggregation is observed. This work represents a step forward in using this tool in actual in vivo experimentation.



http://ift.tt/2l1YlIK

Computer-Based Algorithmic Determination of Muscle Movement Onset Using M-Mode Ultrasonography

Publication date: Available online 22 February 2017
Source:Ultrasound in Medicine & Biology
Author(s): Andrew J. Tweedell, Courtney A. Haynes, Matthew S. Tenan
The study purpose was to evaluate the use of computer-automated algorithms as a replacement for subjective, visual determination of muscle contraction onset using M-mode ultrasonography. Biceps and quadriceps contraction images were analyzed visually and with three different classes of algorithms: pixel standard deviation (SD), high-pass filter and Teager Kaiser energy operator transformation. Algorithmic parameters and muscle onset threshold criteria were systematically varied within each class of algorithm. Linear relationships and agreements between computed and visual muscle onset were calculated. The top algorithms were high-pass filtered with a 30 Hz cutoff frequency and 20 SD above baseline, Teager Kaiser energy operator transformation with a 1200 absolute SD above baseline and SD at 10% pixel deviation with intra-class correlation coefficients (mean difference) of 0.74 (37.7 ms), 0.80 (61.8 ms) and 0.72 (109.8 ms), respectively. The results suggest that computer automated determination using high-pass filtering is a potential objective alternative to visual determination in human movement science.



http://ift.tt/2l29j0P

Significant differences of function and expression of microRNAs between ground state and serum-cultured pluripotent stem cells

Publication date: Available online 22 February 2017
Source:Journal of Genetics and Genomics
Author(s): Ying Yan, Xi Yang, Ting-Ting Li, Kai-Li Gu, Jing Hao, Qiang Zhang, Yangming Wang
Serum- and 2i-cultured embryonic stem cells (ESCs) show different epigenetic landscapes and transcriptomic profiles. The difference in the function and expression of microRNAs (miRNAs) between these two states remains unclear. Here, we showed that 2i- and serum-cultured ESCs exhibited distinctive miRNA expression profiles with >100 miRNAs differentially expressed, and the expression changes were largely due to transcriptional regulation. We further characterized the function of miRNAs differentially expressed under two conditions and found that ESCs exhibited higher degree of dependency on miRNAs for rapid proliferation; since Dgcr8-/- or Dicer1-/- but not wild-type ESCs showed slower growth rate and more accumulation in the G1 phase under 2i than serum condition. More interestingly, introduction of various self-renewal-silencing miRNAs in wild-type or Dgcr8-/- ESCs failed to silence the self-renewal in 2i media, but regained the ability to silence the self-renewal upon the addition of serum. Our findings reveal significant differences in the expression and function of miRNAs between serum- and 2i-cultured ESCs.



http://ift.tt/2lHQowg

Synthesis of clarithromycin ketolides chemically modified at the unreactive C10-methyl group

Publication date: Available online 23 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Hany Fakhry Anwar, Mioara Andrei, Kjell Undheim
Chemoselective substitutions in the C10-methyl group of erythromycin A ketolides is reported. The C10-methyl group in the clarithromycin derived substrate 10,11-anhydro-O⁶-methyl-descladinosylerythromycin was activated by conversion into an allyl acetate and thereafter to the corresponding allylic cyanide. Both the allylic acetate and the cyanide reacted with carbonyldiimidazole and ammonia to afford a C11,C12-cyclic carbamate with concurrent elimination of the allylic function to yield a methylene α,β-unsaturated ketone. Conjugate addition with amines resulted in stereoselective C-N bond formation between the terminal methylene carbon and the amino nitrogen. Carbylation in the methylene group was effected under Stille conditions for cross-coupling with Pd-catalysis. With anion stabilized nucleophiles, such as a sodium salt of a malonate, stereoselectivity was observed in the formation of the 10-substituent. Stereoselective cycloaddition with trimethylsilyldiazomethane afforded a spirane where the C10 carbon of the macrolide skeleton had become a quaternary spirocarbon. Antibacterial in vitro data for a selected group of compounds against strains of respiratory pathogens S. pneumoniae and S. aureus are reported. Most of the compounds tested showed improved activities over CLA as a reference compound against efflux resistant S. pneumoniae as well as against efflux and inducibly resistant strains of S. aureus.

Graphical abstract

http://ift.tt/2kOCgCm

Identification of compounds with cytotoxic activity from the leaf of the Nigerian medicinal plant, Anacardium occidentale L. (Anacardiaceae)

Publication date: Available online 22 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Bamigboye J. Taiwo, Amos A. Fatokun, Olujide O. Olubiyi, Olukemi T. Bamigboye-Taiwo, Fanie R. van Herdeen, Colin W. Wright
Cancer is now the second-leading cause of mortality and morbidity, behind only heart disease, necessitating urgent development of (chemo)therapeutic interventions to stem the growing burden of cancer cases and cancer death. Plants represent a credible source of promising drug leads in this regard, with a long history of proven use in the indigenous treatment of cancer. This study therefore investigated Anacardium occidentale, one of the plants in a Nigerian Traditional Medicine formulation commonly used to manage cancerous diseases, for cytotoxic activity. Bioassay-guided fractionation, spectroscopy, Alamar blue fluorescence-based viability assay in cultured HeLa cells and microscopy were used. Four compounds, zoapatanolide A (1), agathisflavone (2), 1,2-bis(2,6-dimethoxy-4-methoxycarbonylphenyl)ethane (anacardicin, 3) and methyl gallate (4), were isolated, with the most potent being zoapatanolide A with an IC50 value of 36.2 ± 9.8 µM in the viability assay. To gain an insight into the likely molecular basis of their observed cytotoxic effects, Autodock Vina binding free energies of each of the isolated compounds with seven molecular targets implicated in cancer development (MAPK8, MAPK10, MAP3K12, MAPK3, MAPK1, MAPK7 and VEGF), were calculated. Pearson correlation coefficients were obtained with experimentally-determined IC50 in the Alamar blue viability assay. While these compounds were not as potent as a standard anticancer compound, doxorubicin, the results provide reasonable evidence that the plant species contains compounds with cytotoxic activity. This study provides some evidence of why this plant is used ethnobotanically in anticancer herbal formulations and justifies investigating Nigerian medicinal plants highlighted in recent ethnobotanical surveys.

Graphical abstract

http://ift.tt/2kOChGq

Design and synthesis of selective CDK8/19 dual inhibitors: Discovery of 4,5-dihydrothieno[3',4':3,4]benzo[1,2-d]isothiazole derivatives

Publication date: Available online 22 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Koji Ono, Hiroshi Banno, Masanori Okaniwa, Takaharu Hirayama, Naoki Iwamura, Yukiko Hikichi, Saomi Murai, Maki Hasegawa, Yuka Hasegawa, Kazuko Yonemori, Akito Hata, Kazunobu Aoyama, Douglas R. Cary
To develop a novel series of CDK8/19 dual inhibitors, we employed structure-based drug design using docking models based on a library compound, 4,5-dihydroimidazolo[3',4':3,4]benzo[1,2-d]isothiazole 16 bound to CDK8. We designed various [5,6,5]-fused tricyclic scaffolds bearing a carboxamide group to maintain predicted interactions with the backbone C=O and NH of Ala100 in the CDK8 kinase hinge region. We found that 4,5-dihydrothieno[3',4':3,4]benzo[1,2-d]isothiazole derivative 29a showed particularly potent enzymatic inhibitory activity in both CDK8/19 (CDK8 IC50: 0.76 nM, CDK19 IC50: 1.7 nM). To improve the physicochemical properties and kinase selectivity of this compound, we introduced a substituted 3-pyridyloxy group into the scaffold 8-position. The resulting optimized compound 52h showed excellent in vitro potency (CDK8 IC50: 0.46 nM, CDK19 IC50: 0.99 nM), physicochemical properties, and kinase selectivity (only 5 kinases showed <35% unbound fraction at 300 nM. CDK19: 4.6%, CDK8: 8.3%, HASPIN: 23%, DYRK1B: 27%, HIP1: 32%). Based on a docking model of 52h bound to CDK8, we could explain the highly specific kinase activity profile found for this compound, based on the interaction of the pyridyl group of 52h interacting with Met174 of the CDK8 DMG activation loop.In vitro pharmacological evaluation of 52h revealed potent suppression of phosphorylated STAT1 in various cancer cells. The high oral bioavailability found for this compound enabled in vivo studies, in which we demonstrated a mechanism-based in vivo PD effect as well as tumor growth suppression in an RPMI8226 human hematopoietic and lymphoid xenograft model in mouse [T/C: −1% (2.5 mg/kg, qd)].

Graphical abstract

http://ift.tt/2kOyg4K

Synthesis of native-like crosslinked duplex RNA and study of its properties

Publication date: Available online 21 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Kazumitsu Onizuka, Madoka E. Hazemi, Justin M. Thomas, Leanna R. Monteleone, Ken Yamada, Shuhei Imoto, Peter A. Beal, Fumi Nagatsugi
A variety of enzymes have been found to interact with double-stranded RNA (dsRNA) in order to carry out its functions. We have endeavored to prepare the covalently crosslinked native-like duplex RNA, which could be useful for biochemical studies and RNA nanotechnology. In this study, the interstrand covalently linked duplex RNA was formed by a crosslinking reaction between vinylpurine (VP) and the target cytosine or uracil in RNA. We measured melting temperatures and CD spectra to identify the properties of the VP crosslinked duplex RNA. The crosslinking formation increased the thermodynamic stability without disturbing the natural conformation of dsRNA. In addition, a competitive binding experiment with the duplex RNA binding enzyme, ADAR2, showed the crosslinked dsRNA bound the protein with nearly the same binding affinity as the natural dsRNA, confirming that it has finely preserved the natural traits of duplex RNA.

