Survival Gains from First-Line Systemic Therapy in Metastatic Non-Small Cell Lung Cancer in the U.S., 1990-2015: Progress and Opportunities

Background.

Approximately 190,000 Americans are diagnosed with non-small cell lung cancer (NSCLC) annually, and about half have metastatic (Stage IV) disease. These patients have historically had poor survival prognosis, but several new therapies introduced since 2000 provide options for improved outcomes. The objectives of this study were to quantify survival gains from 1990, when best supportive care (BSC) only was standard, to 2015 and to estimate the impact of expanded use of systemic therapies in clinically appropriate patients.

Materials and Methods.

We developed a simulation model to estimate survival gains for patients with metastatic NSCLC from 1990–2015. Survival estimates were derived from major clinical trials and extrapolated to a lifetime horizon. Proportions of patients receiving available therapies were derived from the Surveillance, Epidemiology, and End Results database and a commercial treatment registry. We also estimated gains in overall survival (OS) in scenarios in which systemic therapy use increased by 10% and 30% relative to current use.

Results.

From 1990–2015, one-year survival proportion increased by 14.1% and mean per-patient survival improved by 4.2 months (32,700 population life years). Increasing treated patients by 10% or 30% increased OS by 5.1 months (39,700 population life years) and 6.9 months (53,800 population life years), respectively.

Conclusion.

Although survival remains poor in metastatic NSCLC relative to other common cancers, meaningful progress in per-patient and population-level outcomes has been realized over the past 25 years. These advances can be improved even further by increasing use of systemic therapies in the substantial proportion of patients who are suitable for treatment yet who currently receive BSC only. The Oncologist 2017;22:1–7

Implications for Practice: Approximately 93,500 Americans are diagnosed with metastatic non-small cell lung cancer (NSCLC) annually. Historically, these patients have had poor survival prognosis, but newer therapies provide options for improved outcomes. This simulation modeling study quantified metastatic NSCLC survival gains from 1990–2015. Over this period, the one-year survival proportion and mean per-patient survival increased by 14.1% and 4.2 months, respectively. Though metastatic NSCLC survival remains poor, the past 25 years have brought meaningful gains. Additional gains could be realized by increasing systemic therapy use in the substantial proportion of patients who are suitable for treatment, yet currently receive only supportive care.

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Response to Tyrosine Kinase Inhibitors in Myeloproliferative Neoplasia with 8p11 Translocation and CEP110-FGFR1 Rearrangement

This brief communication reports on a patient with an exceedingly rare "8p11 (eight-p-eleven) myeloproliferative syndrome" (EMS) with CEP110-FGFR1 rearrangement who responded to treatment with the multi-tyrosine kinase inhibitor (TKI) dasatinib. Dasatinib improved quality of life substantially by increasing blood counts and reducing the need for transfusions. This report demonstrates that the second-generation TKI may provide a therapeutic option for elderly and frail EMS patients who cannot be offered aggressive therapy, including allogeneic hematopoietic cell transplantation. The Oncologist 2017;22:1–4

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Cross-cultural consistency and diversity in intrinsic functional organization of Broca's Region

Publication date: 15 April 2017
Source:NeuroImage, Volume 150
Author(s): Yu Zhang, Lingzhong Fan, Svenja Caspers, Stefan Heim, Ming Song, Cirong Liu, Yin Mo, Simon B. Eickhoff, Katrin Amunts, Tianzi Jiang
As a core language area, Broca's region was consistently activated in a variety of language studies even across different language systems. Moreover, a high degree of structural and functional heterogeneity in Broca's region has been reported in many studies. This raised the issue of how the intrinsic organization of Broca's region effects by different language experiences in light of its subdivisions. To address this question, we used multi-center resting-state fMRI data to explore the cross-cultural consistency and diversity of Broca's region in terms of its subdivisions, connectivity patterns and modularity organization in Chinese and German speakers. A consistent topological organization of the 13 subdivisions within the extended Broca's region was revealed on the basis of a new in-vivo parcellation map, which corresponded well to the previously reported receptorarchitectonic map. Based on this parcellation map, consistent functional connectivity patterns and modularity organization of these subdivisions were found. Some cultural difference in the functional connectivity patterns was also found, for instance stronger connectivity in Chinese subjects between area 6v2 and the motor hand area, as well as higher correlations between area 45p and middle frontal gyrus. Our study suggests that a generally invariant organization of Broca's region, together with certain regulations of different language experiences on functional connectivity, might exists to support language processing in human brain.



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Amyloid and tau PET demonstrate region-specific associations in normal older people

Publication date: 15 April 2017
Source:NeuroImage, Volume 150
Author(s): Samuel N. Lockhart, Michael Schöll, Suzanne L. Baker, Nagehan Ayakta, Kaitlin N. Swinnerton, Rachel K. Bell, Taylor J. Mellinger, Vyoma D. Shah, James P. O'Neil, Mustafa Janabi, William J. Jagust
β-amyloid (Aβ) and tau pathology become increasingly prevalent with age, however, the spatial relationship between the two pathologies remains unknown. We examined local (same region) and non-local (different region) associations between these 2 aggregated proteins in 46 normal older adults using [¹⁸F]AV-1451 (for tau) and [¹¹C]PiB (for Aβ) positron emission tomography (PET) and 1.5T magnetic resonance imaging (MRI) images. While local voxelwise analyses showed associations between PiB and AV-1451 tracer largely in the temporal lobes, k-means clustering revealed that some of these associations were driven by regions with low tracer retention. We followed this up with a whole-brain region-by-region (local and non-local) partial correlational analysis. We calculated each participant's mean AV-1451 and PiB uptake values within 87 regions of interest (ROI). Pairwise ROI analysis demonstrated many positive PiB—AV-1451 associations. Importantly, strong positive partial correlations (controlling for age, sex, and global gray matter fraction, p<.01) were identified between PiB in multiple regions of association cortex and AV-1451 in temporal cortical ROIs. There were also less frequent and weaker positive associations of regional PiB with frontoparietal AV-1451 uptake. Particularly in temporal lobe ROIs, AV-1451 uptake was strongly predicted by PiB across multiple ROI locations. These data indicate that Aβ and tau pathology show significant local and non-local regional associations among cognitively normal elderly, with increased PiB uptake throughout the cortex correlating with increased temporal lobe AV-1451 uptake. The spatial relationship between Aβ and tau accumulation does not appear to be specific to Aβ location, suggesting a regional vulnerability of temporal brain regions to tau accumulation regardless of where Aβ accumulates.



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On the neural basis of sensory weighting: Alpha, beta and gamma modulations during complex movements

Publication date: 15 April 2017
Source:NeuroImage, Volume 150
Author(s): Nicolas Lebar, Jérémy Danna, Simon Moré, Laurence Mouchnino, Jean Blouin
Previous studies have revealed that visual and somatosensory information is processed as a function of its relevance during movement execution. We thus performed spectral decompositions of ongoing neural activities within the somatosensory and visual areas while human participants performed a complex visuomotor task. In this task, participants followed the outline of irregular polygons with a pen-controlled cursor. At unpredictable times, the motion of the cursor deviated 120° with respect to the actual pen position creating an incongruence between visual and somatosensory inputs, thus increasing the importance of visual feedback to control the movement as suggested in previous studies. We found that alpha and beta power significantly decreased in the visual cortex during sensory incongruence when compared to unperturbed conditions. This result is in line with an increased gain of visual inputs during sensory incongruence. In parallel, we also found a simultaneous decrease of gamma and beta power in sensorimotor areas which has not been reported previously. The gamma desynchronization suggests a reduced integration of somatosensory inputs for controlling movements with sensory incongruence while beta ERD could be more specifically linked to sensorimotor adaptation processes.



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The global signal in fMRI: Nuisance or Information?

Publication date: 15 April 2017
Source:NeuroImage, Volume 150
Author(s): Thomas T. Liu, Alican Nalci, Maryam Falahpour
The global signal is widely used as a regressor or normalization factor for removing the effects of global variations in the analysis of functional magnetic resonance imaging (fMRI) studies. However, there is considerable controversy over its use because of the potential bias that can be introduced when it is applied to the analysis of both task-related and resting-state fMRI studies. In this paper we take a closer look at the global signal, examining in detail the various sources that can contribute to the signal. For the most part, the global signal has been treated as a nuisance term, but there is growing evidence that it may also contain valuable information. We also examine the various ways that the global signal has been used in the analysis of fMRI data, including global signal regression, global signal subtraction, and global signal normalization. Furthermore, we describe new ways for understanding the effects of global signal regression and its relation to the other approaches.



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Early processing in primary visual cortex is necessary for conscious and unconscious vision while late processing is necessary only for conscious vision in neurologically healthy humans

Publication date: 15 April 2017
Source:NeuroImage, Volume 150
Author(s): Mikko Hurme, Mika Koivisto, Antti Revonsuo, Henry Railo
The neural mechanisms underlying conscious and unconscious visual processes remain controversial. Blindsight patients may process visual stimuli unconsciously despite their V1 lesion, promoting anatomical models, which suggest that pathways bypassing the V1 support unconscious vision. On the other hand, physiological models argue that the major geniculostriate pathway via V1 is involved in both unconscious and conscious vision, but in different time windows and in different types of neural activity. According to physiological models, feedforward activity via V1 to higher areas mediates unconscious processes whereas feedback loops of recurrent activity from higher areas back to V1 support conscious vision. With transcranial magnetic stimulation (TMS) it is possible to study the causal role of a brain region during specific time points in neurologically healthy participants. In the present study, we measured unconscious processing with redundant target effect, a phenomenon where participants respond faster to two stimuli than one even when one of the stimuli is not consciously perceived. We tested the physiological feedforward-feedback model of vision by suppressing conscious vision by interfering selectively either with early or later V1 activity with TMS. Our results show that early V1 activity (60ms) is necessary for both unconscious and conscious vision. During later processing stages (90ms), V1 contributes selectively to conscious vision. These findings support the feedforward-feedback-model of consciousness.



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Internet use, online information seeking and knowledge among third molar patients attending public dental services

Abstract

Background

While Australians are searching the Internet for third molar (TM) information, the usefulness of online sources might be questioned due to quality variation. This study explored: (1) internet use, online information seeking behavior among TM patients attending public dental services and (2) whether patients' TM knowledge scores are associated with the level of internet use and eHealth Literacy Scale (eHEALS) scores.

Methods

Baseline survey data from the "Engaging Patients in Decision-Making" study were used. Variables included: socio-demographics, internet access status, online information seeking behavior, eHEALS, the Control Preferences Scale (CPS) and TM knowledge.

Results

Participants (n=165) were mainly female (73.8%), aged 19-25 years (42.4%) and had "secondary school or less" education (58.4%). A majority (n=79, 52.7%) had sought online dental information which was associated with active decisional control preference (OR=3.1, P=.034) and higher educational attainment (OR=2.7, P=.040). TM knowledge scores were not associated with either the level of Internet use (F _{(2, 152)} =2.1, P=.094, ƞ²=^.031). or the eHEALS scores (r=.147, P=.335).

Conclusion

The internet prepared patient" phenomena exists among public TM patients and was explained by preference for involvement in decision-making. However, Internet use was not associated with better TM knowledge. Providing TM patients with internet guidance might be an opportunity to improve TM knowledge.

This article is protected by copyright. All rights reserved.

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Necrotising fasciitis as a complication of odontogenic infection: a review of management and case series

Abstract

Objective

To establish the incidence of head and neck necrotising fasciitis (NF) in the Adelaide Oral and Maxillofacial Surgery Unit. To review the current literature regarding the management of head and neck NF. To determine the evidence for the role of hyperbaric oxygen therapy in the management of NF.

