Gene therapy: Human genome editing in heart disease

Nature Reviews Genetics. doi:10.1038/nrg.2017.69

Author: Gregory B. Lim

http://ift.tt/2fXosUc

Human genetic variation and the gut microbiome in disease

Nature Reviews Genetics. doi:10.1038/nrg.2017.63

Authors: Andrew Brantley Hall, Andrew C. Tolonen & Ramnik J. Xavier

http://ift.tt/2ijzLHi

Tracking MET de-addiction in lung cancer: a road towards the oncogenic target.

Publication date: Available online 20 August 2017
Source:Cancer Treatment Reviews
Author(s): S. Pilotto, L. Carbognin, N. Karachaliou, P.C. Ma, R. Rosell, G. Tortora, E. Bria
The discovery of druggable oncogenic drivers (i.e. EGFR and ALK), along with the introduction of comprehensive tumor genotyping techniques into the daily clinical practice define non-small-cell lung cancer (NSCLC) as a group of heterogeneous diseases, requiring a context-personalized clinico-therapeutical approach. Among the most investigated biomarkers, the MET proto-oncogene has been extensively demonstrated to play a crucial role throughout the lung oncogenesis, unbalancing the proliferation/apoptosis signaling and influencing the epithelial-mesenchymal transition and the invasive phenotype. Nevertheless, although different mechanisms eliciting the aberrant MET-associated oncogenic stimulus have been detected in lung cancer (such as gene amplification, increased gene copy number, mutations and MET/HGF overexpression), to date no clinically impactful results have been achieved with anti-MET tyrosine kinase inhibitors and monoclonal antibodies in the context of an unselected or MET enriched population. Recently, MET exon 14 splicing abnormalities have been identified as a potential oncogenic target in lung cancer, able to drive the activity of MET inhibitors in molecularly selected patients.In this paper, the major advancement and drawbacks of MET history in lung cancer are reviewed, underlying the renewed scientific euphoria related to the recent identification of MET exon 14 splicing variants as an actionable oncogenic target.



http://ift.tt/2vRxrw5

Elizabeth Croll: ASPS Patient of Courage 2016

Summary: Mrs. Elizabeth Croll was selected as an American Society of Plastic Surgeons (ASPS) Patient of Courage in 2016. During a boating accident that occurred within 1 month after graduating from Harvard Business School, she was struck by an oncoming boat and suffered severe facial trauma, resulting in an open skull injury with loss of her right eye. She has since undergone multiple reconstructive surgical procedures beginning in 1997 and continuing up to the month before she was awarded the ASPS Patient of Courage. During this time, she got married, started a family, and continued an ambitious business career. Mrs. Croll is the epitome of an individual who has overcome tragedy to further her career, her community, and access to medical care for indigent children.

http://ift.tt/2vMoZyr

An Unusual Presentation of an Osteoid Osteoma in the Lunate Bone

Summary: An osteoid osteoma is a rare benign tumor of the carpal bones. It is extremely rarely found in the lunate bone in patients above 30 years of age. We present a case report of a 61-year-old man with an osteoid osteoma of the left wrist, which was masked by degenerative carpal bone disease and a comorbidity of an inflammatory bowel disease. The mainstay of imaging including plain radiographs, computed tomography, magnetic resonance imaging, and bone scintigraphy led to the clinical diagnosis of a lunatomalacia. The tumor was removed by coincidence during removal of the diseased lunate bone. Postoperatively, the patient was immediately free of pain and remained free at his 3 months postoperative follow-up.

http://ift.tt/2wsMyu4

Zinc-doped BSCF perovskite membranes for oxygen separation

Publication date: 22 December 2017
Source:Separation and Purification Technology, Volume 189
Author(s): Xiaozhen Zhang, Julius Motuzas, Shaomin Liu, João C. Diniz da Costa
This work investigates the partial substitution of Zn in the B-site of perovskite as Ba0.5Sr0.5(Co0.8Fe0.2)1−xZnxO3−δ. The membranes were tested for oxygen separation from air and Zn incorporation into the BSCFZ cubic crystal structure proved to be effective as oxygen fluxes increased as compared with a pure BSCF (x=0, no Zn). This was attribute to the increase in oxygen vacancy concentration as a function of Zn concentration. As a result, oxygen fluxes for the BSCFZ membranes were 200% (700°C) and 32% (900°C) higher than the BSCF analogue membrane. However, the correlation between oxygen vacancy concentration and oxygen flux diverged for Zn concentrations x≥0.08, which was associated with the shift and broadening of the main XRD peak 2θ=31.81° of the BSCFZ cubic structure caused by an additional oxide phase (ZnO). Zn doping also affected the microstructure of the sintered BSCFZ membranes. Grain boundary dimensions reduced as Zn substitution in the B-site increased to x=0.06 up to 800°C, resulting in improved oxygen fluxes. Contrary to this, high Zn concentration x≥0.08 increased grain boundary and reduced oxygen fluxes. Therefore, the Zn solubility into BSCF impact upon the oxygen vacancy and microstructural formation, which in turn affected the transport of oxygen ions through the membrane.

Graphical abstract

http://ift.tt/2wvHck1

Synthesis, characterization and activity evaluation of Cu-based catalysts derived from layered double hydroxides (LDHs) for DeNOx reaction

Publication date: 15 December 2017
Source:Chemical Engineering Journal, Volume 330
Author(s): Yu-sheng Zhang, Changming Li, Chao Yu, Tuyetsuong Tran, Feng Guo, Yunquan Yang, Jian Yu, Guangwen Xu
Catalytic filter for DeNOx reaction composed of practical ceramic filter and catalytic active component enables simultaneous removal of dusts and NOx and therefore is of great potential for industrial application. To find out catalytically active components for DeNOx reaction and concurrently which can be grown on ceramic filter by an in-situ method, the Cu-based catalysts derived from LDHs precursor with different promoters (Co, Ni, Zn, Mg) were synthesized. The results of catalytic activity evaluation showed Zn is the most suitable promoter. Then, the effect of the Cu/Zn ratio on the catalytic performance was examined. It was found that the (CuxZny)2Al-MMO with an Cu/Zn ratio of 4 exhibited the maximum NOx conversion of 80% at 240°C and a NH3/NO ratio of 0.8. The addition of Zn could weaken the catalytic oxidation of ammonia (NH3-SCO) and then improve turnover frequency (TOF) of NOx reduction per Cu atom. The characterizations of the TEM and H2-N2O titration to catalysts reveal that the addition of Zn helps the dispersity of CuO on the surface of the support. The H2-TPR results further demonstrates that the added Zn species facilitate the reducibility of CuO species at low temperature. At last, in-situ growth of Cu-Zn-Al-LDHs on a practical ceramic filter for DeNOx reaction was first successfully carried out and the resulted catalytic filter showed a reasonably high DeNOx activity and strong bonding strength between catalyst and filter.

Graphical abstract

http://ift.tt/2wvFRd0

Volatilization and leaching behavior of heavy metals in MSW incineration fly ash in a DC arc plasma furnace

Publication date: 15 December 2017
Source:Fuel, Volume 210
Author(s): Wenchao Ma, Yunhao Fang, Dongmei Chen, Guanyi Chen, Yongxiang Xu, Hongzhi Sheng, Zhihua Zhou
Three fly ash samples collected from different waste incinerators were vitrified using a direct current arc plasma furnace at 1250–1400°C. The influence of water-wash extraction and wrapping pretreatment on the volatilization and leaching behavior of heavy metals was investigated. Results showed: After thermal arc plasma treatment, the volume reduction and weight loss of fly ash were in the range of 68.7–82.2% and 23.8–56.7%, respectively. The residual fractions (wt.%) of heavy metals in slag are in the following sequence: Cr<Ni<Cd<Pb<Cu<Zn. Water-washing could reduce the volatilization rate of heavy metals due to some volatile salts removed by washing, while wrapping of fly ash could most effectively resist heavy metals against volatilizing, especially for Zn and Ni. The possible CaO – Al2O3 – SiO2 (CAS) ratio for successful melting of fly ash is suggested to be CaO in range of 20–48%, Al2O3 in range of 10–15%, and SiO2 in range of 40–65%. Moreover, toxicity characteristic leaching procedure results showed that the leaching of heavy metals in slags was much lower than the standard limit of toxicity characteristic leaching procedure (TCLP).



http://ift.tt/2wvIJH2

Electrospun dual-layer mats with covalently bonded ZnO nanoparticles for moisture wicking and antibacterial textiles

Publication date: 15 November 2017
Source:Materials & Design, Volume 134
Author(s): Yuliang Dong, Noreen L. Thomas, Xuehong Lu
The fast growing demand for advanced sportswear suitable for tropical countries has led to research on fabrics with both moisture wicking and anti-bacterial properties. In this work, to improve the water transport behaviour, dual-layer nanofibrous nonwoven mats composed of a hydrophilic polyacrylonitrile (PAN) outer layer and a hydrophobic poly(vinylidene fluoride) (PVDF) inner layer are fabricated by electrospinning. The distinct difference in surface hydrophobicity between the inner and outer layers induces a push-pull effect to transport water from the inner to the outer surface efficiently. To render an antibacterial property, zinc oxide (ZnO) nanoparticles are covalently attached to the PVDF nanofibers. The good anti-wash properties and anti-bacterial function of the ZnO-PDVF/PAN dual layer mats are demonstrated.

Graphical abstract

http://ift.tt/2wvFxek

Title: A novel stereotaxic system for implanting a curved lead to two intracranial targets with high accuracy

Publication date: Available online 20 August 2017
Source:Journal of Neuroscience Methods
Author(s): Chen-Yu Ding, Liang-Hong Yu, Yuan-Xiang Lin, Fan Chen, Wei-Xiong Wang, Zhang-Ya Lin, De-Zhi Kang
BackgroundThe multi-target deep brain stimulation (DBS) aimed at improving symptoms related to different nuclei is a promising research direction. However, to implant a single lead into multiple targets simultaneously is difficult with the current lead implantation method.New MethodWe proposed a novel stereotaxic system used for implanting a curved lead to any two targets of the brain, and used the theoretical "curved lead method". First, a customized novel stereotaxic system was fabricated, and a solid cranial model with six fixed internal targets was made; second, CT scan was performed to locate the fixed internal targets; third, five curved leads were implanted to five selected pairs of targets, each following the calculated parameters of "curved lead pathway" with the novel stereotaxic system, respectively. Finally, CT scans were performed again to determine the exact locations of the curved leads.ResultsThe five curved leads accurately passed through the five pairs of combined targets, respectively, and the average vector error of curved lead implantation was 0.70±0.24mm.Comparison with Existing Method(s): In most situations, performing a multiple-target DBS procedure with the current stereotaxic systems means increased number of implanted leads, increased incidence of operative complications, and increased medical costs. However, the novel stereotaxic system could guide a single lead to reach two selected targets of the brain with high accuracy.ConclusionsThe novel stereotaxic system enables curved lead implantation with high accuracy, and can be considered as a useful complement to the current stereotaxic system.



http://ift.tt/2v5a0MH

Combined treatment with fractional carbon dioxide laser, autologous platelet-rich plasma, and narrow band ultraviolet B for vitiligo in different body sites: A prospective, randomized comparative trial

Summary

Background

Multiple treatment options are introduced in treatment of vitiligo but the response is unsatisfactory.

