Putative biomarkers for cervical cancer: SNVs, methylation and expression profiles

Publication date: Available online 30 June 2017
Source:Mutation Research/Reviews in Mutation Research
Author(s): Maria de Fátima Senra Cardoso, Carlos Henrique Madeiros Castelletti, José Luiz de Lima-Filho, Danyelly Bruneska Gondim Martins, José António Couto Teixeira
Cervical cancer is primarily caused by Human papillomavirus (HPV) infection, but other factors such as smoking habits, co-infections and genetic background, can also contribute to its development. Although this cancer is avoidable, it is the fourth most frequent type of cancer in females worldwide and can only be treated with chemotherapy and radical surgery. There is a need for biomarkers that will enable early diagnosis and targeted therapy for this type of cancer. Therefore, a systems biology pipeline was applied in order to identify potential biomarkers for cervical cancer, which show significant reports in three molecular aspects: DNA sequence variants, DNA methylation pattern and alterations in mRNA/protein expression levels. CDH1, CDKN2A, RB1 and TP53 genes were selected as putative biomarkers, being involved in metastasis, cell cycle regulation and tumour suppression. The other ten genes (CDH13, FHIT, PTEN, MLH1, TP73, CDKN1A, CACNA2D2, TERT, WIF1, APC) seemed to play a role in cervical cancer, but the lack of studies prevented their inclusion as possible biomarkers. Our results highlight the importance of these genes. However, further studies should be performed to elucidate the impact of DNA sequence variants and/or epigenetic deregulation and altered expression of these genes in cervical carcinogenesis and their potential as biomarkers for cervical cancer diagnosis and prognosis.



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Perioperative Retinal Artery Occlusion: Incidence and Risk Factors in Spinal Fusion Surgery From the US National Inpatient Sample 1998-2013.

Background: Retinal artery occlusion (RAO) is a rare but devastating complication of spinal fusion surgery. We aimed to determine its incidence and associated risk factors. Methods: Hospitalizations involving spinal fusion surgery were identified by searching the National Inpatient Sample, a database of hospital discharges, from 1998 to 2013. RAO cases were identified using ICD-9-CM codes. Using the STROBE guidelines, postulated risk factors were chosen based on literature review and identified using ICD-9-CM codes. Multivariate logistic models with RAO as outcome, and risk factors, race, age, admission, and surgery type evaluated associations. Results: Of an estimated 4,784,275 spine fusions in the United States from 1998 to 2013, there were 363 (CI: 291-460) instances of RAO (0.76/10,000 spine fusions, CI: 0.61-0.96). Incidence ranged from 0.35/10,000 (CI: 0.11-1.73) in 2001-2002 to 1.29 (CI: 0.85-2.08) in 2012-2013, with no significant trend over time (P = 0.39). Most strongly associated with RAO were stroke, unidentified type (odds ratio, OR: 14.33, CI: 4.54-45.28, P

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Intracranial Aneurysms of Neuro-Ophthalmologic Relevance.

Background: Intracranial saccular aneurysms are acquired lesions that often present with neuro-ophthalmologic symptoms and signs. Recent advances in neurosurgical techniques, endovascular treatments, and neurocritical care have improved the optimal management of symptomatic unruptured aneurysms, but whether the chosen treatment has an impact on neuro-ophthalmologic outcomes remains debated. Evidence Acquisition: A review of the literature focused on neuro-ophthalmic manifestations and treatment of intracranial aneurysms with specific relevance to neuro-ophthalmologic outcomes was conducted using Ovid MEDLINE and EMBASE databases. Cavernous sinus aneurysms were not included in this review. Results: Surgical clipping vs endovascular coiling for aneurysms causing third nerve palsies was compared in 13 retrospective studies representing 447 patients. Complete recovery was achieved in 78% of surgical patients compared with 44% of patients treated with endovascular coiling. However, the complication rate, hospital costs, and days spent in intensive care were reported as higher in surgically treated patients. Retrospective reviews of surgical clipping and endovascular coiling for all ocular motor nerve palsies (third, fourth, or sixth cranial nerves) revealed similar results of complete resolution in 76% and 49%, respectively. Improvement in visual deficits related to aneurysmal compression of the anterior visual pathways was also better among patients treated with clipping than with coiling. The time to treatment from onset of visual symptoms was a predictive factor of visual recovery in several studies. Few reports have specifically assessed the improvement of visual deficits after treatment with flow diverters. Conclusions: Decisions regarding the choice of therapy for intracranial aneurysms causing neuro-ophthalmologic signs ideally should be made at high-volume centers with access to both surgical and endovascular treatments. The status of the patient, location of the aneurysm, and experience of the treating physicians are important factors to consider. Although a higher rate of visual recovery was reported with neurosurgical clipping, this must be weighed against the potentially longer intensive care stays and increased early morbidity. (C) 2017 by North American Neuro-Ophthalmology Society

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History of Neuro-Ophthalmology in Argentina.

