Functional brain networks during picture encoding and recognition in different odor contexts

Publication date: 30 August 2017
Source:Behavioural Brain Research, Volume 333
Author(s): J.L. Reichert, M. Ninaus, W. Schuehly, C. Hirschmann, D. Bagga, V. Schöpf
Contextual odors can serve as retrieval cues when applied during encoding and recall/recognition of information. To investigate the neuronal basis of these observations, we collected functional MRI data while participants (n=51) performed an encoding and recognition memory task during which odors (congruent: CO or incongruent: IO) were presented as contextual cues. Recognition performance was not influenced by odor, but there was increased activation in the piriform cortex during successful encoding in the CO group, possibly indicating enhanced retrieval of information previously integrated with an olfactory percept. Moreover, group-independent component analysis revealed a stronger task-modulation of subcortical networks for IO versus CO during the recognition task, pointing to differences in olfactory processing. These observations provide a deeper understanding of the involvement of functional neuronal networks in memory tasks and a basis for further evaluation of the impact of odor contexts.



http://ift.tt/2u2Ymoc

Age-related deficits in the mnemonic similarity task for objects and scenes

Publication date: 30 August 2017
Source:Behavioural Brain Research, Volume 333
Author(s): Shauna M. Stark, Craig E.L. Stark
Using the Mnemonic Similarity Task (MST), we have demonstrated an age-related impairment in lure discrimination, or the ability to recognize an item as distinct from one that was similar, but not identical to one viewed earlier. A growing body of evidence links these behavioral changes to age-related alterations in the hippocampus. In this study, we sought to evaluate a novel version of this task, utilizing scenes that might emphasize the role of the hippocampus in contextual and spatial processing. In addition, we investigated whether, by utilizing two stimulus classes (scenes and objects), we could also interrogate the roles of the PRC and PHC in aging. Thus, we evaluated differential contributions to these tasks by relating performance on objects versus scenes to volumes of the hippocampus and surrounding medial temporal lobe structures. We found that while there was an age-related impairment on lure discrimination performance for both objects and scenes, relationships to brain volumes and other measure of memory performance were stronger when using objects. In particular, lure discrimination performance for objects showed a positive relationship with the volume of the hippocampus, specifically the combined dentate gyrus (DG) and CA3 subfields, and the subiculum. We conclude that though using scenes was effective in detecting age-related lure discrimination impairments, it does not provide as strong a brain-behavior relationship as using objects.



http://ift.tt/2sK6CFN

Prefrontal mRNA expression of long and short isoforms of D2 dopamine receptor: Possible role in delayed learning deficit caused by early life interleukin-1β treatment

Publication date: 30 August 2017
Source:Behavioural Brain Research, Volume 333
Author(s): Alexander P. Schwarz, Alexander N. Trofimov, Olga E. Zubareva, Victoria I. Lioudyno, Vera V. Kosheverova, Alexander M. Ischenko, Victor M. Klimenko
Long (D2L) and short (D2S) isoform of the D2 dopamine receptor are believed to play different roles in behavioral regulation. However, little is known about differential regulation of these isoforms mRNA expression during the process of learning in physiological and pathological states. In this study, we have investigated the combined effect of training in active avoidance (AA) paradigm and chronic early life treatment with pro-inflammatory cytokine interleukin (IL)-1β (1μg/kg i.p., P15-21) on D2S and D2L dopamine receptor mRNA expression in the medial prefrontal cortex (mPFC) of adult rats. We have shown differential regulation of D2 short and long mRNA isoform expression in the mPFC. There was no effect of AA-training on D2S mRNA expression, while D2L mRNA was downregulated in AA-trained control (intact and saline-treated) animals, and this effect was not observed in rats treated with IL-1β. D2S mRNA expression level negatively correlated with learning ability within control (saline-treated and intact) groups but not in IL-1β-treated animals. Thus, prefrontal expression of distinct D2 dopamine receptor splice variants is supposed to be implicated in cognitive decline caused by early life immune challenge.



http://ift.tt/2u39zVR

Abnormal cortical-basal ganglia network in amyotrophic lateral sclerosis: A voxel-wise network efficiency analysis

Publication date: 30 August 2017
Source:Behavioural Brain Research, Volume 333
Author(s): Jinping Xu, Hong Li, Chong Li, Jen-Chih Yao, Jun Hu, Jian Wang, Qingmao Hu, Yuanchao Zhang, Jiuquan Zhang
Evidence suggests that dysfunctional cortical-basal ganglia (CBG) network plays important roles in the motor symptoms in amyotrophic lateral sclerosis (ALS). However, little effort has been made to investigate the functional abnormalities of CBG network in ALS. Here, we constructed voxel-wise CBG networks using the resting-state fMRI data of 20 patients with ALS and 21 normal controls, and characterized the differences of their efficiency parameters between the two groups. Compared to normal controls, patients with ALS exhibited decreased nodal efficiency in the right thalamus (THA), the left caudate (CAU) and the right precentral gyrus (preCG), and increased nodal efficiency in the left preCG. In the patient group, we observed a significant negative correlation between the nodal efficiency of the right preCG and disease progression rate. These results demonstrate that both ineffective information transfer and compensatory mechanisms are involved in the pathophysiological mechanism underlying the motor dysfunctions in patients with ALS. In summary, the present study provides a novel perspective on pathophysiological explanation for the motor symptoms in patients with ALS.



http://ift.tt/2sK5cvf

Significance of the nicotinic alpha7 receptor in cognition and antipsychotic-like behavior in the rat

Publication date: 30 August 2017
Source:Behavioural Brain Research, Volume 333
Author(s): Marie-Louise G. Wadenberg, Dina Manetti, Maria Novella Romanelli, Hugo R. Arias
Schizophrenic (SCH) patients show cognitive impairment in attentional performance. Positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (nAChRs) such as the Alzheimer's drug galantamine (GAL) and PAM-2 are documented to have pro-cognitive properties. However, it is not well established if these properties would be lost, or may hamper antipsychotic efficacy, when given as an adjunct to an antipsychotic which is needed for managing psychotic symptoms. Using adult male Wistar rats, we here investigated the effects of: a) GAL, alone or co-administered with the antipsychotic risperidone (RISP), on acute phencyclidine (PCP)-induced deficits in the attentional set-shifting (ASST) test; b) PAM-2, alone and co-administered with RISP, in the conditioned avoidance response (CAR) test for antipsychotic activity.Acute PCP produced selective and significant SCH-like impairment in extra dimensional shift (EDS) performance, which was completely reversed by GAL. The ability of GAL to reverse PCP-induced EDS impairment was not prevented when co-administered with RISP, suggesting that the combination of GAL and low doses of RISP may be used to improve the cognitive impairment in SCH. Pretreatment with methyllycaconitine (MLA), a selective α7 nAChR antagonist, completely prevented the reversal elicited by GAL, supporting the concept that α7 nAChRs are involved in this process. On the other hand, PAM-2 alone had no effects on CAR, but enhanced, although not significantly, the antipsychotic-like effect of RISP when administered together. In conclusion, α7 PAMs, in addition to alleviate the cognitive impairments observed in SCH patients, may enhance the antipsychotic efficacy of atypical antipsychotics.



http://ift.tt/2u37JVj

Behavioral activation sensitivity and default mode network-subgenual cingulate cortex connectivity in youth

Publication date: 30 August 2017
Source:Behavioural Brain Research, Volume 333
Author(s): Allesandra S. Iadipaolo, Hilary A. Marusak, Kelsey Sala-Hamrick, Laura M. Crespo, Moriah E. Thomason, Christine A. Rabinak
Increased resting-state functional connectivity (rsFC) between the default mode network (DMN) and subgenual anterior cingulate cortex (sgACC) is consistently reported in adults and youth with psychopathologies related to affect dysregulation (e.g. depression, posttraumatic stress disorder). This pattern of increased rsFC is thought to underlie ruminative thought patterns through integration of negative affect (via sgACC) into self-referential operations supported by the DMN. Neurobiological studies in adults show that behavioral activation system (BAS) sensitivity is a potential protective factor against the development of psychopathology, particularly in the context of stress and trauma exposure. However, whether BAS sensitivity is associated with variation in DMN-sgACC stress-vulnerability circuitry in youth, particularly those at risk for affect dysregulation, has not yet been studied. This association was tested in a sample of ninety-eight children and adolescents (ages 6–17) at high sociodemographic risk for psychopathology (i.e., urban, lower income, high frequency of violence and abuse exposure). Participants underwent a six-minute resting-state functional magnetic resonance imaging scan. Using a targeted, small-volume corrected approach, we found that youth with higher BAS sensitivity demonstrated lower DMN-sgACC rsFC, suggesting a potential link between the purported protective effects of BAS sensitivity and stress-vulnerability circuitry. This work suggests that interventions that augment BAS sensitivity, such as behavioral activation therapy, may protect against the development of stress-related psychopathology by modifying a critical rumination circuitry in the brain. Such interventions may be especially important for bolstering resiliency in at-risk urban youth, who are disproportionately burdened by early stress and associated psychopathology.



http://ift.tt/2sKu2uK

Evaluating aged mice in three touchscreen tests that differ in visual demands: Impaired cognitive function and impaired visual abilities

Publication date: 30 August 2017
Source:Behavioural Brain Research, Volume 333
Author(s): Nathalie Buscher, Pascal van Dorsselaer, Thomas Steckler, John C. Talpos
Normal aging is often accompanied by reductions in cognitive abilities as well as impairments in visual acuity in men and mice. In preclinical models of human cognition this concomitance can make it difficult to assess the relative contributions of declined vision and cognitive ability on behavioral measures of cognition. To assess the influence of age on cognition and the impact of visual decline on the performance of touchscreen-based behavioral paradigms in mice, aged (11, 12, 16, 17, 19 and 21 months old) male C57BL/6J mice were compared to young (3 or 4 months old) male C57BL/6J mice using three tests of cognition as well as an assessment of visual acuity. Performance of a Visual Discrimination, Spatial Reversal, and an Automated Search Task were all affected by age. However, there was no relationship between reduced visual acuity and the observed performance impairments. Moreover, the visual acuity of animals with profound cognitive impairments overlapped with those showing normal cognitive ability. Despite the potential confound of impaired visual ability, it appears that the touchscreen approach might be particularly effective in studying age-related cognitive decline. This approach will increase the utility of aged mice as a model of decreased cognitive flexibility and may be particularly important for the study of age-related disorders such as Alzheimer's disease.



http://ift.tt/2u2KNFC

Brain infusion of α-synuclein oligomers induces motor and non-motor Parkinson’s disease-like symptoms in mice