Objective

In this prospective, randomized, comparative trial, we studied the effect of combined treatment with fractional carbon dioxide (CO₂) laser, platelet-rich plasma (PRP) injection, and narrowband ultraviolet B (NB-UVB) for stable nonsegmental vitiligo regarding repigmentation grade, patient's satisfaction, and side effects.

Methods

Eighty adult patients with localized nonsegmental vitiligo were enrolled in this study. The patients were randomly categorized to receive 4 lines of treatment; fractional CO₂ laser, PRP, combined fractional CO₂ laser and PRP, and combined fractional CO₂ laser and NB-UVB. The treatment period was 2 months. Patients were clinically evaluated 3 months after the last treatment. Outcome was evaluated by 5-point scale for repigmentation, 10-point visual analog scale for patient's satisfaction, and side effects.

Results

Laser and PRP group achieved the best results regarding repigmentation and patient's satisfaction. Sixty percent of the patients developed repigmentation >50% and 40% of patients developed repigmentation >75%. In laser and NB-UVB group, 5% developed repigmentation >75% and 25% developed repigmentation >50%. Only 10% of patients developed repigmentation >75% in laser group and only 20% of patients developed repigmentation >75% in PRP group.

Conclusions

Combination of fractional CO₂ laser with PRP injection is a promising treatment for vitiligo, followed by combination of fractional CO₂ laser with NB-UVB phototherapy. Both fractional CO₂ laser and PRP injection gave poor results if they received alone.

http://ift.tt/2wvEgE2

Gene therapy: Human genome editing in heart disease

http://ift.tt/2v592Ak

Human genetic variation and the gut microbiome in disease

Recent microbiome genome-wide association studies have identified numerous associations between human genetic variants and the gut microbiome. Here, the authors review how genetic variation in the host can alter the composition of the gut microbiome towards a disease state, with a focus on disorders of immunity and metabolism.

http://ift.tt/2wvBEWM

Cutaneous lupus erythematosus. Quality of life and related factors in a cohort of 260 patients of A Coruña, Spain

Abstract

Dermatological disease has a significant impact on quality of life (QoL). However, information is scarce for cutaneous lupus erythematosus (CLE) in this regard. Thus, the manifestation of and co-morbidities associated with CLE were assessed in the current study to determine factors predictive of QoL impairment. A descriptive cross-sectional study was performed on predominantly Caucasian patients with CLE, recruited at our institution between April 2013 and August 2016 (α = 0.050; precision ± 6.5%).

This article is protected by copyright. All rights reserved.

http://ift.tt/2ihwB6S

Comparison of pyoderma gangrenosum and hypertensive ischemic leg ulcer Martorell in a Swiss cohort

Abstract

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis presenting with painful and sterile skin ulcerations (1). Its aetiology remains largely unknown although an autoinflammatory background seems possible. Several comorbidities as well as triggering factors such as surgery, trauma or pharmacological therapies have been associated with the development of PG (2). Different topical and systemic treatments are recommended for PG, most commonly topical steroids or calcineurin inhibitors as well as systemic steroids, dapsone, infliximab and others, as well as by our group and others canakinumab and ustekinumab (3, 4).

This article is protected by copyright. All rights reserved.

http://ift.tt/2fXuFzK

The coexistence of psychiatric and gastrointestinal problems in children with restrictive eating in a nationwide Swedish twin study

Abstract

Background

Restrictive eating problems are rare in children but overrepresented in those with neurodevelopmental problems. Comorbidities decrease wellbeing in affected individuals but research in the area is relatively scarce. This study describes phenotypes, regarding psychiatric and gastrointestinal comorbidities, in children with restrictive eating problems.

Methods

A parental telephone interview was conducted in 9- or 12-year old twins (n = 19,130) in the Child and Adolescent Twin Study in Sweden. Cases of restrictive eating problems and comorbid problems were established using the Autism, Tics-AD/HD and other Comorbidities inventory, parental reports of comorbidity as well as data from a national patient register. In restrictive eating problem cases, presence of psychiatric and gastrointestinal comorbidity was mapped individually in probands and their co-twin. Two-tailed Mann–Whitney U tests were used to test differences in the mean number of coexisting disorders between boys and girls. Odds ratios were used to compare prevalence figures between individuals with or without restrictive eating problems, and Fisher exact test was used to establish significance.

Results

Prevalence of restrictive eating problems was 0.6% (concordant in 15% monozygotic and 3% of dizygotic twins). The presence of restrictive eating problems drastically increased odds of all psychiatric problems, especially autism spectrum disorder in both sexes (odds ratio = 11.9 in boys, odds ratio = 10.1 in girls), obsessive-compulsive disorder in boys (odds ratio = 11.6) and oppositional defiant disorder in girls (odds ratio = 9.22). Comorbid gastrointestinal problems, such as lactose intolerance (odds ratio = 4.43) and constipation (odds ratio = 2.91), were the most frequent in girls. Boy co-twins to a proband with restrictive eating problems generally had more psychiatric problems than girl co-twins and more girl co-twins had neither somatic nor any psychiatric problems at all.

Conclusions

In children with restrictive eating problems odds of all coexisting psychiatric problems and gastrointestinal problems are significantly increased. The study shows the importance of considering comorbidities in clinical assessment of children with restrictive eating problems.

http://ift.tt/2uWKKfL

Clinical Thyroidology for the Public – Highlighted Article

From Clinical Thyroidology for the Public: While it is clear that overt hypothyroidism in the mother during pregnancy can affect the baby's brain development or cause other problems with the pregnancy, it is not clear if subclinical hypothyroidism would have similar adverse effects. Read More….

We welcome your feedback and suggestions. Let us know what you want to see in this publication.

Feedback & Suggestions

The post Clinical Thyroidology for the Public – Highlighted Article appeared first on American Thyroid Association.

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RGD peptide-modified fluorescent gold nanoclusters as highly efficient tumor-targeted radiotherapy sensitizers

Publication date: November 2017
Source:Biomaterials, Volume 144
Author(s): Guohai Liang, Xudong Jin, Shuxu Zhang, Da Xing
Radiotherapy is a leading treatment approach of cancer therapy. While it is effective in killing tumor cells, it can also cause serious damage to surrounding normal tissue. Targeted radiotherapy with gold nanoparticle-based radiosensitizers is actively being investigated, and considered as a promising means to enhance the efficacy of radiotherapy against tumors under a relatively low and safe radiation dose. In this work, we report a green and one-step strategy to synthesize fluorescent gold nanoclusters by using a commercialized cyclic arginine-glycine-aspartic acid (c(RGDyC)) peptide as the template. The nanoclusters inherit special properties of both the Au core (red/NIR fluorescence emission and strong radiosensitizing effect) and c(RGDyC) shell (active cancer cell-targeting ability and good biocompatibility), and can be applied as fluorescent probes to stain αvβ3 integrin-positive cancer cells, as well as radiosensitizing agents to boost the killing efficacy of radiotherapy. Our data suggest that the as-designed gold nanoclusters have excellent biocompatibility, bright red/NIR fluorescence, active tumor targeting property, and strong radiosensitizing effect, making them highly promising towards potential clinical translation.



http://ift.tt/2x4ITCP

Overcoming resistance to cisplatin by inhibition of glutathione S-transferases (GSTs) with ethacraplatin micelles in vitro and in vivo

Publication date: November 2017
Source:Biomaterials, Volume 144
Author(s): Shuyi Li, Chan Li, Shubin Jin, Juan Liu, Xiangdong Xue, Ahmed Shaker Eltahan, Jiadong Sun, Jingjie Tan, Jinchen Dong, Xing-Jie Liang
Platinum-based DNA-adducting agents are used extensively in the clinic for cancer chemotherapy. However, the anti-tumor efficacy of these drugs is severely limited by cisplatin resistance, and this can lead to the failure of chemotherapy. One of cisplatin resistance mechanisms is associated with overexpression of glutathione S-transferases (GSTs), which would accelerate the deactivation of cisplatin and decrease its antitumor efficiency. Nanoscale micelles encapsulating ethacraplatin, a conjugate of cisplatin and ethacrynic acid (an effective GSTs inhibitor), can enhance the accumulation of active cisplatin in cancer cells by inhibiting the activity of GSTs and circumventing deactivation of cisplatin. In vitro and in vivo results provide strong evidence that GSTs inhibitor-modified cisplatin prodrug combined with nanoparticle encapsulation favor high effective platinum accumulation, significantly enhanced antitumor efficacy against cisplatin-resistant cancer and decreased system toxicity. It is believed that these ethacraplatin-loaded micelles have the ability of overcoming resistance of cancers toward cisplatin and will improve the prospects for chemotherapy of cisplatin-resistant cancers in the near future.

Graphical abstract

http://ift.tt/2vQWxv2

Metal–carbenicillin framework-based nanoantibiotics with enhanced penetration and highly efficient inhibition of MRSA

Publication date: November 2017
Source:Biomaterials, Volume 144
Author(s): Fei Duan, Xiaochen Feng, Yan Jin, Dawei Liu, Xinjian Yang, Guoqiang Zhou, Dandan Liu, Zhenhua Li, Xing-Jie Liang, Jinchao Zhang
The development of effective therapies to control methicillin-resistant Staphylococcus aureus (MRSA) infections is challenging because antibiotics can be degraded by the production of certain enzymes, for example, β-lactamases. Additionally, the antibiotics themselves fail to penetrate the full depth of biofilms formed from extracellular polymers. Nanoparticle-based carriers can deliver antibiotics with better biofilm penetration, thus combating bacterial resistance. In this study, we describe a general approach for the construction of β-lactam antibiotics and β-lactamase inhibitors co-delivery of nanoantibiotics based on metal–carbenicillin framework-coated mesoporous silica nanoparticles (MSN) to overcome MRSA. Carbenicillin, a β-lactam antibiotic, was used as an organic ligand that coordinates with Fe³⁺ to form a metal–carbenicillin framework to block the pores of the MSN. Furthermore, these β-lactamase inhibitor-loaded nanoantibiotics were stable under physiological conditions and could synchronously release antibiotic molecules and inhibitors at the bacterial infection site to achieve a better elimination of antibiotic resistant bacterial strains and biofilms. We confirmed that these β-lactamase inhibitor-loaded nanoantibiotics had better penetration depth into biofilms and an obvious effect on the inhibition of MRSA both in vitro and in vivo.



http://ift.tt/2vQKaPl

If Cellular Blue Melanocytic Lesions Do Not Form a Spectrum…

No abstract available

http://ift.tt/2vV5B0e

Inespecific Macules in Legs: Challenge

No abstract available

http://ift.tt/2vVqgBn

Anogenital Mammary-Like Glands: A Study of Their Normal Histology With Emphasis on Glandular Depth, Presence of Columnar Epithelial Cells, and Distribution of Elastic Fibers