Graphical abstract

http://ift.tt/2kOxaG1

Providing Feedback

Publication date: Available online 22 February 2017
Source:Academic Radiology
Author(s): David Sarkany, Lori Deitte
Feedback is an essential component of education. It is designed to influence, reinforce, and change behaviors, concepts, and attitudes in learners. Although providing constructive feedback can be challenging, it is a learnable skill. The negative consequences of destructive feedback or lack of feedback all together are far-reaching. This article summarizes the components of constructive feedback and provides readers with tangible skills to enhance their ability to give effective feedback to learners and peers.



http://ift.tt/2lrxEAS

Exosomes derived from human amniotic epithelial cells accelerate wound healing and inhibit scar formation

Abstract

Wound healing is a highly orchestrated physiological process consisting of a complex events, and scarless wound healing is highly desired for the development and application in clinical medicine. Recently, we have demonstrated that human amniotic epithelial cells (hAECs) promoted wound healing and inhibited scar formation through a paracrine mechanism. However, exosomes (Exo) are one of the most important paracrine factors. Whether exosomes derived from human amniotic epithelial cells (hAECs-Exo) have positive effects on scarless wound healing have not been reported yet. In this study, we examined the role of hAECs-Exo on wound healing in a rat model. We found that hAECs, which exhibit characteristics of both embryonic and mesenchymal stem cells, have the potential to differentiate into all three germ layers. hAECs-Exo ranged from 50 to 150 nm in diameter, and positive for exosomal markers CD9, CD63, CD81, Alix, TSG101 and HLA-G. Internalization of hAECs-Exo promoted the migration and proliferation of fibroblasts. Moreover, the deposition of extracellular matrix (ECM) were partly abolished by the treatment of high concentration of hAECs-Exo (100 μg/mL), which may be through stimulating the expression of matrix metalloproteinase-1 (MMP-1). In vivo animal experiments showed that hAECs-Exo improved the skin wound healing with well-organized collagen fibers. Taken together, These findings represent that hAECs-Exo can be used as a novel hope in cell-free therapy for scarless wound healing.

http://ift.tt/2kOmQ0I

Adjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: Long-term results of a phase 3 multicentre randomised controlled trial

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Lei Chen, Chao-Su Hu, Xiao-Zhong Chen, Guo-Qing Hu, Zhi-Bin Cheng, Yan Sun, Wei-Xiong Li, Yuan-Yuan Chen, Fang-Yun Xie, Shao-Bo Liang, Yong Chen, Ting-Ting Xu, Bin Li, Guo-Xian Long, Si-Yang Wang, Bao-Min Zheng, Ying Guo, Ying Sun, Yan-Ping Mao, Ling-Long Tang, Yu-Ming Chen, Meng-Zhong Liu, Jun Ma
Aim of the studyPrevious results from our trial showed that adjuvant cisplatin and fluorouracil chemotherapy did not significantly improve survival after concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (NPC) at 2 years. Here, we present the data of long-term survival and late toxicities to further assess the ultimate therapeutic index of adjuvant chemotherapy (AC).MethodsPatients with stage III–IVB (except T3-4N0) NPC were randomly assigned to receive CCRT plus AC or CCRT only at seven institutions in China. Patients in both groups received cisplatin 40 mg/m² weekly up to 7 weeks concurrently with radiotherapy. The CCRT plus AC group subsequently received adjuvant cisplatin 80 mg/m² and fluorouracil 800 mg/m²/d for 120 h every 4 weeks for three cycles. The primary end-point was failure-free survival.ResultsTwo hundred and fifty-one patients were randomised to the CCRT plus AC group and 257 to the CCRT only group. After a median follow-up of 68.4 months, estimated 5-year failure-free survival rate was 75% in the CCRT plus AC group and 71% in the CCRT only group (hazard ratio 0.88, 95% confidence interval 0.64–1.22; p = 0.45). 66 (27%) of 249 patients in the CCRT plus AC group and 53 (21%) of 254 patients in the CCRT only group developed one or more late grade 3–4 toxicities (p = 0.14).ConclusionAdjuvant cisplatin and fluorouracil chemotherapy still failed to demonstrate significant survival benefit after CCRT in locoregionally advanced NPC based on the long-term follow-up data, and addition of adjuvant cisplatin and fluorouracil did not significantly increase late toxicities.Registration numberNCT00677118.



http://ift.tt/2lap2M7

Acceptable regret model in the end-of-life setting: Patients require high level of certainty before forgoing management recommendations

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Athanasios Tsalatsanis, Iztok Hozo, Benjamin Djulbegovic
BackgroundThe acceptable regret model postulates that under some circumstances decision-makers may tolerate wrong decisions. The purpose of this work is to empirically evaluate the acceptable regret model of decision-making in the end-of-life care setting, where terminally ill patients consider seeking curative treatment versus accepting hospice/palliative care.MethodsWe conducted interviews with 48 terminally ill patients to assess their preferences about end-of-life treatment choices. We first elicited the patient's regret of potentially wrong choices with regards to the recommended management and provided information on life expectancy estimated by two prognostication models. We then elicited the patients' level of acceptable regret by assessing their tolerance for potentially wrongly accepting hospice care versus continuing unnecessary treatment. Using the levels of acceptable regret, we computed: (1) the probability of death above which a patient would tolerate wrongly accepting hospice care and (2) the probability of death below which the patient would tolerate unnecessary treatment. We also assessed patients' understanding of the interview questions using a 7-point Likert scale.ResultsWe found that the median probability of death above which a patient would tolerate wrongly accepting hospice care was 96% (95% CI 94–98%), whereas the median probability of death below which a patient would tolerate unnecessary treatment was 2.5% (95% CI 0.3–5%). We also found that the levels of acceptable regret measured for wrong hospice referral (mean = 1.52; SD = 2.26; min = 0; max = 7.72) were similar to the levels of acceptable regret measured for unnecessary treatment (mean = 2.10; SD = 4.33; min = 0; max = 23) (KW test; p = 0.68) indicating that acceptable regret levels for either of the wrong decisions is felt similarly. The results were independent of the estimated probability of death communicated to patients before the acceptable regret interview.ConclusionsWe have elicited empirical data that corroborated the acceptable regret hypothesis. The requirement for high level of certainty before accepting recommended management may explain the difficulties related to decision-making in the end-of-life setting.



http://ift.tt/2lrDd1Y

Systematic analysis of early phase clinical studies for patients with breast cancer: Inclusion of patients with brain metastasis

Publication date: Available online 22 February 2017
Source:Cancer Treatment Reviews
Author(s): R. Costa, N. Gill, A.W. Rademaker, B.A. Carneiro, Y.K. Chae, P. Kumthekar, W.J. Gradishar, R. Kurzrock, F.J. Giles
PurposeThis systematic review aims to better define the limitations and patterns with which patients with MBC and CNS metastasis are enrolled into early phase developmental therapeutics trials.MethodsIn June 2016, PubMed search was conducted using the following keywords: "Breast cancer". Drug-development phase 1, phase 2 or phase 1/2 trials for patients with MBC were included. Multiple-histology trials and trials without an efficacy endpoint were excluded.ResultsIn total, 1,474 studies were included; Inclusion criteria for 423 (29%) allowed for CNS metastasis, 770 (52%) either excluded or did not document eligibility of patients with CNS disease. Trials accruing patients with HER2-positive MBC and including targeted therapies had higher odds of allowing for patients with CNS disease (adjusted OR 1.56, 95% CI 1.08-2.2.6;p = 0.019 and 1.49, 95% 1.08-2.06; p = 0.014, respectively). There were also higher odds of accrual of patients with CNS involvement into clinical trials over time (odds ratio = 1.10, 95% CI 1.07-1.12; p < 0.0001).ConclusionMost published early phase clinical trials either did not clearly document or did not allow for accrual of patients with CNS disease. Early phase trials with targeted agents or enrolling HER2+ MBC had higher odds of permitting CNS metastases.



http://ift.tt/2me814O

Ovarian Ablation for Premenopausal Breast Cancer: A Review of Treatment Considerations and the Impact of Premature Menopause