Publication date: 30 August 2017
Source:Behavioural Brain Research, Volume 333
Author(s): Juliana T.S. Fortuna, Matthias Gralle, Danielle Beckman, Fernanda S. Neves, Luan P. Diniz, Paula S. Frost, Fernanda Barros-Aragão, Luís E. Santos, Rafaella A. Gonçalves, Luciana Romão, Daniele C. Zamberlan, Felix A.A. Soares, Carolina Braga, Debora Foguel, Flávia C.A. Gomes, Fernanda G. De Felice, Sergio T. Ferreira, Julia R. Clarke, Cláudia P. Figueiredo
Parkinson's disease (PD) is characterized by motor dysfunction, which is preceded by a number of non-motor symptoms including olfactory deficits. Aggregation of α-synuclein (α-syn) gives rise to Lewy bodies in dopaminergic neurons and is thought to play a central role in PD pathology. However, whether amyloid fibrils or soluble oligomers of α–syn are the main neurotoxic species in PD remains controversial. Here, we performed a single intracerebroventricular (i.c.v.) infusion of α-syn oligomers (α-SYOs) in mice and evaluated motor and non-motor symptoms. Familiar bedding and vanillin essence discrimination tasks showed that α-SYOs impaired olfactory performance of mice, and decreased TH and dopamine levels in the olfactory bulb early after infusion. The olfactory deficit persisted until 45days post-infusion (dpi). α- SYO-infused mice behaved normally in the object recognition and forced swim tests, but showed increased anxiety-like behavior in the open field and elevated plus maze tests 20 dpi. Finally, administration of α-SYOs induced late motor impairment in the pole test and rotarod paradigms, along with reduced TH and dopamine content in the caudate putamen, 45 dpi. Reduced number of TH-positive cells was also seen in the substantia nigra of α-SYO-injected mice compared to control. In conclusion, i.c.v. infusion of α-SYOs recapitulated some of PD-associated non-motor symptoms, such as increased anxiety and olfactory dysfunction, but failed to recapitulate memory impairment and depressive-like behavior typical of the disease. Moreover, α-SYOs i.c.v. administration induced motor deficits and loss of TH and dopamine levels, key features of PD. Results point to α-syn oligomers as the proximal neurotoxins responsible for early non-motor and motor deficits in PD and suggest that the i.c.v. infusion model characterized here may comprise a useful tool for identification of PD novel therapeutic targets and drug screening.



http://ift.tt/2sJYghL

Operant responding for optogenetic excitation of LDTg inputs to the VTA requires D1 and D2 dopamine receptor activation in the NAcc

Publication date: 30 August 2017
Source:Behavioural Brain Research, Volume 333
Author(s): Stephan Steidl, Shannon O'Sullivan, Dustin Pilat, Nancy Bubula, Jason Brown, Paul Vezina
Behavioral studies in rats and mice indicate that laterodorsal tegmental nucleus (LDTg) inputs to the ventral tegmental area (VTA) importantly contribute to reward function. Further evidence from anesthetized rat and mouse preparations suggests that these LTDg inputs may exert this effect by regulating mesolimbic dopamine (DA) signaling. Direct evidence supporting this possibility remains lacking however. To address this lack, rat LDTg neurons were transfected with adeno-associated viral vectors encoding channelrhodopsin2 and eYFP (ChR2) or eYFP alone (eYFP) and rats were subsequently trained to lever press for intracranial self-stimulation (ICSS) of the inputs of these neurons to the VTA. First, we found that DA overflow in the forebrain nucleus accumbens (NAcc) increased maximally during ICSS to approximately 240% of baseline levels in ChR2, but not in eYFP, rats. Based on these findings, we next tested the contribution of NAcc D1 and D2 DA receptors to the reinforcing effects of optogenetic excitation of LDTg inputs to the VTA. Microinjecting SCH23390 or raclopride, D1 and D2 DA receptor antagonists respectively, into the NAcc significantly reduced operant responding for this stimulation. Together these results demonstrate for the first time that optogenetic ICSS of LDTg inputs to the VTA increases DA overflow in the NAcc and requires activation of D1 and D2 DA receptors in this site.



http://ift.tt/2u39vp5

Enhanced limbic/impaired cortical-loop connection onto the hippocampus of NHE rats: Application of resting-state functional connectivity in a preclinical ADHD model

Publication date: 30 August 2017
Source:Behavioural Brain Research, Volume 333
Author(s): F. Zoratto, G.M. Palombelli, L.A. Ruocco, E. Carboni, G. Laviola, A.G. Sadile, W. Adriani, R. Canese
Due to a hyperfunctioning mesocorticolimbic system, Naples-High-Excitability (NHE) rats have been proposed to model for the meso-cortical variant of attention deficit/hyperactivity disorder (ADHD). Compared to Naples Random-Bred (NRB) controls, NHE rats show hyperactivity, impaired non-selective attention (Aspide et al., 1998), and impaired selective spatial attention (Ruocco et al., 2009a, 2014). Alteration in limbic functions has been proposed; however, resulting unbalance among forebrain areas has not been assessed yet. By resting-state functional Magnetic-Resonance Imaging (fMRI) in vivo, we investigated the connectivity of neuronal networks belonging to limbic vs. cortical loops in NHE and NRB rats (n=10 each). Notably, resting-state fMRI was applied using a multi-slice sagittal, gradient-echo sequence. Voxel-wise connectivity maps at rest, based on temporal correlation among fMRI time-series, were computed by seeding the hippocampus (Hip), nucleus accumbens (NAcc), dorsal striatum (dStr), amygdala (Amy) and dorsal/medial prefrontal cortex (PFC), both hemispheres. To summarize patterns of altered connection, clearly directional connectivity was evident within the cortical loop: bilaterally and specularly, from orbital and dorsal PFCs through dStr and hence towards Hip. Such network communication was reduced in NHE rats (also, with less mesencephalic/pontine innervation). Conversely, enhanced network activity emerged within the limbic loop of NHE rats: from left PFC, both through the NAcc and directly, to the Hip (all of which received greater ventral tegmental innervation, likely dopamine). Together with tuned-down cortical loop, this potentiated limbic loop may serve a major role in controlling ADHD-like behavioral symptoms in NHE rats.



http://ift.tt/2u33nxl

Two Recent Advances in Local Anesthesia: Intranasal Tetracaine/Oxymetazoline and Liposomal Bupivacaine

Abstract

Purpose of Review

This paper reviews the efficacy, safety, and clinical utility of two novel formulations of local anesthetics; intranasal 3% tetracaine plus 0.05% oxymetazoline and 1.3% liposomal bupivacaine.

Recent Findings

Intranasal 3% tetracaine/oxymetazoline when delivered into the ipsilateral nostril of the target tooth has a success rate of 84–90% in completing a single restorative procedure from the second premolar forward. The maximum recommended dose is 18 mg tetracaine/0.3 mg oxymetazoline (three 0.2-ml sprays). The most common adverse effects are nasal congestion and nasal runniness. Liposomal bupivacaine is administered by infiltration injection solely for postoperative pain control and appears to provide analgesic and opioid-sparing effects in knee arthroplasty, bunionectomy, hemorrhoidectomy, and laparotomy. The maximum recommended dose is 20 ml or 266 mg although for dental impaction surgery, a maximum of 10 ml or 133 mg is all that may be required.

Summary

Intranasal tetracaine/oxymetazoline is currently FDA approved only for single maxillary restorative procedures in patients weighing 88 lb or greater. Further clinical trials should include more invasive dental procedures and pediatric patients. The utility of liposomal bupivacaine following dental surgery needs to be further explored.

http://ift.tt/2sZfLP7

Assessment of nonsteroidal anti-inflammatory drugs by ultrasonic-assisted extraction and GC-MS in Mgeni and Msunduzi river sediments, KwaZulu-Natal, South Africa

Abstract

The occurrence of eight pharmaceuticals was monitored during four seasons (spring, summer, autumn, and winter) along a 250-km stretch of the Msunduzi and Mgeni rivers in KwaZulu-Natal, South Africa. This paper describes an optimized method for the determination of nonsteroidal anti-inflammatory drugs (NSAIDs) in sediments. The method combines ultrasonic, centrifuge, and gas chromatography-mass spectrometry for the detection of these drugs in solid samples. Most of the parameters that affect the extraction step were optimized. Solid samples were placed in a centrifuge tube and extracted with ethyl acetate:acetone (1:1, two cycles), followed by clean-up with Oasis HLB cartridge and derivatization with N, O-bis(trimethylsilyl) trifluoroacetamide (BSTFA). Satisfactory recoveries were obtained ranging from 66 to 130%, depending on the analyte. Precision expressed as RSD (%) (n = 3) was less than 20% for all analytes. The LODs and LOQs were in the range of 0.024 to 1.90 ng g⁻¹ which allowed to be applied in the analysis solid samples in Msunduzi and Mgeni rivers. In the solid samples analyzed, NSAID concentration ranged from not detected to 221 ng g⁻¹.

http://ift.tt/2uLBbfK

Adsorption and mineralization of REE—lanthanum onto bacterial cell surface

Abstract

A large number of rare earth element mining and application resulted in a series of problems of soil and water pollution. Environmental remediation of these REE-contaminated sites has become a top priority. This paper explores the use of Bacillus licheniformis to adsorb lanthanum and subsequent mineralization process in contaminated water. The maximum adsorption capacity of lanthanum on bacteria was 113.98 mg/g (dry weight) biomass. X-ray diffraction (XRD) and transmission electron microscopy (TEM) data indicated that adsorbed lanthanum on bacterial cell surface occurred in an amorphous form at the initial stage. Scanning electron microscopy with X-ray energy-dispersive spectroscopy (SEM/EDS) results indicated that lanthanum adsorption was correlated with phosphate. The amorphous material was converted into scorpion-like monazite (LaPO₄ nanoparticles) in a month. The above results provide a method of using bacterial surface as adsorption and nucleation sites to treat REE-contaminated water.

http://ift.tt/2ucESy9

RA Gets Out of the Way to Allow High-Acuity Vision

Publication date: 10 July 2017
Source:Developmental Cell, Volume 42, Issue 1
Author(s): Adele Tufford, Michel Cayouette
Specialized areas in the vertebrate retina are critical for high-acuity vision, yet the molecular mechanisms driving the development of high-acuity areas (HAAs) remain largely unknown. In Developmental Cell, da Silva and Cepko (2017) show that restricted degradation of retinoic acid and elevated FGF8 signaling give rise to the chick HAA.

Teaser

Specialized areas in the vertebrate retina are critical for high-acuity vision, yet the molecular mechanisms driving the development of high-acuity areas (HAAs) remain largely unknown. In Developmental Cell, da Silva and Cepko (2017) show that restricted degradation of retinoic acid and elevated FGF8 signaling give rise to the chick HAA.


http://ift.tt/2sZdSSx

Gating Ciliary Transport

Publication date: 10 July 2017
Source:Developmental Cell, Volume 42, Issue 1
Author(s): Irma Sánchez, Brian D. Dynlacht
Cilia lack the ability to synthesize proteins and thus require dynamic transport. Reporting in this issue of Developmental Cell, Kanie et al. (2017) shed light on the mechanism of transport by implicating CEP19, which is associated with an autosomal-recessive obesity syndrome when mutated, in the triggering of intraflagellar transport.

Teaser

Cilia lack the ability to synthesize proteins and thus require dynamic transport. Reporting in this issue of Developmental Cell, Kanie et al. (2017) shed light on the mechanism of transport by implicating CEP19, which is associated with an autosomal-recessive obesity syndrome when mutated, in the triggering of intraflagellar transport.


http://ift.tt/2tIm86A

Heart Regeneration 4.0: Matrix Medicine

Publication date: 10 July 2017
Source:Developmental Cell, Volume 42, Issue 1
Author(s): Elif Eroglu, Kenneth R. Chien
The heart has a markedly limited capacity for regeneration. Reporting in Nature, Bassat et al. (2017) and Morikawa et al. (2017) have uncovered a new mechanism of Yap inhibition by the dystrophin glycoprotein complex (DGC) that is released by the extracellular matrix protein Agrin in order to promote cardiac regeneration.