Abstract: The normal histology of anogenital mammary-like glands (AGMLG) has been studied previously, but some aspects, including glandular depth, presence of columnar epithelium resembling columnar cell change/hyperplasia as defined in mammary pathology, and distribution of elastic fibers, have not been previously investigated. To address these issues, we studied 148 AGMLG identified in 133 paraffin blocks sampled from 64 vulvar wide excision or vulvectomy specimens (64 patients, various indications for surgery). The depth of AGMLG ranged from 0.64 to 3.9 mm. Epithelial columnar cell change was noted in 33.1% of all AGMLG, whereas columnar cell hyperplasia was detected in 10.1%. Occasionally, combinations of cuboidal epithelium and columnar cell change were seen within 1 histological section. Of 22 specimens stained for elastic fibers, in only 6 (27.3%) cases were elastic fibers found around glands. Periductal elastic fibers were demonstrated around 3 of the only 5 ducts, which were available for analysis in slides stained for elastic fibers. The depth of AGMLG should be taken into account when planning topical and surgical therapies for lesions derived or evolving from AGMLG. Alterations identical to columnar cell change may represent a normal variation of AGMLG.

http://ift.tt/2wf4s6j

Palisaded Neutrophilic and Granulomatous Dermatitis/Interstitial Granulomatous Dermatitis Overlap: A Striking Clinical and Histologic Presentation With “Burning Rope Sign” and Subsequent Mirror-Image Contralateral Recurrence

Abstract: Palisaded neutrophilic and granulomatous dermatitis and interstitial granulomatous dermatitis are uncommon granulomatous dermatoses that often arise in association with rheumatoid arthritis. These 2 entities have overlapping features and may exist on a spectrum. We report an intriguing case of a 53-year-old man with advanced rheumatoid arthritis who presented with a large indurated painful truncal plaque with a palpable cord in addition to a papulonodular eruption on his dorsal hands. Furthermore, our patient had a recurrence in a near-identical mirror-image pattern on the contralateral trunk. The constellation of clinical and histopathological findings in our patient further suggests that palisaded neutrophilic and granulomatous dermatitis and interstitial granulomatous dermatitis exist as overlapping disease entities on a continuum. In addition, we propose that recurrence of skin findings may be indicative of the severity of the underlying systemic disease process.

http://ift.tt/2wfnj18

Eccrine Duct Dilation as a Marker of Cicatricial Alopecia

Background: Eccrine duct dilation (EDD) and syringoma-like sweat duct proliferation have been described as reactive changes occurring in a variety of skin conditions. However, extensive evaluation of EDD in scalp biopsies performed for alopecia has not been performed. Methods: We retrospectively examined 129 cases of cicatricial alopecia (lichen planopilaris, central centrifugal cicatricial alopecia, and discoid lupus erythematosus) and 130 cases of noncicatricial alopecias (androgenetic alopecia, telogen effluvium, and alopecia areata) for the presence of EDD. Results: Overall, EDD occurred in 4% (5/130) of noncicatricial alopecia (2/43 of androgenetic alopecia, 0/15 of telogen effluvium, 3/72 of alopecia areata) and 35% (45/129) of cicatricial alopecia (10/31 of lichen planopilaris, 17/36 central centrifugal cicatricial alopecia, and 18/62 of discoid lupus erythematosus; P

http://ift.tt/2wfkRaZ

Prognostic Implication of Lymphovascular Invasion Detected by Double Immunostaining for D-40 and MITF1 in Primary Cutaneous Melanoma: Beware of MITF1 Specificity and Sensitivity in Unusual Melanoma Subtypes

No abstract available

http://ift.tt/2vVwlxm

Loss of E-cadherin as Part of a Migratory Phenotype in Melanoma Is Associated With Ulceration

Abstract: It has been suggested that embryogenic properties of migratory cells are reactivated during wound healing and metastasis in adults. This might explain the association between wound-induced inflammation and poor survival in patients with ulcerated melanoma. Linking inflammation with a migratory phenotype, we characterize the infiltration of innate inflammatory cells, loss of cell-to-cell adhesion (E-cadherin), factors associated with extracellular matrix degradation [matrix metalloproteinase-9 (MMP-9), and neutrophil elastase (NE)], and spindle-shaped cell morphology, between ulcerated (n = 179) and nonulcerated (n = 206) melanoma. In addition, the presence of "extravascular migratory metastasis" (angiotropism) and tumor-vessel density were evaluated as important factors for tumor cell dispersal in ulcerated melanoma. We showed a correlation between expression of the granulocyte marker cd66b+ and the expression of NE and MMP-9, reflecting activated neutrophils. Ulcerated melanoma correlated with a low global E-cadherin score (P = 0.041) and weak-spot score (P = 0.0004). Thus, 28% of the nonulcerated, 42% of the minimally/moderately ulcerated melanoma, and 53% of the excessively ulcerated melanoma presented low scores as opposed to a high E-cadherin score. In addition, the presence of ulceration was correlated with angiotropism (P

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Inespecific Macules in Legs: Answer

No abstract available

http://ift.tt/2vVwXTR

Broadening the Anatomic Landscape of Sclerosing Perineurioma: A Series of 5 Cases in Nonacral Sites

Abstract: Sclerosing perineurioma is a rare perineurioma variant thought to occur almost exclusively in digits and palms, predominantly in young adult men. It clinically presents as a solitary slow-growing nodule, sometimes associated with prior trauma. Since 01/01/2000, our institution has received 5 cases in consultation of sclerosing perineurioma presenting in atypical locations. Four of 5 patients were women. The median age at presentation was 45 years (range, 31–62 years). Sites included dorsal tongue, anterior neck, mid upper back, forearm, and proximal anterior thigh. Complete clinical histories were not available, although lesions were reported as subcentimeter nodules with at least 1 suspected to have formed after trauma. Histologically, all lesions were circumscribed to dermal/submucosal tumors. Some extended into subcutaneous fat. The neoplasms were composed of an admixture of bland spindled to epithelioid cells with uniform, wavy, thin-to-oval nuclei forming linear cords to whorled sheets in an extensively hyalinized stroma. Mitotic activity was inconspicuous. All tumors expressed epithelial membrane antigen and were negative for S100 protein. All cases stained for CD34 were positive (3/3). This series highlights a broader clinical presentation of sclerosing perineurioma than previously recognized. Acknowledgment of this anatomic variability should provide confidence to dermatopathologists faced with similar cases.

http://ift.tt/2vVkyzd

Occlusive Nonvasculitic Vasculopathy

Abstract: We review the most characteristic clinical and histopathologic findings of the cutaneous manifestations of the occlusive nonvasculitic vasculopathic disorders. Clinically, most of these conditions are characterized by retiform purpura. Histopathologic findings consist of occlusion of the vessel lumina with no vasculitis. Different disorders may produce nonvasculitic occlusive vasculopathy in cutaneous blood and lymphatic vessels, including embolization due to cholesterol and oxalate emboli, cutaneous intravascular metastasis from visceral malignancies, atrial myxomas, intravascular angiosarcoma, intralymphatic histiocytosis, intravascular lymphomas, endocarditis, crystal globulin vasculopathy, hypereosinophilic syndrome, and foreign material. Other times, the occlusive disorder is due to platelet pugging, including heparin necrosis, thrombocytosis secondary to myeloproliferative disorders, paroxysmal nocturnal hemoglobinuria, and thrombotic thrombocytopenic purpura. Occlusive vasculopathy may also appear in cold-related gelling agglutination, like that occurring in cryofibrinogenemia, cryoglobulinemia, cold agglutinin syndrome, and crystalglobulinemia. Microorganisms may also occlude the vessels lumina and this is especially frequent in ecthyma gangrenosum, opportunistic fungi as aspergillosis or fusariosis, Lucio phenomenon of lepromatous leprosy and disseminated strongyloidiasis. Systemic coagulopathies due to defects of C and S proteins, coumarin/warfarin-induced skin necrosis, disseminated intravascular coagulation, and antiphospholipid antibody/lupus anticoagulant syndrome may also result in occlusive nonvasculitic vasculopathy. Finally, vascular coagulopathies such as Sneddon syndrome, livedoid vasculopathy, and atrophic papulosis may also cause occlusion of the vessels of the dermis and/or subcutis. Histopathologic study of occlusive vasculopathic lesions is the first step to achieve an accurate diagnosis, and they should be correlated with clinical history, physical examination, and laboratory findings to reach a final diagnosis.

http://ift.tt/2vVqSqu

Cutaneous Collagenous Vasculopathy: Report of Two Cases Presenting as Disseminated Telangiectasias and Review of the Literature

Abstract: Cutaneous collagenous vasculopathy is a recently described idiopathic microangiopathy characterized by acquired diffuse cutaneous telangiectasias and specific histological features: dilated capillaries in the superficial dermis, with walls thickened by hyaline material containing collagen IV by immunohistochemistry. The authors describe 2 cases and review all cases reported in the literature to date, 34 cases including our own. Cases were mainly observed in women (sex ratio 0.41), median age 63.5 (16–85). Hypertension and diabetes seem more frequent in these patients than in the general population. Typical clinical presentation is fine hair telangiectasias appearing on the lower limbs and progressing toward the trunk and upper limbs, sparing the face. Facial and neck involvement are however reported. When faced with isolated acquired diffuse cutaneous telangiectasias, clinicians should perform a skin biopsy to rule out cutaneous collagenous vasculopathy.

http://ift.tt/2vVq6Kh

Subungual Pigmented Tumor With Onychodystrophy: Challenge

No abstract available

http://ift.tt/2vVq8ln

Mass Spectrometry Imaging Can Distinguish on a Proteomic Level Between Proliferative Nodules Within a Benign Congenital Nevus and Malignant Melanoma

Abstract: Histopathological interpretation of proliferative nodules occurring in association with congenital melanocytic nevi can be very challenging due to their similarities with congenital malignant melanoma and malignant melanoma arising in association with congenital nevi. We hereby report a diagnostically challenging case of congenital melanocytic nevus with proliferative nodules and ulcerations, which was originally misdiagnosed as congenital malignant melanoma. Subsequent histopathological examination in consultation by one of the authors (R.L.) and mass spectrometry imaging analysis rendered a diagnosis of congenital melanocytic nevus with proliferative nodules. In this case, mass spectrometry imaging, a novel method capable of distinguishing benign from malignant melanocytic lesions on a proteomic level, was instrumental in making the diagnosis of a benign nevus. We emphasize the importance of this method as an ancillary tool in the diagnosis of difficult melanocytic lesions.

http://ift.tt/2vVq84R

Periodic Acid-Schiff Stain in Circumscribed Hypokeratosis

No abstract available

http://ift.tt/2vVIqCW

Cutaneous Indeterminate Cell Histiocytosis of Donor Origin After Allogeneic Hematopoietic Stem-Cell Transplantation

Abstract: Allogeneic hematopoietic stem-cell transplantation and solid-organ transplantation are associated with an increased risk of secondary neoplasms. Indeterminate cell histiocytosis (ICH) is a rare disease composed of so-called indeterminate cells, an alleged cutaneous dendritic cell subset displaying histological and some ultrastructural and immunophenotypic features of Langerhans cells but lacking Birbeck granules. We report a case of cutaneous ICH occurring after allogeneic hematopoietic stem-cell transplantation for a myelodysplastic syndrome in a 56-year-old man. Microsatellite analysis demonstrated that the neoplastic cells were derived from the donor's hematopoietic system. This case broadens the spectrum of complications after stem-cell transplantation and demonstrates that cutaneous ICH in the setting of myelodysplastic syndromes may have a nonrelated origin to dysplastic myeloid cells.