Method

A retrospective audit of all patients admitted to the Royal Adelaide Hospital Oral and Maxillofacial Surgery Unit 2006-2015 with severe odontogenic infections was carried out. Patient demographics were recorded and treatment details were collected and analysed.

Results

A total of 672 patients were admitted for management of severe odontogenic infections. Of these, three were identified as NF. One case was treated using hyperbaric oxygen as an adjunct to conventional surgical and medical management. Two cases were managed using aggressive surgical management alone. Two patients survived. The incidence of head and neck NF in South Australia is 48 per 100,000 infections per year.

Conclusion

The first line treatment of severe odontogenic infections remains conventional surgical and medical management, however hyperbaric oxygen therapy may have an additional role in the management of NF and other rare severe infections in medically complex patients.

This article is protected by copyright. All rights reserved.

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Referral Patterns of General Dental Practitioners for Bone Grafting and Implant Placement

Abstract

Dental implant rehabilitation is a well-established procedure often conducted in the general dental practice setting. The outcomes for implant placement are reliable when the recipient site is favorable. Our goal has been to assess the accuracy with which general dental practitioners (GDP's) assess the bone volume available for implant placement and their referral patterns for implant sites, which may require bone grafting.

Fifty-three GDP's were surveyed and asked to assess 5 different scenarios and cone beam scans for difficulty (0 no difficulty - 5 the most difficult), and bone grafting requirements (yes/no and who to perform), prior to implant placement.

This article is protected by copyright. All rights reserved.

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Potential application and prevalence of the CD30 (Ki-1) antigen among solid tumors: A focus review of the literature

Publication date: Available online 27 February 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Garrett K. Berger, Kevin Gee, Cassandra Votruba, Ali McBride, Faiz Anwer
BackgroundCD30 (Ki-1) is a cell membrane protein derived from the tumor necrosis factor (TNF) receptor family. The CD30 antigen has been associated primarily with Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). Brentuximab vedotin (BV) is an antibody-drug conjugate targeting the CD30 antigen. FDA approval for BV includes relapsed and refractory HL and sALCL. The CD30 antigen also has been identified in many solid tumors, predominantly of germ cell origins and early clinical data is promising.ObjectivePerform a focus literature review evaluating the prevalence of the CD30 antigen among nonlymphomatous tumors with a potential correlate for CD30 targeted therapy.Eligibility criteriaInclusion criteria: all retrospective reviews and case reports citing CD30 positivity or negativity in non-lymphomatous malignancies in which data were presented based on location. Exclusion criteria: studies with hematopoetic malignancies, cutaneous malignancies, non-human populations, and non-english publications.Included studiesA total of 119 articles met these criteria and are summarized in this manuscript.ConclusionThe CD30 antigen has shown variable prevalence among non-hematopoetic tumors, most notably among germ cell tumors and mesothelioma. With additional, preclinical and properly powered clinical studies, CD30 targeted therapy such as that of BV, alone or in combination with other agents may prove to be a strong candidate in the treatment of various CD30⁺ malignancies.



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Role of brain-derived neurotrophic factor and nerve growth factor in the regulation of Neuropeptide W in vitro and in vivo

Publication date: Available online 27 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Rikang Wang, Fengxia Yan, Rifang Liao, Pei Wan, Peter J. Little, Wenhua Zheng
Nerve growth factor (NGF) and Brain-derived neurotrophic factor (BDNF) are neurotrophic factors involved in the growth, survival and functioning of neurons. In addition, a possible role of neurotrophins, particularly BDNF, in HPA axis hyperactivation has recently been proposed. Neuropeptide W (NPW) is an endogenous peptide ligand for the GPR7 and GPR8 and a stress mediator in the hypothalamus. It activates the HPA axis by working on hypothalamic corticotrophin-releasing hormone (CRH). No information is available about the interrelationships between neurotrophines like NGF/BDNF and NPW. We studied the effect and underlying mechanisms of NGF/BDNF on the production of NPW in PC12 cells and hypothalamus. NGF time- and concentration-dependently stimulated the expression of NPW in PC12 cells. The effect of NGF was blocked by the inhibition of PI3K/Akt signal pathway with specific inhibitors for PI3K or Akt siRNA for Akt while inhibition of ERK pathway had no effect. Moreover, BDNF concentration-dependently induced the expression of NPW mRNA and decreased the expression of NPY mRNA in primary cultured hypothalamic neurons which was also blocked by a PI3K kinase inhibitor. Finally, in vivo study showed that exogenous BDNF injected icv increased NPW production in the hypothalamus and this effect was reversed by a PI3 kinase inhibitor. These results and the fact that BDNF was able to stimulate the expression of CRH demonstrated that neurotrophines can modulate the expression of NPW in neuronal cells via the PI3K/Akt pathway and suggest that BDNF might be involved in functions of the HPA axis, at least in part by modulating the expression of NPW/NPY and CRH.

Graphical abstract

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Evolution of thyroid hormone distributor proteins

Publication date: Available online 27 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Thomas R. McLean, Michelle M. Rank, Peter M. Smooker, Samantha J. Richardson
Thyroid hormones (THs) are evolutionarily old hormones, having effects on metabolism in bacteria, invertebrates and vertebrates. THs bind specific distributor proteins (THDPs) to ensure their efficient distribution through the blood and cerebrospinal fluid in vertebrates. Albumin is a THDP in the blood of all studied species of vertebrates, so may be the original vertebrate THDP. However, albumin has weak affinity for THs. Transthyretin (TTR) has been identified in the blood across different lineages in adults vs juveniles. TTR has intermediate affinity for THs. Thyroxine-binding globulin has only been identified in mammals and has high affinity for THs. Of these THDPs, TTR is the only one known to be synthesised in the brain and is involved in moving THs from the blood into the cerebrospinal fluid. We analysed the rates of evolution of these three THDPs: TTR has been most highly conserved and albumin has had the highest rate of divergence.

Graphical abstract

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Sex chromosome complement involvement in angiotensin receptor sexual dimorphism

Publication date: Available online 27 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Florencia M. Dadam, Carla D. Cisternas, Ana F. Macchione, Andrea Godino, José Antunes-Rodrigues, María J. Cambiasso, Laura M. Vivas, Ximena E. Caeiro
This study aimed to define whether sex chromosome complement (SCC) may differentially modulate sex differences in relative gene expression of basal Agtr1a, Agtr2, and Mas1 receptors at fore/hindbrain nuclei and at medulla/cortical kidney.Samples were collected from gonadectomized male (XX and XY) and female (XX and XY) mice of the "four core genotypes" model. At brain level, a SCC effect at the area postrema was demonstrated. An increase in mRNA level of Agtr1a and Agtr1a/Agtr2 ratio in XY-SCC mice was associated with a decrease in Mas1 compared to XX-SCC mice. In the renal cortex, a SCC effect for Agtr2 and Mas1 was observed. Regardless of sex (male or female), XX-SCC mice expressed higher levels of mRNA Agtr2 and Mas1 than XY-SCC mice {F(1,12) = 6,126,p < 0.05; F(1,21) = 5,143,p < 0.05}. Furthermore, XX-female mice showed a significant increase in Mas1 expression compared to XY-female mice.These results reveal a SCC modulatory effect at central and kidney level on angiotensin receptor expression, with an enhancement of the vasodilatory arm in XX-mice and an increase in the vasoconstriction arm in XY-mice, which may underlie sex differences in the regulation of arterial pressure.



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The small RNA miR-375– a pancreatic islet abundant miRNA with multiple roles in endocrine beta cell function

Publication date: Available online 27 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Lena Eliasson
The pathophysiology of diabetes is complex and recent research put focus on the pancreatic islets of Langerhans and the insulin-secreting beta cells as central in the development of the disease. MicroRNAs (miRNAs), the small non-coding RNAs regulating post-transcriptional gene expression, are significant regulators of beta cell function. One of the most abundant miRNAs in the islets is miR-375. This review focus on the role of miR-375 in beta cell function, including effects in development and differentiation, proliferation and regulation of insulin secretion. It also discusses the regulation of miR-375 expression, miR-375 as a potential circulating biomarker in type 1 and type 2 diabetes, and the need for the beta cell to keep expression of miR-375 within optimal levels. The summed picture of miR-375 is a miRNA with multiple functions with importance in the formation of beta cell identity, control of beta cell mass and regulation of insulin secretion.



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Role of cancer stem-cell marker doublecortin-like kinase 1 in head and neck squamous cell carcinoma

Publication date: April 2017
Source:Oral Oncology, Volume 67
Author(s): Lorenz Kadletz, Dietmar Thurnher, Robert Wiebringhaus, Boban M. Erovic, Ulana Kotowski, Sven Schneider, Rainer Schmid, Lukas Kenner, Gregor Heiduschka
BackgroundSo far, no data is available on the role of the tumor stem cell marker doublecortin-like kinase 1 (DCLK1) in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to evaluate DCLK1 expression in HNSCC patients that underwent surgery and postoperative radiotherapy, and to assess its potential as a therapeutic target in vitro.MethodsWe immunohistochemically stained for DCLK1 in 127 sections of HNSCC samples obtained during surgery of HNSCC patients and correlated the expression to patients' overall- and disease-free survival, as well as human papilloma virus (HPV) status. Additionally, we compared our survival data with data obtained from The Cancer Genome Atlas (TCGA). The effects of the DCLK1 inhibitor LRRK-2-in-1 on HNSCC cell lines alone and in combination with irradiation.ResultsExpression of DCLK1 in 127 patients was associated with poor survival. In particular, DCLK1 expression had a significant impact on survival of oropharyngeal carcinoma patients. Specifically, DCLK1⁺/HPV⁻ patients had the worst prognosis after simultaneous assessment of DCLK1 and HPV status in comparison to the other three possible DCLK1/HPV constellations. Higher levels of DCLK1 mRNA were also associated with poor clinical outcome. Inhibition of DCLK1 in our HNSCC cell lines led to growth arrest and induction of apoptosis. The combination of DCLK1 inhibition with irradiation had a synergistic effect.ConclusionFirstly, DCLK1 is a prognostic biomarker for shortened survival. Secondly, through inhibition of DCLK1, it may serve as a therapeutic target as well.



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Functional characterisation of the Drosophila cg6568 gene in host defence against Mycobacterium marinum

Publication date: Available online 27 February 2017
Source:Microbes and Infection
Author(s): Hyo Sun Jin, Hye-Mi Lee, Da-Hye Lee, Guang-Ho Cha, Kyoung Sang Cho, Ji-Chan Jang, Eun-Kyeong Jo
Mycobacterium marinum is a pathogenic mycobacterial species closely related to Mycobacterium tuberculosis. In this study, we established a mycobacterial infection model of Drosophila melanogaster to characterize the role played by cg6568, a homolog of the human cathelicidin gene, in the innate defense against infection. Drosophila cg6568 was expressed at various levels during all developmental stages, and the expression levels were modulated by M. marinum in a time-dependent manner. 20-hydroxyecdysone induced Drosophila cg6568 transcription both in vitro and in vivo. Using flies expressing cg6568 RNAi, we found that cg6568 was essential both for D. melanogaster survival and the exertion of antimicrobial effects during M. marinum infection. Thus, we named the gene product a cathelicidin-like antimicrobial protein of D. melanogaster (dCAMP). Our results indicate that dCAMP is crucial in terms of the innate D. melanogaster defense during M. marinum infection.