Publication date: Available online 22 February 2017
Source:Cancer Treatment Reviews
Author(s): Melica Nourmoussavi, Gary Pansegrau, Jason Popesku, Geoffrey L. Hammond, Janice S. Kwon, Mark S. Carey
Historically, ovarian ablation (OA) was used as therapy for women with recurrent hormone-receptor-positive (HRP) premenopausal breast cancer. With the publication of the SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial) randomized trials, there is considerable interest in OA as an adjuvant treatment, either in combination with tamoxifen or an aromatase inhibitor (AI). Thus, we have reviewed current guidelines and key studies on this important topic and have highlighted the relevant biological and pharmacological aspects of the various endocrine therapies. The results of two key randomized trials addressing the use and controversies of OA in premenopausal breast cancer are discussed and recent research emphasizing the detrimental consequences of premature menopause and the cost-effectiveness of OA is presented. In low-risk patients with HRP premenopausal breast cancer, OA is not beneficial and tamoxifen remains the anti-hormone treatment of choice. In high-risk women (previous chemotherapy or women younger than 35), OA in combination with AI is more effective but is arguably not cost-effective, particularly when OA is achieved medically using a GnRH agonist/antagonist. Compared to tamoxifen alone, the SOFT trial showed a 4.5-7.7% reduction in breast cancer relapse using OA (in combination with either tamoxifen or AI) in high-risk women, though the 5-year overall survival benefit was limited (1.4-3.6%). Premature menopause is associated with long-term mortality risks and women often experience significant menopausal symptoms that impact on quality of life. These considerations should play a role in the treatment selection of those patients who may benefit from adjuvant OA.



http://ift.tt/2kOmOGm

Hepatitis C virus infection and risk of thyroid cancer: A systematic review and meta-analysis

Publication date: Available online 20 February 2017
Source:Arab Journal of Gastroenterology
Author(s): Peng Wang, Zhaohai Jing, Changjiang Liu, Meihua Xu, Pei Wang, Xiao Wang, Yulei Yin, Ying Cui, Dunlin Ren, Xiaopang Rao
PurposeSeveral epidemiological studies investigated the relationship between hepatitis C virus (HCV) infection and risk of thyroid cancer, but the results were not consistent. A systematic review and meta-analysis was conducted to assess the impact of HCV infection on thyroid cancer risk.MethodsThe literature was searched up to March 15, 2016 for case-control or cohort studies on the association between HCV infection and thyroid cancer risk. The summary relative risks (RR) and 95% confidence intervals (CI) were calculated.ResultsFive studies (two case-control studies and three cohort studies) were included in the meta-analysis, with a total of 751,551 participants and 367 cases of thyroid cancer. Meta-analysis of those 5 studies found that there was no statistically significant association between HCV infection and thyroid cancer risk (summary RR=2.09, 95%CI 0.78–5.64, p=0.145; I²=81.2%). However, HCV infection was significantly associated with increased risk of thyroid cancer (summary RR=2.86, 95%CI 1.63–5.03, p=0.003; I²=24.9%) after adjusting the heterogeneity.ConclusionThere is a possible association between HCV infection and increased risk of thyroid cancer, and more cohort studies are needed to validate the possible association.



http://ift.tt/2m9E8FM

Gastric heterotopia in the rectum. A rare cause of ectopic gastric tissue

Publication date: Available online 20 February 2017
Source:Arab Journal of Gastroenterology
Author(s): George A. Salem, Javid Fazili, Tauseef Ali
Gastric heterotopia refers to the discovery of normal gastric tissue at foreign, unexpected sites. It has been described anywhere in the alimentary tract, even in the mediastinum, scrotum, and spinal cord. It is not uncommonly seen in the oesophagus or small intestine. However, large bowel lesions are rare, with the most common location of colonic lesions is the rectum. Although it is a rare entity, it may be the source for significant problems such as rectal bleeding, abdominal pain, deep rectal pain, and malignancy. Here, we report an additional case of gastric heterotopia in the rectum of a 56year old gentleman, and review the literature.



http://ift.tt/2mn8DEv

Cannabidiol Treatment for Refractory Seizures in Sturge-Weber syndrome

Publication date: Available online 22 February 2017
Source:Pediatric Neurology
Author(s): Emma H. Kaplan, Elizabeth A. Offermann, Jacqueline W. Sievers, Anne M. Comi
BackgroundSturge-Weber syndrome (SWS) results in leptomeningeal vascular malformations, medically-refractory epilepsy, stroke(s), and cognitive impairments. Cannabidiol (CBD), a cannabinoid without psychoactive properties, has been demonstrated in preclinical models to possibly have anticonvulsant, anti-oxidant, and neuroprotective actions.MethodsFive subjects with SWS brain involvement and treatment-resistant epilepsy were enrolled. Motor seizure frequency, quality of life (QoL), and adverse events were recorded from the 8 week pre-treatment period, 8 weeks after starting maintenance dose (Week 14), and most recent visit.ResultsFour subjects had data through Week 14; one of whom initially withdrew for lack of efficacy, but because of other benefits re-enrolled with a lower dose. Two subjects at Week 14 and three bilaterally brain involved subjects at last visit had greater than 50% seizure reduction, reported improved quality of life, and remain on CBD 63 to 80 weeks after starting drug. Three subjects reported mild side effects considered related to CBD.ConclusionThis study suggests that CBD may be well-tolerated as adjunctive medication for seizure management and provides initial data supporting further study of CBD in SWS patients.



http://ift.tt/2kOcDBx

Primary Amoebic Meningoencephalitis in children: a report of two fatal cases and review of the Literature

Publication date: Available online 22 February 2017
Source:Pediatric Neurology
Author(s): Robert C. Stowe, Davut Pehlivan, Katie E. Friederich, Michael A. Lopez, Shannon M. DiCarlo, Varina L. Boerwinkle
BackgroundPrimary amoebic meningoencephalitis (PAM) is a rare, almost uniformly fatal disease of cerebral invasion by Naegleria fowleri, occurring most commonly after swimming in warm fresh water in summer months. Treatment using the experimental medication miltefosine has demonstrated improved survival and favorable neurocognitive outcome in a 2013 North American case. Little has been described regarding electrographic recordings of such patients and little to compare known pediatric cases of survival.Patient DescriptionsWe describe two children, aged 4 and 14 years, who both presented with seizures and altered mental status after recent fresh water swimming exposures. With evidence of pyogenic meningitis and examination of cerebrospinal fluid (CSF) demonstrating motile trophozoites on wet mount, N. fowleri meningoencephalitis was diagnosed. Amoebicidal antibiotic regimens with miltefosine were administered. Continuous electroencephalographam (EEG) monitoring demonstrated evolution from diffuse slowing to seizures, status epilepticus, and eventually global attenuation and absence of activity. Both patients ultimately died following complications of progressively increasing intracranial pressure (ICP) and hemodynamic compromise.ConclusionsPrimary amoebic meningoencephalitis is a serious, sporadic infection. Herein describes our experience with two fatal pediatric cases, the evolution of EEG findings, and comparisons to the 13 reported cases of pediatric survivors.



http://ift.tt/2laihKn

Hypertrophic neuropathy of Sciatic nerve

Publication date: Available online 22 February 2017
Source:Pediatric Neurology
Author(s): Uluç Yiş, Mutluay Arslan, Handan Güleryüz




http://ift.tt/2laje5k

Propeller Perforator Flaps of Extremities Seem Less Reliable

J reconstr Microsurg
DOI: 10.1055/s-0036-1597991

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Full text

http://ift.tt/2lMLIFM

Controversies in the risk of neoplasia in GH deficiency

Publication date: Available online 22 February 2017
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): S. Pekic, M. Stojanovic, V. Popovic
Growth hormone (GH) replacement in GH deficient (GHD) children secures normal linear growth, while in GHD adults it improves metabolic status, body composition and quality of life. Safety of GH treatment is an important issue in particular concerning the controversy of potential cancer risk. Unlike in congenital IGF-1 deficiency, there is no complete protection against cancer in GHD patients. Important modifiable risk factors in GHD patients are obesity, insulin resistance, sedentary behaviour, circadian rhythm disruption, chronic low grade inflammation and concomitant sex hormone replacement. Age, family history, hereditary cancer predisposition syndromes or cranial irradiation may present non-modifiable risk factors. Quantifying the risk of cancer in relation to GH therapy in adult GHD patients is complex. There is evidence that links GH to cancer occurrence or promotion, but the evidence is progressively weaker when moving from in vitro studies to in vivo animal studies to epidemiological studies and finally to studies on GH treated patients. GH-IGF inhibition in experimental animals leads to decreased cancer incidence and progression. Epidemiological studies suggest an association of high normal circulating IGF-1 or GH to cancer incidence in general population. Data regarding cancer incidence in acromegaly are inconsistent but thyroid and colorectal neoplasias are the main source of concern. Replacement therapy with rhGH for GHD is generally safe. Overall the rate of de novo cancers was not increased in studies of GH-treated GHD patients. Additional caution is mandated in patients with history of cancer, strong family history of cancer and with advancing age. Childhood cancer survivors may be at increased risk for secondary neoplasms compared with general population. In this subgroup GH therapy should be used cautiously and with respect to other risk factors (cranial irradiation etc). We believe that the benefits of GH therapy against the morbidity of untreated GH deficiency outweigh the theoretical cancer risk. Proper monitoring of GH treatment with diligent cancer surveillance remains essential.



http://ift.tt/2lrc8w8

Focus on growth hormone deficiency and bone in adults

Publication date: Available online 22 February 2017
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Nicholas A. Tritos
Growth hormone (GH) exerts several effects on the skeleton, mediated either directly or indirectly, leading to increased bone formation and resorption rates. Patients with growth hormone deficiency (GHD) of adult onset have decreased bone mineral density (BMD) and increased fracture risk. Some, but not all, studies have found that adults with childhood onset GHD also have lower BMD than healthy control s. Adults with GHD of childhood onset have smaller bone dimensions, leading to possible underestimation of areal BMD (measured by dual energy X-ray absorptiometry), thus potentially confounding the interpretation of densitometric data. Available data suggest that patients with childhood onset GHD are at increased fracture risk.Prospective studies and some clinical trials found that GH replacement for at least 18-24 months leads to increased BMD. Retrospective and prospective data suggest that GH replacement is associated with decreased fracture risk in adults. However, data from randomized clinical trials are lacking.