http://ift.tt/2vV4TQI

Extensive Hyperkeratotic, Scaly Papules and Plaques in a 56-Year-Old Female: Answer

No abstract available

http://ift.tt/2wfiWTs

Metastatic Cutaneous Paraganglioma: A Case Report and Review of the Literature

Abstract: Paragangliomas are rare neoplasms that arise from chromaffin cells of the sympathetic and parasympathetic nervous system. These tumors are often cured by surgical resection but the risk for metastatic disease exists, particularly for extra-adrenal paragangliomas. The behavior of these tumors is unpredictable, and clinical and histopathological features associated with malignancy have not been determined. The most common sites of metastases include local and distant lymph nodes, bone, liver, and lung. Cutaneous metastases are exceedingly rare with only 2 reported cases, both of which presented on the scalp. Here we describe a 78-year-old woman with cutaneous metastatic paraganglioma presenting as a forehead nodule, which developed 15 years after her initial diagnosis of paraganglioma.

http://ift.tt/2wfpt0A

A Subungual Pigmented Tumor With Onychodystrophy: Answer

No abstract available

http://ift.tt/2vUNjfv

Extensive Hyperkeratotic Scaly Papules and Plaques in a 56-Year-Old Woman: Challenge

No abstract available

http://ift.tt/2vVkGin

Folliculotropic Metastatic Melanoma: A Case Report and Review of the Literature

Abstract: Folliculotropic metastasis of cutaneous melanoma is rare, with only 5 published case reports in the English language literature since it was first described in 2009. We report a 41-year-old man with a primary cutaneous melanoma of the right upper preauricular region with metastatic spread to the parotid gland and pulmonary lymph nodes. Excision of the primary lesion was performed and immunotherapy was initiated. Sixteen months later, the patient presented with 2 new lesions of the left forehead and left neck. Histopathological examination was consistent with folliculotropic dermal deposits of metastatic melanoma. Deeper sectioning into the blocks revealed only sparse perifollicular pigment deposition and rare dermal melanocytes—a potential diagnostic pitfall had this been seen in the initial sections. This case represents the sixth and youngest patient to date with folliculotropic metastatic melanoma. This entity often presents in patients with advanced disease, including increased Breslow thickness and/or multiple metastases to lymph nodes, internal organs, or both. The folliculotropic metastases tend to be small and are often multiple. The precise relationship between folliculotropic primary melanoma and folliculotropic metastasis is unclear. In one reported case and in our patient, the primary tumor was noted to have a "folliculocentric" pattern. Because of the latter finding, the differential diagnosis includes multiple primary folliculotropic melanomas. Thus, clinical correlation and knowledge concerning the evolution of disease in the patient are critical. This case highlights a rare and unusual pattern of metastatic melanoma and potential problems in differential diagnosis.

http://ift.tt/2vVhJ14

CT and MRI features of pseudoaneurysms of the mitral-aortic intervalvular fibrosa

Publication date: Available online 20 August 2017
Source:Clinical Imaging
Author(s): Low Choon Seng Shoen, Anil Attili, David Bach, Prachi Agarwal
ObjectiveTo describe the CT and MR features of pseudoaneurysms of the mitral-aortic intervalvular fibrosa (PMAIVF).Materials and methodsThis retrospective study included 9 patients with a diagnosis of PMAIVF who had CT or MRI within 3months of echocardiography. Echocardiography images were reviewed by a cardiologist and CT and MRI images were reviewed by two experienced cardiothoracic radiologists.ResultsRecognizable imaging features of PMAIVFs were communication with the Left ventricular outflow tract, location between the anterior leaflet of the mitral valve and the aortic valve, systolic expansion and diastolic collapse.ConclusionCT and MRI show characteristic appearances of PMAIVFs and are complementary to echocardiography.



http://ift.tt/2vfcTtC

Clinical Thyroidology High-Impact Articles

FREE ACCESS through September 1, 2017
Read Now:

Parathyroid Lesions Can Be Distinguished from Thyroid Lesions on FNA but May Require Ancillary Studies and Molecular Analysis
Stephanie A. Fish

Older Age and Advanced Disease Are Risk Factors for Complications after Thyroid Cancer Surgery
Masha J. Livhits, Michael W. Yeh 

The Merits of Ultrasound Screening for Familial Nonmedullary Thyroid Cancer Are Strongly Dependent on the Number of Affected Family Members
Charles H. Emerson 

¹⁸F-FDOPA-PET Is More Sensitive than F-18-FDG-PET in Persistent or Recurrent Medullary Thyroid Cancer
Martin Biermann

The post Clinical Thyroidology High-Impact Articles appeared first on American Thyroid Association.

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Keeping Residents in the Dark: Do Night-Float Rotations Provide a Valuable Educational Experience?

Publication date: Available online 18 August 2017
Source:Journal of Surgical Education
Author(s): Alessandra Landmann, Heidi Mahnken, Mara B. Antonoff, SuAnn White, Arpit Patel, Aaron M. Scifres, Jason S. Lees
ObjectiveTo qualify and characterize resident overnight activity.DesignA prospective 3-phase study was conducted of surgical residents with attention to activities performed on the overnight rotation: needs assessment, direct observation of activities, and feedback.SettingThis study was conducted at the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. This is both a tertiary referral center and the only American College of Surgeons (ACS) verified level 1 trauma center in the state.ParticipantsThis study included current surgical residents within the residency program.ResultsDuring the study period, 270 pages were individually recorded, with 60% of these pages defined as time-sensitive activities. In addition, most of the pages involved pressing patient-care issues irrespective of postgraduate year level. Analyses revealed that residents spend most of their time performing educational activities (62%).On feedback, residents reported overall satisfaction with the learning opportunities during night-shift (6.4/7.0) and indicated their perceptions of an adequate balance of service and education on night float (6.6/7.0). This correlates with our annual rotation assessment where residents identify night-float as an overall positive experience which provides educational benefit.ConclusionsWork-hour restrictions induce residency programs to adapt to new training models. Our results report a breakdown of resident activities while on night-float and demonstrate that overnight shifts continue to provide important educational opportunities during training.



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Surgical Practical Skills Learning Curriculum: Implementation and Interns' Confidence Perceptions

Publication date: Available online 19 August 2017
Source:Journal of Surgical Education
Author(s): Danilo Acosta, Manuel Castillo-Angeles, Alejandro Garces-Descovich, Ammara A. Watkins, Alok Gupta, Jonathan F. Critchlow, Tara S. Kent
ObjectiveTo provide an overview of the practical skills learning curriculum and assess its effects over time on the surgical interns' perceptions of their technical skills, patient management, administrative tasks, and knowledge.DesignAn 84-hour practical skills curriculum composed of didactic, simulation, and practical sessions was implemented during the 2015 to 2016 academic year for general surgery interns. Totally, 40% of the sessions were held during orientation, whereas the remainder sessions were held throughout the academic year. Interns' perceptions of their technical skills, administrative tasks, patient management, and knowledge were assessed by the practical skills curriculum residents' perception survey at various time points during their intern year (baseline, midpoint, and final). Interns were also asked to fill out an evaluation survey at the completion of each session to obtain feedback on the curriculum.SettingGeneral Surgery Residency program at a tertiary care academic institution.Participants20 General Surgery categorical and preliminary interns.ResultsSignificant differences were found over time in interns' perceptions on their technical skills, patient management, administrative tasks, and knowledge (p < 0.001 for all). The results were also statistically significant when accounting for a prior boot camp course in medical school, intern status (categorical or preliminary), and gender (p < 0.05 for all). Differences in interns' perceptions occurred both from baseline to midpoint, and from midpoint to final time point evaluations (p < 0.001 for all). Prior surgical boot camp in medical school status, intern status (categorical vs. preliminary), and gender did not differ in the interns' baseline perceptions of their technical skills, patient management, administrative tasks, and knowledge (p > 0.05 for all).ConclusionsImplementation of a Practical Skills Curriculum in surgical internships can improve interns' confidence perception on their technical skills, patient management skills, administrative tasks, and knowledge.



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From Symptom to Diagnosis – the Pre-Diagnostic Symptomatic Interval of Paediatric Central Nervous System Tumours in Austria

Publication date: Available online 18 August 2017
Source:Pediatric Neurology
Author(s): Amedeo A. Azizi, Kirsten Heßler, Ulrike Leiss, Chryssa Grylli, Monika Chocholous, Andreas Peyrl, Johannes Gojo, Irene Slavc
BackgroundChildren with central nervous system (CNS) tumours may present with a multitude of symptoms, ranging from elevated intracranial pressure (ICP) to focal neurologic deficit. In every-day practice, some signs may be misleading, thereby causing prolonged pre-diagnostic symptomatic intervals (PSI). PSI are longer for paediatric brain tumours than for other childhood malignancies. This study evaluated PSI, and parental and diagnostic intervals for paediatric patients with CNS tumours in Austria. It also considered socio-economic factors.ProcedurePatients ≤ 19 years of age treated at the Medical University of Vienna and diagnosed during the years 2008-2013 were included. Patients diagnosed incidentally or by screening were excluded.ResultsTwo hundred and twelve consecutive patients were included in the study. They reflected the expected spectrum of CNS tumours. Patients presented with a median of five symptoms at diagnosis, most frequently with signs of elevated ICP. The median PSI was 60 days (0 days – 7 years), the median parental interval 30 days (0 days – 6.7 years) and the median diagnostic interval 3 days (0 days – 6.5 years).In spinal tumours alone (n=7) median PSI was 70 days (10 days – 7 years), and 3/7 patients had a PSI longer than 320 days.Young age, higher tumour grade and ataxia were associated with shorter PSI. Localisation in the supratentorial midline, histology of craniopharyngioma and endocrine symptoms prolonged PSI. There was a clear trend for longer PSI in non-native speakers.ConclusionsResults are comparable to other industrialised countries. However, long delays in diagnosis of CNS tumours still occur, urging increased awareness.



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Inhibition of EGF-induced migration and invasion by sulfated polysaccharide of Sepiella maindroni ink via the suppression of EGFR/Akt/p38 MAPK/MMP-2 signaling pathway in KB cells

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Wenjie Jiang, Weilu Tian, Muhammad Ijaz, Fengshan Wang
SIP-SII, the sulfated Sepiella maindroni ink polysaccharide (SIP), has been manifested to possess anti-tumor and anti-metastasis activity in vivo and in vitro. In the present study, we evaluated its inhibitory effect on the epidermal growth factor (EGF)-induced migration and invasion of human epidermoid carcinoma cell (KB cell line) as well as the related signaling pathways. The results of MTT assay indicated that SIP-SII inhibited the proliferation of KB cells in a concentration and time dependent manner. Notably, the attenuation of cell growth by SIP-SII was enlarged in the presence of EGF. The wound healing assay and transwell invasion assay were used to evaluate the effect of SIP-SII on the EGF-induced migration and invasion of KB cells and the results showed that SIP-SII markedly attenuated the EGF-induced migration and invasion. Besides, the EGF-induced matrix metalloproteinase-2 (MMP-2) expression was also suppressed by SIP-SII. However, SIP-SII showed no significant inhibition of the EGF-induced matrix metalloproteinase-9 (MMP-9) expression. Further research revealed that SIP-SII decreased the EGF-induced phosphorylation of epidermal growth factor receptor (EGFR), Akt and p38, but no significant suppression on EGF-induced phosphorylation of extracellular signal-regulated kinase 1 and 2 (Erk1/2) and c-Jun N-terminal kinases (JNK) by SIP-SII treatment was observed. The involvement of EGFR/Akt/p38 pathway was confirmed by evidence that SIP-SII would enlarge the inhibitory effect of the specific signal pathway inhibitors. These results indicate that SIP-SII has the potential to be used as the inhibitor of tumor metastasis especially for cancers characterized by over-activation of EGF/EGFR signaling.