No abstract available

http://ift.tt/2u87bdC

Criterion-Referenced Fitness Standards Associated with Maintaining Functional Capacity in Chilean Older Adults

Rejuvenation Research , Vol. 0, No. 0.


http://ift.tt/2turvZl

Central Focused Convolutional Neural Networks: Developing a Data-driven Model for Lung Nodule Segmentation

Publication date: Available online 30 June 2017
Source:Medical Image Analysis
Author(s): Shuo Wang, Mu Zhou, Zaiyi Liu, Zhenyu Liu, Dongsheng Gu, Yali Zang, Di Dong, Olivier Gevaert, Jie Tian
Accurate lung nodule segmentation from computed tomography (CT) images is of great importance for image-driven lung cancer analysis. However, the heterogeneity of lung nodules and the presence of similar visual characteristics between nodules and their surroundings make it difficult for robust nodule segmentation. In this study, we propose a data-driven model, termed the Central Focused Convolutional Neural Networks (CF-CNN), to segment lung nodules from heterogeneous CT images. Our approach combines two key insights: 1) the proposed model captures a diverse set of nodule-sensitive features from both 3-D and 2-D CT images simultaneously; 2) when classifying an image voxel, the effects of its neighbor voxels can vary according to their spatial locations. We describe this phenomenon by proposing a novel central pooling layer retaining much information on voxel patch center, followed by a multi-scale patch learning strategy. Moreover, we design a weighted sampling to facilitate the model training, where training samples are selected according to their degree of segmentation difficulty. The proposed method has been extensively evaluated on the public LIDC dataset including 893 nodules and an independent dataset with 74 nodules from Guangdong General Hospital (GDGH). We showed that CF-CNN achieved superior segmentation performance with average dice scores of 82.15% and 80.02% for the two datasets respectively. Moreover, we compared our results with the inter-radiologists consistency on LIDC dataset, showing a difference in average dice score of only 1.98%.

Graphical abstract

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Inflammation and myeloproliferative neoplasms

Publication date: Available online 30 June 2017
Source:Journal of Autoimmunity
Author(s): Federico Lussana, Alessandro Rambaldi
Myeloproliferative neoplasms (MPN) include three main entities: Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Myelofibrosis (MF). MPN represent a unique model of the relationship between the clonal development of a hematologic malignancy and chronic inflammation. The neoplastic clone is the main driver of this inflammatory reaction as demonstrated by the curative effect of allogeneic stem cell transplantation which leads not only to a complete restore of the hematopoiesis, but also to regression of bone marrow fibrosis. The neoplastic clone and its differentiated progeny are also the main source of an indirect paracrine secretion of inflammatory cytokines released by different normal cells present within the tumor microenvironment. In the end, the cytokine storm within the bone marrow niche leads to fibrosis. In addition, chronic inflammation is responsible of the constitutional symptoms which negatively affect the quality of life of MPN patients and represents a major driver for the development of premature atherosclerosis and disease progression. Here we describe the available data about the link between MPN and chronic inflammation in animal models as well as in clinical studies. We also review the practical value of including acute phase inflammatory proteins such as high sensitivity C-reactive protein (hs-CRP) and pentraxin 3 (PTX-3) in prognostic stratification of MPN patients. Interestingly, the plasma levels of these proteins is often increase in MPN patients and this may be important when considering the well-established link between these two inflammatory proteins and the risk of both arterial and venous thrombosis. Although the available drugs are unable to eradicate the malignant clone, the ability to identify patient with a high inflammatory burden and an adverse molecular profile is important to advise therapy with ruxolitinib or even allogeneic stem cell transplantation that currently represents the only potentially curative option for these diseases.



http://ift.tt/2uu1hD4

Cold atmospheric plasma restores tamoxifen sensitivity in resistant MCF-7 breast cancer cell