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Nano-grained perovskite LEDs shine more brightly

Publication date: Available online 24 February 2017
Source:Nano Today





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“La Monstrua Desnuda”: an artistic textbook representation of Prader–Willi syndrome in a painting of Juan Carreño de Miranda (1680)

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Effect of metformin and oral contraceptives on polycystic ovary syndrome and IVF cycles

Abstract

Aim

The aim of this study is to investigate the effect of metformin and/or OC added to the treatment of PCOS patients at our clinic on IVF outcome.

Materials and methods

This study is a retrospective study that assesses the data of PCOS patients who received IVF between 2005 and 2015 at a private IVF center. The study included 496 PCOS cases aged between 24 and 40. Participants diagnosed with PCOS were divided into 4 groups according to the use of metformin and OC prior to the IVF cycle: 11.1% were in the metformin group, 31.3% in the OC group, 14.9% in the Metformin + OC group, and 42.7% in the control group.

Results

No difference was found in the total gonadotropin dose and duration of stimulation between the groups. Clinical pregnancy rates and implantation rates were similar in all groups, although the numbers of oocytes, mature oocytes, fertilized oocytes, and transferred embryos were lower in the treatment groups received metformin compared to the OC group and control group. There was no significant difference in the presence of OHSS and the singleton and multiple pregnancies between the four groups.

Conclusion

The present study established no positive role of metformin and OC use in increasing the treatment success in IVF/ICSI cycles in PCOS patients. It would be appropriate to limit the use of these agents with special indications such as decreasing insulin resistance or synchronizing follicular cohort.

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Pronounced effect of hapten binding on thermal stability of an anti-(4-hydroxy-3-nitrophenyl)acetyl antibody possessing a glycine residue at position 95 of the heavy chain

Publication date: May 2017
Source:Molecular Immunology, Volume 85
Author(s): Yusui Sato, Satomi Inaba, Harumi Fukada, Takachika Azuma, Masayuki Oda
Immune response to T-cell-dependent antigens is highly dynamic; several B-cell clones responsible for antibody production appear alternately during immunization. It was previously shown that at least two-types of antibodies are secreted after immunization with (4-hydroxy-3-nitrophenyl)acetyl (NP); one has Tyr and another has Gly at position 95 of the heavy chain (referred to as Tyr95- and Gly95-type). The former appeared at an early stage, while the latter appeared at a late stage, i.e., after secondary immunization, although Fv domains of these antibodies were encoded by same genes of variable heavy and light chains. We examined whether any biophysical properties of antigen-combing sites relate to this shift in B-cell clones by preparing single-chain Fv (scFv). Thermodynamic and kinetic parameters of the interaction of scFv with various haptens are in accordance with those of intact antibodies, indicating that scFvs are appropriate models for the study on structure and function of antibodies. Next, we measured thermal stability of scFvs using differential scanning calorimetry and found that the apparent melting temperature of free Tyr95-type was 64–66°C,while that of Gly95-type was 47–48°C, indicating that the latter was highly unstable. However, Gly95-type greatly gained thermal stability because of hapten binding. We discussed the relationship between thermal stability resulted by hapten binding and dynamism of antibody response during immunization.



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Validation of the prognostic role of the “Helsinki Score” in 225 cases of adrenocortical carcinoma

Publication date: April 2017
Source:Human Pathology, Volume 62
Author(s): Eleonora Duregon, Rocco Cappellesso, Valeria Maffeis, Barbara Zaggia, Laura Ventura, Alfredo Berruti, Massimo Terzolo, Ambrogio Fassina, Marco Volante, Mauro Papotti
Adrenocortical carcinoma patient prognosis is extremely variable and poorly predictable. The newly introduced Helsinki Score is the first so far proposed diagnostic and prognostic system based on the combined evaluation of morphological (mitoses and necrosis) and immunohistochemical (Ki-67) parameters. The aim of the study was to validate the prognostic role of the Helsinki Score for adrenocortical carcinoma characterization. Thus, 225 adrenocortical carcinomas were reclassified using the Weiss Score and the Helsinki Score (3× mitotic count + 5 × necrosis + Ki-67 index). At univariate analysis, statistically significant prognostic values were observed at the log-rank test for mitotic count (cutoff values: <6 and ≥55; P<.0001), Ki-67 (cutoff values: <20 and ≥50; P<.0001), Weiss Score (cutoff values: <5 and ≥8; P<.0001), Helsinki Score (cutoff values: <13 and ≥19; P<.0001), histological variant (conventional versus oncocytic; P=.009), necrosis (P=.001), and stage (P=.005). Cox multivariate analysis using a backward stepwise selection method retained only Helsinki Score and Weiss Score as predictors of poor prognosis (P<.0001 and P=.0005, respectively). Helsinki Score (with a threshold of 28.5 points; area under the curve [AUC]=0.729, 95% confidence interval=0.66-0.79) and Ki-67 (with a threshold of 20.5%; AUC=0.727, 95% confidence interval=0.66-0.79) showed the best and equivalent AUCs predicting disease-related deaths determined using receiver operating characteristic statistics. In conclusion, the Helsinki Score is a valuable system to predict prognosis in adrenocortical carcinoma, outperforming the currently established prognostic parameters.



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miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

Abstract

Lung cancer is the most common cancer worldwide. Up to 85% of lung cancer cases are diagnosed as non-small cell lung cancer (NSCLC). The effectiveness of NSCLC treatment is expected to be improved through the implementation of robust and specific biomarkers. MicroRNAs (miRNAs) are small, non-coding molecules that play a key role in the regulation of basic cellular processes, including differentiation, proliferation and apoptosis, by controlling gene expression at the post-transcriptional level. Deregulation of miRNA activity results in the loss of homeostasis and the development of a number of pathologies, including lung cancer. During lung carcinogenesis, miRNAs exhibit dual regulatory function: they act as oncogenes to promote cancer development or as tumour suppressors. Unique miRNA sequences have been detected in malignant tissues and corresponding healthy tissues. Furthermore, stable forms of tumour-related miRNAs are detectable in the peripheral blood of patients with NSCLC. The potential benefits of using extracellular miRNAs present in body fluids as part of the diagnostic evaluation of cancer include low invasiveness (compared with tumour cell/tissue sampling), and the repeatability and ease of obtaining the specimens. Apart from the diagnostic applications of altered miRNA expression profiles, the dual regulatory role of miRNA in cancer might drive the further development of personalised therapies in NSCLC. The clinical usefulness of miRNA expression analysis to predict the efficacy of various treatment strategies including surgery, radio- and chemotherapy, and targeted therapies has been evaluated in NSCLC. Also, the capacity of a single miRNA to regulate the expression of multiple genes simultaneously presents an opportunity to use these small molecules in personalised therapy as individualised therapeutic tools.

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Photobiomodulation therapy for the management of radiation-induced dermatitis

Abstract

Background

Radiation therapy (RT) comprises a key component in the treatment of breast cancer. Radiation-induced skin toxicity is the major adverse event experienced by patients; however, radiodermatitis (RD) prevention and management remains trivial. It is proven that photobiomodulation (PBM) therapy using light-emitting diode (LED) increases wound healing and depicts an anti-inflammatory effect. This single-institute study evaluates the beneficial role of PBM-LED in preventing/reducing RD during breast cancer RT.

Patients and methods

Of 70 consecutively treated patients, 25 patients were treated with PBM-LED twice a week prior to adjuvant 3D conformal RT after breast-conserving surgery. RD was reported using Common Toxicity Criteria for Adverse Events Version 4.0 and pain intensity using a visual analog scale (VAS). For comparison, a control group (n = 45) received RT without PBM-LED. In addition, a "matched" group (n = 25) was generated from the control group based on propensity for potentially confounding variables.

Results

In the PBM group, 22 patients (88%) presented grade 1 and 3 (12%) grade 2 RD. In the control group, 25 patients (55.6%) developed grade 1 reactions, 18 patients (40%) grade 2, and 2 (4.4%) patients grade 3 RD. Concerning pain intensity, 15 patients (60%) of the PBM treatment arm reported no pain, 5 patients (20%) VAS 2, and 5 (20%) VAS 3. In the control group, 13 patients (28.9%) reported no pain, 2 (4.4%) VAS 1, 7 (15.6%) VAS 2, 9 patients (20%) reported VAS 3, 12 (26.7%) patients VAS 4, and 2 (4.4%) patients VAS 5.

Conclusion

PBM-LED therapy applied prior to RT might be effective in decreasing the incidence and sequelae of radiation-induced skin toxicity in breast cancer patients treated with breast-conserving surgery.

http://ift.tt/2lPfmaY

Radiotherapy of painful heel spur with two fractionation regimens

Abstract

Background

In this randomized multicenter trial, we compared the effect of a lower single dose of 0.5 Gy vs. a standard single dose of 1 Gy concerning pain relief and quality of life, while maintaining a uniform total dose of 6 Gy. On the basis of laboratory observations, the lower single dose would be expected to be more effective.

Patients and methods

A total of 127 patients suffering from painful heel spur were randomized: Patients in the standard group were treated with single fractions of 6 × 1 Gy twice a week, while the experimental group was treated with single fractions of 12 × 0.5 Gy three times a week. Patients who did not show satisfactory pain relief after 12 weeks were offered re-irradiation with the standard dose. The study's primary endpoints were pain relief and quality of life. Therapy results were evaluated and compared based on follow-up examinations after 12 and 48 weeks.

Results

The data of 117 patients could be evaluated. There was no significant difference between the groups concerning the results of a visual analogue scale (VAS), Calcaneodynia Score (CS), and the somatic scale of the 12-Item Short-Form Health Survey(SF-12). Patients undergoing re-irradiation showed a significant benefit concerning pain relief. Their total outcome was comparable to patients showing a good response from the beginning. No relevant acute or chronic side effects were recorded.

Conclusion

Both patient groups showed good results concerning pain relief. A fractionation schedule of 12 × 0.5 Gy was not superior to the current standard dose of 6 × 1 Gy. Further trials are necessary to explore the best fractionation schedule.

http://ift.tt/2l5Z2ph

Neurocognitive functions and social functioning in young females with recent-onset anorexia nervosa and recovered individuals

Abstract

Background

Young individuals with anorexia nervosa (AN) or recovered from AN display impairments of social function. To date, however, it is not clear whether they differ from controls with respect to neurocognitive performance and whether those functions contribute to the compromised social function observed in individuals with AN.

Methods

We included 43 young females with first-episode AN, 28 individuals recovered from adolescent-onset AN, and 41 control individuals (14–22 yr), all without comorbid autism spectrum disorder. We compared the performance of participants across groups in seven neurocognitive functions relevant to social functioning: set-shifting, local processing, processing speed, working memory, sustained attention, verbal memory, and verbal abstraction. Further, we tested the association between neurocognitive function and social function, measured by Autism Diagnostic Observation Schedule (ADOS), with an ordinal logistic regression model.

Results

First, participants did not differ on any neurocognitive function across groups. Second, only the neurocognitive function "verbal memory" was significantly associated with social function. Higher performance in verbal memory was associated with lower odds of impaired social function. Diagnostic group remained a significant factor, but the absence of an interaction between group and neurocognitive performance indicated that the association between verbal memory and social function was independent of group membership.

Conclusion

Young individuals with AN and those recovered from AN did not differ from controls with respect to neurocognitive performance. Verbal memory was associated with social function in all groups.

http://ift.tt/2lZlcZO

A Sisyphean task: experiences of perfectionism in patients with eating disorders

Abstract

Background

Despite the theoretical links between eating disorders and perfectionism, the definition of perfectionism in practice is complicated. The present study explored descriptions and experiences of perfectionism described by a transdiagnostic sample of patients.