Teaser

The heart has a markedly limited capacity for regeneration. Reporting in Nature, Bassat et al. (2017) and Morikawa et al. (2017) have uncovered a new mechanism of Yap inhibition by the dystrophin glycoprotein complex (DGC) that is released by the extracellular matrix protein Agrin in order to promote cardiac regeneration.


http://ift.tt/2sZ7Tgm

DGAT1-Dependent Lipid Droplet Biogenesis Protects Mitochondrial Function during Starvation-Induced Autophagy

Publication date: 10 July 2017
Source:Developmental Cell, Volume 42, Issue 1
Author(s): Truc B. Nguyen, Sharon M. Louie, Joseph R. Daniele, Quan Tran, Andrew Dillin, Roberto Zoncu, Daniel K. Nomura, James A. Olzmann
Lipid droplets (LDs) provide an "on-demand" source of fatty acids (FAs) that can be mobilized in response to fluctuations in nutrient abundance. Surprisingly, the amount of LDs increases during prolonged periods of nutrient deprivation. Why cells store FAs in LDs during an energy crisis is unknown. Our data demonstrate that mTORC1-regulated autophagy is necessary and sufficient for starvation-induced LD biogenesis. The ER-resident diacylglycerol acyltransferase 1 (DGAT1) selectively channels autophagy-liberated FAs into new, clustered LDs that are in close proximity to mitochondria and are lipolytically degraded. However, LDs are not required for FA delivery to mitochondria but instead function to prevent acylcarnitine accumulation and lipotoxic dysregulation of mitochondria. Our data support a model in which LDs provide a lipid buffering system that sequesters FAs released during the autophagic degradation of membranous organelles, reducing lipotoxicity. These findings reveal an unrecognized aspect of the cellular adaptive response to starvation, mediated by LDs.

Graphical abstract

Teaser

Nguyen et al. demonstrate that lipid droplet biogenesis is a general, protective cellular response during periods of high autophagic flux. Under these conditions, lipid droplets prevent lipotoxicity by sequestering FAs released during the autophagic breakdown of organelles. In the absence of lipid droplets, acylcarnitines accumulate and cause mitochondrial uncoupling.


http://ift.tt/2tI9fcE

Lipid Droplets Guard Mitochondria during Autophagy

Publication date: 10 July 2017
Source:Developmental Cell, Volume 42, Issue 1
Author(s): Till Klecker, Ralf J. Braun, Benedikt Westermann
In this issue of Developmental Cell, Nguyen et al. (2017) show that lipid droplets serve a dual purpose during starvation. First, they act as an energy source by supplying fatty acids for mitochondrial β oxidation. Second, they sequester toxic lipids that arise during autophagic degradation of membranous organelles, thereby protecting mitochondria.

Teaser

In this issue of Developmental Cell, Nguyen et al. (2017) show that lipid droplets serve a dual purpose during starvation. First, they act as an energy source by supplying fatty acids for mitochondrial β oxidation. Second, they sequester toxic lipids that arise during autophagic degradation of membranous organelles, thereby protecting mitochondria.


http://ift.tt/2tIDUXq

A Tubulin Binding Switch Underlies Kip3/Kinesin-8 Depolymerase Activity

Publication date: 10 July 2017
Source:Developmental Cell, Volume 42, Issue 1
Author(s): Hugo Arellano-Santoyo, Elisabeth A. Geyer, Ema Stokasimov, Geng-Yuan Chen, Xiaolei Su, William Hancock, Luke M. Rice, David Pellman
Kinesin-8 motors regulate the size of microtubule structures, using length-dependent accumulation at the plus end to preferentially disassemble long microtubules. Despite extensive study, the kinesin-8 depolymerase mechanism remains under debate. Here, we provide evidence for an alternative, tubulin curvature-sensing model of microtubule depolymerization by the budding yeast kinesin-8, Kip3. Kinesin-8/Kip3 uses ATP hydrolysis, like other kinesins, for stepping on the microtubule lattice, but at the plus end Kip3 undergoes a switch: its ATPase activity is suppressed when it binds tightly to the curved conformation of tubulin. This prolongs plus-end binding, stabilizes protofilament curvature, and ultimately promotes microtubule disassembly. The tubulin curvature-sensing model is supported by our identification of Kip3 structural elements necessary and sufficient for plus-end binding and depolymerase activity, as well as by the identification of an α-tubulin residue specifically required for the Kip3-curved tubulin interaction. Together, these findings elucidate a major regulatory mechanism controlling the size of cellular microtubule structures.

Teaser

Kinesin-8s promote length-dependent microtubule disassembly. Arellano and colleagues define a mechanism for Kip3/kinesin-8 depolymerization that involves a tubulin curvature-sensing binding switch. They propose that high affinity curved tubulin binding, which is accompanied by suppressed ATPse activity, enables its depolymerase activity. This Kip3 binding switch is thus central to Kip3's ability to selectively trim long microtubules, narrowing the length distribution of microtubules in cells.


http://ift.tt/2sZg6Bg

The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage

Publication date: 10 July 2017
Source:Developmental Cell, Volume 42, Issue 1
Author(s): Dhananjay Yellajoshyula, Chun-Chi Liang, Samuel S. Pappas, Silvia Penati, Angela Yang, Rodan Mecano, Ravindran Kumaran, Stephanie Jou, Mark R. Cookson, William T. Dauer
The childhood-onset motor disorder DYT6 dystonia is caused by loss-of-function mutations in the transcription factor THAP1, but the neurodevelopmental processes in which THAP1 participates are unknown. We find that THAP1 is essential for the timing of myelination initiation during CNS maturation. Conditional deletion of THAP1 in the CNS retards maturation of the oligodendrocyte (OL) lineage, delaying myelination and causing persistent motor deficits. The CNS myelination defect results from a cell-autonomous requirement for THAP1 in the OL lineage and is recapitulated in developmental assays performed on OL progenitor cells purified from Thap1 null mice. Loss of THAP1 function disrupts a core set of OL maturation genes and reduces the DNA occupancy of YY1, a transcription factor required for OL maturation. These studies establish a role for THAP1 transcriptional regulation at the inception of myelination and implicate abnormal timing of myelination in the pathogenesis of childhood-onset dystonia.

Graphical abstract

Teaser

DYT6 dystonia is a motor disorder caused by loss-of-function mutations in the transcription factor THAP1. Yellajoshyula et al. demonstrate that loss of THAP1 impairs CNS myelination through a cell-autonomous role in the oligodendrocyte lineage and decreases the DNA occupancy of YY1, a transcription factor with an established role in myelination.


http://ift.tt/2tI99BH

Chk1 Inhibition of the Replication Factor Drf1 Guarantees Cell-Cycle Elongation at the Xenopus laevis Mid-blastula Transition

Publication date: 10 July 2017
Source:Developmental Cell, Volume 42, Issue 1
Author(s): Clara Collart, James C. Smith, Philip Zegerman
The early cell divisions of many metazoan embryos are rapid and occur in the near absence of transcription. At the mid-blastula transition (MBT), the cell cycle elongates and several processes become established including the onset of bulk transcription and cell-cycle checkpoints. How these events are timed and coordinated is poorly understood. Here we show in Xenopus laevis that developmental activation of the checkpoint kinase Chk1 at the MBT results in the SCF^β-TRCP-dependent degradation of a limiting replication initiation factor Drf1. Inhibition of Drf1 is the primary mechanism by which Chk1 blocks cell-cycle progression in the early embryo and is an essential function of Chk1 at the blastula-to-gastrula stage of development. This study defines the downregulation of Drf1 as an important mechanism to coordinate the lengthening of the cell cycle and subsequent developmental processes.

Graphical abstract

Teaser

Embryonic divisions lengthen at the mid-blastula transition (MBT) in many metazoa. Collart et al. show in Xenopus laevis that the checkpoint kinase Chk1 causes SCF^β-TRCP-dependent degradation of the replication factor Drf1 at the MBT. Inhibition of Drf1 is an essential function of Chk1, guaranteeing timely cell-cycle elongation.


http://ift.tt/2tIAWlB

Basement Membrane Manipulation in Drosophila Wing Discs Affects Dpp Retention but Not Growth Mechanoregulation

Publication date: 10 July 2017
Source:Developmental Cell, Volume 42, Issue 1
Author(s): Mengqi Ma, Xueya Cao, Jianli Dai, José C. Pastor-Pareja
Basement membranes (BMs) are extracellular matrix polymers basally underlying epithelia, where they regulate cell signaling and tissue mechanics. Constriction by the BM shapes Drosophila wing discs, a well-characterized model of tissue growth. Recently, the hypothesis that mechanical factors govern wing growth has received much attention, but it has not been definitively tested. In this study, we manipulated BM composition to cause dramatic changes in tissue tension. We found that increased tissue compression when perlecan was knocked down did not affect adult wing size. BM elimination, decreasing compression, reduced wing size but did not visibly affect Hippo signaling, widely postulated to mediate growth mechanoregulation. BM elimination, in contrast, attenuated signaling by bone morphogenetic protein/transforming growth factor β ligand Dpp, which was not efficiently retained within the tissue and escaped to the body cavity. Our results challenge mechanoregulation of wing growth, while uncovering a function of BMs in preserving a growth-promoting tissue environment.

Graphical abstract

Teaser

To test the hypothesis that mechanical inputs regulate wing growth, Ma et al. deformed wings by changing basement membrane composition. This failed to affect Hippo signaling, widely believed to be involved in growth mechanoregulation. In contrast, they found that the basement membrane affects growth through retention of growth-promoting ligand Dpp.


http://ift.tt/2tIvdw3

Atomic Resolution Conformational Dynamics of Intrinsically Disordered Proteins from NMR Spin Relaxation

Publication date: Available online 10 July 2017
Source:Progress in Nuclear Magnetic Resonance Spectroscopy
Author(s): Nicola Salvi, Anton Abyzov, Martin Blackledge
Nuclear magnetic resonance (NMR) spectroscopy is one of the most powerful experimental approaches for investigating the conformational behavior of intrinsically disordered proteins (IDPs). IDPs represent a significant fraction of all proteomes, and, despite their importance for understanding fundamental biological processes, the molecular basis of their activity still remains largely unknown. The functional mechanisms exploited by IDPs in their interactions with other biomolecules are defined by their intrinsic dynamic modes and associated timescales, justifying the considerable interest over recent years in the development of technologies adapted to measure and describe this behavior. NMR spin relaxation delivers information-rich, site-specific data reporting on conformational fluctuations occurring throughout the molecule. Here we review recent progress in the use of ¹⁵N relaxation to identify local backbone dynamics and long-range chain-like motions in unfolded proteins.

Graphical abstract

http://ift.tt/2u2Usvy

The impact of repeated cycles of radioligand therapy using [ 177 Lu]Lu-PSMA-617 on renal function in patients with hormone refractory metastatic prostate cancer

Abstract

Background

[¹⁷⁷Lu]Lu-PSMA-617 is a well-tolerated therapy for the treatment of metastatic prostate cancer. However, because of the mainly renal excretion of the tracer, the kidneys are one of the most limiting organs. The purpose of this study was to examine the post-therapeutic changes in renal function over time and to identify risk factors for developing renal toxicity. We also tested the reliability of markers for renal function monitoring.

Methods

Fifty-five patients with castrate-resistant metastatic prostate cancer treated with at least three cycles of [¹⁷⁷Lu]Lu-PSMA-617 were investigated. Renal function was assessed through laboratory tests (creatinine, GFR, cystatin C) and Tc-99 m-MAG3 measurements. Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. To identify risk factors for renal toxicity, we used Pearson's correlation coefficient and the corresponding p values.

Results

None of the 55 patients experienced severe nephrotoxicity (grade 3/4). In 14 patients (25%), we observed increased creatinine levels of CTC 1° or 2°. There were 16 cases of increased GFR (grade 1/2). At the baseline, only 14 patients had elevated cystatin C. However, post-therapeutic cystatin C was elevated in 32 patients (58%). A significant effect on renal function was found for age (p = 0.049), hypertension (p = 0.001) and pre-existing kidney disease (p = 0.001). The most reliable predictive markers of nephrotoxicity were TER-MAG3 and cystatin C.