http://ift.tt/2kO5ZeL

Vitamin D analogues: Potential use in cancer treatment

Publication date: Available online 22 February 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Michael J. Duffy, Alyson Murray, Naoise C. Synnott, Norma O'Donovan, John Crown
The vitamin D receptor (VDR) is a member of the thyroid-steroid family of nuclear transcription factors. Following binding of the active form of vitamin D, i.e., 1,25(OH)2D3 (also known as calcitriol) and interaction with co-activators and co-repressors, VDR regulates the expression of several different genes. Although relatively little work has been carried out on VDR in human cancers, several epidemiological studies suggest that low circulating levels of vitamin D are associated with both an increased risk of developing specific cancer types and poor outcome in patients with specific diagnosed cancers. These associations apply especially in colorectal and breast cancer. Consistent with these findings, calcitriol as well as several of its synthetic analogues have been shown to inhibit tumor cell growth in vitro and in diverse animal model systems. Indeed, some of these vitamin D analogues with low calcemic inducing activity (e.g., EB1089, inecalcitol, paricalcitol) have progressed to clinical trials in patients with cancer. Preliminary results from these trials suggest that these vitamin D analogues have minimal toxicity, but clear evidence of efficacy remains to be shown. Although evidence of efficacy for mono-treatment with vitamin D analogues is currently lacking, several studies have reported that supplementation with calcitriol or the presence of high endogenous circulating levels of vitamin D enhances response to standard therapies.



http://ift.tt/2lxceAJ

MR Imaging

Publication date: Available online 22 February 2017
Source:Radiologic Clinics of North America
Author(s): Lilian C. Wang

Teaser

Breast MR imaging is the most sensitive modality for breast cancer detection. This high sensitivity has led to widespread adoption of this technique, particularly in screening women at elevated risk for breast cancer. Despite its high sensitivity, standard breast MR imaging protocols are limited by moderate specificity and relative higher cost, longer examination time, longer interpretation time, and lower availability compared with mammography and ultrasound. As such, new techniques in MR imaging, including abbreviated breast MR imaging, pharmacokinetic modeling, and diffusion-weighted imaging, are active areas of research. This article discusses the rationale, current evidence, and limitations of these new MR imaging techniques.


http://ift.tt/2lr4kKx

11β-hydroxysteroid dehydrogenase type 1 and pregnancy: Role in the timing of labour onset and in myometrial contraction

Publication date: Available online 22 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Francesco Damiani, Sofia Makieva, Sara F. Rinaldi, Lei Hua, Paola Marcolongo, Felice Petraglia, Jane E. Norman
Glucocorticoids play a primary role in the maturation of fetal organs and may contribute to the onset of labour. Glucocorticoid activity depends on the 11β-hydroxysteroid dehydrogenase family (11β-HSDs), catalysing the interconversion between "active" cortisol into inactive cortisone. No definitive study exists on 11β-HSD expression profile in human decidua and myometrium during pregnancy.We investigated the implications of 11β-HSD1 in the regulation of uterine activity in pregnancy, examining its role on contraction of a myocyte cell line and murine 11β-hsd1 levels in utero. Murine 11β-hsd1 mRNA and protein levels in utero progressively increased until the last day of gestation and significantly decreased at the onset of labour (P < 0.0001) (n = 3 to 5 in the various gestational days analysed). Experiments on human myometrial samples confirm the significant fall in 11β-hsd1 mRNA levels at labour, compared to end pregnancy samples (n = 5 to 8). In vitro experiments showed that human myometrial contraction is inhibited by using a non-selective inhibitor of 11β-HSD1. The present study shows the temporal localisation of 11β-HSD1 in uterus, highlighting its importance in the timing of gestation and suggesting its contribution in the myometrium contraction.



http://ift.tt/2lHaWF7

Androgen-mediated regulation of skeletal muscle protein balance

Publication date: Available online 22 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Michael L. Rossetti, Jennifer L. Steiner, Bradley S. Gordon
Androgens significantly alter muscle mass in part by shifting protein balance in favor of net protein accretion. During various atrophic conditions, the clinical impact of decreased production or bioavailability of androgens (termed hypogonadism) is important as a loss of muscle mass is intimately linked with survival outcome. While androgen replacement therapy increases muscle mass in part by restoring protein balance, this is not a comprehensive treatment option due to potential side effects. Therefore, an understanding of the mechanisms by which androgens alter protein balance is needed for the development of androgen-independent therapies. While the data in humans suggest androgens alter protein balance (both synthesis and breakdown) in the fasted metabolic state, a predominant molecular mechanism(s) behind this observation is still lacking. This failure is likely due in part to inconsistent experimental design between studies including failure to control nutrient/feeding status, the method of altering androgens, and the model systems utilized.



http://ift.tt/2l9RA8y

IL-1β directly suppress ghrelin mRNA expression in ghrelin-producing cells

Publication date: Available online 22 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Mika Bando, Hiroshi Iwakura, Yoko Ueda, Hiroyuki Ariyasu, Hidefumi Inaba, Yasushi Furukawa, Hiroto Furuta, Masahiro Nishi, Takashi Akamizu
In animal models, ghrelin production is suppressed by LPS administration. To elucidate the detailed molecular mechanisms involved in the phenomenon, we investigated the effects of LPS and LPS-inducible cytokines, including TNF-α, IL-1β, and IL-6, on the expression of ghrelin in the ghrelin-producing cell line MGN3-1. These cells expressed IL-1R, and IL-1β significantly suppressed ghrelin mRNA levels. The suppressive effects of IL-1β were attenuated by knockdown of IKKβ, suggesting the involvement of the NF-κB pathway. These results suggested that IL-1β is a major regulator of ghrelin expression during inflammatory processes.



http://ift.tt/2lH99QK

External-beam radiation therapy combined with limb-sparing surgery in elderly patients (>70 years) with primary soft tissue sarcomas of the extremities

Abstract

Purpose

To report our experience with EBRT combined with limb-sparing surgery in elderly patients (>70 years) with primary extremity soft tissue sarcomas (STS).

Methods

Retrospectively analyzed were 35 patients (m:f 18:17, median 78 years) who all presented in primary situation without nodal/distant metastases (Charlson score 0/1 in 18 patients; ≥2 in 17 patients). Median tumor size was 10 cm, mainly located in lower limb (83%). Stage at presentation (UICC7th) was Ib:3%, 2a:20%, 2b:20%, and 3:57%. Most lesions were high grade (97%), predominantly leiomyosarcoma (26%) and undifferentiated pleomorphic/malignant fibrous histiocytoma (23%). Limb-sparing surgery was preceded (median 50 Gy) or followed (median 66 Gy) by EBRT.

Results

Median follow-up was 37 months (range 1–128 months). Margins were free in 26 patients (74%) and microscopically positive in 9 (26%). Actuarial 3‑ and 5‑year local control rates were 88 and 81% (4 local recurrences). Corresponding rates for distant control, disease-specific survival, and overall survival were 57/52%, 76/60%, and 72/41%. The 30-day mortality was 0%. Severe postoperative complications were scored in 8 patients (23%). Severe acute radiation-related toxicity was observed in 2 patients (6%). Patients with Charlson score ≥2 had a significantly increased risk for severe postoperative complications and acute radiation-related side effects. Severe late toxicities were found in 7 patients (20%), including fractures in 3 (8.6%). Final limb preservation rate was 97%.

Conclusion

Combination of EBRT and limb-sparing surgery is feasible in elderly patients with acceptable toxicities and encouraging but slightly inferior outcome compared to younger patients. Comorbidity correlated with postoperative complications and acute toxicities. Late fracture risk seems slightly increased.

http://ift.tt/2l1aNZc

Florid splenic gamma/delta T-cell proliferation in patients with splenomegaly and cytopenias: A "high stakes" diagnostic challenge

Publication date: Available online 22 February 2017
Source:Human Pathology
Author(s): Shanxiang Zhang, Michael G. Bayerl
ObjectivesSplenic gamma/delta T-cell proliferation is rare and correct diagnosis is critical for adequate clinical management.MethodsTwo splenectomy cases from patients with splenomegaly and cytopenias were studied by morphological evaluation, extensive immunophenotyping, FISH and molecular studies. The clinicopathologic findings were compared with splenic T gamma/delta neoplasia, notably hepatosplenic T-cell lymphoma (HSTL) and T-cell large granular lymphocytic leukemia (TLGL) of the variety T gamma/delta.ResultsThe enlarged spleens showed expanded red pulp with markedly increased gamma/delta T cells, which share significant to complete overlapping morphology and immunophenotype with the neoplastic gamma/delta T cells in HSTL and gamma/delta TLGL. However, they were polyclonal by molecular study and showed no evidence of isochromosome 7q. Splenectomy alone led to long-term clinical remission in both patients.ConclusionsTwo florid reactive splenic gamma/delta T-cell proliferations mimicking gamma/delta T-cell neoplasia were reported for the first time in English literature. Recognition of this exceedingly rare phenomenon is critical in prevention of misdiagnosis with potentially catastrophic consequences.