Methods

In-depth, semi-structured interviews were carried out with 15 patients. The interviews were analyzed by Thematic Analysis. A comparison between the patients' scorings on the Eating Disorder Inventory-Perfectionism scale was also performed.

Results

Seven themes were found: The origins of perfectionism, Top performance, Order and self-control, A perfect body, Looking good in the eyes of others, A double-edged coping strategy, and A Sisyphean task. The women in this study did not emphasize weight and body as the main perfectionistic strivings. Core descriptions were instead order, self-control and top performances. All of the participants described the awareness of reaching perfectionism as impossible. Scorings of self-oriented perfectionism was significantly higher compared to socially prescribed perfectionism. No differences in the narratives related to perfectionism scores or eating disorder diagnoses were found.

Conclusions

The results showed that psychometric measures do not always capture the patients' definitions of perfectionism, but regarding that perfectionism serves as a means to regulate affects and may lead into an exacerbation of the eating disorder, and the development of obsessive-compulsive symptoms, it is important to investigate the personal definitions of perfectionism.

http://ift.tt/2mDSBq1

Reverse dorsal metacarpal flaps for reconstruction of proximal phalanx defects following skin tumor excision: A case series

Abstract

Background

Reverse dorsal metacarpal flaps (RDMFs) are widely used to cover significant skin and soft tissues defects of the finger.However, there is a current lack of information regarding the use of RDMFs in the reconstruction of phalanx defects following skin tumor excision.

Methods

From October 2012 to April 2016, medical records of all patients who underwent reconstruction of proximal phalanx defects with RDMF were retrospectively reviewed. Patient age and gender, tumor type, tumor location, donor site coverage, flap dimensions, range of motion of the metacarpophalangeal joint, and postoperative complications were evaluated.

Results

Seven patients underwent closure of skin defects of the proximal phalanx with RDMF. All flaps survived completely without complication. Flap size ranged from 1.5 × 2 to 3 × 3.5 cm. Good coverage was obtained in all cases. Skin paddle was taken from the dorsal aspect of the second, third, and fourth intermetacarpal area. All patients had full range of movement of the reconstructed and donor digits when followed at 6 months after surgery.

Conclusions

The RDMF is a flap which is safe, easy to apply in the context of soft tissue coverage procedures, and does not result in the loss of finger functions. It also confers excellent aesthetic skin suitability and does not require debulking procedures.

Level of Evidence: Level V, therapeutic study.

http://ift.tt/2lhBwkD

The tubed pedicle flap centennial: its concept, origin, rise and fall

Abstract

Part of the conceptual thinking that characterizes reconstructive surgery is to consider the way tissue is transferred: locally pedicled, pedicled from a distance, or free. In 1917, now 100 years ago, the concept of the distant tubed pedicle skin flap was published. The tubed flap has raised a debate about priority in the past. This historical review elucidates this debate and identifies Filatov from Odessa, Ukraine, as the originator of the procedure. Ganzer in Germany published a little later, independently from Filatov, about tubing, while Gillies in England, not knowing the work of either, started to use pedicled flaps at the end of 1917, which primeur was contested by his colleague Aymard. Tubing a pedicle was the final refinement of the distantly pedicled flap. The high volume of facial wounds during the First World War gave army surgeons like Ganzer and Gillies the opportunity to gain experience with all kinds of tubed pedicled flaps. This resulted in a real impetus of reconstructive surgery in the interbellum. This made the tubed pedicle flap the main reconstructive method for large skin defects until the 1970s of the last century, when pedicled myocutaneous flaps and free flap surgery were introduced. There is still a modest place for tubed pedicled flaps in reconstructive surgery. Tubed groin flaps are still useful to cover hand defects and tubed deltopectoral flaps are still used for facial reconstruction in hospitals in less-privileged countries where free flap surgery is not feasible.

Level of Evidence: Not ratable.

http://ift.tt/2mniMFe

Optimizing the coupled effects of Hall-Petch and precipitation strengthening in a Al0.3CoCrFeNi high entropy alloy

Publication date: 5 May 2017
Source:Materials & Design, Volume 121
Author(s): B. Gwalani, Vishal Soni, Michael Lee, SA Mantri, Yang Ren, R. Banerjee
A successful demonstration of applying integrated strengthening using Hall-Petch strengthening (grains size effect) and precipitation strengthening is shown in the fcc based high entropy alloy (HEA) Al0.3CoCrFeNi, leading to quantitative determinations of the Hall-Petch coefficients for both hardness and tensile yield strength, as well as the enhancements in the yield strength from two distinct types of ordered precipitates, L12 and B2. An excellent combination of yield strength (~490MPa), ultimate tensile strength (~850MPa), and ductility (~45% elongation) was achieved by optimizing and coupling both strengthening mechanisms, resulting from a refined grain size as well as both L12 and B2 ordered precipitates. This opens up new avenues for the future development of HEAs, with the appropriate balance of properties required for engineering applications.

Graphical abstract

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Oxidation fabrication and enhanced soft magnetic properties for core-shell FeCo/CoFe2O4 micron-nano composites

Publication date: 5 May 2017
Source:Materials & Design, Volume 121
Author(s): Bai Yang, Xiaopan Li, Ruiyuan Guo, Ronghai Yu
FeCo/CoFe2O4 micron-nano composites have been fabricated by controllably oxidizing micron-sized FeCo particles. High-purity 60-nm-thick CoFe2O4 layers can be formed in situ on the surface of the unoxidized FeCo particles to form a dense FeCo/CoFe2O4 core-shell structure. The good intrinsic magnetic properties, including a high saturation magnetization of 210A·m²·kg⁻¹ and a low coercivity of 11.7Oe, are obtained in these FeCo/CoFe2O4 composites due to the nanoscale thickness of the ferrimagnetic CoFe2O4 layers. For traditional soft magnetic composites, low core loss can only be obtained by seriously sacrificing their magnetic induction. In this work, balanced soft magnetic properties with low core loss and high magnetic induction are obtained in the fully compacted FeCo/CoFe2O4 composites, which promise great potential applications in high-power and high-frequency magnetic devices. This controlled surface oxidation may also provide an effective surface treatment for metal-based soft magnets to improve their overall performance.

Graphical abstract

http://ift.tt/2mn2nAC

A comprehensive MCDM-based approach using TOPSIS, COPRAS and DEA as an auxiliary tool for material selection problems

Publication date: 5 May 2017
Source:Materials & Design, Volume 121
Author(s): Seyed Hadi Mousavi-Nasab, Alireza Sotoudeh-Anvari
Material selection problem can be interpreted as an intricate MCDM problem. The aim of this work is to provide a simple and comprehensive MCDM-based framework for solving this problem. First, we review basic characteristics of general material selection problem under MCDM paradigm. For doing so, we have studied over 60 papers¹1 This study demonstrates that a very important number of articles in this field have been published in "Materials and Design" (published by Elsevier). published between 2010 and 2016 as a brief continuation of previous review [42] in this field. On the other hand, many researchers have emphasized in complicated decision problems more than one MCDM methods should be applied to obtain a more trustworthy and safer decision. Under the scrutiny of over 100 scientific articles, COPRAS and TOPSIS are chosen for tackling material selection problem in general. It is observed that the suggested approach by integrating these MCDM techniques is simple and effective. Also we examine the use of DEA as an MCDM tool in material selection problem. It is found that DEA can be employed to handle this problem by considering a classical remark, but MCDM cannot be generally replaced by DEA in this area.

Graphical abstract

http://ift.tt/2mniDBF

Corrigendum to “Microstructure evolution and mechanical properties of friction stir welding super-austenitic stainless steel S32654” [Mater. Des. 118 (2017) 207-217]

Publication date: 5 May 2017
Source:Materials & Design, Volume 121
Author(s): Huabing Li, Shouxing Yang, Shucai Zhang, Binbin Zhang, Zhouhua Jiang, Hao Feng, Peide Han, Jizhong Li




http://ift.tt/2mndERh

Synthesis, characterization, and catalytic properties of nano-SnO by chemical vapor transport (CVT) process under CO-CO2 atmosphere

Publication date: 5 May 2017
Source:Materials & Design, Volume 121
Author(s): Zijian Su, Yuanbo Zhang, Benlai Han, Bingbing Liu, Manman Lu, Zhiwei Peng, Guanghui Li, Tao Jiang
Chemical vapor transport (CVT) process is a simple and efficient method for synthesizing nano-SnO products, and previous references reveal that the CVT process is characterized as high temperature and long synthesis time. Our previous studies indicated that SnO2 was easily reduced to solid-state SnO and then volatilized as gaseous SnO under certain CO-CO2 atmosphere, so that a novel CVT process under CO-CO2 atmosphere was proposed in the present work. The nano-SnOs synthesized by the CVT under 15vol% CO/(CO+CO2) atmosphere were characterized using XRD, SEM, TEM, XPS, etc. The results showed that tetragonal structure nano-SnO diskette and sphere with uniform granularity of 50–100nm were obtained with high purity. During the CVT process, CO-CO2 mixed gases could reduce SnO2 to SnO and act as a CVT medium to take away the newly formed gaseous SnO, resulting in the decrease of the partial pressure of SnO. In addition, the nano-SnOs could enhance the SCR deNOx activity of activated carbon (AC), and both the reaction temperature window of AC and the NO conversion were increased if the AC was coated by nano-SnOs.

Graphical abstract

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Brazing of stainless steels using Cu-Ag-Mn-Zn braze filler: Studies on wettability, mechanical properties, and microstructural aspects

Publication date: 5 May 2017
Source:Materials & Design, Volume 121
Author(s): Venkateswaran T., Vincent Xavier, Sivakumar D., Bhanu Pant, Janaki Ram G.D.
In this study, a Cu-37.5Ag-8Mn-5Zn braze filler with a liquidus temperature of 810°C was used for brazing of Martensitic Stainless Steel (MSS) to AISI 321 Austenitic Stainless Steel (ASS). By providing a layer of Ni coating (5μm) over the base materials, satisfactory wetting and spreading of the braze filler was achieved. Brazing experiments were carried out at different temperatures (835°C to 935°C) for different times (5 to 25min) employing braze foils of different thicknesses (75μm to 300μm) to arrive at the optimum brazing conditions. The joints brazed at 910°C for 15min using a braze foil of 150μm thickness showed the highest lap-shear strength of 213MPa. The microstructure of braze metal consisted of Cu- and Ag-rich solid solution phases with varying amount of Ag/Cu, Mn, Zn, and Ni. The Ni coating was found to minimize the intergranular penetration of the braze metal into the base materials. The changes in tensile properties of the base materials after the brazing thermal cycle were also discussed.