Conclusion

Renal toxicity in patients treated with [¹⁷⁷Lu]Lu-PSMA-617 was low. There was no (sub)acute grade 3 or 4 nephrotoxicity.

http://ift.tt/2uLUK7F

Microsurgery guided by sequential preoperative lymphography using 68 Ga-NEB PET and MRI in patients with lower-limb lymphedema

Abstract

Objective

The popularity of contemporary microsurgical techniques in treatment of lower-limb lymphedema calls for better visualization of the lymphatic system, both preoperatively and intra-operatively. The aim of this prospective study was to investigate the feasibility of a novel combination of ⁶⁸Ga-NEB positron emission tomography (PET) with magnetic resonance lymphography (MRL) in evaluating lymphedema and guiding surgical intervention.

Methods

A total of 11 patients (F 9, M 2, age range 29–69 y) with lower-limb lymphedema classified into stage I to III were recruited. PET acquisition was performed at 30, 60 and 90 min after subcutaneous injection of the albumin-binding radiotracer ⁶⁸Ga-NEB into the bilateral first web spaces of the feet. All the patients were also subjected to ^99mTc-sulfur colloid (SC) lymphoscintigraphy for comparison. Gd-DTPA-enhanced magnetic resonance imaging (MRI) was performed using sequences specialized for lymphatic vessel scans. All the patients underwent surgical interventions within a week. The surgical approach includes the use of a linear marker for edema localization and indocyanine green (ICG) lymphography with a near-infrared surgical navigation system intra-operatively.

Results

Lymph transport in lymphatic channels was clearly observed by visualization of ⁶⁸Ga-NEB activity in the lymphatic vessels and within lymph nodes for all 11 patients as well as the visualization of the edema section plane with dermal backflow (DB), abnormally increased and disconnected uptake along the lymphatic channels. Preoperative ⁶⁸Ga-NEB PET combined with MRL provides advantageous three-dimensional images, higher temporal resolution, significantly shorter time lapse before image acquisition after tracer injection and more accurate pathological lymphatic vessel distribution than ^99mTc-SC lymphoscintigraphy combined with MRI.

Conclusion

This study documented an effective imaging pattern to combine ⁶⁸Ga-NEB PET and MRL in patients with lower-limb lymphedema. This strategy demonstrated significant advantage over ^99mTc-SC lymphoscintigraphy/MRL in the evaluation of lymphedema severity, staging and pathological location of lymph vessels to make an individualized treatment plan. Dual ⁶⁸Ga-NEB PET/MRL is thus recommended before the operation for staging and therapy planning.

http://ift.tt/2ud5zCJ

Inter-heterogeneity and intra-heterogeneity of α v β 3 in non-small cell lung cancer and small cell lung cancer patients as revealed by 68 Ga-RGD 2 PET imaging

Abstract

Purpose

Integrin α_vβ₃ is the therapeutic target of the anti-angiogenic drug cilengitide. The objective of this study was to compare α_vβ₃ levels in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients, by using the positron emission tomography (PET) tracer ⁶⁸Ga-labeled dimerized-RGD (⁶⁸Ga-RGD₂).

Methods

Thirty-one patients with pathologically confirmed lung cancer were enrolled (21 were NSCLC and 10 were SCLC). PET/CT images were acquired using ⁶⁸Ga-RGD₂.¹⁸F-FDG PET/CT images were also acquired on the consecutive day as reference. The standard uptake values (SUV) and the tumor/nontarget (T/NT) values were quantitatively compared. Expression of the angiogenesis marker α_vβ₃ in NSCLC and SCLC lesions was analyzed by immunohistochemistry.

Results

The ¹⁸F-FDG SUVmax and the SUVmean were not significantly different between NSCLC and SCLC patients. The ⁶⁸Ga-RGD₂ uptake of SCLC patients was at background levels in both SUV and T/NT measurements and was significantly lower than that of NSCLC patients. The range value of ⁶⁸Ga-RGD₂ SUVmean was 4.5 in the NSCLC group and 2.2 in the SCLC group, while the variation coefficient was 36.2% and 39.3% in NSCLC and SCLC primary lesions, respectively. Heterogeneity between primary lesions and putative distant metastases was also observed in some NSCLC cases. Immunostaining showed that α_vβ₃ integrin was expressed in the cells and neovasculature of NSCLC lesions, while SCLC samples had negative expression.

Conclusions

The uptake of ⁶⁸Ga-RGD₂ in SCLC patients is significantly lower than that in NSCLC patients, indicating a lower α_vβ₃ target level for cilengitide in SCLC. Apparent intra-tumor heterogeneities of α_vβ₃ also exist in both NSCLC and SCLC. Such inter- and intra-heterogeneity of α_vβ₃ may potentially improve current applications of α_vβ₃-targeted therapy and diagnostic imaging in lung cancer.

http://ift.tt/2uLwVNi

Diffuse 18 F-FDG uptake throughout the spinal cord in the acute phase of Neuromyelitis Optica Spectrum disorder

http://ift.tt/2ucC3gF

18 F–FDG-PET/CT for systemic staging of patients with newly diagnosed ER-positive and HER2-positive breast cancer

Abstract

Objectives

This study assesses ¹⁸F–FDG-PET/CT for patients with newly diagnosed estrogen receptor-positive/human epidermal growth factor receptor-negative (ER+/HER2-) and human epidermal growth factor receptor-positive (HER2+) breast cancer.

Methods

In this Institutional Review Board-approved retrospective study, our Healthcare Information System was screened for patients with ER+/HER2- and HER2+ breast cancer who underwent ¹⁸F–FDG-PET/CT prior to systemic or radiation therapy. The initial stage was determined from mammography, ultrasound, magnetic resonance imaging, and/or surgery.¹⁸F–FDG-PET/CT was evaluated to identify unsuspected extra-axillary regional nodal and distant metastases. The proportion of patients upstaged overall and stratified by stage and receptor phenotypes was calculated along with confidence intervals (CI).

Results

A total of 238 patients with ER+/HER2- and 245 patients with HER2+ who met inclusion criteria were evaluated. For patients with ER+/HER2-breast cancer, ¹⁸F–FDG-PET/CT revealed unsuspected distant metastases in 3/71 (4%) initial stage IIA, 13/95 (14%) stage IIB, and 15/57 (26%) stage III. For patients with HER2+ breast cancer, ¹⁸F–FDG-PET/CT revealed unsuspected distant metastases in 3/72 (4%) initial stage IIA, 13/93 (14%) stage IIB, and 13/59 (22%) stage III. The overall upstaging rate for IIB was 14% (95% confidence interval (CI): 9–20%).

Conclusions

¹⁸F–FDG-PET/CT revealed distant metastases in 14% (95% CI: 9–20%) of patients with stage IIB ER+/HER2- and HER2+ breast cancer, which is similar to upstaging rates previously seen in patients with stage IIB triple-negative breast cancer (15%, 95% CI: 9–24%). The detection of unsuspected distant metastases in these patients alters treatment and prognosis. NCCN guidelines should consider adding patients with stage IIB breast cancer for consideration of systemic staging with ¹⁸F–FDG-PET/CT at the time of initial diagnosis.

http://ift.tt/2uLlZzc

Fibrous dysplasia mimicking bone metastasis on 68 GA-PSMA PET/MRI

http://ift.tt/2ucPX2c

Comparison of PSMA-HBED and PSMA-I&T as diagnostic agents in prostate carcinoma

Abstract

Purpose

Gallium(68)-labelled prostate-specific membrane antigen (PSMA) radiopharmaceuticals can be used to detect prostate cancer (PCa) cells due the their over expression of PSMA. The ⁶⁸Ga HBED-PSMA (PSMA-HBED) ligand has been most widely used and can be considered the current gold standard agent. Further PSMA ligands based on the DOTAGA and DOTA conjugates have more recently been developed. These agents (PSMA-I&T and PSMA-617) have potential theranostic capabilities as they can be conjugated with therapeutic radioisotopes. In this study, we examine whether PSMA-I&T has comparative efficacy, such that it could replace PSMA-HBED as a diagnostic agent in prostate carcinoma.

Methods

19 patients with PCa referred for ⁶⁸Ga-PSMA imaging were imaged with PSMA-HBED and PSMA-I&T PET-CT imaging within a 2-week period. The two pharmaceuticals were synthesised using click chemistry. Imaging was performed using the same standardised methodology on a Siemens Biograph mCT. All sites of PSMA binding thought to represent PCa (probable or definite) were included in a lesion analysis that examined lesion concordance and lesional binding efficiency (SUV_peak) between the two radiopharmaceuticals. For each patient, SUV_mean of the LV cavity blood pool, bone, muscle and liver were determined as image background measures.

Results

Across all patients, PSMA uptake was observed in 47 lesions (10 bone lesions, 19 nodal lesions, 18 high-grade intraprostatic binding). Lesions were concordant between the agents in all except for two small (<4 mm) nodal lesions which were not visualised with PSMA-I&T. SUV_peak assessment showed significantly greater overall lesion binding with HBED (paired t test, p = 0.0001). LV blood pool and bone marrow SUV_mean were significantly higher for I&T than HBED (paired t test, blood pool p < 1 × 10–5, bone marrow p < 0.005).

Conclusion

Intra-patient comparative imaging demonstrates higher lesional PSMA-HBED binding than PSMA-I&T and that the HBED agent is likely to have better lesion contrast. While there was concordance in 96% of lesions, 2 small nodal lesions were appreciated with PSMA-HBED imaging while considered normal with PSMA-I&T. These findings suggest that HBED-PSMA has a slightly higher diagnostic accuracy in comparison to PSMA-I&T.

http://ift.tt/2uL4BLd

FDG PET for therapy monitoring in Hodgkin’s and non-Hodgkin’s lymphomas: qPET versus rPET

http://ift.tt/2ucUW2X

Quantification of temporal changes in calcium score in active atherosclerotic plaque in major vessels by 18 F-sodium fluoride PET/CT

Abstract

Purpose

Our aim was to assess whether ¹⁸F-NaF PET/CT is able to predict progression of the CT calcium score.

Methods

Between August 2007 and November 2015, 34 patients (18 women, 16 men; age, mean ± standard deviation, 57.5 ± 13.9 years; age range 19–78 years) with malignancy or orthopaedic disease were enrolled in this study, with approximately 1-year follow-up data. Baseline and follow-up CT images were retrospectively evaluated for the presence of calcification sites in major vessel walls. The maximum and mean CT values (CTmax and CTmean, in Hounsfield units), calcification volumetric score (CVS, in cubic millimetres) and Agatston units score (AU) were evaluated for each site. Subsequent changes in CTmax, CTmean, CVS and AU were calculated and expressed as ΔCTmax, ΔCTmean, ΔCVS and ΔAU, respectively. We then evaluated the relationship between ¹⁸F-NaF uptake (using the maximum target-to-background ratio, TBRmax, and the maximum blood-subtracted ¹⁸F-NaF activity, bsNaFmax, which was obtained by subtracting the SUVmax of each calcified plaque lesion and NaF-avid site from the SUVmean in the right atrium blood pool) and the change in calcified plaque volume and characteristics obtained after 1 year.

Results

We detected and analysed 182 calcified plaque sites and 96 hot spots on major vessel walls. ¹⁸F-NaF uptake showed very weak correlations with CTmax, CTmean, CVS, CVS after 1 year, AU and AU after 1 year on both baseline and follow-up PET/CT scans for each site. ¹⁸F-NaF uptake showed no correlation with ΔCTmax or ΔCTmean. However, there was a significant correlation between the intensity of ¹⁸F-NaF uptake and ΔCVS and ΔAU.