http://ift.tt/2lGXBwL

Clinicopathologic Features of Peripheral Nerve Sheath Tumors Involving the Eye and Ocular Adnexa

Publication date: Available online 22 February 2017
Source:Human Pathology
Author(s): Mingjuan L. Zhang, Maria J. Suarez, Thomas M. Bosley, Fausto J. Rodriguez
Peripheral nerve sheath tumors (PNSTs) are known to occur in the orbit and comprise 4% of all orbital tumors, but have not been well-studied in contemporary literature. Ninety specimens involving the eye and ocular adnexa (1979–2015) from 67 patients were studied. The mean age was 32.5years. Locations included orbit (58.9%), eyelid (60.0%) and other ocular adnexa. A large majority of specimens were neurofibromas (70.0%), followed by schwannomas (11.1%), neuromas (11.1%), granular cell tumors (n=4), nerve sheath myxomas (n=2), and malignant peripheral nerve sheath tumor (n=1). Fifty-six (88.9%) neurofibroma cases were neurofibromatosis 1 (NF1)-associated. Among neurofibromas, 31.7% were localized, 38.1% were plexiform, 25.4% were diffuse, and 4.8% were diffuse and plexiform. These tumors involved skin (31.7%), soft tissue (11.1%), skeletal muscle (22.2%), peripheral nerve (63.0%), lacrimal gland (20.6%) and choroid (n=1). Other histologic findings included pseudo-Meissner corpuscles (27%), Schwann cell nodules (4.8%), prominent myxoid component (7.9%), melanin-like pigment (3.2%), and inflammation (14.3%). Available immunostains included S100 (+ in 15/15 cases), EMA (+ in 2/4 cases), CD34 (+ in 4/4 cases), and Ki67 (<1% in 4/4 cases). Among 10 schwannomas, 8 were conventional and 2 were plexiform. Observed features included capsule (n=5), hyalinized vessels (n=5), Verocay bodies (n=7), and Antoni B pattern (n=5). Immunostaining included S100+ in 4/4 cases, collagen IV+ and Ki67<1% in 3/3 cases. Neurofibromas are the most common PNST involving the eye and ocular adnexa and the majority are associated with NF1. Plexiform and diffuse patterns and the presence of pseudo-Meissner corpuscles are relatively frequent in this area.



http://ift.tt/2l9RRID

Denosumab-Treated Giant Cell Tumor of Bone Its Histologic Spectrum and Potential Diagnostic Pitfalls

Publication date: Available online 22 February 2017
Source:Human Pathology
Author(s): Pablo Daniel Roitman, Federico Jauk, Germán Luis Farfalli, José Ignacio Albergo, Luis Alberto Aponte-Tinao
Giant cell tumor of bone (GCT) is a locally aggressive, rarely metastasizing primary bone neoplasm that occurs most frequently in the epiphysis of long bones of young adults. It is composed of round, oval or elongated mononuclear cells admixed with osteoclast-like giant cells that express receptor activator of nuclear factor- қB (RANK). The mononuclear stromal cells express RANK ligand (RANKL), a mediator of osteoclast activation. Denosumab, a monoclonal antibody that inhibits RANKL reducing tumor-associated bone lysis, has been used to treat selected cases of GCT. We reviewed the clinical records and histologic slides of 9 patients with GCT that had received denosumab therapy and were subsequently surgically treated. There were 5 males and 4 females, aged 20 to 66 (mean 36). Duration of treatment varied from 2,5 to 13months (mean 5,9). In all cases, different degrees of ossification, fibrosis, depletion of giant cells and proliferation of mononuclear cells were seen. With this combination of changes, denosumab-treated GCT may mimick other lesions such as fibrous dysplasia, juvenile ossifying fibroma, nonossifying fibroma and osteoblastoma. Less frequent but more relevant is the presence of cellular atypia or patterns of ossification that resemble an undifferentiated pleomorphic sarcoma, a conventional osteosarcoma or a low-grade central osteosarcoma. The presence of clinical and radiological response to denosumab along with the lack of high mitotic activity, atypical mitotic figures, extensive necrosis or a permeative pattern of growth, represent clues to achieve a correct diagnosis.



http://ift.tt/2lH1wd4

Comprehensive immunohistochemical analysis of histone deacetylases in pancreatic neuroendocrine tumors: HDAC5 as a predictor of poor clinical outcome

Publication date: Available online 22 February 2017
Source:Human Pathology
Author(s): Eckhard Klieser, Romana Urbas, Stefan Stättner, Florian Primavesi, Tarkan Jäger, Adam Dinnewitzer, Christian Mayr, Tobias Kiesslich, Klaus Holzmann, Pietro Di Fazio, Daniel Neureiter, Stefan Swierczynski
Epigenetic factors contribute to carcinogenesis, tumor promotion and chemoresistance. Histone deacetylases (HDACs) are epigenetic regulators that primarily cause chromatin compaction, leading to inaccessibility of promoter regions and eventually gene silencing. Many cancer entities feature over-expression of HDACs. Currently, the role of HDACs in pancreatic neuroendocrine tumors (pNETs) is unclear. We analyzed expression patterns of all HDAC classes (Class I, IIA, IIB, III & IV) in five human tissue microarrays (TMA) representing 57 pNETs resected between 1997 and 2013 and corresponding control tissue. All pNET cases were characterized clinically and pathologically according to recent staging guidelines. The investigated cases included 32 (56.1%) female and 25 (43.9%) male pNET patients (total n=57, 47.4% immunohistochemically endocrine positive). Immunohistochemical profiling revealed a significant up-regulation of all HDAC classes in pNET versus control with different levels of intensity and extensity ranging from 1.5 to >7-fold up-regulation. Additionally, expression of several HDACs (HDAC-1, −2, −5, −11 and Sirt 1) was significantly increased in G3 tumors. Correlation analysis showed a significant association between the protein expression of HDAC classes I, III and IV and rate of the pHH3/Ki-67-associated mitotic and proliferation index. Furthermore, especially HDAC-5 proved as a negative predictor of disease-free and overall survival in pNET patients. Overall, we demonstrate that specific members of all four HDAC classes are heterogeneously expressed in pNET. Moreover, expression of HDACs was associated with tumor grading, proliferation markers and patient survival, therefore representing interesting new targets in pNET treatment.



http://ift.tt/2l9H80R

Primary extraskeletal osteosarcoma: a clinicopathological study of 18 cases focusing on MDM2 amplification status

Publication date: Available online 22 February 2017
Source:Human Pathology
Author(s): Kyoko Yamashita, Kenichi Kohashi, Yuichi Yamada, Yoshihiro Nishida, Hiroshi Urakawa, Yoshinao Oda, Shinya Toyokuni
Extraskeletal osteosarcoma (ESOS) is an uncommon malignant neoplasm. Most ESOSs are high grade, although some low-grade cases have been reported. A few cases of ESOS with MDM2 amplification have also been reported, suggesting some similarity to skeletal low-grade osteosarcoma such as parosteal osteosarcoma, where MDM2 is often amplified. However, the frequency of low-grade cases and cases with MDM2 amplification among ESOSs remains unknown and their relationship is unclear. To clarify this, we examined 18 primary ESOS cases clinically, pathologically, and genetically, focusing on their MDM2 amplification status. Our cases comprised 10 males and 8 females whose mean age was 58.6 years; the most common site of the lesion was the thigh and buttock. There were one histologically low grade case evaluated by biopsy specimen with an aggressive course and 2 relatively low grade cases whose lesions were of low grade for the most part. MDM2 amplification status was revealed by fluorescence in situ hybridization in all 18 cases; 2 patients—histologically intermediate and high-grade cases—were found to have MDM2 amplification. In conclusion, this study indicates that histologically low-grade and relatively low-grade cases of ESOS are not always associated with MDM2 amplification. The ESOS case with MDM2 amplification could be high grade, although MDM2-amplified dedifferentiated liposarcoma with osteogenic differentiation should be ruled out in making the diagnosis.



http://ift.tt/2lGY4Pm

Utility of comprehensive genomic sequencing for detecting HER2-positive colorectal cancer

Publication date: Available online 22 February 2017
Source:Human Pathology
Author(s): Yoshifumi Shimada, Ryoma Yagi, Hitoshi Kameyama, Masayuki Nagahashi, Hiroshi Ichikawa, Yosuke Tajima, Takuma Okamura, Mae Nakano, Masato Nakano, Yo Sato, Takeaki Matsuzawa, Jun Sakata, Takashi Kobayashi, Hitoshi Nogami, Satoshi Maruyama, Yasumasa Takii, Takashi Kawasaki, Kei-ichi Homma, Hiroshi Izutsu, Keisuke Kodama, Jennifer E. Ring, Alexei Protopopov, Stephen Lyle, Shujiro Okuda, Kohei Akazawa, Toshifumi Wakai
HER2-targeted therapy is considered effective for KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (CRC). In general, HER2 status is determined by the use of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Comprehensive genomic sequencing (CGS) enables the detection of gene mutations and copy number alterations including KRAS mutation and HER2 amplification; however, little is known about the utility of CGS for detecting HER2-positive CRC. To assess its utility, we retrospectively investigated 201 patients with stage I–IV CRC. The HER2 status of the primary site was assessed using IHC and FISH, and HER2 amplification of the primary site was also assessed using CGS, and the findings of these approaches were compared in each patient. CGS successfully detected alterations in 415 genes including KRAS codon 12/13 mutation and HER2 amplification. Fifty-nine (29%) patients had a KRAS codon 12/13 mutation. Ten (5%) patients were diagnosed as HER2-positive because of HER2 IHC 3+, and the same 10 (5%) patients had HER2 amplification evaluated using CGS. The results of HER2 status and HER2 amplification were completely identical in all 201 patients (P < 0.001). Nine of the 10 HER2-positive patients were KRAS 12/13 wild-type and were considered possible candidates for HER2-targeted therapy. CGS has the same utility as IHC and FISH for detecting HER2-positive patients who are candidates for HER2-targeted therapy, and facilitates precision medicine and tailor-made treatment.