Graphical abstract

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Correction

http://ift.tt/2l5r8B4

Reply: Apixaban Dosing in Chronic Kidney Disease: Differences Between U.S. and E.U. Labeling

http://ift.tt/2lP0RUK

JACC Instructions for Authors

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Reply: A Distinct Cardiomyopathy: HCN4 Syndrome Comprising Myocardial Noncompaction, Bradycardia, Mitral Valve Defects, and Aortic Dilation

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A Distinct Cardiomyopathy: HCN4 Syndrome Comprising Myocardial Noncompaction, Bradycardia, Mitral Valve Defects, and Aortic Dilation

http://ift.tt/2l5BVeF

Apixaban Dosing in Chronic Kidney Disease: Differences Between U.S. and E.U. Labeling

http://ift.tt/2l5BalL

Herbal Medications in Cardiovascular Medicine

Abstract

Herbal medications are commonly used for clinical purposes, including the treatment of cardiovascular conditions. Compared with conventional medications, herbal medications do not require clinical studies before their marketing or formal approval from regulatory agencies, and for this reason their efficacy and safety are rarely proven. In this review, we summarize available evidence on herbal medications mostly used in cardiovascular medicine. We show that the use of these medications for the treatment of cardiovascular diseases is often not supported by scientific evidence. Despite most of these herbs showing an effect on biological mechanisms related to the cardiovascular system, data on their clinical effects are lacking. Potential relevant side effects, including increased risk of drug interactions, are described, and the possibility of contamination or substitution with other medications represents a concern. Physicians should always assess the use of herbal medications with patients and discuss the possible benefits and side effects with them.

http://ift.tt/2l5zUPy

The Efficacy of Exercise-Based Cardiac Rehabilitation: The Changing Face of Usual Care

http://ift.tt/2l5Hr0S

A Clinical and Biomarker Scoring System to Predict the Presence of Obstructive Coronary Artery Disease

AbstractBackground

Noninvasive models to predict the presence of coronary artery disease (CAD) may help reduce the societal burden of CAD.

Objectives

From a prospective registry of patients referred for coronary angiography, the goal of this study was to develop a clinical and biomarker score to predict the presence of significant CAD.

Methods

In a training cohort of 649 subjects, predictors of ≥70% stenosis in at least 1 major coronary vessel were identified from >200 candidate variables, including 109 biomarkers. The final model was then validated in a separate cohort (n = 278).

Results

The scoring system consisted of clinical variables (male sex and previous percutaneous coronary intervention) and 4 biomarkers (midkine, adiponectin, apolipoprotein C-I, and kidney injury molecule–1). In the training cohort, elevated scores were predictive of ≥70% stenosis in all subjects (odds ratio [OR]: 9.74; p < 0.001), men (OR: 7.88; p <0.001), women (OR: 24.8; p < 0.001), and those with no previous CAD (OR: 8.67; p < 0.001). In the validation cohort, the score had an area under the receiver-operating characteristic curve of 0.87 (p < 0.001) for coronary stenosis ≥70%. Higher scores were associated with greater severity of angiographic stenosis. At optimal cutoff, the score had 77% sensitivity, 84% specificity, and a positive predictive value of 90% for ≥70% stenosis. Partitioning the score into 5 levels allowed for identifying or excluding CAD with >90% predictive value in 42% of subjects. An elevated score predicted incident acute myocardial infarction during 3.6 years of follow up (hazard ratio: 2.39; p < 0.001).

Conclusions

We described a clinical and biomarker score with high accuracy for predicting the presence of anatomically significant CAD. (The CASABLANCA Study: Catheter Sampled Blood Archive in Cardiovascular Diseases; NCT00842868)

http://ift.tt/2lP55M4

Independent Associations Between Metabolic Syndrome Severity and Future Coronary Heart Disease by Sex and Race

http://ift.tt/2l5vtEv

Biomarkers of High-Grade Coronary Stenosis: Searching for Seventies

http://ift.tt/2l5tj7S

Sedentary Lifestyle and the Risk for HFpEF: Are "Huff-Puff Health Clubs" the Answer?

http://ift.tt/2lOZbKP

Neutrophil Counts and Initial Presentation of 12 Cardiovascular Diseases: A CALIBER Cohort Study

AbstractBackground

Neutrophil counts are a ubiquitous measure of inflammation, but previous studies on their association with cardiovascular disease (CVD) were limited by small numbers of patients or a narrow range of endpoints.

Objectives

This study investigated associations of clinically recorded neutrophil counts with initial presentation for a range of CVDs.

Methods

We used linked primary care, hospitalization, disease registry, and mortality data in England. We included people 30 years or older with complete blood counts performed in usual clinical care and no history of CVD. We used Cox models to estimate cause-specific hazard ratios (HRs) for 12 CVDs, adjusted for cardiovascular risk factors and acute conditions affecting neutrophil counts (such as infections and cancer).

Results

Among 775,231 individuals in the cohort, 154,179 had complete blood counts performed under acute conditions and 621,052 when they were stable. Over a median 3.8 years of follow-up, 55,004 individuals developed CVD. Adjusted HRs comparing neutrophil counts 6 to 7 versus 2 to 3 x 10⁹/l (both within the 'normal' range) showed strong associations with heart failure (HR: 2.04; 95% confidence interval [CI]: 1.82 to 2.29), peripheral arterial disease (HR: 1.95; 95% CI: 1.72 to 2.21), unheralded coronary death (HR: 1.78; 95% CI: 1.51 to 2.10), abdominal aortic aneurysm (HR: 1.72; 95% CI: 1.34 to 2.21), and nonfatal myocardial infarction (HR: 1.58; 95% CI: 1.42 to 1.76). These associations were linear, with greater risk even among individuals with neutrophil counts of 3 to 4 versus 2 to 3 x 10⁹/l. There was a weak association with ischemic stroke (HR: 1.36; 95% CI: 1.17 to 1.57), but no association with stable angina or intracerebral hemorrhage.

Conclusions

Neutrophil counts were strongly associated with the incidence of some CVDs, but not others, even within the normal range, consistent with underlying disease mechanisms differing across CVDs. (White Blood Cell Counts and Onset of Cardiovascular Diseases: a CALIBER Study [CALIBER]; NCT02014610)

http://ift.tt/2lP7fvj

International Subspecialty Fellowship Training, the Path for Cardiologists of Tomorrow?: A European Perspective

http://ift.tt/2lPa7Z8

Inside front cover

Publication date: March 2017
Source:Journal of Anxiety Disorders, Volume 46





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Transdiagnostic approaches to the understanding and treatment of anxiety and related disorders

Publication date: March 2017
Source:Journal of Anxiety Disorders, Volume 46
Author(s): Peter Norton




http://ift.tt/2m3Ufo0

Bisphenol A Induces Sox2 in ER + Breast Cancer Stem-Like Cells

Abstract

Bisphenol A (BPA) is an endocrine disrupting compound used in food and beverage plastic containers and has been shown to increase breast cancer cellular proliferation. However, the concentrations of BPA used in these experiments are far higher than the physiological levels of BPA detected in the human body. We observed in vitro that exposure of MCF-7 cells to physiological concentrations of BPA failed to increase cell proliferation or to induce canonical estrogen-responsive genes (pS2 and progesterone receptor (PR)), in contrast to 17β-estradiol (E2) treatment. However, MCF-7 cells treated with 10 nM BPA induced ALDH1 expression, a marker of human mammary stem cells. When treated with 10 nM BPA, mammospheres derived either from MCF-7 cells, a patient-derived xenograft, or the normal mouse mammary gland exhibited increased size; however, these effects were not observed in MDA-MB-231 mammospheres. Mechanistically, BPA induced SOX2 mRNA and protein in MCF-7 mammospheres, resulting from enhanced CREB phosphorylation, and subsequent binding of pCREB to a SOX2 downstream enhancer. These findings suggest that physiological levels of BPA increase estrogen receptor-positive breast cancer tumor maintenance through enhanced cancer stem-like cell activity via direct regulation of SOX2 transcription.

http://ift.tt/2ls8zTZ

Light and laser treatment modalities for disseminated superficial actinic porokeratosis: a systematic review

Abstract

Treatment of disseminated superficial actinic porokeratosis (DSAP) is poorly standardized. The present review seeks to comprehensively discuss the potential for laser and light modalities in the treatment of DSAP. A systematic review of light and laser treatment modalities was conducted to include 26 cases of patients with DSAP. Systematic review resulted in 14 articles to be included. Photodynamic therapy (PDT) overall was the least successful treatment modality, with clinical improvement seen in a minority of patients (MAL-PDT: N = 9 patients, 33.3% showed improvement; ALA-PDT: N = 3 patients, 0% improvement; hypericin-PDT: N = 2 patients, 0% improvement) after numerous post-procedural side effects of hyperpigmentation, inflammation, erythema, and discomfort. Overall, in the available reports, PDT demonstrates poor outcomes with greater incidence of side effects. The response rates of DSAP lesions treated with lasers were as follows: (Q-switched ruby lasers: N = 2, 100%; CO₂ laser: N = 1, 100%; PDT and CO₂ combination therapy: N = 2, 0–50%; erbium and neodymium YAG lasers: N = 2, 100%; fractional 1927-nm thulium fiber lasers: N = 2, 100%; Grenz rays: N = 1, 100%; and fractional photothermolysis: N = 2, 100%). The side effects of laser therapy were minimal and included mild erythema, slight hyperpigmentation, and moderate edema. Laser therapy is a promising treatment option for DSAP with an excellent side effect profile. However, higher power studies are required to determine optimal guidelines for laser treatment of DSAP.

http://ift.tt/2lhsNPp

Effect of radiant heat on conventional glass ionomer cements during setting by using a blue light diode laser system (445 nm)

Abstract

The aim of this in vitro study was to evaluate the effect of radiant heat on surface hardness of three conventional glass ionomer cements (GICs) by using a blue diode laser system (445 nm) and a light-emitting diode (LED) unit. Additionally, the safety of the laser treatment was evaluated. Thirty disk-shaped specimens were prepared of each tested GIC (Equia Fil, Ketac Universal Aplicap and Riva Self Cure). The experimental groups (n = 10) of the study were as follows: group 1 was the control group of the study; in group 2, the specimens were irradiated for 60 s at the top surface using a LED light-curing unit; and in group 3, the specimens were irradiated for 60 s at the top surface using a blue light diode laser system (445 nm). Statistical analysis was performed using one-way ANOVA and Tukey post-hoc tests at a level of significance of a = 0.05. Radiant heat treatments, with both laser and LED devices, increased surface hardness (p < 0.05) but in different extent. Blue diode laser treatment was seemed to be more effective compared to LED treatment. There were no alterations in surface morphology or chemical composition after laser treatment. The tested radiant heat treatment with a blue diode laser may be advantageous for the longevity of GIC restorations. The safety of the use of blue diode laser for this application was confirmed.

http://ift.tt/2mn5NmU

A reaction-based near-infrared fluorescent sensor for Cu2+ detection in aqueous buffer and its application in living cells and tissues imaging

Publication date: 15 August 2017
Source:Biosensors and Bioelectronics, Volume 94
Author(s): Huatang Zhang, Ling Feng, Yin Jiang, Yin-Ting Wong, Yonghe He, Guansheng Zheng, Jun He, Yi Tan, Hongyan Sun, Derek Ho
Copper (II) is one of the most of important cofactors for numerous enzymes and has captured broad attention due to its role as a neurotransmitters for physiological and pathological functions. In this article, we present a reaction-based fluorescent sensor for Cu²⁺ detection (NIR-Cu) with near-infrared excitation and emission, including probe design, structure characterization, optical property test and biological imaging application. NIR-Cu is equipped with a functional group, 2-picolinic ester, which hydrolyzes in the presence of Cu²⁺ with high selectivity over completed cations. With the experimental conditions optimized, NIR-Cu (5μM) exhibits linear response for Cu²⁺ range from 0.1 to 5μM, with a detection limit of 29nM. NIR-Cu also shows excellent water solubility and are highly responsive, both desirable properties for Cu²⁺ detection in water samples. In addition, due to its near-infrared excitation and emission properties, NIR-Cu demonstrates outstanding fluorescent imaging in living cells and tissues.