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Mid-radiotherapy PET/CT for prognostication and detection of early progression in patients with stage III non-small cell lung cancer

Publication date: Available online 19 August 2017
Source:Radiotherapy and Oncology
Author(s): Michael F. Gensheimer, Julian C. Hong, Christine Chang-Halpenny, Hui Zhu, Neville C.W. Eclov, Jacqueline To, James D. Murphy, Heather A. Wakelee, Joel W. Neal, Quynh-Thu Le, Wendy Y. Hara, Andrew Quon, Peter G. Maxim, Edward E. Graves, Michael R. Olson, Maximilian Diehn, Billy W. Loo
Background and purposePre- and mid-radiotherapy FDG-PET metrics have been proposed as biomarkers of recurrence and survival in patients treated for stage III non-small cell lung cancer. We evaluated these metrics in patients treated with definitive radiation therapy (RT). We also evaluated outcomes after progression on mid-radiotherapy PET/CT.Material and methodsSeventy-seven patients treated with RT with or without chemotherapy were included in this retrospective study. Primary tumor and involved nodes were delineated. PET metrics included metabolic tumor volume (MTV), total lesion glycolysis (TLG), and SUVmax. For mid-radiotherapy PET, both absolute value of these metrics and percentage decrease were analyzed. The influence of PET metrics on time to death, local recurrence, and regional/distant recurrence was assessed using Cox regression.Results91% of patients had concurrent chemotherapy. Median follow-up was 14months. None of the PET metrics were associated with overall survival. Several were positively associated with local recurrence: pre-radiotherapy MTV, and mid-radiotherapy MTV and TLG (p=0.03–0.05). Ratio of mid- to pre-treatment SUVmax was associated with regional/distant recurrence (p=0.02). 5/77 mid-radiotherapy scans showed early out-of-field progression. All of these patients died.ConclusionsSeveral PET metrics were associated with risk of recurrence. Progression on mid-radiotherapy PET/CT was a poor prognostic factor.



http://ift.tt/2vdIlbI

Assessment of an air pollution monitoring network to generate urban air pollution maps using Shannon information index, fuzzy overlay, and Dempster-Shafer theory, A case study: Tehran, Iran

Publication date: October 2017
Source:Atmospheric Environment, Volume 167
Author(s): Parham Pahlavani, Hossein Sheikhian, Behnaz Bigdeli
Air pollution assessment is an imperative part of megacities planning and control. Hence, a new comprehensive approach for air pollution monitoring and assessment was introduced in this research. It comprises of three main sections: optimizing the existing air pollutant monitoring network, locating new stations to complete the coverage of the existing network, and finally, generating an air pollution map. In the first section, Shannon information index was used to find less informative stations to be candidate for removal. Then, a methodology was proposed to determine the areas which are not sufficiently covered by the current network. These areas are candidates for establishing new monitoring stations. The current air pollution monitoring network of Tehran was used as a case study, where the air pollution issue has been worsened due to the huge population, considerable commuters' absorption and topographic barriers. In this regard, O3, NO, NO2, NOx, CO, PM10, and PM2.5 were considered as the main pollutants of Tehran. Optimization step concluded that all the 16 active monitoring stations should be preserved. Analysis showed that about 35% of the Tehran's area is not properly covered by monitoring stations and about 30% of the area needs additional stations. The winter period in Tehran always faces the most severe air pollution in the year. Hence, to produce the air pollution map of Tehran, three-month of winter measurements of the mentioned pollutants, repeated for five years in the same period, were selected and extended to the entire area using the kriging method. Experts specified the contribution of each pollutant in overall air pollution. Experts' rankings aggregated by a fuzzy-overlay process. Resulted maps characterized the study area with crucial air pollution situation. According to the maps, more than 45% of the city area faced high pollution in the study period, while only less than 10% of the area showed low pollution. This situation confirms the need for effective plans to mitigate the severity of the problem. In addition, an effort made to investigate the rationality of the acquired air pollution map respect to the urban, cultural, and environmental characteristics of Tehran, which also confirmed the results.



http://ift.tt/2uVqawb

The Mechanisms of T Cell Selection in the Thymus

Publication date: Available online 19 August 2017
Source:Trends in Immunology
Author(s): Hiroyuki Takaba, Hiroshi Takayanagi
T cells undergo positive and negative selection in the thymic cortex and medulla, respectively. A promiscuous expression of a wide array of self-antigens in the thymus is essential for the negative selection of self-reactive T cells and the establishment of central tolerance. Aire was originally thought to be the exclusive factor regulating the expression of tissue-restricted antigens, but Fezf2 recently emerged as a critical transcription factor in this regulatory activity. Fezf2 is selectively expressed in thymic medullary epithelial cells, regulates a large number of tissue-restricted antigens and suppresses the onset of autoimmune responses. Here, we discuss novel findings on the transcriptional mechanisms of tissue restricted-antigen expression in the medullary thymic epithelial cells and its effects on T cell selection.



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cGAS–STING and Cancer: Dichotomous Roles in Tumor Immunity and Development

Publication date: Available online 19 August 2017
Source:Trends in Immunology
Author(s): Kevin W. Ng, Erin A. Marshall, John C. Bell, Wan L. Lam
cGMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) sensing has emerged as a key regulator of innate immune responses to both exogenous and endogenous DNA. Recent studies reveal critical roles for this pathway in natural antitumor immunity across cancer types as well as in immune checkpoint blockade therapy. However, it is also clear that some tumors evade cGAS–STING-mediated immune responses, and immunomodulatory therapeutics are currently being explored to target this pathway. Finally, we also discuss recent observations that cGAS–STING-mediated inflammation may promote tumor initiation, growth, and metastasis in certain malignancies and how this may complicate the utility of this pathway in therapeutic development.



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Design, synthesis and biological evaluation of novel hydroxamic acid based histone deacetylase 6 selective inhibitors bearing phenylpyrazol scaffold as surface recognition motif

Publication date: Available online 19 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Jinyu Yang, Gaoliang Cheng, Qihao Xu, Shenglin Luan, Shuxiang Wang, Dan Liu, Linxiang Zhao
In recent years, inhibition of HDAC6 became a promising therapeutic strategy for the treatment of cancer and HDAC6 inhibitors were considered to be potent anti-cancer agents. In this work, celecoxib showed moderate degree of HDAC6 inhibition activity and selectivity in preliminary enzyme inhibition activity assay. A series of hydroxamic acid derivatives bearing phenylpyrazol moiety were designed and synthesized as HDAC6 inhibitors. Most compounds showed potent HDAC6 inhibition activity. 11i was the most selective compound against HDAC6 with IC50 values of 0.020 µM and selective factor of 101.1. Structure-activity relationship analysis indicated that locating the linker group at 1' of pyrazol gave the most selectivity. The most compounds 11i (GI50 = 3.63 μM) exhibited 6-fold more potent than vorinostat in HepG2 cells. Considering of the high selectivity against HDAC6 and anti-proliferation activity, such compounds have potential to be developed as anti-cancer agents.

Graphical abstract

http://ift.tt/2x34Z8W

Advances in macrocyclic peptide-based antibiotics

Publication date: Available online 19 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Anatol Luther, Christian Bisang, Daniel Obrecht
Macrocyclic peptide-based natural products have provided powerful new antibiotic drugs, drug candidates, and scaffolds for medicinal chemists as a source of inspiration to design novel antibiotics. While most of those natural products are active mainly against Gram-positive pathogens, novel macrocyclic peptide-based compounds have recently been described, which exhibit potent and specific activity against some of the most problematic Gram-negative ESKAPE pathogens. This mini-review gives an up-date on recent developments.

Graphical abstract

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Structural basis of the broad substrate tolerance of the antibody 7B9-catalyzed hydrolysis of p-nitrobenzyl esters

Publication date: Available online 19 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Naoki Miyamoto, Miho Yoshimura, Yuji Okubo, Kayo Suzuki-Nagata, Takeshi Tsumuraya, Nobutoshi Ito, Ikuo Fujii
Catalytic antibody 7B9, which was elicited against p-nitrobenzyl phosphonate transition-state analogue (TSA) 1, hydrolyzes a wide range of p-nitrobenzyl monoesters and thus shows broad substrate tolerance. To reveal the molecular basis of this substrate tolerance, the 7B9 Fab fragment complexed with p-nitrobenzyl ethylphosphonate 2 was crystallized and the three-dimensional structure was determined. The crystal structure showed that the strongly antigenic p-nitrobenzyl moiety occupied a relatively shallow antigen-combining site and therefore the alkyl moiety was located outside the pocket. These results support the observed broad substrate tolerance of 7B9 and help rationalize how 7B9 can catalyze various p-nitrobenzyl ester derivatives. The crystal structure also showed that three amino acid residues (Asn^H33, Ser^H95, and Arg^L96) were placed in key positions to form hydrogen bonds with the phosphonate oxygens of the transitions-state analogue. In addition, the role of these amino acid residues was examined by site-directed mutagenesis to alanine: all mutants (Asn^H33Ala, Ser^H95Ala, and Arg^L96Ala) showed no detectable catalytic activity. Coupling the findings from our structural studies with these mutagenesis results clarified the structural basis of the observed broad substrate tolerance of antibody 7B9-catalyzed hydrolyses. Our findings provide new strategies for the generation of catalytic antibodies that accept a broad range of substrates, aiding their practical application in synthetic organic chemistry.

Graphical abstract

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Interlaboratory variability of Ki67 staining in breast cancer

Publication date: October 2017
Source:European Journal of Cancer, Volume 84
Author(s): Cornelia M. Focke, Horst Bürger, Paul J. van Diest, Kai Finsterbusch, Doreen Gläser, Eberhard Korsching, Thomas Decker
BackgroundPostanalytic issues of Ki67 assessment in breast cancers like counting method standardisation and interrater bias have been subject of various studies, but little is known about analytic variability of Ki67 staining between pathology labs. Our aim was to study interlaboratory variability of Ki67 staining in breast cancer using tissue microarrays (TMAs) and central assessment to minimise preanalytic and postanalytic influences.MethodsThirty European pathology labs stained serial slides of a TMA set of breast cancer tissues with Ki67 according to their routine in-house protocol. The Ki67-labelling index (Ki67-LI) of 70 matched samples was centrally assessed by one observer who counted all cancer cells per sample. We then tested for differences between the labs in Ki67-LI medians by analysing variance on ranks and in proportions of tumours classified as luminal A after dichotomising oestrogen receptor–positive cancers into cancers showing low (<14%, luminal A) and high (≥14%, luminal B HER2 negative) Ki67-LI using Cochran's Q.ResultsSubstantial differences between the 30 labs were indicated for median Ki67-LI (0.65%–33.0%, p < 0.0001) and proportion of cancers classified as luminal A (17%–57%, p < 0.0001). The differences remained significant when labs using the same antibody (MIB-1, SP6, or 30-9) were analysed separately or labs without prior participation in external quality assurance programs were excluded (p < 0.0001, respectively).ConclusionSubstantial variability in Ki67 staining of breast cancer tissue was found between 30 routine pathology labs. Clinical use of the Ki67-LI for therapeutic decisions should be considered only fully aware of lab-specific reference values.