Conclusion

¹⁸F-NaF uptake has a strong correlation with calcium score progression which was a predictor of future cardiovascular disease risk. PET/CT using ¹⁸F-NaF may be able to predict calcium score progression which is known to be the major characteristic of atherosclerosis.

http://ift.tt/2uL4BuH

Sentinel lymph node mapping using SPECT/CT and gamma probe in endometrial cancer: an analysis of parameters affecting detection rate

Abstract

Purpose

SPECT/CT after pericervical injection of technetium-99 m-nanocolloid was shown to be suitable for sentinel lymph node (SLN) mapping in endometrial cancer (EC). The aim of this study was to analyze factors affecting successful SLN detection by means of SPECT/CT such as imaging findings, patient characteristics and tumor biology in a large cohort of patients.

Methods

One hundred and forty-five consecutive patients suffering from EC who received pre-surgical SLN mapping at our institution between 2011 and 2016 were included in this analysis. SPECT/CT data of abdomen and pelvis (mean 4:20 ± 1:20 h p.i.) were acquired after pericervical injection of technetium-99 m-nanocolloid (mean 230 ± 45 MBq) in all patients. Surgical staging was performed on the day after. Acquisition parameters, patient characteristics, SPECT/CT findings as well as histopathological results were collected.

Results

A total of 282 SLNs were identified by means of SPECT/CT. Overall, preoperative and intraoperative SLN detection rates were 86%, 76% and 74% respectively. The most important factor associated with failure to detect SLNs was the presence of high bone marrow on SPECT/CT (p = 0.005). Peritoneal/abdominal radioactivity was also associated with missed SLN detection in SPECT/CT (p = 0.02). However, the presence of liver/spleen uptake on its own was not predictive for detection failure. Low numbers of detected SLNs in SPECT/CT were slightly related with older age and lower injected activity. No significant influence was found for the parameters of tumor histology and stage, lymph node involvement and the time gap between injection and imaging.

Conclusions

Venous drainage as indicated by bone marrow uptake is the most important factor associated with scintigraphic SLN detection failure. Moreover, high peritoneal and abdominal activity was also associated with detection failure. Thus, meticulous application of the radiotracer is crucial in EC.

http://ift.tt/2ucKAA0

Overall survival and response pattern of castration-resistant metastatic prostate cancer to multiple cycles of radioligand therapy using [ 177 Lu]Lu-PSMA-617

Abstract

Purpose

Up to 30% of patients with castration-resistant prostate cancer (CRPC) do not show any response to the first cycle of radioligand therapy (RLT) with [¹⁷⁷Lu]Lu-PSMA-617 (Lu-PSMA). We evaluated patient response to the second and third cycles of RLT in patients that underwent at least three cycles. The second aim of this study was to calculate the median overall survival (OS) of responders and non-responders after the first cycle and after all three cycles of RLT.

Methods

CRPC patients were treated with Lu-PSMA, with a median interval of 8 weeks between each cycle. The tumour marker prostate-specific antigen (PSA) was used as the marker for response evaluation.

Results

Fifty-two patients underwent a total of 190 cycles of RLT (3–6 cycles per patient). Of these, 80.8% showed a decline in PSA 2 months after the first cycle, with 44.2% showing a PSA decline of ≥50%. When compared to baseline PSA, 73.1% showed a PSA decline after the third cycle. 50% of patients that did not show any response to the first cycle also did not respond to the second and third cycles. The median OS was 60 weeks in all patients. The median OS was significantly longer for patients that showed any PSA decline after the first cycle compared to patients without PSA decline (68 vs. 33 weeks). There was a significant difference in median OS between responders and non-responders for a change in PSA after the third cycle compared to baseline PSA.

Conclusion

Patients with a positive response to RLT, regardless of the rate of decline, had a significantly longer median OS. Of the patients that did not show any response to the first cycle, 50% responded to the second or third cycles.

http://ift.tt/2uLlBRl

MUC-king with HIF May Rewire Pyrimidine Biosynthesis and Curb Gemcitabine Resistance in Pancreatic Cancer

Publication date: 10 July 2017
Source:Cancer Cell, Volume 32, Issue 1
Author(s): Chi V. Dang
In this issue of Cancer Cell, Singh and colleagues report a role for MUC1-induced HIF expression in rewiring ribose synthesis, which drives pyridimine production as a possible resistance mechanism to gemcitabine, adding to complexity and multiple paths to resistance.

Teaser

In this issue of Cancer Cell, Singh and colleagues report a role for MUC1-induced HIF expression in rewiring ribose synthesis, which drives pyridimine production as a possible resistance mechanism to gemcitabine, adding to complexity and multiple paths to resistance.


http://ift.tt/2u7D4Wn

Redefining Hormonal Therapy for Advanced Prostate Cancer: Results from the LATITUDE and CHAARTED Studies

Publication date: 10 July 2017
Source:Cancer Cell, Volume 32, Issue 1
Author(s): Eric J. Small
Two papers published recently in the New England Journal of Medicine describe the utility of abiraterone acetate, an androgen biosynthesis inhibitor, in the early treatment of metastatic prostate cancer. In addition to establishing a new standard of care, these two articles pose a number of important questions for future investigation.

Teaser

Two papers published recently in the New England Journal of Medicine describe the utility of abiraterone acetate, an androgen biosynthesis inhibitor, in the early treatment of metastatic prostate cancer. In addition to establishing a new standard of care, these two articles pose a number of important questions for future investigation.


http://ift.tt/2v66P76

Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology

Publication date: 10 July 2017
Source:Cancer Cell, Volume 32, Issue 1
Author(s): Julian Blagg, Paul Workman
Small-molecule chemical probes or tools have become progressively more important in recent years as valuable reagents to investigate fundamental biological mechanisms and processes causing disease, including cancer. Chemical probes have also achieved greater prominence alongside complementary biological reagents for target validation in drug discovery. However, there is evidence of widespread continuing misuse and promulgation of poor-quality and insufficiently selective chemical probes, perpetuating a worrisome and misleading pollution of the scientific literature. We discuss current challenges with the selection and use of chemical probes, and suggest how biologists can and should be more discriminating in the probes they employ.

Teaser

Small-molecule chemical probes or tools have become progressively more important in recent years as valuable reagents to investigate fundamental biological mechanisms and processes causing disease, including cancer. Chemical probes have also achieved greater prominence alongside complementary biological reagents for target validation in drug discovery. However, there is evidence of widespread continuing misuse and promulgation of poor-quality and insufficiently selective chemical probes, perpetuating a worrisome and misleading pollution of the scientific literature. We discuss current challenges with the selection and use of chemical probes, and suggest how biologists can and should be more discriminating in the probes they employ.


http://ift.tt/2u7Nbu8

Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment

Publication date: 10 July 2017
Source:Cancer Cell, Volume 32, Issue 1
Author(s): Qianghu Wang, Baoli Hu, Xin Hu, Hoon Kim, Massimo Squatrito, Lisa Scarpace, Ana C. deCarvalho, Sali Lyu, Pengping Li, Yan Li, Floris Barthel, Hee Jin Cho, Yu-Hsi Lin, Nikunj Satani, Emmanuel Martinez-Ledesma, Siyuan Zheng, Edward Chang, Charles-Etienne Gabriel Sauvé, Adriana Olar, Zheng D. Lan, Gaetano Finocchiaro, Joanna J. Phillips, Mitchel S. Berger, Konrad R. Gabrusiewicz, Guocan Wang, Eskil Eskilsson, Jian Hu, Tom Mikkelsen, Ronald A. DePinho, Florian Muller, Amy B. Heimberger, Erik P. Sulman, Do-Hyun Nam, Roel G.W. Verhaak
We leveraged IDH wild-type glioblastomas, derivative neurospheres, and single-cell gene expression profiles to define three tumor-intrinsic transcriptional subtypes designated as proneural, mesenchymal, and classical. Transcriptomic subtype multiplicity correlated with increased intratumoral heterogeneity and presence of tumor microenvironment. In silico cell sorting identified macrophages/microglia, CD4⁺ T lymphocytes, and neutrophils in the glioma microenvironment. NF1 deficiency resulted in increased tumor-associated macrophages/microglia infiltration. Longitudinal transcriptome analysis showed that expression subtype is retained in 55% of cases. Gene signature-based tumor microenvironment inference revealed a decrease in invading monocytes and a subtype-dependent increase in macrophages/microglia cells upon disease recurrence. Hypermutation at diagnosis or at recurrence associated with CD8⁺ T cell enrichment. Frequency of M2 macrophages detection associated with short-term relapse after radiation therapy.

Graphical abstract

Teaser

Wang et al. define three IDH wild-type glioblastoma-intrinsic gene expression subtypes, which are partly shaped by the tumor immune environment. NF1 deficiency results in increased macrophage/microglia infiltration. Comparison of matched primary and recurrent tumors reveals frequent expression subtype changes.


http://ift.tt/2v6cXMP

HDAC Inhibitors Finally Open Up: Chromatin Accessibility Signatures of CTCL

Publication date: 10 July 2017
Source:Cancer Cell, Volume 32, Issue 1
Author(s): Christopher J. Ott, Catherine J. Wu
In this issue of Cancer Cell, Qu et al. describe the chromatin accessibility profiles of cutaneous T cell lymphoma, with dynamic assessments of response and resistance to histone deacetylase inhibitor therapy. Their "personal regulome" analysis framework reveals chromatin features that may be predictive of clinical response to epigenetic therapy.

Teaser

In this issue of Cancer Cell, Qu et al. describe the chromatin accessibility profiles of cutaneous T cell lymphoma, with dynamic assessments of response and resistance to histone deacetylase inhibitor therapy. Their "personal regulome" analysis framework reveals chromatin features that may be predictive of clinical response to epigenetic therapy.


http://ift.tt/2v6cJ8l

MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer

Publication date: 10 July 2017
Source:Cancer Cell, Volume 32, Issue 1
Author(s): Surendra K. Shukla, Vinee Purohit, Kamiya Mehla, Venugopal Gunda, Nina V. Chaika, Enza Vernucci, Ryan J. King, Jaime Abrego, Gennifer D. Goode, Aneesha Dasgupta, Alysha L. Illies, Teklab Gebregiworgis, Bingbing Dai, Jithesh J. Augustine, Divya Murthy, Kuldeep S. Attri, Oksana Mashadova, Paul M. Grandgenett, Robert Powers, Quan P. Ly, Audrey J. Lazenby, Jean L. Grem, Fang Yu, José M. Matés, John M. Asara, Jung-whan Kim, Jordan H. Hankins, Colin Weekes, Michael A. Hollingsworth, Natalie J. Sarkova, Aaron R. Sasson, Jason B. Fleming, Jennifer M. Oliveto, Costas A. Lyssiotis, Lewis C. Cantley, Lyudmyla Berim, Pankaj K. Singh
Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. We also demonstrate that MUC1-regulated stabilization of hypoxia inducible factor-1α (HIF-1α) mediates such metabolic reprogramming. Targeting HIF-1α or de novo pyrimidine biosynthesis, in combination with gemcitabine, strongly diminishes tumor burden. Finally, reduced expression of TKT and CTPS, which regulate flux into pyrimidine biosynthesis, correlates with better prognosis in pancreatic cancer patients on fluoropyrimidine analogs.