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Fabrication of nitrogen-doped carbon dots for screening the purine metabolic disorder in human fluids

Publication date: 15 August 2017
Source:Biosensors and Bioelectronics, Volume 94
Author(s): N.S.K. Gowthaman, Bharathi Sinduja, Rangasamy Karthikeyan, K. Rubini, S. Abraham John
Fabrication of nitrogen-doped carbon dots (N-CDs) electrode for the screening of purine metabolic disorder was described in this paper. Peroxynitrite is a short-lived oxidant species that is a potent inducer of cell death. Uric acid (UA) can scavenge the peroxynitrite to avoid the formation of nitrotyrosine, which is formed from the reaction between peroxynitrite and tyrosine (Try). Scavenging the peroxynitrite avoids the inactivation of cellular enzymes and modification of the cytoskeleton. Reduced level of UA decreases the ability of the body from preventing the peroxynitrite toxicity. On the other hand, the abnormal level of UA leads to gout and hyperuricemia. Allopurinol (AP) is administered in UA lowering therapy. Thus, the simultaneous determination of UA, Try and AP using N-CDs modified glassy carbon (GC) electrode was demonstrated for the first time. Initially, N-CDs were prepared from L-asparagine by pyrolysis and characterized by different spectroscopic and microscopic techniques. The HR-TEM image shows that the average size of the prepared N-CDs was 1.8±0.03nm. Further, the N-CDs were directly attached on GC electrode by simple immersion, follows Micheal's nucleophilic addition. XPS of N-CDs shows a peak at 285.3eV corresponds to the formation of C–N bond. The GC/N-CDs electrode shows higher electrocatalytic activity towards UA, Tyr and AP by not only shifting their oxidation potentials toward less positive potential but also enhanced their oxidation currents in contrast to bare GC electrode. The GC/N-CDs electrode shows the limit of detection of 13×10⁻¹⁰M (S/N=3) and the sensitivity of 924μAmM⁻¹cm⁻² towards the determination of UA. Finally, the N-CDs modified electrode was utilized for the determination of UA, Tyr and AP in human blood serum and urine samples.

Graphical abstract

http://ift.tt/2lhnfUY

Synthesis of hydrophilic and conductive molecularly imprinted polyaniline particles for the sensitive and selective protein detection

Publication date: 15 August 2017
Source:Biosensors and Bioelectronics, Volume 94
Author(s): Jing Luo, Jing Huang, Yunan Wu, Jun Sun, Wei Wei, Xiaoya Liu
In this work, a novel kind of water-dispersible molecular imprinted conductive polyaniline particles was prepared through a facile and efficient macromolecular co-assembly of polyaniline with amphiphilic copolymer, and applied as the molecular recognition element to construct protein electrochemical sensor. In our strategy, an amphiphilic copolymer P(AMPS-co-St) was first synthesized using 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS) and styrene (St) as monomer, which could co-assemble with PANI in aqueous solution to generate PANI particles driven by the electrostatic interaction. During this process, ovalbumin (OVA) as template protein was added and trapped into the PANI NPs particles owing to their interactions, resulting in the formation of molecular imprinted polyaniline (MIP-PANI) particles. When utilizing the MIP-PANI particles as recognition element, the resultant imprinted PANI sensor not only exhibited good selectivity toward template protein (the imprinting factor α is 5.31), but also a wide linear range over OVA concentration from 10^–11 to 10⁻⁶mgmL⁻¹ with a significantly lower detection limit of 10^–12mgmL⁻¹, which outperformed most of reported OVA detecting methods. In addition, an ultrafast response time of less than 3min has also been demonstrated. The superior performance is ascribed to the water compatibility, large specific surface area of PANI particles and the electrical conductivity of PANI which provides a direct path for the conduction of electrons from the imprinting sites to the electrode surface. The outstanding sensing performance combined with its facile, quick, green preparation procedure as well as low production cost makes the MIP-PANI particles attractive in specific protein recognition and sensing.



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Bull's Eye of the Abdominal Aorta

Publication date: Available online 27 February 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): E.H. Pasveer, H.T.C. Veger




http://ift.tt/2lOYAsC

Down-regulation of tripartite motif protein 59 inhibits proliferation, migration and invasion in breast cancer cells

Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Yan Zhang, Wen-Bin Yang
Tripartite motif protein 59 (TRIM59), also known as mouse ring finger protein 1 (MRF1), is a surface molecule and belongs to the TRIM family. Recently, TRIM59 has been described in multiple cancers such as gastric, prostatic and lung cancer. However, there have been no reports on its functions in breast cancer. In this study, we elucidated the biological roles of TRIM59 in breast cancer. We found that TRIM59 was up-regulated in breast cancer cells. Down-regulation of TRIM59 inhibited breast cancer cell proliferation, migration and invasion in vitro as well as tumor growth in vivo. In addition, TRIM59 down-regulation reduced the protein expression level of p-Smad2 and thus inhibited the activity of transforming growth factor-β (TGF-β) signaling. Taken together, our study results provided new evidence showing that TRIM59 may be considered as a promising therapeutic target for breast cancer.



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Antibacterial evaluation of sliver nanoparticles synthesized by polysaccharides from Astragalus membranaceus roots

Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Yihua Ma, Congyan Liu, Ding Qu, Yan Chen, Mengmeng Huang, Yuping Liu
This work introduced an eco-friendly approach for the synthesis of sliver nanoparticles (AgNPs) with a water-soluble fraction of polysaccharides extracted from the roots of Astragalus membranaceus (AMWP). AMWP mediated AgNPs (AMWP-AgNPs) were successfully synthesized using 1.0mM AgNO3 and 1.25mg/mL AMWP, reacting in aqueous environment at 25°C for 6h. The synthesized AMWP-AgNPs exhibited a broad surface plasmon resonance peak (SPR) at 445nm in Ultraviolet-visible (UV–vis) spectrum, which was characteristic of a poly-dispersed AMWP-AgNPs. Transmission electron microscopy (TEM) and Dynamic light scattering (DLS) analysis revealed that the AMWP-AgNPs were almost spherical shaped with an average diameter of 65.08nm. The antibacterial activities of AMWP-AgNPs were assessed on four strains of clinical isolated multidrug resistant (MDR) bacteria and four relative reference strains using modified agar disk diffusion and tetrazolium methods. All strains, especially the resistant strains, were significantly inhibited by AMWP-AgNPs at comparatively low concentration (minimum inhibition concentrations (MICs) ranging from 0.032 to 0.063mg/mL). Therefore, we propose that the AMWP-AgNPs will have a great potential in anti-MDR bacterial applications.



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Biophenols pharmacology against the amyloidogenic activity in Alzheimer’s disease

Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Syed Haris Omar
Alzheimer's disease characterized by misfolding, aggregation, and accumulation of amyloid fibrils in an insoluble form in the brain, is often known as amyloidosis. The process of aggregation follows a mechanism of seeded polymerization. For decades, a great number of failures in Alzheimer's disease (AD) drug development, with both small molecules and immunotherapies failing to establish a drug/placebo difference or having an unacceptable toxicity have led to the therapeutic research interest towards a group of anti-amyloidogenic compounds originated from plants called biophenols. A number of in vitro and in vivo studies have demonstrated that the plant biophenols bind with amyloid beta (Aβ) toxic oligomers and reducing the fibril formation and toxicity. The exact mechanism of biophenols action against Aβ toxicity is unknown, while studies have suggested the amyloid-binding affinity of biophenols affecting Aβ on various levels, e.g. by direct inhibiting fibril formation or steering oligomer formation into unstructured, inhibiting Aβ aggregation, and promoting nontoxic pathways. Furthermore, biophenols involved in the inhibition of Aβ progression (e.g., oxidative stress and neuroinflammation) and effecting the amyloid precursor protein processing through the direct or indirect inhibition of β-secretase (BACE-1), γ-secretase and/or activation of α-secretase. This critical review account for the biophenols as magic bullet targeting against Aβ, and simulation the results on how biophenols interact with the Aβ monomers and oligomers, highly desirable knowledge for predicting new efficient nutraceutical drugs.

Graphical abstract

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Identification of novel dual-specificity phosphatase 26 inhibitors by a hybrid virtual screening approach based on pharmacophore and molecular docking

Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Ji-Xia Ren, Zhong Cheng, Yu-Xin Huang, Jing-Feng Zhao, Peng Guo, Zhong-Mei Zou, Yong Xie
Dual-specificity phosphatase 26 (DUSP26) has recently emerged as a target for treatment of human cancers. However, only two small-molecule inhibitors of DUSP26 are known so far, namely NSC-87877 and ethyl-3, 4-dephostatin. DUSP26 contains an N-terminal region (residues 1–60) and a conserved C-terminal catalytic domain (residues 61–211, DUSP26-C). The crystal structure of DUSP26-C, showing a catalytically inactive conformation of the active site, was reported in a previous study. However, the detailed catalytic mechanism of DUSP26 cannot be described based on that structure. In this study, the 3D structure of DUSP26 (residues 42–211) adopting catalytically active conformation, was built by homology modeling, and the established 3D structure was validated using enzyme kinetic assays. Pharmacophore modeling based on the validated 3D structure of human DUSP26 was carried out. The established pharmacophore model was considered as a 3D query for retrieving novel DUSP26 inhibitors from the chemical databases "Diversity Libraries" (129,087 compounds). Next, a docking study was performed to refine the obtained hit compounds. Then a total of 100 compounds were selected based on the ranking order and visual examination, which were then evaluated by an enzyme-based assay. Eight compounds were found to have inhibitory activities against DUSP26, and the most potent compound was assigned No. F1063-0967 with an IC50 value of 11.62μM. The inhibitory activity of F1063-0967 against DUSP26 is higher than that of NCS87877 (IC50 value: 16.67±2.89μM), but lower than that of ethyl-3, 4-dephostatin (IC50 value: 6.8±0.41μM). MTT assay results revealed that F1063-0967 can induce apoptosis in IMR-32 cell line with an IC50 value of 4.13μM. These results suggest that F1063-0967 should be investigated further for other pharmacological properties.

Graphical abstract

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A recombinant IgG-like bispecific antibody acting as interleukin-1β and interleukin-17A inhibitor exhibits a promising efficacy for rheumatoid arthritis

Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Yunxin Wang, Qiang Wu, Zhihang Liu, Xiaochen Guo, Lijiao Zhou, Yuyang Wang, Liying Song, Nan Wang, Qi Zheng, Wenfei Wang, Guiping Ren, Deshan Li
Recently, targeting inflammatory cytokines in the pathogenic process of rheumatoid arthritis is now performed as a feasible biological method in therapy. However, treatments against single cytokine are often difficult to achieve the ideal therapeutic effect. Multi-target drugs permit more effective suppression of inflammation. In this study, we constructed an IgG-like bispecific antibody targeting IL-1β and IL-17A and expressed it in mammalian cells. The therapeutic efficacy was studied in CIA (collagen-induced arthritis) mice, which were administrated with either FL-BsAb1/17 (IgG-like bispecific antibody targeting IL-1β and IL-17A) or monovalent IL-1β Mab or IL-17A Mab (anti-IL-1β/IL-17A monoclonal antibody). We noticed that FL-BsAb1/17 had better effect on alleviating clinical symptom by significantly lowering arthritis score and relieving histological lesion on aspect of less damnification in synovial hyperplasia and cartilage destruction than monovalent Mab alone. In addition, FL-BsAb1/17 was more potent in inhibiting IL-1β, IL-17A, IL-6, TNF-α and anti-CCP antibody in the serum and in down-regulating the expression of IL-1β, IL-17A, IL-6, TNF-α, MMP-3 and RANKL in the spleen, compared to monovalent Mab alone. Further, the anti-inflammatory effect of FL-BsAb1/17 was demonstrated by significantly depressing Th17 cells expansion through decreasing phosphorylated STAT3 in the spleen of the CIA mice. FLS (fibroblast-like synoviocytes) from RA patients were used to examine the therapeutic efficacy of FL-BsAb1/17 in human pathological tissue. FL-BsAb1/17 could significantly decrease the production of IL-6 induced by IL-1β and/or IL-17A in FLS. In conclusion, FL-BsAb1/17 has the possibility to be a promising therapeutic agent for RA.