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Pro-inflammatory fatty acid profile and colorectal cancer risk: A Mendelian randomisation analysis

Publication date: October 2017
Source:European Journal of Cancer, Volume 84
Author(s): Sebastian May-Wilson, Amit Sud, Philip J. Law, Kimmo Palin, Sari Tuupanen, Alexandra Gylfe, Ulrika A. Hänninen, Tatiana Cajuso, Tomas Tanskanen, Johanna Kondelin, Eevi Kaasinen, Antti-Pekka Sarin, Johan G. Eriksson, Harri Rissanen, Paul Knekt, Eero Pukkala, Pekka Jousilahti, Veikko Salomaa, Samuli Ripatti, Aarno Palotie, Laura Renkonen-Sinisalo, Anna Lepistö, Jan Böhm, Jukka-Pekka Mecklin, Nada A. Al-Tassan, Claire Palles, Susan M. Farrington, Maria N. Timofeeva, Brian F. Meyer, Salma M. Wakil, Harry Campbell, Christopher G. Smith, Shelley Idziaszczyk, Timothy S. Maughan, David Fisher, Rachel Kerr, David Kerr, Michael N. Passarelli, Jane C. Figueiredo, Daniel D. Buchanan, Aung K. Win, John L. Hopper, Mark A. Jenkins, Noralane M. Lindor, Polly A. Newcomb, Steven Gallinger, David Conti, Fred Schumacher, Graham Casey, Lauri A. Aaltonen, Jeremy P. Cheadle, Ian P. Tomlinson, Malcolm G. Dunlop, Richard S. Houlston
BackgroundWhile dietary fat has been established as a risk factor for colorectal cancer (CRC), associations between fatty acids (FAs) and CRC have been inconsistent. Using Mendelian randomisation (MR), we sought to evaluate associations between polyunsaturated (PUFA), monounsaturated (MUFA) and saturated FAs (SFAs) and CRC risk.MethodsWe analysed genotype data on 9254 CRC cases and 18,386 controls of European ancestry. Externally weighted polygenic risk scores were generated and used to evaluate associations with CRC per one standard deviation increase in genetically defined plasma FA levels.ResultsRisk reduction was observed for oleic and palmitoleic MUFAs (OROA = 0.77, 95% CI: 0.65–0.92, P = 3.9 × 10⁻³; ORPOA = 0.36, 95% CI: 0.15–0.84, P = 0.018). PUFAs linoleic and arachidonic acid had negative and positive associations with CRC respectively (ORLA = 0.95, 95% CI: 0.93–0.98, P = 3.7 × 10⁻⁴; ORAA = 1.05, 95% CI: 1.02–1.07, P = 1.7 × 10⁻⁴). The SFA stearic acid was associated with increased CRC risk (ORSA = 1.17, 95% CI: 1.01–1.35, P = 0.041).ConclusionResults from our analysis are broadly consistent with a pro-inflammatory FA profile having a detrimental effect in terms of CRC risk.



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Health-related quality of life results from the PRODIGE 5/ACCORD 17 randomised trial of FOLFOX versus fluorouracil–cisplatin regimen in oesophageal cancer

Publication date: October 2017
Source:European Journal of Cancer, Volume 84
Author(s): C. Bascoul-Mollevi, S. Gourgou, M.-P. Galais, J.-L. Raoul, O. Bouché, J.-Y. Douillard, A. Adenis, P.-L. Etienne, B. Juzyna, L. Bedenne, T. Conroy
BackgroundA recent prospective randomised trial did not reveal significant differences in median progression-free survival between two chemoradiotherapy (CRT) regimens for inoperable non-metastatic oesophageal cancer patients. This secondary analysis aimed to describe the impact of CRT on health-related quality of life (HRQOL), physical functioning, dysphagia, fatigue and pain and to evaluate whether baseline HRQOL domains can predict overall survival.Patients and methodsA total of 267 patients were randomly assigned to receive with 50 Gy of radiotherapy in 25 fractions six cycles of FOLFOX or four cycles of fluorouracil and cisplatin on day 1. HRQOL was prospectively assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire version 3.0 with the oesophageal cancer module (QLQ-OES18).ResultsBoth groups showed high baseline compliance. Subsequently, compliance reduced to 41% at the 6-month follow-up. Baseline HRQOL scores showed no statistical differences between treatment arms. During treatment, both groups exhibited lower physical and social functioning and increased fatigue and dyspnoea, although dysphagia moderately improved in the fluorouracil–cisplatin arm only (p = 0.047).During follow-up, HRQOL scores revealed no significant differences between chemotherapy regimens. Linear mixed model exhibited a treatment-by-time interaction effect for dysphagia (p = 0.017) with a greater decrease in dysphagia in the fluorouracil–cisplatin group. Time until definitive deterioration analysis showed no significant differences in global HRQOL, functional or main symptom domains. However, time until definitive deterioration was significantly longer for the fluorouracil and cisplatin arm compared with FOLFOX for appetite loss (p = 0.002), QLQ-OES-18 pain (p = 0.008), trouble swallowing saliva (p = 0.011) and trouble talking (p = 0.020).ConclusionAnalyses of HRQOL scores revealed no statistically significant differences between patients with inoperable non-metastatic oesophageal cancer treated by FOLFOX versus those treated with a fluorouracil–cisplatin regimen as part of definitive CRT.



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Humanization of JAA-F11, a Highly Specific Anti-Thomsen-Friedenreich Pancarcinoma Antibody and In Vitro Efficacy Analysis

Publication date: September 2017
Source:Neoplasia, Volume 19, Issue 9
Author(s): Swetha Tati, John C. Fisk, Julia Abdullah, Loukia Karacosta, Taylor Chrisikos, Padraic Philbin, Susan Morey, Diala Ghazal, Fatma Zazala, Joseph Jessee, Sally Quataert, Stephen Koury, David Moreno, Jing Ying Eng, Vladislav V. Glinsky, Olga V. Glinskii, Muctarr Sesay, Anthony W. Gebhard, Karamveer Birthare, James R. Olson, Kate Rittenhouse-Olson
JAA-F11 is a highly specific mouse monoclonal to the Thomsen-Friedenreich Antigen (TF-Ag) which is an alpha-O-linked disaccharide antigen on the surface of ~80% of human carcinomas, including breast, lung, colon, bladder, ovarian, and prostate cancers, and is cryptic on normal cells. JAA-F11 has potential, when humanized, for cancer immunotherapy for multiple cancer types. Humanization of JAA-F11, was performed utilizing complementarity determining regions grafting on a homology framework. The objective herein is to test the specificity, affinity and biology efficacy of the humanized JAA-F11 (hJAA-F11). Using a 609 target glycan array, 2 hJAA-F11 constructs were shown to have excellent chemical specificity, binding only to TF-Ag alpha-linked structures and not to TF-Ag beta-linked structures. The relative affinity of these hJAA-F11 constructs for TF-Ag was improved over the mouse antibody, while T20 scoring predicted low clinical immunogenicity. The hJAA-F11 constructs produced antibody-dependent cellular cytotoxicity in breast and lung tumor lines shown to express TF-Ag by flow cytometry. Internalization of hJAA-F11 into cancer cells was also shown using a surface binding ELISA and confirmed by immunofluorescence microscopy. Both the naked hJAA-F11 and a maytansine-conjugated antibody (hJAA-F11-DM1) suppressed in vivo tumor progression in a human breast cancer xenograft model in SCID mice. Together, our results support the conclusion that the humanized antibody to the TF-Ag has potential as an adjunct therapy, either directly or as part of an antibody drug conjugate, to treat breast cancer, including triple negative breast cancer which currently has no targeted therapy, as well as lung cancer.



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Clinical and Genetic Features of 64 Young Male Paediatric Patients with Congenital Hypogonadotropic Hypogonadism (CHH)

Summary

Context

The diagnosis of congenital hypogonadotropic hypogonadism (CHH) in prepuberty has always been challenging. Here, we aimed at studying the clinical and genetic features of paediatric CHH, especially the phenotype of hypospadias and dual defects (patients showing hypothalamic and/or pituitary defects and testicular hypoplasia), so as to have a better understanding of CHH.

Design

The clinical and genetic features of CHH patients were analysed and the relationships between hypospadias, dual defects and genetics investigated.

Patients

Patients who visited Beijing Children's Hospital and were positively diagnosed with CHH.

Measurements

The collected data included sex hormones, MRI of the olfactory bulb, human chorionic gonadotropin (hCG) test and genetic testing. We analysed clinical features and genetic results, especially hypospadias and dual defects, and compared the stimulated testosterone (T) levels in patients with and without cryptorchidism.

Results

Sixty-four patients were positively diagnosed, and forty-seven (73.4%) had Kallmann Syndrome (KS). Four patients (6.3%) had hypospadias, including 2 KS. Micropenis combined with cryptorchidism was the most common phenotype (39%). Approximately 2/3 patients showed a poor response to hCG; 15 cases were diagnosed with dual defects, and there were no significant differences between those with and without cryptorchidism. Twenty-six cases in 51 patients (51%) were identified as having classical HH mutations, affecting 10 different genes, with oligogenic mutations in 5 cases (9.8%). The most common mutations were in PROKR2 (17.6%), FGFR1 (13.7%) and CHD7 (7.8%). The frequency of PROKR2 mutations was higher in dual HH when compared to other HH cases (6/15 vs 3/36, p=0.021).

Conclusions

Micropenis and/or cryptorchidism can serve as important signs for the diagnosis of HH in paediatrics and the coexistence of hypospadias, does not exclude the diagnosis of CHH, including KS or normosmic isolated HH (nIHH). <comment> Au: OK? Author: OK. Thank you!</comment>Testicular function may be impaired earlier than expected, and PROKR2 mutations need to be evaluated to identify presumed dual defects.

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Quartz crystal microbalance: Sensing cell-substrate adhesion and beyond

Publication date: 15 January 2018
Source:Biosensors and Bioelectronics, Volume 99
Author(s): Jennifer Y. Chen, Lynn S. Penn, Jun Xi
Cell adhesion is an essential aspect of cellular behavior. Finding innovative methods to probe the adhesion of cells in their native state can greatly advance the understanding of control and regulation of cellular behavior and their impact on human health. The quartz crystal microbalance (QCM) is a label-free, biosensing system that has, in the past fifty years, evolved from a simple acoustic based mass sensor to a powerful bioanalytical tool. Its unique capability of monitoring the cell-substrate interaction non-invasively in real time has led to the emergence of its applications in areas that are relevant to fundamental cell biology and medical research. This review is intended to provide readers an overview of the use of the QCM for examination of cell-substrate adhesion. It also describes how this innovative approach can be extended to the study of other aspects of cellular behavior, such as cell morphology, cell mechanics, cell motility, cell signaling, all of which can potentially be applied to medical diagnosis and/or pharmaceutical development. In this review a major emphasis is placed on informing readers about some of the most important practical aspects of the QCM-based cell study including data acquisition and analysis, the substrate surface manipulation, and cell manipulation.