Graphical abstract

Teaser

Shukla et al. identify that HIF-1α mediates increased glycolytic flux and de novo pyrimidine biosynthesis, leading to gemcitabine resistance in pancreatic cancer cells. Targeting HIF-1α or de novo pyrimidine biosynthesis increases the efficacy of gemcitabine.


http://ift.tt/2u7vjje

Oncogenic Activation of the RNA Binding Protein NELFE and MYC Signaling in Hepatocellular Carcinoma

Publication date: 10 July 2017
Source:Cancer Cell, Volume 32, Issue 1
Author(s): Hien Dang, Atsushi Takai, Marshonna Forgues, Yotsowat Pomyen, Haiwei Mou, Wen Xue, Debashish Ray, Kevin C.H. Ha, Quaid D. Morris, Timothy R. Hughes, Xin Wei Wang
Global transcriptomic imbalance is a ubiquitous feature associated with cancer, including hepatocellular carcinoma (HCC). Analyses of 1,225 clinical HCC samples revealed that a large numbers of RNA binding proteins (RBPs) are dysregulated and that RBP dysregulation is associated with poor prognosis. We further identified that oncogenic activation of a top candidate RBP, negative elongation factor E (NELFE), via somatic copy-number alterations enhanced MYC signaling and promoted HCC progression. Interestingly, NELFE induces a unique tumor transcriptome by selectively regulating MYC-associated genes. Thus, our results revealed NELFE as an oncogenic protein that may contribute to transcriptome imbalance in HCC through the regulation of MYC signaling.

Graphical abstract

Teaser

Dang et al. show that a large numbers of RNA binding proteins (RBPs) are dysregulated in hepatocellular carcinoma (HCC) and that NELFE, an RBP, enhances MYC-induced HCC development by regulating the binding of MYC to target promoters and the mRNA stability of several MYC-regulated genes.


http://ift.tt/2u7W4UJ

Stabilization of the c-Myc Protein by CAMKIIγ Promotes T Cell Lymphoma

Publication date: 10 July 2017
Source:Cancer Cell, Volume 32, Issue 1
Author(s): Ying Gu, Jiawei Zhang, Xiaoxiao Ma, Byung-wook Kim, Hailong Wang, Jinfan Li, Yi Pan, Yang Xu, Lili Ding, Lu Yang, Chao Guo, Xiwei Wu, Jun Wu, Kirk Wu, Xiaoxian Gan, Gang Li, Ling Li, Stephen J. Forman, Wing-Chung Chan, Rongzhen Xu, Wendong Huang
Although high c-Myc protein expression is observed alongside MYC amplification in some cancers, in most cases protein overexpression occurs in the absence of gene amplification, e.g., T cell lymphoma (TCL). Here, Ca²⁺/calmodulin-dependent protein kinase II γ (CAMKIIγ) was shown to stabilize the c-Myc protein by directly phosphorylating it at serine 62 (S62). Furthermore, CAMKIIγ was shown to be essential for tumor maintenance. Inhibition of CAMKIIγ with a specific inhibitor destabilized c-Myc and reduced tumor burden. Importantly, high CAMKIIγ levels in patient TCL specimens correlate with increased c-Myc and pS62-c-Myc levels. Together, the CAMKIIγ:c-Myc axis critically influences the development and maintenance of TCL and represents a potential therapeutic target for TCL.

Graphical abstract

Teaser

T cell lymphomas (TCL) overexpress the c-Myc protein without MYC rearrangements or amplification. Gu et al. show that CAMKIIγ stabilizes c-Myc by phosphorylating it at Ser62, that the CAMKIIγ level positively correlates with the c-Myc level in patient TCL, and that inhibition of CAMKIIγ reduces TCL burden in mice.


http://ift.tt/2v64nNN

Bacillus Calmette-Guérin (BCG) vaccination patterns in the province of Québec, Canada, 1956–1974

Publication date: Available online 10 July 2017
Source:Vaccine
Author(s): Marie-Claude Rousseau, Florence Conus, Khady Kâ, Mariam El-Zein, Marie-Élise Parent, Dick Menzies
BackgroundIn the province of Québec, Canada, the Bacillus Calmette-Guérin (BCG) vaccine was offered to newborns and school-age children from the 1950s to mid-1970s in an organized tuberculosis prevention program.ObjectiveWe aimed to describe the annual rates of skin test administration, proportion of skin tests that were positive, and rates of BCG vaccination from 1956 to 1974 according to age, sex, and administrative region.MethodsFor rates, numerators were extracted from the Québec BCG Vaccination Registry whereas population denominators were obtained from the Canadian Census and governmental publications. Time trends were assessed with linear regression.ResultsA total of 2,755,336 skin tests and 2,531,366 BCG vaccinations were administered. Yearly rates of skin tests, routinely administered before vaccination among all except newborns, were highest among children aged 5–9 (9.3 per 100) and 10–14years (7.9 per 100). The proportion of positive skin tests varied greatly by age, ranging from 10.2% among children <1year to 67.2% among adults ≥20years. The vast majority of individuals who had a negative skin test were subsequently vaccinated, whereas those with a positive result were not, as per recommended guidelines. The average annual vaccination rate was highest among children aged <1year (43.8 per 100) and 5–9year-olds (6.9 per 100). There were salient differences in immunization rates, including positive skin tests and vaccinations, across administrative regions but no difference by sex.ConclusionThis is the first comprehensive description of the tuberculosis prevention program in Québec which offered free, non-mandatory BCG vaccination. Our results confirm that the targeted groups, newborns and school-age children, were preferentially reached. Socioeconomic, demographic, and organizational factors may explain regional differences in immunization rates. Beyond presenting a historical context for this vaccination campaign, our findings are relevant to contemporary uses of the Québec BCG Vaccination Registry in epidemiological research.



http://ift.tt/2tCuCOf

Combination vaccine strategies to prevent enteric infections

Publication date: Available online 10 July 2017
Source:Vaccine
Author(s): Richard Walker, Peter Dull
New vaccine candidates entering the current routine immunization schedule can best be accommodated as combination vaccines. A combined Shigella and enterotoxigenic E. coli (ETEC) vaccine could greatly benefit children in disease-endemic areas. New candidates are getting closer to being able to meet these needs, but they raise numerous strategic questions related to presentation, formulation, and regulatory approach. The "Combination Vaccine Strategies to Prevent Enteric Infections" workshop at the 2016 Vaccines Against Shigella and ETEC (VASE) Conference examined some of the considerations for developing such vaccines against enteric pathogens.



http://ift.tt/2tCsru4

Silk fibroin degumming affects scaffold structure and release of macromolecular drugs

Publication date: 30 August 2017
Source:European Journal of Pharmaceutical Sciences, Volume 106
Author(s): Kira Nultsch, Oliver Germershaus
Silk fibroin (SF) is a natural polymer with tremendous potential as a matrix for drug delivery systems as well as for tissue engineering. Silk sericin (SS) removal (degumming) is a critical step during SF purification, potentially affecting SF integrity and resulting in structural changes such as partial hydrolysis and inhibition of micelle formation. In addition to SF composition itself, the molecular weight and charge of encapsulated drugs may significantly affect drug release from SF matrices. The effect of these parameters on drug release was investigated by varying SF degumming time and charge of the model compound encapsulated in SF films. With increasing degumming time, average SF molecular weight decreased, molecular weight distribution became broader and formation of SF micelles was impaired. However, β-sheet content was not affected by degumming time, suggesting that degradation occurred mainly in hydrophilic domains of SF. The release of differently charged dextran derivatives, used as macromolecular model drugs, was significantly affected by SF degumming. Release of neutral dextran increased with increasing degumming time. In contrast, negatively charged dextran showed an inverse effect potentially due to reduced SF charge density with increased degumming time. Interestingly, positively charged dextran were shown to partly form polyelectrolyte complexes with SF by isothermal titration calorimetry but also exhibited phase separation during film drying resulting in fast burst release. These results demonstrate that both, SF preparation as well as drug charge significantly affect drug release from SF matrices.

Graphical abstract

http://ift.tt/2u2YCDV

Antitumor efficacy of Lf modified daunorubicin plus honokiol liposomes in treatment of brain glioma

Publication date: 30 August 2017
Source:European Journal of Pharmaceutical Sciences, Volume 106
Author(s): Shuang Liu, Shi-meng Zhang, Rui-jun Ju, Yao Xiao, Xin Wang, Xiao-li Song, Li-yan Gu, Lan Cheng, Xue-tao Li, Gui-rong Chen
Malignant brain glioma is the most common and aggressive type of primary intracranial neoplasm. Regular chemotherapy cannot eradicate brain glioma cells and the residual glioma cells could form vasculogenic mimicry (VM) channels under hypoxic conditions to provide nutrients for tumor cell invasion. In addition, the existence of the blood-brain barrier (BBB) restricts most antitumor drugs into brain glioma. In this study, we developed a kind of lactoferrin (Lf) modified daunorubicin plus honokiol liposomes to transport antitumor drugs across BBB, eliminate the VM channels and block tumor cell invasion. The evaluations were performed on BBB model, brain glioma cells and glioma-bearing mice. In vitro results showed that the targeting liposomes with suitable physicochemical property could enhance the drug transportation acrossing the BBB, inhibit C6 cells invasion and destroy VM channels. Action mechanism studies indicated that Lf modified daunorubicin plus honokiol liposomes could activate apoptotic enzymes caspase 3 as well as down-regulate VM protein indicators (PI3K, MMP-2, MMP-9, VE-Cadherin and FAK). In vivo results displayed the targeting liposomes improved accumulation in brain tumor tissue and exhibited obvious antitumor efficacy. Therefore, Lf modified daunorubicin plus honokiol liposomes could be used as a potential therapy for treatment of brain glioma.

Graphical abstract

http://ift.tt/2ud1sqh

Pharmacological evaluation and molecular docking of new di-tert-butylphenol compound, LQFM-091, a new dual 5-LOX/COX inhibitor

Publication date: 30 August 2017
Source:European Journal of Pharmaceutical Sciences, Volume 106
Author(s): Roberta Campos Lino, Daiany Priscila Bueno da Silva, Iziara Ferreira Florentino, Dayane Moreira da Silva, José Luís Rodrigues Martins, Daniel da Costa Batista, Karla Carneiro de Siqueira Leite, Bianca Villavicencio, Géssica A. Vasconcelos, Andreia Luiza Pereira Silva, Renato Ivan de Ávila, Hugo Verli, Marize Campos Valadares, Eric de Souza Gil, Boniek G. Vaz, Luciano M. Lião, Ricardo Menegatti, Elson Alves Costa
Dual 5-LOX/COX inhibitors are potential new dual drugs to treat inflammatory conditions. This research aimed to design, synthesis and to evaluate the anti-inflammatory and antinociceptive effects of the new compound, which is derived from nimesulide and darbufelone lead compounds. The new dual inhibitor 5-LOX/COX has the possible advantage of gastrointestinal safety. A voltammetric experiment was conducted to observe the drug's antioxidative effect. A formalin test, a hot plate test and carrageenan-induced mechanical hyperalgesia were employed to evaluate the analgesic nature of LQFM-091. To evaluate anti-inflammatory activity, we measured edema, leukocyte count, myeloperoxidase activity and cytokines levels in carrageenan-induced inflammation tests. We elucidated the underlying mechanisms by assessing the interaction the with COXs and LOX enzymes by colorimetric screening assay and molecular docking. The lethal dose (LD50) was estimated using 3T3 Neutral Red Uptake assay. Our results indicate that the LQFM-091 prototype is a powerful antioxidant, as well as able to inhibit COX-1, COX-2 and LOX activities. LQFM091 was classified in GHS category 4 (300<LD50<2000mg/Kg). This prototype showed analgesic activity in the formalin test and decreased carrageenan-induced mechanical hyperalgesia. Furthermore, LQFM-091 reduced the paw edema induced by carrageenan and reduced the leukocyte count, myeloperoxidase activity, TNF-α and IL-1β levels in the pleural exudate. Another interesting finding was the absence of gastrointestinal lesions. These data indicate that LQFM-091 produced antinociceptive and anti-inflammatory effects while maintaining gastrointestinal safety. Furthermore, this compound presented a safe toxicological profile. Blocked COXs and LOX enzymes are important targets for manipulating the mechanism of this compound.