http://ift.tt/2l9yGP5

Reply to: comment on “Meta-analysis of GSTP1, GSTM1, and GSTT1 polymorphisms as predictors of response to chemotherapy in patients with breast cancer”

http://ift.tt/2lnC2AO

Collaboration with an infection control team for patients with infection after spine surgery

Publication date: Available online 22 February 2017
Source:American Journal of Infection Control
Author(s): Kazuyoshi Kobayashi, Shiro Imagama, Daizo Kato, Kei Ando, Tetsuro Hida, Kenyu Ito, Mikito Tsushima, Akiyuki Matsumoto, Masayoshi Morozumi, Satoshi Tanaka, Tetsuya Yagi, Yoshihiro Nishida, Naoki Ishiguro
BackgroundThe risk of infection, including surgical site infection (SSI), after spine surgery has increased due to aging and more immunocompromised hosts. An infection control team (ICT) is responsible for management of health care-associated infections at our institution.MethodsThe study subjects were 40 patients (18 men and 22 women with an average age of 54 years) referred to the ICT after spine surgery since 2010. Pathogenic bacteria and treatment in these cases were reviewed.ResultsCollaboration with the ICT involved guidance on use of antibiotics for infection in 30 patients (16 SSI and 14 non-SSI) and a search for the infection focus for fever of unknown origin in 10 patients (7 patients were found to have urinary tract infections and 2 patients were found to have pneumonia). The detection rate of causative bacteria in ICT consultation was 88% (35 out of 40 patients). SSI patients with instrumentation involved had a significantly higher rate of methicillin-resistant Staphylococcus aureus infection compared with those without instrumentation (42% vs 13%; P < .05).DiscussionAll cases of SSI with instrumentation involved were cured by ICT support without removal of instrumentation. Early assistance from the ICT was important for prevention of worsening of methicillin-resistant S aureus infection.ConclusionsCollaboration with the ICT was helpful for detection of pathogenic bacteria and allowed appropriate use of antibiotics at an early stage.



http://ift.tt/2mdkmpO

Self-sanitizing copper-impregnated surfaces for bioburden reduction in patient rooms

Publication date: Available online 22 February 2017
Source:American Journal of Infection Control
Author(s): John D. Coppin, Frank C. Villamaria, Marjory D. Williams, Laurel A. Copeland, John E. Zeber, Chetan Jinadatha
Novel self-sanitizing copper oxide-impregnated solid surfaces have the potential to influence bioburden levels, potentially lowering the risk of transmission of pathogens in patient care environments. Our study showed persistently lower microbial burden over a 30-hour sampling period on a copper-impregnated tray table compared with a standard noncopper surface in occupied patient rooms after thorough initial disinfection.



http://ift.tt/2lqmtYY

Catheter-related Saccharomyces cerevisiae Fungemia Following Saccharomyces boulardii Probiotic Treatment: In a Child in Intensive Care Unit and Review of the Literature

Publication date: Available online 22 February 2017
Source:Medical Mycology Case Reports
Author(s): Serkan Atıcı, Ahmet Soysal, Kıvılcım Karadeniz Cerit, Şerife Yılmaz, Burak Aksu, Gürsu Kıyan, Mustafa Bakır
Although Saccharomyces boulardii is usually a non-pathogenic fungus, in rare occasions it can cause invasive infection in children. We present the case of an 8-year-old patient in pediatric surgical intensive care unit who developed S. cerevisiae fungemia following probiotic treatment containing S. boulardii. Caspofungin was not effective in this case and he was treated with amphotericin B. We want to emphasize that physicians should be careful about probiotic usage in critically ill patients.



http://ift.tt/2l9n3HX

Early Assessment of Treatment Responses during Radiation Therapy of Lung Cancer Based on Quantitative Analysis of Daily CT

Publication date: Available online 21 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jijo Paul, Cungeng Yang, Hui Wu, An Tai, Entesar Dalah, Cheng Zheng, Candice Johnstone, Feng-Ming Kong, Elizabeth Gore, X. Allen Li
PurposeTo investigate early tumor and normal tissue responses during the course of radiation therapy (RT) of lung cancer based on quantitative analysis of daily CTs.Methods and materialsDaily diagnostic-quality CTs acquired using CT-on-Rails during CT-guided RT for 20 lung cancer patients were quantitatively analyzed. On each daily CT set, contours of gross tumor volume (GTV) and lungs were generated and the x-ray dose delivered was reconstructed. The changes in CT image intensity (Hounsfield unit, HU) features in the GTV and in the multiple normal lung tissue shells around GTV were extracted from daily CTs. Associations between the changes in mean HU, GTV volume, accumulated dose during RT delivery and patient survival rate were analyzed.ResultsDuring the course of RT, radiation can induce substantial changes in HU histogram features in the daily CTs with reductions of GTV mean HU (dH) observed in the range of 11- 48HU (median 30HU). The dH is statistically related to the accumulated GTV dose (R² >0.99), while it is weakly correlated with the change of GTV (R²= 0.3481). Statistically significant increases in patient survival rates (p= 0.038) were observed for patients with higher dH in GTV. In normal lung, the four regions proximal to the GTV showed statistically significant (<0.001) HU reductions from the first to last fractions.ConclusionQuantitative analysis of daily CT indicates that the mean HUs in lung tumor and the surrounding normal tissue were reduced during RT delivery. This reduction was observed in the early phase of the treatment and is patient specific and correlated to the delivered dose. Larger HU reduction in GTV is significantly correlated with higher patient survival. The change of daily CT feature, such as mean HU, may be used for early assessment of radiation responses during RT delivery for lung cancer.

Teaser

Changes in CT intensity, including Hounsfield Unit (HU) histogram and mean HU, on daily diagnostic-quality CTs acquired during CT-guided radiation therapy delivery for lung cancers were studied. The observed mean HU reductions in the tumor and in the surrounding lung tissues were patient specific and significantly correlated with the radiation doses delivered and with patient survival rate. Such HU reduction may potentially be used as early assessment of radiation response.


http://ift.tt/2l0xAnW

Use of Stereotactic Radiosurgery in Elderly and Very Elderly Patients with Brain Metastases to Limit Toxicity Associated with Whole Brain Radiation Therapy

Publication date: Available online 21 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Linda Chen, Colette Shen, Kristin Redmond, Brandi R. Page, Megan Kummerlowe, Todd Mcnutt, Chetan Bettegowda, Daniele Rigamonti, Michael Lim, Lawrence Kleinberg
Stereotactic radiosurgery (SRS) is a well-tolerated ablative therapy for brain metastases, but its role in the management of elderly patients traditionally managed with whole brain radiotherapy (WBRT) is unclear. We retrospectively compared toxicity rates in elderly and very elderly patients. When comparing treatment modalities we found that patients clinically selected for WBRT had poor overall survival and that WBRT was associated with higher rates of acute neurocognitive toxicity compared to SRS using multi-variate analysis.



http://ift.tt/2kNdC50

National trends and predictors for androgen deprivation therapy use in low-risk prostate cancer

Publication date: Available online 21 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): David D. Yang, Vinayak Muralidhar, Brandon A. Mahal, Shelby A. Labe, Michelle D. Nezolosky, Marie E. Vastola, Martin T. King, Neil E. Martin, Peter F. Orio, Toni K. Choueiri, Quoc-Dien Trinh, Daniel E. Spratt, Karen E. Hoffman, Felix Y. Feng, Paul L. Nguyen
PurposeAndrogen deprivation therapy (ADT) is not recommended for low-risk prostate cancer due to its lack of benefit and potential for harm. We evaluated the incidence and predictors of ADT use in low-risk disease.Methods and MaterialsWe identified 197,957 patients in the National Cancer Database with low-risk prostate cancer (Gleason 3+3=6, PSA<10 ng/mL, and cT1-T2a) diagnosed from 2004 to 2012 with complete demographic and treatment information. We utilized multiple logistic regression to evaluate predictors of ADT use and Cox regression to examine its association with all-cause mortality.ResultsOverall ADT use decreased from 17.6% in 2004 to 3.5% in 2012. In 2012, 11.5% of low-risk brachytherapy and 7.6% of external beam radiation therapy (EBRT) patients received ADT. Among 82,352 radiation-managed patients, predictors of ADT use include treatment in a community vs. academic cancer program (adjusted odds ratio [AOR] 1.60, 95% CI 1.50-1.71, p<0.001; incidence 14.0% vs. 6.0% in 2012); treatment in the South (AOR 1.51), Midwest (AOR 1.81), or Northeast (AOR 1.90) vs. West (p<0.001); and brachytherapy use vs. EBRT (AOR 1.32, 1.27-1.37, p<0.001). Among 25,196 patients who did not receive local therapy, predictors of primary ADT use include Charlson-Deyo comorbidity score of 2+ vs. 0 (AOR 1.42, 1.06-1.91, p=0.018); treatment in a community vs. academic cancer program (AOR 1.61, 1.37-1.90, p<0.001); and treatment in the South (AOR 1.26), Midwest (AOR 1.52), or Northeast (AOR 1.28) vs. West (p≤0.008). Primary ADT use was associated with increased all-cause mortality in patients who did not receive local therapy (adjusted hazard ratio [AHR] 1.28, 1.14-1.43, p<0.001) after adjusting for age and comorbidity.ConclusionADT use in low-risk prostate cancer has declined nationally but may still remain an issue of concern in certain populations and regions.