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Phytofabricated gold nanoparticles and their biomedical applications

Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Bashir Ahmad, Nabia Hafeez, Shumaila Bashir, Abdur Rauf, Mujeeb-ur-Rehman
In a couple of decades, nanotechnology has become a trending technology owing to its integrated science collection that incorporates variety of fields such as chemistry, physics, medicine, catalytic processes, food processing industries, electronics and energy sectors. One of the emerging fields of nanotechnology that has gained momentous admiration is nano-biotechnology. Nano-biotechnology is an integrated combination of biology with nanotechnology that encompasses the tailoring, and synthesis of small particles that are less than 100nm in size and subsequent exploitation of these particles for their biological applications. Though the variety of physical techniques and chemical procedures are known for the nanoparticles synthesis, biological approach is considered to be the preferred one. Environmental hazards and concerns associated with the physical and chemical approaches of nanoparticles synthesis has added impetus and zenith to the biological approach involving the use of plants and microorganisms. The current review article is focused on the synthesis of plant-derived (phytochemical) gold nanoparticles alongside their scope in biomedical applications.



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Characterization and evaluation of bioactive polyphenolic constituents from Zanthoxylum armatum DC., a traditionally used plant

Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Zulfa Nooreen, Shilpi Singh, Dhananjay Kumar Singh, Sudeep Tandon, Ateeque Ahmad, Suaib Luqman
Zanthoxylum armatum or Timoor has been used in different traditional system of medicine due to its aromatic properties and also in the treatment of cancer, diarrhea and cholera. In the present investigation, four chemically distinct compounds namely Tambulin (6), Prudomestin (7), Ombuin (8) and 3, 4, 5, 3′, 4′, 5′-hexahydroxydiphenyl ether (9) have been isolated and quantified from the fruits. To explore the biological activities, we have further studied the antiproliferative, antimicrobial and antioxidant efficacy. Tambulin which was also found in maximum amount (0.125%) in fruits revealed significant antiproliferative activity (IC50 37.96±0.36 to 48.7±0.21μg/mL) against breast, liver, colon and skin cancer cell lines corroborated by resilient binding interaction with SDH (−6.76Kcal/mol) and inhibition constant (Ki: 11.02μM). Hexane and ethyl acetate fraction exhibited moderate antibacterial efficacy (MIC: 250–1000μg/mL) against selected pathogenic microbes while Ombuin displayed broad spectrum antibacterial effect with MIC ranges from 125 to 500μg/mL. Total phenolic content (5.27±0.06 to 46.12±0.40mg/g of gallic acid equivalents), total flavonoids content (6.05±0.24 to 14.46±0.73mg/g of quercetin equivalents), ferric reducing power (42.35±0.85 to 62.52±0.66mg/g of ferrous sulfate equivalents) and percent free radical scavenging activity (59.56±0.38 to 64.85±1.78) were also estimated. Our findings infer that Tambulin exhibited significant antiproliferative activity whereas Ombuin was found to display broad spectrum antibacterial activity which adds one more positive attribute to its traditional usage.

Graphical abstract

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Pharmacological evaluation of aqueous extract of syzigium cumini for its antihyperglycemic and antidyslipidemic properties in diabetic rats fed a high cholesterol diet—Role of PPARγ and PPARα

Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Sandhya Sharma, Sachchidanand Pathak, Gaurav Gupta, Satish Kumar Sharma, Lalit Singh, Rakesh Kumar Sharma, Anurag Mishra, Kamal Dua
In India syzygium cumini (Myrtaceae) is commonly used traditional medicine to treat diabetes. The present study was undertaken to assess an investigation of antihyperglycemic and antidyslipidemic properties of aqueous extract of Syzigium Cumini (SC) in diabetic rats fed a high cholesterol diet. The aqueous extract of SC was screened for antihyperglycemic and antidyslipidemic activity by streptozotocin induced diabetes in rats. Animals were treated with 100, 200 and 400mg/kg body weight of aqueous extract of SC. Metformin were used as reference antihyperglycemic drugs for comparison. Administration of aqueous extract of SC or metformin for 21days resulted in a significant (P<0.05) reduction in serum glucose, insulin and Homeostasis model assessment of insulin resistance (HOMA-IR) compared with diabetic controls. Treatment with 100mg/kg/day aqueous extract of SC did not result in a significant reduction in serum insulin levels, but 200mg/kg/day and 400mg/kg/day, aqueous extract of SC and metformin showed significant reductions 17.89%, 19.60% and 24.40%, respectively. Furthermore, administration of 100, 200 and 400mg/kg/day, aqueous extract of SC and metformin resulted in significant decrease in insulin resistance of 19.20%, 41.59%, 51.55% and 68.68%, respectively. In high fat diet- streptozotocin (HFD – STZ) treated rats β-cells function (HOMA-B) were markedly reduced (5.8-fold), however observed a significant (P<0.01) improvement of β-cell function with aqueous extract of SC (400mg/kg/day) and metformin. The aqueous extract of SC seeds exhibits significant insulin-sensitizing, antidyslipidemic, antioxidant, anti-inflammatory and β-cell salvaging activity in HFD-STZ-induced type 2 diabetic rats via overexpression of PPARγ and PPARα activity, affirming its potential to be used in the prevention and treatment of type 2 diabetes mellitus (T2DM). Further isolation and characterization of active components in SC seed extract are needed to explore the other possible mechanisms and pathways that are involved in its anti-diabetic effect.



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Protective effect of Azolla microphylla on biochemical, histopathological and molecular changes induced by isoproterenol in rats

Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Sreenath Kunnathupara Bhaskaran, Poornima Kannappan
Azolla microphylla is an important fast-growing aquatic plant trusted for its agronomic, nutritious and therapeutic uses. The present work is undertaken to investigate the protective effect of the ethanolic extract of Azolla microphylla (EAM) against the Isoproterenol (ISO) induced cardiotoxicity in rats. Rats were pre-treated with EAM (250 and 500mg/kg b.w.) for 28 days along with ISO (85mg/kg; s.c.) on the 29th and 30th days. ISO-induced rats displayed significant diminution in cardiac antioxidant enzymes activities, increased lipid peroxidation and alteration in cardiac marker enzymes. The same group also displayed an increase in levels of serum lipid profiles and pro-inflammatory cytokines (IL-6 and IL-8) accompanied with a significant reduction in the anti-inflammatory cytokine levels (IL-10). Moreover, the histopathological investigations in the heart tissue of ISO-induced group exhibited myocardial necrosis and inflammation, which correlated with the increased immunoreactivity for Bax/iNOS, whereas an absence of reactivity for Bcl-2 proteins. However, in EAM pre-treated rats, the activities of antioxidant enzymes, cardiac marker enzymes, membrane-bound ATPases together with the levels of lipid profile, non-enzymatic antioxidants, pro and anti-inflammatory cytokines were maintained at normalcy that was further supported by improving histopathological changes and myocardial architecture. The IHC results of EAM pre-treated rats indicate up-regulated and down-regulated expressions of Bcl-2 and Bax/iNOS proteins, respectively. Thus, the present study reveals that A. microphylla alleviates myocardial damage in ISO-induced cardiac injury and demonstrates cardioprotective potential which could be attributed to its potent antioxidant and free radical scavenging activity. A possible mechanism for the protective effect is the elevated expression of endogenous antioxidant defense enzymes, anti-inflammatory cytokines, degraded lipid peroxidation products and improved energy metabolism of cardiac mitochondria, thus attenuating necrosis of the myocytes.



http://ift.tt/2mBD6ij

Fructose-1,6-bisphosphate decreases IL-8 levels and increases the activity of pro-apoptotic proteins in HepG2 cells

Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Gabriele Catyana Krause, Kelly Goulart Lima, Gabriela Viegas Haute, Aline Daniele Schuster, Henrique Bregolin Dias, Fernanda Cristina Mesquita, Leonardo Pedrazza, Elisa Simon Marczak, Bruno Souza Basso, Anderson Catarina Velasque, Bianca Andrade Martha, Fernanda Bordignon Nunes, Márcio Vinícius Fagundes Donadio, Jarbas Rodrigues de Oliveira
Hepatocellular carcinoma (HCC) is the most prevalent primary liver tumor that affects the world population. Liver cancer inevitably causes great harms and its treatment is extremely difficult. Its development is related to the existence of chronic liver injury, such as in cirrhosis. Cancer is a disease related to the process of inflammation so, research with anti-inflammatory agents has been performed for the development of anti-tumor drugs. Fructose-1,6-bisphosphate (FBP), a metabolite of the glycolytic route, has shown anti-inflammatory actions. The purpose of this study is to investigate the effect of FBP on HepG2 cells growth and inflammatory parameters. Results showed that FBP decreased the proliferation of HepG2 cells through trypan blue assay, without causing necrosis, shown by the intracellular release of LDH. By flow cytometry, we observed a significant IL-8 decrease which is closely related to the tumoral progression and chemotherapeutic resistance, especially in HCC. Then, we found, by RT-PCR, a high expression level of pro-apoptotic protein, such as Bax and p53, and decreased the expression levels of anti-apoptotic proteins, like Bcl-2 suggesting apoptosis. Finally, our results showed that FBP can be a potential therapeutic agent to slow the progress of HCC.



http://ift.tt/2lN98dp

Hair growth promoting effect of white wax and policosanol from white wax on the mouse model of testosterone-induced hair loss

Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Zhan-di Wang, Ying Feng, Li-yi Ma, Xian Li, Wei-feng Ding, Xiao-ming Chen
White wax (WW) has been traditionally used to treat hair loss in China. However there has been no reporter WW and its extract responsible for hair growth-promoting effect on androgenetic alopecia. In this paper, we examined the hair growth-promoting effects of WW and policosanol of white wax (WWP) on model animal of androgenetic alopecia and the potential target cell of WW and WWP. WW (1, 10 and 20%) and WWP (0.5, 1 and 2%) were applied topically to the backs of mice. Finasteride (2%) was applied topically as a positive control. MTS assays were performed to evaluate cell proliferation in culture human follicle dermal papilla cells (HFDPCs). The inhibition of WW and WWP for 5α- reductase were tested in Vitro. Results showed more lost hairs were clearly seen in mice treated with TP only and TP plus vehicle. Mice which received TP plus WW and WWP showed less hair loss. WW and WWP showed an outstanding hair growth-promoting activity as reflected by the follicular length, follicular density, A/T ratio, and hair bulb diameter. The optimal treatment effect was observed at 10% WW and 1% WWP, which were better than 2% finasteride treatment. MTS assay results suggested that WW and WWP remarkably increased the proliferation of HFDPCs. Inhibitor assay of 5α- reductase showed that WW and WWP inhibited significantly the conversion of testosterone to dihydrotesterone, and the IC50 values of WW and WWP were higher than that of finasteride. In Conclusion, WW and WWP could act against testosterone-induced alopecia in mice, and they promoted hair growth by inhibiting 5α-reductase activity and HFDPCs proliferation. DPCs is the target cell of WW and WWP.