Graphical abstract

http://ift.tt/2u2QdAh

Impact of capillary flow hydrodynamics on carrier-mediated transport of opioid derivatives at the blood-brain barrier, based on pH-dependent Michaelis-Menten and Crone-Renkin analyses

Publication date: 30 August 2017
Source:European Journal of Pharmaceutical Sciences, Volume 106
Author(s): Siti R. Yusof, N. Joan Abbott, Alex Avdeef
Most studies of blood-brain barrier (BBB) permeability and transport are conducted at a single pH, but more detailed information can be revealed by using multiple pH values. A pH-dependent biophysical model was applied to the mechanistic analysis of published pH-dependent BBB luminal uptake data from three opioid derivatives in rat: pentazocine (Suzuki et al., 2002a, 2002b), naloxone (Suzuki et al., 2010a), and oxycodone (Okura et al., 2008). Two types of data were processed: in situ brain perfusion (ISBP) and brain uptake index (BUI). The published perfusion data were converted to apparent luminal permeability values, Papp, and analyzed by the pCEL-X program (Yusof et al., 2014), using the pH-dependent Crone-Renkin equation (pH-CRE) to determine the impact of cerebrovascular flow on the Michaelis-Menten transport parameters (Avdeef and Sun, 2011). For oxycodone, the ISBP data had been measured at pH7.4 and 8.4. The present analysis indicates a 7-fold lower value of the cerebrovascular flow velocity, Fpf, than that expected in the original study. From the pyrilamine-inhibited data, the flow-corrected passive intrinsic permeability value was determined to be P0=398×10⁻⁶cm·s⁻¹. The uptake data indicate that the neutral form of oxycodone is affected by a transporter at pH8.4. The extent of the cation uptake was less certain from the available data. For pentazocine, the brain uptake by the BUI method had been measured at pH5.5, 6.5, and 7.4, in a concentration range 0.1–40mM. Under similar conditions, ISBP data were also available. The pH-CRE determined values of Fpf from both methods were nearly the same, and were smaller than the expected value in the original publication. The transport of the cationic pentazocine was not fully saturated at pH5.5 at 40mM. The transport of the neutral species at pH7.4 appeared to reach saturation at 40mM pentazocine concentration, but not at 12mM. In the case of naloxone, a pH-dependent Michaelis-Menten equation (pH-MME) analysis of the data indicated a smooth sigmoidal transition from a higher capacity uptake process affecting cationic naloxone (pH5.0–7.0) to a lower capacity uptake process affecting the neutral drug (pH8.0–8.5), with cross-over point near pH7.4. Evidently, measurements at multiple pH values can reveal important information about both cerebrovascular flow and BBB transport kinetics.

Graphical abstract

http://ift.tt/2u2UjIJ

Editorial board members

Publication date: 30 August 2017
Source:European Journal of Pharmaceutical Sciences, Volume 106





http://ift.tt/2u2aGp6

Antimicrobial activity of polymyxin-loaded solid lipid nanoparticles (PLX-SLN): Characterization of physicochemical properties and in vitro efficacy

Publication date: 30 August 2017
Source:European Journal of Pharmaceutical Sciences, Volume 106
Author(s): Patrícia Severino, Elisânia F. Silveira, Kahynna Loureiro, Marco V. Chaud, Danilo Antonini, Marcelo Lancellotti, Victor Hugo Sarmento, Classius F. da Silva, Maria Helena A. Santana, Eliana B. Souto
Antimicrobial resistance is a current public health concern, limiting the available therapeutic options used for the treatment of common bacterial infections. The development of new drug entities via biotechnological processes is however expensive and time-consuming. Therefore, old antimicrobial agents have been recovered for clinical use. An example of these drugs is polymyxin, which is known for its serious adverse side effects, such as nephrotoxicity, neurotoxicity and promotion of skin pigmentation. To overcome these limitations, the use of biodegradable nanoparticles has been proposed to allow site-specific targeting, increasing the drug's bioavailability and decreasing its side effects. The aim of this work was the development of an optimized pharmaceutical formulation composed of solid lipid nanoparticles (SLN) loading polymyxin B sulphate (PLX) for the treatment of bacterial infections. The PLX-loaded SLN were produced by a double emulsion method (w/o/w), obtaining particles with a mean size of approximately 200nm, polydispersity of 0.3 and zeta potential of −30mV. The encapsulation efficiency reached values above 90% for all developed formulations. SLN remained stable for a period of 6months of storage at room temperature. The occlusive properties of the SLN was shown to be dependent on the type of lipid, while the antimicrobial properties of PLX-loaded SLN were effective against resistant strains of Pseudomonas aeruginosa. Results from the differential scanning calorimetry (DSC), wide angle X-ray diffraction (WAXD) and small angle X-ray scattering (SAXS) analyses confirmed the crystallinity of the inner SLN matrices, suggesting the capacity of these particles to modify the release profile of the loaded drug.

Graphical abstract

http://ift.tt/2sK7NoW

Evaluation of anti-diabetic activity of glycyrrhizin-loaded nanoparticles in nicotinamide-streptozotocin-induced diabetic rats

Publication date: 30 August 2017
Source:European Journal of Pharmaceutical Sciences, Volume 106
Author(s): Ruma Rani, Shakti Dahiya, Dinesh Dhingra, Neeraj Dilbaghi, Ki-Hyun Kim, Sandeep Kumar
Glycyrrhizin is an active constituent of the roots and rhizomes of Glycyrrhiza glabra and has anti-hyperglycemic effects. In this study, nanoparticles (NPs) loaded with glycyrrhizin or metformin were evaluated in vivo for their anti-hyperglycemic potency towards type-II diabetes in rats. The NPs were produced via the ionotropic gelation method using the biocompatible polymers chitosan and gum arabic. The polymer concentration was optimized using the 3² factorial method to acquire both minimum particle size and maximum encapsulation efficiency. The NPs were then characterized with respect to particle size, encapsulation efficiency, stability, chemical interactions, and in vitro drug dissolution profiles using spectroscopic and microscopic analysis. Furthermore, glycyrrhizin and metformin and their nanoformulations were administered for 21 successive days to diabetic rats. Glycyrrhizin-loaded NPs had significant anti-diabetic effects even though they contained approximately one quarter of the dosage relative to the pure form.

Graphical abstract

http://ift.tt/2sKoJLK

Development of a Sigma-2 Receptor affinity filter through a Monte Carlo based QSAR analysis

Publication date: 30 August 2017
Source:European Journal of Pharmaceutical Sciences, Volume 106
Author(s): Antonio Rescifina, Giuseppe Floresta, Agostino Marrazzo, Carmela Parenti, Orazio Prezzavento, Giovanni Nastasi, Maria Dichiara, Emanuele Amata
For the first time in sigma-2 (σ2) receptor field, a quantitative structure–activity relationship (QSAR) model has been built using pKi values of the whole set of known selective σ2 receptor ligands (548 compounds), taken from the Sigma-2 Receptor Selective Ligands Database (S2RSLDB) (http://ift.tt/2sJY6qr), through the Monte Carlo technique and employing the software CORAL. The model has been developed by using a large and structurally diverse set of compounds, allowing for a prediction of different populations of chemical compounds endpoint (σ2 receptor pKi). The statistical quality reached, suggested that model for pKi determination is robust and possesses a satisfactory predictive potential. The statistical quality is high for both visible and invisible sets. The screening of the FDA approved drugs, external to our dataset, suggested that sixteen compounds might be repositioned as σ2 receptor ligands (predicted pKi≥8). A literature check showed that six of these compounds have already been tested for affinity at σ2 receptor and, of these, two (Flunarizine and Terbinafine) have shown an experimental σ2 receptor pKi>7. This suggests that this QSAR model may be used as focusing screening filter in order to prospectively find or repurpose new drugs with high affinity for the σ2 receptor, and overall allowing for an enhanced hit rate respect to a random screening.

Graphical abstract

http://ift.tt/2sJDMFD

A delayed proinflammatory response of human preadipocytes to PCB126 is dependent on the aryl hydrocarbon receptor

Abstract

Inflammation in adipose tissue is recognized as a causative factor in the development of type II diabetes. Adipocyte hypertrophy as well as bacterial and environmental factors have been implicated in causing inflammation in mature adipocytes. Exposure to persistent organic pollutants such as polychlorinated biphenyls (PCBs) has been associated with the development of type II diabetes. We show here that PCB126, a dioxin-like PCB, activates a robust proinflammatory state in fat cell precursors (preadipocytes). The response was found to be dependent on aryl hydrocarbon receptor (AhR) activation, although induction of the response was delayed compared to upregulation of CYP1A1, a classic AhR-responsive gene. Treatment of preadipocytes with a nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) inhibitor partially attenuated the PCB126-induced inflammatory response and partly, but not completely, ameliorated disruption of adipogenesis caused by PCB126. Our results indicate a role for PCB126 in mediating an inflammatory response through AhR in preadipocytes that interferes with adipogenesis.

http://ift.tt/2u2Q7J8

Study of chlordecone desorption from activated carbons and subsequent dechlorination by reduced cobalamin

Abstract

Since 1972, the French departments of Guadeloupe and Martinique have intensively used organochlorinated pesticides such as chlordecone (CLD) and hexachlorocyclohexane (HCH) isomers to prevent the proliferation of banana weevil (Cosmopolite sordidus). These molecules are stable in the environment, leading to a continuous contamination of soils, water, and food chain in the banana-producing areas. In these polluted areas, water treatment plants are equipped with activated carbon (AC) filters. In order to improve treatment of CLD-contaminated waters by AC, CLD adsorption and desorption kinetic studies are carried out using different ACs produced from sugar cane bagasse as adsorbents and subsequent CLD degradation is performed using reduced vitamin B12 (VB12). A GC-MS method for CLD quantification is as well optimized. This study shows that bagasse ACs are able to capture the pollutant, leading to a CLD concentration decrease from 1 to 73 μg L⁻¹, with an adsorption capacity of 162 μg mg⁻¹. Adsorption capacity increase with the temperature indicates an endothermic process. Polar solvents favor CLD desorption from ACs, suggesting hydrogen bonding between CLD and surface groups of ACs, the best solvent for chemical desorption being ethanol. Subsequent degradation of CLD in ethanol is performed using vitamin B12 reduced by either 1,4-dithiotreitol (DTT) or zerovalent zinc, leading to 90% of CLD removal and to the molecule cage structure opening for formation of a pentachloroindene intermediate product, characterized by GC MS/MS. A pathway for pentachloroindene formation from CLD is proposed.

http://ift.tt/2sKd93B

DNA mismatch repair and its many roles in eukaryotic cells

Publication date: Available online 9 July 2017
Source:Mutation Research/Reviews in Mutation Research
Author(s): Dekang Liu, Guido Keijzers, Lene Juel Rasmussen
DNA mismatch repair (MMR) is an important DNA repair pathway that plays critical roles in DNA replication fidelity, mutation avoidance and genome stability, all of which contribute significantly to the viability of cells and organisms. MMR is widely-used as a diagnostic biomarker for human cancers in the clinic, and as a biomarker of cancer susceptibility in animal model systems. Prokaryotic MMR is well-characterized at the molecular and mechanistic level; however, MMR is considerably more complex in eukaryotic cells than in prokaryotic cells, and in recent years, it has become evident that MMR plays novel roles in eukaryotic cells, several of which are not yet well-defined or understood. Many MMR-deficient human cancer cells lack mutations in known human MMR genes, which strongly suggests that essential eukaryotic MMR components/cofactors remain unidentified and uncharacterized. Furthermore, the mechanism by which the eukaryotic MMR machinery discriminates between the parental (template) and the daughter (nascent) DNA strand is incompletely understood and how cells choose between the EXO1-dependent and the EXO1–independent subpathways of MMR is not known. This review summarizes recent literature on eukaryotic MMR, with emphasis on the diverse cellular roles of eukaryotic MMR proteins, the mechanism of strand discrimination and cross-talk/interactions between and co-regulation of MMR and other DNA repair pathways in eukaryotic cells. The main conclusion of the review is that MMR proteins contribute to genome stability through their ability to recognize and promote an appropriate cellular response to aberrant DNA structures, especially when they arise during DNA replication. Although the molecular mechanism of MMR in the eukaryotic cell is still not completely understood, increased used of single-molecule analyses in the future may yield new insight into these unsolved questions.