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In vitro polyphenol effects on apoptosis: an update of literature data

Publication date: Available online 19 August 2017
Source:Seminars in Cancer Biology
Author(s): Valeria Curti, Arianna Di Lorenzo, Marco Dacrema, Jianbo Xiao, Sayed Mohammad Nabavi, Maria Daglia
Polyphenols are secondary plant metabolites which have been studied extensively for their health-promoting properties, and which could also exert pharmacological activities ranging from anti-inflammatory effects, to cytotoxic activity against cancer cells. The main mechanism for programmed cell death is represented by apoptosis, and its dysregulation is involved in the etiopathology of cancer. As such, substances able to induce apoptosis in cancer cells could be used as new anticancer agents. The aim of this paper is to review literature data on the apoptotic effects of polyphenols and the molecular mechanisms through which they induce these effects in cancer cells. In addition, a brief summary of the new delivery forms used to increase the bioavailability, and clinical impact of polyphenols is provided. The studies reported show that many polyphenol rich plant extracts, originating from food and herbal medicine, as well as isolated polyphenols administered individually or in combination, can regulate cell apoptosis primarily through intrinsic and extrinsic mechanisms of action in in vitro conditions. Due to these promising results, the use of polyphenols in the treatment of cancer should therefore be deeply investigated. In particular, because of the low number of clinical trials, further studies are required to evaluate the anticancer activity of polyphenols in in vivo conditions.



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Neural androgen receptor overexpression affects cell number in the spinal nucleus of the bulbocavernosus

Abstract

The spinal nucleus of the bulbocavernosus (SNB) is a sexually dimorphic neuromuscular system in which masculinization of cell number is thought to depend on perinatal androgen action in non-neural targets, but masculinization of cell size is thought to depend primarily on adult androgen action on SNB cells themselves. In order to test these hypotheses, we characterized the SNB of Cre/loxP transgenic mice that overexpress androgen receptor (AR) throughout the body (CMV-AR) or in neural tissue only (Nestin-AR). We additionally examined the effects of androgen manipulation in male mutants and wild type controls. We reproduced the expected sex differences in both motoneuron number and size, and the expected adult androgen dependence of SNB size. We found effects of genotype such that both Nestin-AR and CMV-AR have more SNB motoneurons than wildtype littermates, and that CMV-AR females have larger SNB motoneurons than Nes-AR or wild type females. These results raise the possibility that AR can act in neurons and/or glia to rescue SNB motoneurons, and on non-neural AR to increase SNB cell size.

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Review of anti-inflammatory, immune-modulatory and wound healing properties of molluscs

Publication date: Available online 19 August 2017
Source:Journal of Ethnopharmacology
Author(s): Tarek B. Ahmad, Lei Liu, Michael Kotiw, Kirsten Benkendorff
Ethnopharmacological relevanceThis review focuses on traditional and contemporary anti-inflammatory uses of mollusc–derived products summarising all the in vitro, in vivo and human clinical trials that have tested the anti-inflammatory activity of molluscan natural products. Inflammatory conditions, burns and wounds have been an ongoing concern for human health since the early era of civilisation. Many texts from ancient medicine have recorded the symptoms, signs and treatments for these conditions. Natural treatments are well-documented in traditional European medicine, Traditional Chinese Medicine (TCM), Siddha and ancient Mediterranean and African traditional medicine and include a surprisingly large number of molluscan species.Materials and methodsAn extensive review of the Materia Medica and scientific literature was undertaken using key word searches for "mollusc" and "anti-inflammatory" or "immunomodulatory" or "wound healing".ResultsMolluscs have been used in ethnomedicine by many traditional cultures to treat different aspects of inflammatory conditions. We found 104 different anti-inflammatory preparations from a variety of molluscan species, of which 70 were from the well-documented Traditional Chinese Medicine (TCM). This traditional use of molluscs has driven the testing for inflammatory activity in extracts from some species in the phylum Mollusca, with 20 in vitro studies, 40 in vivo animal studies and 14 human clinical trials performed to substantiate the anti-inflammatory and wound healing activity of molluscs. Some of these studies have led to the approval of mollusc-derived products to be used as over-the-counter (OTC) nutraceuticals, like Lyprinol® and Biolane™ from the New Zealand green lipped mussel Perna canaliculus.ConclusionNatural products provide important leads for the development of pharmaceuticals, including anti-inflammatory agents. Only a small proportion of the molluscan traditional medicines have been tested to confirm their anti-inflammatory activity and most screening studies have tested crude extracts from molluscs without any chemical characterisation. This highlights the need for further research to strategically identify the anti-inflammatory compounds in molluscan medicines to provide leads for novel anti-inflammatory drugs in the future.

Graphical abstract

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Evaluation of the aphrodisiac potential of a chemically characterized aqueous extract of Tamarindus indica pulp

Publication date: Available online 19 August 2017
Source:Journal of Ethnopharmacology
Author(s): Amita Rai, Snehashis Das, Mallikarjuna Rao Chamallamudi, Krishnadas Nandakumar, Raghavendra Shetty, Meghna Gill, Suhani Sumalatha, Raviraj Devkar, Karthik Gourishetti, Nitesh Kumar
Ethnopharmacological relevanceTamarindus indica is an ingredient in the traditional aphrodisiac formulations in Africa and India. It is also a widely used food ingredient in other tropical countries.Aim of the studyThe present study was aimed to evaluate the aphrodisiac potential and reproductive safety profile of aqueous extract of Tamarindus indica in male Wistar rats.Materials and MethodsThe aqueous extract was prepared by maceration of pulp followed by reduction of volume in rotavapor under heat followed by freeze drying. The prepared extract was characterized for contents of total phenol, flavonoid, and saponin. It was also subjected to phytoconstituent analysis using GCMS. Further, the extract was evaluated for acute toxicity study. The aphrodisiac and reproductive toxicity potential were evaluated in animals after grouping them in four with six animals each namely, normal control, standard (Sildenafil citrate, 4mg/kg p.o.) and extract of Tamarindus indica treated groups at two dose levels, 125 and 250mg/kg p.o. The study was conducted for 54 days with daily once dosing of extract and standard. Equal number of females was grouped without treatment for evaluation of parameters of sexual desire (mount frequency and intromission frequency) and parameters of sexual arousal (mount latency and intromission latency). These parameters were evaluated on day 14, 28, 42 and 54. Animals were sacrificed on day 54, testes were removed and studied for histopathological changes.ResultsThe extract showed 6.6mg gallic acid equivalent/g of total phenol, 2.3mg catechin equivalent/g of flavonoid and 11.6% saponin. Forty chemical constituents were identified by GCMS analysis. In acute toxicity study, the extract was found to be safe till 2000mg/kg p.o. Efficacy study showed significant (p<0.05) improvement in parameters of sexual desire (mount frequency and intromission frequency) and parameters of sexual arousal on all observed days except mount frequency for 125mg/kg on 42^nd day and intromission frequency for both doses of tamarind compared to normal control. Improvements in these parameters were comparable to the standard drug. Histopathology study and sperm count suggested an increase in sperm production without any sign of toxicity in testis. Sperm motility significantly (p<0.05) increased in the treatment groups that received extract at 250mg/kg compared to normal control.ConclusionAqueous extract of Tamarindus indica possessed aphrodisiac activity together with spermatogenic potential.

Graphical abstract

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Immunogenicity and safety of zoster vaccine live administered with quadrivalent influenza virus vaccine

Publication date: Available online 19 August 2017
Source:Vaccine
Author(s): Myron J. Levin, Ulrike K. Buchwald, Julie Gardner, Jason Martin, Jon E. Stek, Elizabeth Brown, Zoran Popmihajlov
ObjectivesRandomized, blinded, placebo-controlled trial to evaluate the safety and immunogenicity of ZOSTAVAX™ (ZV) administered concomitantly with quadrivalent inactivated influenza vaccine (IIV4) in adults≥50years of age (NCT02519855).MethodsOverall, 440 participants were randomized into the Concomitant Group (CG) and 442 into the Sequential Group (SG). The CG received ZV and IIV4 at separate injection sites on Day 1 and matching placebo at Week 4. The SG received placebo and IIV4 (2015–2016 influenza season) at separate injection sites on Day 1 and ZV at Week 4.Immunogenicity endpointsVaricella-zoster virus (VZV) antibody geometric mean titer (GMT) and geometric mean fold-rise (GMFR) from baseline to 4weeks postvaccination, measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and adjusted for age and prevaccination titer. Influenza strain-specific GMT at baseline and 4weeks postvaccination was measured by hemagglutination inhibition (HAI) assay.Safety endpointsInjection-site and systemic adverse experiences (AEs) within 28days following any vaccination and serious AEs throughout the study.ResultsThe adjusted VZV antibody GMT ratio (CG/SG) was 0.87 (95%CI: 0.80, 0.95), meeting the prespecified noninferiority criterion. The VZV antibody GMFR in the CG was 1.9 (95%CI: 1.76, 2.05), meeting the acceptability criterion. Influenza antibody GMT ratios for A/H1N1, A/H3N2, B/Yamagata and B/Victoria were 1.02 (95%CI: 0.88, 1.18), 1.10 (95%CI: 0.94, 1.29), 1.00 (95%CI: 0.88, 1.14), and 0.99 (95%CI: 0.87, 1.13), respectively. The frequency of vaccine-related injection-site and systemic AEs was comparable between groups. No vaccine-related serious AE was observed.ConclusionThe concomitant administration of ZV and IIV4 to adults≥50years of age induced VZV-specific and influenza-specific antibody responses that were comparable to those following administration of either vaccine alone, and was generally well tolerated.



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Vaccine hesitancy, refusal and access barriers: The need for clarity in terminology

Publication date: Available online 19 August 2017
Source:Vaccine
Author(s): Helen Bedford, Katie Attwell, Margie Danchin, Helen Marshall, Paul Corben, Julie Leask
Although vaccination uptake is high in most countries, pockets of sub-optimal coverage remain posing a threat to individual and population immunity. Increasingly, the term 'vaccine hesitancy' is being used by experts and commentators to explain sub-optimal vaccination coverage. We contend that using this term to explain all partial or non-immunisation risks generating solutions that are a poor match for the problem in a particular community or population. We propose more precision in the term 'vaccine hesitancy' is needed particularly since much under-vaccination arises from factors related to access or pragmatics. Only with clear terminology can we begin to understand where the problem lies, measure it accurately and develop appropriate interventions. This will ensure that our interventions have the best chance of success to make vaccines available to those who want them and in helping those who are uncertain about their vaccination decision.



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Hearts, minds, nudges and shoves: (How) can we mobilise communities for vaccination in a marketised society?