Teaser

We evaluated the incidence and predictors of androgen deprivation therapy (ADT) use in low-risk prostate cancer from 2004 to 2012 using the National Cancer Database. Low-risk patients received ADT mostly as adjuvant therapy to radiation treatment. ADT use in low-risk patients has declined nationally but may still remain of concern in certain populations and regions.


http://ift.tt/2lwagR5

Brachytherapy combined with surgery for conservative treatment of children with bladder neck and/or prostate rhabdomyosarcoma

Publication date: Available online 21 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Cyrus Chargari, Christine Haie-Meder, Florent Guérin, Véronique Minard-Colin, Guénolée de Lambert, Renaud Mazeron, Alexandre Escande, Fanny Marsolat, Isabelle Dumas, Eric Deutsch, Dominique Valteau-Couanet, Georges Audry, Odile Oberlin, Hélène Martelli
PurposeTo report the results of a conservative strategy based on partial surgery combined with brachytherapy in a prospective cohort of children with bladder-prostate rhabdomyosarcoma (BP RMS).Patients and MethodsWe prospectively documented the outcome of children treated in our department between 1991 and 2015 for a BP RMS and undergoing a multimodal approach combining a conservative surgery (partial cystectomy and/or partial prostatectomy) and a perioperative interstitial low-dose rate or pulse-dose rate brachytherapy. Prior to brachytherapy, children had received chemotherapy with modalities depending on their risk group of treatment.Results100 patients were identified, median age of 28 months (5.6 months-14 years). According to the Intergroup Rhabdomyosarcoma Study (IRS) Group group, 84 were IRS-III and 12 were IRS-IV tumors. Four patients were treated at relapse. Median number of chemotherapy cycles before local therapy was 6 (4–13). After surgery, 63 patients had a macroscopical tumor residuum. Five patients underwent a brachytherapy boost before pelvic external beam radiotherapy (EBRT) because of nodal involvement and 95 had exclusive brachytherapy. Median follow-up was 64 months (6 months-24.5 years). Five year disease-free and overall survival rates were 84% (95%CI: 80–88%) and 91% (95%CI: 87–95%), respectively. At last follow-up, most survivors presented with only mild to moderate genito-urinary sequelae and a normal diurnal urinary continence. Five patients required a secondary total cystectomy: 3 for a nonfunctional bladder and 2 for relapse.ConclusionBrachytherapy is effective as part of a conservative strategy on BP RMS, with a relatively low delayed toxicity as compared with previously published studies using EBRT. Longer follow-up is required to ensure that the functional results are maintained over time.

Teaser

We report the outcome of 100 consecutive children with bladder/prostate rhabdomyosarcoma treated in our center according to a multimodal treatment based on chemotherapy, conservative surgery and brachytherapy. With median follow-up of 64 months (6 months-24.5 years), 5-year disease-free and overall survival rates were 84% (95%CI: 80–88%) and 91% (95%CI: 87–95%), respectively. Most survivors presented with mild to moderate genito-urinary sequelae, suggesting that this strategy is effective and associated with acceptable delayed toxicity.


http://ift.tt/2kN6RjJ

Particle Therapy Using Protons or Carbon Ions for Unresectable or Incompletely Resected Bone and Soft Tissue Sarcomas of the Pelvis

Publication date: Available online 22 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Yusuke Demizu, Dongcun Jin, Nor Shazrina Sulaiman, Fumiko Nagano, Kazuki Terashima, Sunao Tokumaru, Takashi Akagi, Osamu Fujii, Takashi Daimon, Ryohei Sasaki, Nobukazu Fuwa, Tomoaki Okimoto
PurposeTo retrospectively analyze the treatment outcomes of particle therapy using protons or carbon ions for unresectable or incompletely resected bone and soft tissue sarcomas (BSTSs) of the pelvis.MethodsBetween May 2005 and December 2014, 91 patients with non-metastatic histologically-proven unresectable or incompletely resected pelvic BSTSs were treated using particle therapy with curative intent at XXXX. The particle therapy used protons (52 patients) or carbon ions (39 patients). All patients received a dose of 70.4 Gy (relative biological effectiveness) in 32 fractions (55 patients) or 16 fractions (36 patients).ResultsThe median patient age was 67 years (range: 18–87 years). The median planning target volume (PTV) was 455 mL (range: 108–1,984 mL). The histological types were chordoma (53 patients), chondrosarcoma (14 patients), osteosarcoma (10 patients), malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma (5 patients), and others (9 patients). Eighty-two patients had a primary tumor, and 9 patients had a recurrent tumor. The median follow-up was 32 months (range: 3–112 months). The 3-year rates of overall survival (OS), progression-free survival (PFS), and local control (LC) were 83%, 72%, and 92%, respectively. A Cox proportional-hazards model revealed that chordoma histology and a PTV of ≤500 mL were significantly associated with better OS, while a primary tumor and a PTV of ≤500 mL were significantly associated with better PFS. Ion type and number of fractions were not significantly associated with OS, PFS, or LC. Late grade ≥3 toxicities were observed in 23 patients. Compared to the 32-fraction protocol, the 16-fraction protocol was associated with significantly more frequent late grade ≥3 toxicities (18/36 versus 5/55; P < 0.001).ConclusionsParticle therapy using protons or carbon ions was effective for unresectable or incompletely resected pelvic BSTSs, and the 32-fraction protocol was effective and relatively less toxic. Nevertheless, a longer follow-up is needed to confirm these results.

Teaser

Ninety-one patients with no metastases from histologically-proven unresectable or incompletely resected bone and soft tissue sarcomas of the pelvis were treated with particle therapy using protons (52 patients) or carbon ions (39 patients). These treatments provided good overall survival, progression-free survival, and local control, although late skin and peripheral nerve toxicities were observed. Particle therapy was effective for unresectable or incompletely resected pelvic bone and soft tissue sarcomas.


http://ift.tt/2lwiOXT

Survival outcome of elderly patients with Glioblastoma Multiforme in their seventy-fifth year or older treated with adjuvant therapy

Publication date: Available online 21 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): G. Harris, D. Jayamanne, H. Wheeler, C. Gzell, M. Kastelan, G. Schembri, D. Brazier, R. Cook, J. Parkinson, M. Khasraw, S. Louw, M. Back
AimTo assess the outcome of the most elderly cohort of patients diagnosed with Glioblastoma Multiforme (GBM) after management with Intensity Modulated Radiation Therapy (IMRT).MethodsPatients with GBM managed with IMRT from May 2007 to December 2015 were entered into a prospective database. Analysis was performed on patients diagnosed in or after their seventy-fifth year of life. The primary endpoint was median survival. Univariate and multivariate analysis were performed with respect to survival for age 74-80 vs >80 years, ECOG performance status of 0-1 vs 2-3, extent of resection, high dose of radiotherapy (60Gy) vs any hypofractionated schedule, MGMT methylation status, PTV volume, and the use of temozolomide (TMZ) vs no TMZ.ResultsOf the 108 patients, 35 were managed with best supportive care, 1 received TMZ alone, 40 received radiotherapy alone and 32 received combined radiotherapy and TMZ. IMRT was delivered with a hypofractionated technique (40Gy) in 58 patients and long course (60Gy) in 11 patients. The median age was 79 with 61.6% of patients being 74-80yrs and 38.4% >80yrs. There were 64 deaths on follow-up with median survival of 10 months (95%CI 7.1-11.9), projected 12-month survival of 35.6% and 24-month survival of 7.9%. On univariate evaluation, independent predictors of survival included younger age (p=0.02), performance status (p=0.014), extent of resection (p=0.002), and TMZ use (p<0.001). MGMT methylation status, RT dose and PTV volume showed no significant difference between the groups. Only chemotherapy use remained statistically significant (p=0.035) on multivariate analysis.ConclusionThe current literature underrepresents elderly patients over the age of 75 years with GBM. Despite elderly patients having a worse prognosis, this study suggests the presence of survival benefits with IMRT in selected patients that can be further extended with addition of TMZ. Further study of this cohort and understanding of appropriate selection criteria is warranted.