Graphical abstract

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Copper sulfate pentahydrate reduced epithelial cytotoxicity induced by lipopolysaccharide from enterogenic bacteria

Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Adel Feyzi, Aref Delkhosh, Hamid Tayefi Nasrabadi, Omid Cheraghi, Mansour khakpour, Mazyar Barekati-Mowahed, Sina Soltani, Seyede Momeneh Mohammadi, Masoumeh Kazemi, Mehdi Hassanpour, Aysa Rezabakhsh, Nasrin Maleki‐Dizaji, Reza Rahbarghazi, Reza Namdarian
The over usage of multiple antibiotics contributes to the emergence of a whole range of antibiotic-resistant strains of bacteria causing enterogenic infections in poultry science. Therefore, finding an appropriate alternative natural substance carrying an antibacterial capacity would be immensely beneficial. It has been previously discovered that the different types of cupric salts, especially copper sulfate pentahydrate (CuSO4·5H2O), to carry a potent bactericidal capacity.We investigated the neutralizing effect of CuSO4·5H2O (6.25μg/ml) on the reactive oxygen species generation, and expression of MyD88, an essential adaptor protein of Toll-like receptor, and NF-κB in three intestinal epithelial cell lines exposed to 50ng/ml lipopolysaccharide. In order to find the optimal cupric sulfate concentration without enteritis-inducing toxicity, broiler chickens were initially fed with water containing 0.4, 0.5, and 1mg/l during a period of 4days. After determination of appropriate dosage, two broiler chickens and turkey flocks with enteritis were fed with cupric compound for 4days.We found that cupric sulfate can lessen the cytotoxic effect of lipopolysaccharide by reducing the reactive oxygen species content (p<0.05). Additionally, the expression of MyD88 and NF-κB was remarkably down-regulated in the presence of lipopolysaccharide and cupric sulfate. The copper sulfate in doses lower than 0.4mg/ml expressed no cytotoxic effect on the liver, kidney, and the intestinal tract while a concentration of 0.5 and 1mg/ml contributed to a moderate to severe tissue injuries. Pearson Chi-Square analysis revealed the copper cation significantly diminished the rate of mortality during 4-day feeding of broiler chicken and turkey with enteritis (p=0.000).Thus, the results briefed above all confirm the potent anti-bactericidal feature of cupric sulfate during the course of enteritis.



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Neuroprotective effects of octreotide on diabetic neuropathy in rats

Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Volkan Solmaz, Bilge Piri Çınar, Gürkan Yiğittürk, Hatice Köse Özlece, Hüseyin Avni Eroglu, Aslan Tekatas, Oytun Erbaş, Dilek Taşkıran
The purpose of the present study is to investigate the possible healing effects of octreotide (OCT) on motor performance, electrophysiological and histopathological findings of diabetic neuropathy in a rat model of diabetes mellitus (DM). To induce diabetes, rats were administered a single dose (60mg/kg) of streptozotocin (STZ). Diabetic rats were treated either with saline (1ml/kg/day, n=7) or OCT (0.1mg/kg/day, n=7) for four weeks. Seven rats served as control group and received no treatment. At the end of the study, electromyography (EMG), gross motor function (inclined plate test), general histology and the perineural thickness of sciatic nerve were evaluated. At the end of study, weight loss was significantly lower in OCT treated rats than that of saline treated ones (p<0.001). Electrophysiologically, compound muscle action potential (CMAP) amplitudes of the saline treated DM group were significantly reduced than those of controls (p<0.0001). Also, distal latency and CMAP durations were significantly prolonged in saline treated DM group (p<0.05) compared to control. However, treatment of diabetic rats with OCT significantly counteracted these alterations in EMG. Furthermore, OCT significantly improved the motor performance scores in diabetic rats (p<0.05). Histomorphometric assessment of the sciatic nerve demonstrated a significant reduction in perineural thickness in OCT treated group compared to saline group. In conclusion, OCT possesses beneficial effects against STZ-induced diabetic neuropathy, which promisingly support the use of OCT as a neuroprotective agent in patients with diabetic neuropathy.



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Stigmasterol retards the proliferation and pathological features of Trypanosoma congolense infection in rats and inhibits trypanosomal sialidase in vitro and in silico

Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Raphael Aminu, Ismaila Alhaji Umar, Md. Atiar Rahman, Mohammed Auwal Ibrahim
Stigmasterol has been reported to possess antitrypanosomal activity using in vitro model but information on the in vivo antitrypanosomal effects which is necessary in drug development process has not been evaluated. Hence, the present study investigates the in vivo effects of stigmasterol against T. congolense in addition to its inhibitory effects of trypanosomal sialidase. Stigmasterol, at 100mg/kg BW, did not significantly (p>0.05) reduce the progression of T. congolense infection in animals but a 200mg/kg BW stigmasterol treatment significantly (p<0.05) reduced the parasitemia, although, it did not completely eliminate the parasite from the bloodstream of infected animals. However, the stigmasterol treatments significantly (p<0.05) ameliorated the T. congolense induced anemia as well as hepatic and renal damages. Furthermore, the T. congolense-associated increase in free serum sialic acid with a corresponding decrease in membrane bound sialic acid were prevented, though insignificantly (p>0.05), by the 200mg/kg BW treatment. Subsequently, in vitro enzyme kinetic studies revealed that stigmasterol is an uncompetitive inhibitor of a partially purified bloodstream T. congolense sialidase with an inhibition binding constant of 356.59μM. Using molecular docking studies, stigmasterol formed a single hydrogen bonding interaction with a major residue (D⁶³) at the catalytic domain of T. rangeli sialidase with a predicted binding free energy of −24.012kcal/mol. We concluded that stigmasterol could retard the proliferation and the major pathological features of T. congolense infection whilst the anemia amelioration was mediated via inhibition of sialidase.

Graphical abstract

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Target position uncertainty during visually guided deep-inspiration breath-hold radiotherapy in locally advanced lung cancer

Publication date: Available online 27 February 2017
Source:Radiotherapy and Oncology
Author(s): Jonas Scherman Rydhög, Steen Riisgaard de Blanck, Mirjana Josipovic, Rasmus Irming Jølck, Klaus Richter Larsen, Paul Clementsen, Thomas Lars Andersen, Per Rugaard Poulsen, Gitte Fredberg Persson, Per Munck af Rosenschold
PurposeThe purpose of this study was to estimate the uncertainty in voluntary deep-inspiration breath-hold (DIBH) radiotherapy for locally advanced non-small cell lung cancer (NSCLC) patients.MethodsPerpendicular fluoroscopic movies were acquired in free breathing (FB) and DIBH during a course of visually guided DIBH radiotherapy of nine patients with NSCLC. Patients had liquid markers injected in mediastinal lymph nodes and primary tumours. Excursion, systematic- and random errors, and inter-breath-hold position uncertainty were investigated using an image based tracking algorithm.ResultsA mean reduction of 2–6mm in marker excursion in DIBH versus FB was seen in the anterior-posterior (AP), left–right (LR) and cranio-caudal (CC) directions. Lymph node motion during DIBH originated from cardiac motion. The systematic- (standard deviation (SD) of all the mean marker positions) and random errors (root-mean-square of the intra-BH SD) during DIBH were 0.5 and 0.3mm (AP), 0.5 and 0.3mm (LR), 0.8 and 0.4mm (CC), respectively. The mean inter-breath-hold shifts were −0.3mm (AP), −0.2mm (LR), and −0.2mm (CC).ConclusionIntra- and inter-breath-hold uncertainty of tumours and lymph nodes were small in visually guided breath-hold radiotherapy of NSCLC. Target motion could be substantially reduced, but not eliminated, using visually guided DIBH.



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Static and Dynamic Shoulder Imaging to Predict Initial Effectiveness and Recurrence After Ultrasound-guided Subacromial Corticosteroid Injections

Publication date: Available online 27 February 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Ke-Vin Chang, Wei-Ting Wu, Der-Sheng Han, Levent Özçakar
ObjectiveTo explore factors contributing to initial effectiveness and recurrence after ultrasound (US)-guided subacromial corticosteroid injections by assessing clinical measurements as well as static and dynamic shoulder US images.DesignRetrospective cohort study.SettingRehabilitation outpatient clinic.ParticipantsAdults with shoulder pain referred for injection therapy.InterventionsUS-guided subacromial corticosteroid injection.Main Outcome MeasuresThe association of initial effectiveness (defined as a more than 50% decrease in any of the three pain subdomains after the first injection) and recurrent shoulder pain that required repeated intervention with record-based clinical measurements and static/dynamic shoulder US.ResultsThe present study included 164 patients, 106 of whom were responsive to a first injection. Among the 106 participants, 42 received a second injection due to recurrent shoulder pain. By using the multivariate logistic regression analysis, initial effectiveness was positively associated with right handedness, grade 2 subacromial impingement during the dynamic US examination and bicipitial groove tenderness. However, these patients had a negative association with subdeltoid bursitis, grade 3 subacromial impingement and shoulder stiffness. Subdeltoid bursitis and a positive painful arc test were predictors of recurrent shoulder pain that necessitated a repeated injection in the cox proportional hazards model.ConclusionThe initial effectiveness and recurrence after US-guided subacromial corticosteroid injection were associated with certain clinical measurements and static and dynamic shoulder US, which should be carefully evaluated (and can be used) to guide the best treatment outcomes.



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NCI launches study of African-American cancer survivors

The Detroit Research on Cancer Survivors (ROCS) study, which will include 5,560 cancer survivors, will look at the major factors affecting cancer progression, recurrence, mortality, and quality of life among African-American cancer survivors.

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Study of the Pan-ERBB Inhibitor Neratinib Given in Combination With Everolimus, Palbociclib or Trametinib in Advanced Cancer Subjects With EGFR Mutation/Amplification, HER2 Mutation/Amplification or HER3/4 Mutation

Conditions:   Malignant Neoplasm of Breast;   Malignant Neoplasms of Digestive Organs;   Malignant Neoplasms of Female Genital Organs;   Malignant Neoplasms of Ill-defined Secondary and Unspecified Sites;   Malignant Neoplasms of Independent (Primary) Multiple Sites;   Malignant Neoplasms of Lip Oral Cavity and Pharynx;   Malignant Neoplasms of Mesothelial and Soft Tissue;   Malignant Neoplasms of Respiratory and Intrathoracic Organs;   Malignant Neoplasms of Thyroid and Other Endocrine Glands;   Malignant Neoplasms of Urinary Tract;   Neoplasms of Uncertain or Unknown Behavior
Interventions:   Drug: Neratinib;   Drug: Everolimus;   Drug: Palbociclib;   Drug: Trametinib
Sponsors:   M.D. Anderson Cancer Center;   Pfizer;   Puma Biotechnology, Inc.
Not yet recruiting - verified February 2017

http://ift.tt/2lOor46

Endoscopic Resection Multicenter Registry

Conditions:   Gastrointestinal Neoplasms;   Gastrointestinal Disease;   Gastric Cancer;   Gastric Neoplasm;   Gastric Polyp;   Esophageal Neoplasms;   Duodenal Neoplasms;   Duodenal Polyp;   Stomach Neoplasm;   Stomach Polyp;   Neoplasms;   Colon Polyp;   Colon Neoplasm
Intervention:   Procedure: Endoscopic Resection
Sponsor:   Weill Medical College of Cornell University
Not yet recruiting - verified February 2017

http://ift.tt/2l4CYeB