http://ift.tt/2uL8waH

Sonodynamic Therapy Based on Combined Use of Low Dose Administration of Epirubicin-Incorporating Drug Delivery System and Focused Ultrasound

Publication date: Available online 10 July 2017
Source:Ultrasound in Medicine & Biology
Author(s): Masanori Maeda, Yoshihiro Muragaki, Jun Okamoto, Shin Yoshizawa, Nobutaka Abe, Hidekazu Nakamoto, Hiroshi Ishii, Kenichi Kawabata, Shinichiro Umemura, Nobuhiro Nishiyama, Kazunori Kataoka, Hiroshi Iseki
Sonodynamic therapy (SDT) is currently considered as one of the promising minimally invasive treatment options for solid cancers. SDT is based on the combined use of a sonosensitizer drug and high-intensity focused ultrasound (HIFU) to produce cytotoxic reactive oxygen species (ROS) in and around neoplastic cells. Anthracycline drugs, including epirubicin (EPI), have been well known as effective sonosensitizers after interaction with focused ultrasound. Recently a new anticancer drug delivery system (DDS), NC-6300, has been developed that comprises EPI through an acid–labile hydrazone bond. In previous in vivo studies, NC-6300 showed basic drug safety and an excellent concentration property of EPI, and recently has been tested in clinical trials. For realizing minimally invasive cancer treatment, the present study demonstrated the effectiveness and feasibility of DDS-based SDT, which combined a small dose of NC-6300 and low energy of HIFU in mouse models of colon cancer and pancreatic cancer.



http://ift.tt/2u2G86r

Supersonic Shear Wave Imaging of the Spleen for Staging of Liver Fibrosis in Rats

Publication date: Available online 10 July 2017
Source:Ultrasound in Medicine & Biology
Author(s): Xiang-Dong Hu, Hui-Ying Geng, Lei Wang, Hu-Feng Xu, Yuan Su, Si Liang, Lin-Xue Qian
The goal of the work described here was to explore the cause of spleen stiffness (SS) in hepatic fibrogenesis and evaluate the value of SS in liver fibrosis (LF) staging. LF was induced with carbon tetrachloride (CCl4) in rats (n = 40). Supersonic shear wave imaging and contrast-enhanced ultrasound were performed to determine liver stiffness (LS), SS and splenic hemodynamics. SS, LS and free portal pressure exhibited moderate correlations with fibrosis stage (r = 0.744–0.835, p < 0.001). Time–intensity curves of contrast-enhanced ultrasound for the spleen were presented as decreasing peak intensity and slope of decrease, and increasing time to peak. Splenic sinus dilation and congestion were observed on histopathologic analysis. The area under the receiver operating characteristic curve of SS was higher than that of LS for differentiating LF stages 0–2 from stages 3–4 (Z = 2.293, p = 0.02). SS is a reliable diagnostic marker for the assessment of LF in the CCl4 model, especially for severe fibrosis. Elevated portal pressure is the cause of increasing SS.



http://ift.tt/2sJtCVv

Automatic Identification of the Optimal Reference Frame for Segmentation and Quantification of Focal Liver Lesions in Contrast-Enhanced Ultrasound

Publication date: Available online 10 July 2017
Source:Ultrasound in Medicine & Biology
Author(s): Spyridon Bakas, Dimitrios Makris, Gordon J.A. Hunter, Cheng Fang, Paul S. Sidhu, Katerina Chatzimichail
Post-examination interpretation of contrast-enhanced ultrasound (CEUS) cineloops of focal liver lesions (FLLs) requires offline manual assessment by experienced radiologists, which is time-consuming and generates subjective results. Such assessment usually starts by manually identifying a reference frame, where FLL and healthy parenchyma are well-distinguished. This study proposes an automatic computational method to objectively identify the optimal reference frame for distinguishing and hence delineating an FLL, by statistically analyzing the temporal intensity variation across the spatially discretized ultrasonographic image. Level of confidence and clinical value of the proposed method were quantitatively evaluated on retrospective multi-institutional data (n = 64) and compared with expert interpretations. Results support the proposed method for facilitating easier, quicker and reproducible assessment of FLLs, further increasing the radiologists' confidence in diagnostic decisions. Finally, our method yields a useful training tool for radiologists, widening CEUS use in non-specialist centers, potentially leading to reduced turnaround times and lower patient anxiety and healthcare costs.



http://ift.tt/2u2ON98

Influence of external cooling on the femtosecond laser ablation of dentin

Abstract

In the present work, the influence of external cooling on the temperature rise in the tooth pulpal chamber during femtosecond laser ablation was investigated. The influence of the cooling method on the morphology and constitution of the laser-treated surfaces was studied as well. The ablation experiments were performed on dentin specimens using an Yb:KYW chirped-pulse-regenerative amplification laser system (560 fs, 1030 nm). Cavities were created by scanning the specimens at a velocity of 5 mm/s while pulsing the stationary laser beam at 1 kHz and with fluences in the range of 2–14 J/cm². The experiments were performed in air and with surface cooling by a lateral air jet and by a combination of an air jet and water irrigation. The temperature in the pulpal chamber of the tooth was measured during the laser experiments. The ablation surfaces were characterized by scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy. The temperature rise reached 17.5 °C for the treatments performed with 14 J/cm² and without cooling, which was reduced to 10.8 ± 1.0 and 6.6 ± 2.3 °C with forced air cooling and water cooling, respectively, without significant reduction of the ablation rate. The ablation surfaces were covered by ablation debris and resolidified droplets containing mainly amorphous calcium phosphate, but the amount of redeposited debris was much lower for the water-cooled specimens. The redeposited debris could be removed by ultrasonication, revealing that the structure and constitution of the tissue remained essentially unaltered. The present results show that water cooling is mandatory for the femtosecond laser treatment of dentin, in particular, when high fluences and high pulse repetition rates are used to achieve high material removal rates.

http://ift.tt/2sZ4w9l

High-fat diet induces skeletal muscle oxidative stress in a fiber type-dependent manner in rats

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Ricardo A. Pinho, Diane M. Sepa-Kishi, George Bikopoulos, Michelle V. Wu, Abinas Uthayakumar, Arta Mohasses, Meghan C. Hughes, Christopher G.R. Perry, Rolando B. Ceddia
This study investigated the effects of high-fat (HF) diet on parameters of oxidative stress among muscles with distinct fiber type composition and oxidative capacities. To accomplish that, male Wistar rats were fed either a low-fat standard chow (SC) or a HF diet for 8 weeks. Soleus, extensor digitorum longus (EDL), and epitrochlearis muscles were collected and mitochondrial H2O2 (mtH2O2) emission, palmitate oxidation, and gene expression and antioxidant system were measured. Chronic HF feeding enhanced fat oxidation in oxidative and glycolytic muscles. It also caused a significant reduction in mtH2O2 emission in the EDL muscle, although a tendency towards a reduction was also found in the soleus and epitrochlearis muscles. In the epitrochlearis, HF diet increased mRNA expression of the NADPH oxidase complex; however, this muscle also showed an increase in the expression of antioxidant proteins, suggesting a higher capacity to generate and buffer ROS. The soleus muscle, despite being highly oxidative, elicited H2O2 emission rates equivalent to only 20% and 35% of the values obtained for EDL and epitrochlearis muscles, respectively. Furthermore, the Epi muscle with the lowest oxidative capacity was the second highest in H2O2 emission. In conclusion, it appears that intrinsic differences related to the distribution of type I and type II fibers, rather than oxidative capacity, drove the activity of the anti- and pro-oxidant systems and determine ROS production in different skeletal muscles. This also suggests that the impact of potentially deleterious effects of ROS production on skeletal muscle metabolism/function under lipotoxic conditions is fiber type-specific.

Graphical abstract

http://ift.tt/2t7YSgb

Involvement of Penicillium digitatum PdSUT1 in fungicide sensitivity and virulence during citrus fruit infection.

Publication date: Available online 10 July 2017
Source:Microbiological Research
Author(s): Marta de Ramón-Carbonell, Paloma Sánchez-Torres
A putative sucrose transporter PdSUT1 included in the same clade that Sut1p from Schizosaccharomyces pombe was identified in Penicillium digitatum, the major citrus postharvest pathogen. PdSUT1 gene was characterized using target gene disruption and gene overexpression. The ΔPdSUT1 mutants generated by gene elimination showed reduction in fungal virulence during citrus fruit infection assayed in mature fruit at 20°C. However, the overexpression mutants did not increased disease severity neither in the mutants coming from a high virulent nor from a low virulent P. digitatum progenitor strains.Moreover, fungicide sensitivity was affected in the deletant mutants but not in the overexpression transformants. The expression analysis of several genes involved in fungicide resistance showed an intensification of MFS transporters and a decrease of sterol demethylases transcriptional abundance in the ΔPdSUT1 mutants compare to the parental wild type strain.PdSUT1 appear not to be directly involved in fungicide resistance although can affect the gene expression of fungicide related genes. These results indicate that PdSUT1 contribute to P. digitatum fungal virulence and influence fungicide sensitivity through carbohydrate uptake and MFS transporters gene activation.



http://ift.tt/2sJmfgN

Influence of Non-Measurable Disease on Progression-Free Survival in Patients with Metastatic Breast Cancer

Publication date: Available online 11 July 2017
Source:Cancer Treatment Reviews
Author(s): Hadar Goldvaser, Domen Ribnikar, Rouhi Fazelzad, Bostjan Seruga, Arnoud J. Templeton, Alberto Ocana, Eitan Amir
BackgroundThe presence of non-measurable disease is common in metastatic breast cancer. It is unknown whether treatment effect on progression free survival (PFS) is consistent among patients with measurable and non-measurable disease.MethodsA systematic literature search identified phase III randomized controlled trials (RCTs) in metastatic breast cancer that reported outcomes in patients with non-measurable and measurable disease. Hazard ratios (HRs) and 95% confidence intervals were computed to compare the individual trial treatment effect on PFS in non-measurable versus measurable disease. Analyses were repeated for bone-only compared to non-bone-only disease and based on drug mechanism of action.ResultsAmong 82 RCTs that enrolled patients with non-measurable disease, data were available from 16 trials comprising 8516 patients. Treatment effect on PFS was similar in patients with non-measurable and measurable disease (HR for intra-study comparison = 1.01, p=0.82). However, compared to non-bone-only disease, a significantly greater effect on PFS was seen in those with bone-only disease (HR 0.83, p=0.03). Compared to patients with measurable disease, there was a greater effect on PFS in those with non-measurable disease in RCTs of signal transduction inhibitors and endocrine therapy (HR 0.74, p=0.01) and a lesser effect on PFS in RCTs of antiangiogenic drugs (HR 1.34, p=0.02). Comparable effect on PFS was shown in RCTs evaluating endocrine therapy (HR 1.13, p=0.23) and chemotherapy (HR 0.73, p=0.22).ConclusionsThere is variability in treatment effect on PFS in patients with measurable and non-measurable disease, especially those with bone-only disease. Standardization of PFS determination in these patients is warranted.



http://ift.tt/2t86CPl