Publication date: Available online 19 August 2017
Source:Vaccine
Author(s): Katie Attwell, David T. Smith




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Zearalenone and alpha-zearalenol inhibit the synthesis and secretion of pig follicle stimulating hormone via the non-classical estrogen membrane receptor GPR30

Publication date: Available online 19 August 2017
Source:Molecular and Cellular Endocrinology
Author(s): Jing He, Chao Wei, Yueqin Li, Ying Liu, Yue Wang, Jirong Pan, Jiali Liu, Yingjie Wu, Sheng Cui
Zearalenone (ZEA) is one of the most popular endocrine-disrupting chemicals and is mainly produced by fungi of the genus Fusarium. The excessive intake of ZEA severely disrupts human and animal fertility by affecting the reproductive axis. However, most studies on the effects of ZEA and its metabolite α-zearalenol (α-ZOL) on reproductive systems have focused on gonads. Few studies have investigated the endocrine-disrupting effects of ZEA and α-ZOL on pituitary gonadotropins, including follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The present study was designed to investigate the effects of ZEA and α-ZOL on the synthesis and secretion of FSH and LH and related mechanisms in female pig pituitary. Our in vivo and in vitro results demonstrated that ZEA significantly inhibited the synthesis and secretion of FSH in the pig pituitary gland, but ZEA and α-ZOL had no effects on LH. Our study also showed that ZEA and α-ZOL decreased FSH synthesis and secretion through non-classical estrogen membrane receptor GPR30, which subsequently induced protein kinase cascades and the phosphorylation of PKC, ERK and p38MAPK signaling pathways in pig pituitary cells. Furthermore, our study showed that the LIM homeodomain transcription factor LHX3 was involved in the mechanisms of ZEA and α-ZOL actions on gonadotropes in the female pig pituitary. These findings elucidate the mechanisms behind the physiological alterations resulting from endocrine-disrupting chemicals and further show that the proposed key molecules of the α-ZOL signaling pathway could be potential pharmacological targets.



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Epigenetic dysregulation in adrenocortical carcinoma, a systematic review of the literature

Publication date: Available online 19 August 2017
Source:Molecular and Cellular Endocrinology
Author(s): P.K.C. Jonker, V.M. Meyer, S. Kruijff
Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with a poor prognosis. Diagnosis and treatment of this tumor remains challenging. The Weiss score, the current gold standard for the histopathological diagnosis of ACC, lacks diagnostic accuracy of borderline tumors (Weiss score 2 or 3) and is subject to inter observer variability. Furthermore, adjuvant and palliative systemic therapy have limited effect and no proven overall survival benefit. A better insight in the molecular background of ACC might identify markers that improve diagnostic accuracy, predict treatment response or even provide novel therapeutic targets. This systematic review of the literature aims to provide an overview of alterations in DNA methylation, histone modifications and their potential clinical relevance in ACC.



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Examining Bias in Studies of Statin Treatment and Survival in Cancer Patients

This SEER-Medicare database study of patients with colorectal, breast, prostate, or bladder cancer compares mortality between those who began therapy with statins within 6 months after cancer diagnosis and those who did not by emulating a trial free of selection bias.

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Urinary biomarkers in prostate cancer detection and monitoring progression

Publication date: Available online 19 August 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Duojia Wu, Jie Ni, Julia Beretov, Paul Cozzi, Mark Willcox, Valerie Wasinger, Bradley Walsh, Peter Graham, Yong Li
Prostate cancer (CaP) is the most common cancer in men and the second leading cause of cancer deaths in males in Australia. Although serum prostate-specific antigen (PSA) has been the most widely used biomarker in CaP detection for decades, PSA screening has limitations such as low specificity and potential association with over-diagnosis. Current biomarkers used in the clinic are not useful for the early detection of CaP, or monitoring its progression, and have limited value in predicting response to treatment. Urine is an ideal body fluid for the detection of protein markers of CaP and is emerging as a potential source for biomarker discovery. Gene-based biomarkers in urine such as prostate cancer antigen-3 (PCA3), and genes for transmembrane protease serine-2 (TMPRSS2), and glutathione S-transferase P (GSTP1) have been developed and evaluated in the past decades. Among these biomarkers, urinary PCA3 is the only one approved by the FDA in the USA for clinical use. The study of urine microRNAs (miRNAs) is another burgeoning area for investigating biomarkers to achieve a pre-biopsy prediction of CaP to contribute to early detection. The development of mass spectrometry (MS)-based proteomic techniques has sparked new searches for novel protein markers for many diseases including CaP.Urinary biomarkers for CaP represent a promising alternative or an addition to traditional biomarkers. Future success in biomarker discovery will rely on collaboration between clinics and laboratories. In addition, research efforts need to be moved from biomarker discovery to validation in a large cohort or separate population and translation of these findings to clinical practice. In this review, we discuss urine as a potential source for CaP biomarker discovery, summarise important genetic urine biomarkers in CaP and focus on MS-based proteomic approaches as well as other recent developments in quantitative techniques for CaP urine biomarker discovery.



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Normalizing shoulder EMG: an optimal set of maximum isometric voluntary contraction tests considering reproducibility

Publication date: Available online 18 August 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Cédric Schwartz, François Tubez, François-Charles Wang, Jean-Louis Croisier, Olivier Brüls, Vincent Denoël, Bénédicte Forthomme
Normalization of the electromyography (EMG) signal is often performed relatively to maximal voluntary activations (MVA) obtained during maximum isometric voluntary contraction (MVIC). The first aim was to provide an inter-session reproducible protocol to normalize the signal of eight shoulder muscles. The protocol should also lead to a level of activation >90% of MVA for >90% of the volunteers. The second aim was to evaluate the influence of the method used to extract the MVA from the EMG envelope on the normalized EMG signal. Thirteen volunteers performed 12 MVICs twice (one week interval). Several time constants (100 ms to 2 s) were compared when extracting the MVA from the EMG envelope. The EMG activity was also acquired during an arm elevation. Our results show that a combination of nine MVIC tests was required to meet our requirements including reproducibility. Both the number of MVIC tests and the size of the time constant influence the normalized EMG signal during the dynamic activity (variations up to 15%). A time constant of 1 s was a good compromise to extract the MVA. These findings are valuable to improve the reproducibility of EMG signal normalization.



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Skin suturing and cortical surface viral infusion improves imaging of neuronal ensemble activity with head-mounted miniature microscopes

Publication date: Available online 19 August 2017
Source:Journal of Neuroscience Methods
Author(s): Xinjian Li, Vania Y. Cao, Wenyu Zhang, Surjeet S. Mastwal, Qing Liu, Stephani Otte, Kuan Hong Wang
BackgroundIn vivo optical imaging of neural activity provides important insights into brain functions at the single-cell level. Cranial windows and virally delivered calcium indicators are commonly used for imaging cortical activity through two-photon microscopes in head-fixed animals. Recently, head-mounted one-photon microscopes have been developed for freely behaving animals. However, minimizing tissue damage from the virus injection procedure and maintaining window clarity for imaging can be technically challenging.New methodWe used a wide-diameter glass pipette at the cortical surface for infusing the viral calcium reporter AAV-GCaMP6 into the cortex. After infusion, the scalp skin over the implanted optical window was sutured to facilitate postoperative recovery. The sutured scalp was removed approximately two weeks later and a miniature microscope was attached above the window to image neuronal activity in freely moving mice.ResultsWe found that cortical surface virus infusion efficiently labeled neurons in superficial layers, and scalp skin suturing helped to maintain the long-term clarity of optical windows. As a result, several hundred neurons could be recorded in freely moving animals.Comparison with existing methodsCompared to intracortical virus injection and open-scalp postoperative recovery, our methods minimized tissue damage and dura overgrowth underneath the optical window, and significantly increased the experimental success rate and the yield of identified neurons.ConclusionOur improved cranial surgery technique allows for high-yield calcium imaging of cortical neurons with head-mounted microscopes in freely behaving animals. This technique may be beneficial for other optical applications such as two-photon microscopy, multi-site imaging, and optogenetic modulation.



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Corrigendum to ‘A system to measure the pupil response to steady lights in freely behaving mice’ [J. Neurosci. Methods 273 (2016) 74–85]

Publication date: Available online 19 August 2017
Source:Journal of Neuroscience Methods
Author(s): Mark Bushnell, Yumiko Umino, Eduardo Solessio




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A high-sensitive nano-modified biosensor for dynamic monitoring of glutamate and neural spike covariation from rat cortex to hippocampal sub-regions

Publication date: Available online 19 August 2017
Source:Journal of Neuroscience Methods
Author(s): Guihua Xiao, Yilin Song, Song Zhang, Lili Yang, Shengwei Xu, Yu Zhang, Huiren Xu, Fei Gao, Ziyue Li, Xinxia Cai
BackgroundHippocampus is a critical part of brain tissue involved in many cognitive neural activities. They are controlled by various neurotransmitters such as glutamate (Glu), and affected by electrophysiology.New methodHerein, we fabricated a 16-site (25μm in diameter) microelectrode array (MEA) biosensor applied in dual-mode tests including Glu and neural spike measurements.MethodsAll the 16 recording sites were electrodeposited with platinum nanoparticles (PtNPs) and 8 sites were used for electrical recording. Glutamate oxidase enzyme (Gluox) and 1,3-Phenylenediamine (mPD) layer were specially modified on the other 8 sites for Glu recording. The dual-mode MEA was implanted from cortex to hippocampus of anesthetized rat to record Glu content and firing rate.ResultsThe electrical sites showed much lower impedance. The Glu sites showed much higher sensitivity(7.807 pA/μM), and ideal selectivity to the major molecules in brain. The post calibration sensitivity (3.935 pA/μM) maintained on a positive level. Different Glu content peaks including cortex (18.32μM) and hippocampal CA1 (4.39μM), CA3 (10.16μM), dentate gyrus (DG, two layers: 5.36μM and 10.34μM) have detected. The corresponded firing rate was recorded, too.Comparison with existingmethods This modification showed much lower impedance and much higher sensitivity. We obtained more neuron activities simultaneously by dual-mode recording. The covariation of Glu and neural spike signals was discovered in the specific hippocampus sub-region.ConclusionsThe covariation between Glu and firing rate changes were synchronous, and effected by regions. The dual-mode signals were useful to find the neurology disease mechanism.



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Covalent and non-covalent chemical engineering of actin for biotechnological applications

Publication date: Available online 19 August 2017
Source:Biotechnology Advances
Author(s): Saroj Kumar, Alf Mansson
The cytoskeletal filaments are self-assembled protein polymers with 8–25nm diameters and up to several tens of micrometres length. They have a range of pivotal roles in eukaryotic cells, including transportation of intracellular cargoes (primarily microtubules with dynein and kinesin motors) and cell motility (primarily actin and myosin) where muscle contraction is one example. For two decades, the cytoskeletal filaments and their associated motor systems have been explored for nanotechnological applications including miniaturized sensor systems and lab-on-a-chip devices. Several developments have also revolved around possible exploitation of the filaments alone without their motor partners. Efforts to use the cytoskeletal filaments for applications often require chemical or genetic engineering of the filaments such as specific conjugation with fluorophores, antibodies, oligonucleotides or various macromolecular complexes e.g. nanoparticles. Similar conjugation methods are also instrumental for a range of fundamental biophysical studies. Here we review methods for non-covalent and covalent chemical modifications of actin filaments with focus on critical advantages and challenges of different methods as well as critical steps in the conjugation procedures. We also review potential uses of the engineered actin filaments in nanotechnological applications and in some key fundamental studies of actin and myosin function. Finally, we consider possible future lines of investigation that may be addressed by applying chemical conjugation of actin in new ways.



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