Teaser

The current literature underrepresents patients over the age of 75 years with GBM. In this study, we retrospectively analyzed the survival outcomes of patients in their seventy-fifth year or older with GBM treated at our centre. Even in the most elderly group of patients, intervention with maximum safe surgical resection and adjuvant IMRT and temozolomide can be delivered safely with possibly superior outcomes to best supportive care alone.


http://ift.tt/2kN2G7o

Patient reported outcomes following radiation therapy in men with prostate cancer: a systematic review of prognostic tool accuracy and validity

Publication date: Available online 21 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Michael E. O'Callaghan, Elspeth Raymond, Jared M. Campbell, Andrew D. Vincent, Kerri Beckmann, David Roder, Sue Evans, John McNeil, Jeremy Millar, John Zalcberg, Martin Borg, Kim Moretti
PurposeProstate cancer is often treated with radiation therapy which can result in a range of toxicities. The accurate assessment of the likelihood of a patient experiencing these toxicities is important for their counselling. This systematic review aimed to identify all validated tools used for the prediction of patient reported outcome measures (PROMs) in patients being treated with radiation therapy for prostate cancer and provide a comparative summary of accuracy and generalisability.Methods and MaterialsPubMed and EMBASE were searched from July 2007. Title/abstract screening, full text review and critical appraisal were undertaken by two reviewers while data extraction was performed by a single reviewer. Eligible papers had to provide a summary measure of accuracy and undertake internal or external validation. Tools were recommended for clinical implementation if they had been externally validated and found to have accuracy ≥70%.ResultsThe search strategy identified 3,839 potential studies, of which 236 progressed to full text review and 22 were included. From these studies 50 tools predicted gastrointestinal/rectal symptoms, 29 tools predicted genitourinary symptoms, four tools predicted erectile dysfunction and no tools predicted quality of life. For patients treated with EBRT three tools could be recommended for the predication of rectal toxicity, gastrointestinal toxicity, and erectile dysfunction. For patients treated with brachytherapy two tools could be recommended for the prediction of urinary retention and erectile dysfunction.ConclusionsA large number of tools for the prediction of PROMs in prostate cancer patients treated with radiation therapy have been developed. Only a small minority are accurate and have been shown to be generalisable through external validation. This review provides an accessible catalogue of tools that are ready for clinical implementation as well as which should be prioritised for validation.

Teaser

This systematic review identified a large number of tools for the prognosis of patient reported outcomes in men undergoing radiation therapy for prostate cancer. However, only minority are accurate and have been shown to be generalisable through external validation. Recommendations are made as to which tools are ready for clinical implementation and which should be prioritised for further validation.


http://ift.tt/2lwo0v3

XXXXXXX: An Analysis of Health Related Quality of Life for A Randomized Trial Comparing Low-Dose-Rate Brachytherapy Boost to Dose-Escalated External Beam Boost for High- and Intermediate-Risk Prostate Cancer

Publication date: Available online 21 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sree Rodda, W. James Morris, Jeremy Hamm, Graeme Duncan
PurposeTo report the patient reported health-related quality of life (HR-QoL) outcomes for a multicenter randomized trial evaluating the safety and efficacy of two different techniques for dose escalation.Materials and Methods357 men with intermediate-and high-risk prostate cancer were stratified by risk group and randomized (1:1) to either a dose escalated external beam (DE-EBRT) boost (N =177) or a low-dose-rate prostate brachytherapy (LDR-PB) boost (N =180) as part of combined modality therapy. HR-QoL was assessed using the SF36v2^TM questionnaire with additional scales for urinary, bowel and sexual function. Date of starting ADT was considered time zero, the median follow up is 6 years.Scales were scored from 0-100; a decline in a mean score ≥10 compared to baseline was considered a clinically significant decline. This is an intent-to-treat analysis.ResultsMean domain scores at baseline were well balanced between two treatment arms. A clinically significant decline in mean scores in both the arms compared to baseline was noted for role physical (DE-EBRT (-11.4) and LDR-PB (-15.3)) and sexual functions scale ((DE-EBRT (-15.1) and LDR-PB (-19.2)). There was a significantly larger drop in mean scores in LDR-PB group compared to DE-EBRT group for physical function (-15.3 vs. -6.9; p=0.03), urinary function (-3.6 vs. -0.5; p=0.04).ConclusionAt 6 years follow up, there were no significant differences in mean scores in nine out of eleven scales compared to baseline in both arms. A clinically significant decline in mean scores was noted in both the arms for role physical and sexual function scales. There was statistically significant decline in physical function and urinary function scale in LDR-PB arm compared to DE-EBRT arm.

Teaser

This study is randomized trial investigating two methods of dose escalation in the context of combined modality therapy for high- and intermediate risk prostate cancer that included 12 months of androgen deprivation therapy and whole pelvic irradiation to 46 Gy. Using a SF36V2^TM QoL instrument, at 6 years follow up, there were no significant differences in mean scores in nine out of eleven scales compared to baseline in both arms. A clinically significant decline in mean scores was noted in both the arms for role physical and sexual function scales. There was statistically significant greater decline in physical function and urinary function scales in subjects randomized to a brachytherapy boost when compared to those randomized to an external beam boost.


http://ift.tt/2kN6k1j

A multi-Institutional analysis of trimodality therapy for esophagus cancer in elderly patients

Publication date: Available online 20 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Scott C. Lester, Steven H. Lin, Michael Chuong, Neha Bhooshan, Zhongxing Liao, Sarah E. James, Jaden D. Evans, Grant M. Spears, Ritsuko Komaki, Michael G. Haddock, Minesh P. Mehta, Christopher L. Hallemeier, Kenneth W. Merrell
PurposeThe therapeutic gains of neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy may be offset by increased incidences of morbidity and mortality in elderly patients. This study aimed to determine the impact of age on the risks and benefits of trimodality therapy for esophagus cancer.Methods and MaterialsWe evaluated 571 patients treated with trimodality therapy at 3 high-volume tertiary U.S. cancer centers from 2007 to 2013. 202 of 571 (35%) patients were 65 years or older at diagnosis and were classified as elderly. Toxicity and treatment parameters for the elderly cohort were compared with the younger cohort (ages 22-64) using univariate (UVA) and multivariable (MVA) logistic analyses. Age was analyzed as a continuous hazard for cardiac and pulmonary toxicities. Survival was assessed using the Kaplan-Meier method.ResultsElderly patients had a higher risk for postoperative cardiac (UVA: OR 2.2, p<0.001; MVA: OR 2.07, p=0.004) and pulmonary toxicities (UVA: OR 2.0, p<0.001; MVA: OR 2.03, p<0.001), and a higher 90-day postoperative mortality (5.4 vs 2.2%, p=0.049). 6.9% of the elderly experienced acute respiratory distress syndrome compared to 3.8% of younger patients (p=0.11). Cardiac toxicity was linearly associated with age and the relative risk increased by 61% for every additional decade of age. There was no difference in postoperative gastrointestinal or wound complications, or length of hospital stay. Grade 3+ acute toxicities from nCRT were infrequent and clinically similar regardless of age. Freedom from esophagus cancer and disease free survival were similar, but overall survival was significantly shorter in the elderly cohort.ConclusionsElderly patients experienced more postoperative cardiopulmonary toxicities and mortality than younger patients after neoadjuvant chemoradiotherapy. Compared with contemporary outcomes for trimodality therapy, both cohorts had acceptable rates for adverse events and disease control. For appropriately selected elderly patients, trimodality therapy for esophagus cancer is a reasonable treatment option.

Teaser

The therapeutic ratio for esophagectomy following chemoradiotherapy for elderly patients is not clear. In this analysis of 202 elderly patients treated with trimodality therapy at 3 high volume cancer centers rates of cardiopulmonary toxicity and postoperative death were increased compared with a younger cohort. Despite relative increases in morbidity and mortality, absolute incidences of toxicity and death were within reported contemporary standards and disease free survival was not significantly impacted by age.


http://ift.tt/2l9iTQA

Adsorption of ammonium in aqueous solutions by pine sawdust and wheat straw biochars

Abstract

Ammonium (NH₄⁺) is a common form of reactive nitrogen in wastewater, and its discharge to water bodies can lead to eutrophication. This study was conducted to understand NH₄⁺ adsorption mechanisms of pine sawdust and wheat straw biochars in aqueous solutions and the factors affecting NH₄⁺ removal. Biochars were produced by pyrolysing pine sawdust at 300 °C (PS300) and 550 °C (PS550) and wheat straw at 550 °C (WS550). Pseudo-second-order and Redlich-Peterson models best fitted the adsorption data. The PS300 showed the highest NH₄⁺ adsorption capacity (5.38 mg g⁻¹), followed by PS550 (3.37 mg g⁻¹) and WS550 (2.08 mg g⁻¹). Higher H/C and O/C ratios of PS300 (0.78 and 0.32, respectively) indicated the greater presence of functional groups on the biochar's surface as compared to PS550 (0.35 and 0.10, respectively) and WS550 (0.36 and 0.08, respectively), resulting in different NH₄⁺ adsorption through electrostatic interactions. The dominant mechanism for NH₄⁺ adsorption by the biochars was likely chemical bonding and electrostatic interaction of NH₄⁺ with the surface functional groups. Lower pyrolysis temperature resulted in a higher NH₄⁺ adsorption capacity by the pine sawdust biochar. At the same pyrolysis temperature (550 °C), the biochar made with pine sawdust as the feedstock had a higher NH₄⁺ adsorption capacity than biochar made from wheat straw. We conclude that biochars can be efficient absorbents for NH₄⁺ removal from wastewater, and the removal efficiency can be optimised by selecting different feedstocks or the pyrolysis condition for biochar production.

http://ift.tt/2lGztdu