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Seungyeon Lee, Hyunkyung Lee, Dawoon Jeong, Juyeon Ham, Sungbin Park, Eun Ha Choi, Sun Jung Kim
Cancer recurrence, which is frequently accompanied by chemotherapy, has been a challenge in cancer treatment. This study was carried out to examine the potential applications of the reactive oxygen species (ROS)-producing cold atmospheric plasma (CAP) to overcome the cancer cells' drug resistance, which has been emerging as an alternative therapeutic tool for cancer. For this, we developed a tamoxifen (Tam)-resistant MCF-7 (MCF-7/TamR) breast cancer cell model and examined the effect of CAP on the recovery of Tam sensitivity at the cellular and molecular level. The ROS level was increased 1.9-fold in CAP-treated MCF-7/TamR cells compared to the non-treated cell. CAP was proven to restore sensitivity by up to 50% for MCF-7/TamR cells against Tam after CAP treatment. The comparison of genome-wide expression between the acquisition of Tam resistance and CAP treatment identified 20 genes that commonly showed significant expression changes. Notably, all the genes except two have been oppositely dysregulated in the two cellular statuses, and the majority of them are known to contribute to the acquisition of Tam resistance. The protein expression of selected genes, MX1 and HOXC6, was recovered to that of their parental cell by CAP. Furthermore, the dysregulation of MX1 and HOXC6 in MCF-7/TamR alleviated the drug sensitivity recovery effect of CAP. Taken together, CAP inhibited the growth of Tam-resistant MCF-7 cancer cells and reset it to the Tam-sensitive status by restoring the expression of drug resistance–related genes. These findings may lend credence to CAP as an alternative or complementary tool in the treatment or prevention of Tam-resistant cancer.

Graphical abstract

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Neuronal nitric oxide synthase mediates insulin- and oxidative stress-induced glucose uptake in skeletal muscle myotubes

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Dean L. Kellogg, Karen M. McCammon, Kathryn S. Hinchee-Rodriguez, Martin L. Adamo, Linda J. Roman
Previously published studies strongly suggested that insulin- and exercise-induced skeletal muscle glucose uptake require nitric oxide (NO) production. However, the signal transduction mechanisms by which insulin and contraction regulated NO production and subsequent glucose transport are not known. In the present study, we utilized the myotube cell lines treated with insulin or hydrogen peroxide, the latter to mimic contraction-induced oxidative stress, to characterize these mechanisms. We found that insulin stimulation of neuronal nitric oxide synthase (nNOS) phosphorylation, NO production, and GLUT4 translocation were all significantly reduced by inhibition of either nNOS or Akt2. Hydrogen peroxide (H2O2) induced phosphorylation of nNOS at the same residue as did insulin, and also stimulated NO production and GLUT4 translocation. nNOS inhibition prevented H2O2-induced GLUT4 translocation. AMP activated protein kinase (AMPK) inhibition prevented H2O2 activation and phosphorylation of nNOS, leading to reduced NO production and significantly attenuated GLUT4 translocation. We conclude that nNOS phosphorylation and subsequently increased NO production are required for both insulin- and H2O2-stimulated glucose transport. Although the two stimuli result in phosphorylation of the same residue on nNOS, they do so through distinct protein kinases. Thus, insulin and H2O2-activated signaling pathways converge on nNOS, which is a common mediator of glucose uptake in both pathways. However, the fact that different kinases are utilized provides a basis for the use of exercise to activate glucose transport in the face of insulin resistance.

Graphical abstract

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Oxidative stress contributes to hepatocyte growth factor-dependent pro-senescence activity of ovarian cancer cells

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Justyna Mikuła-Pietrasik, Paweł Uruski, Martyna Pakuła, Konstantin Maksin, Sebastian Szubert, Aldona Woźniak, Eryk Naumowicz, Dariusz Szpurek, Andrzej Tykarski, Krzysztof Książek
The cancer-promoting activity of senescent peritoneal mesothelial cells (HPMCs) has already been well evidenced both in vitro and in vivo. Here we sought to determine if ovarian cancer cells may activate senescence in HPMCs. The study showed that conditioned medium (CM) from ovarian cancer cells (OVCAR-3, SKOV-3, A2780) inhibited growth and promoted the development of senescence phenotype (increased SA-β-Gal, γ-H2A.X, 53BP1, and decreased Cx43) in HPMCs. An analysis of tumors isolated from the peritoneum of patients with ovarian cancer revealed an abundance of senescent HPMCs in proximity to cancerous tissue. The presence of senescent HPMCs was incidental when fragments of peritoneum free from cancer were evaluated. An analysis of the cells' secretome followed by intervention studies with exogenous proteins and neutralizing antibodies revealed hepatocyte growth factor (HGF) as the mediator of the pro-senescence impact of the cancer cells. The activity of cancerous CM and HGF was associated with an induction of mitochondrial oxidative stress. Signaling pathways involved in the senescence of HPMCs elicited by the cancer-derived CM and HGF included p38 MAPK, AKT and NF-κB. HPMCs that senesced prematurely in response to the cancer-derived CM promoted adhesion of ovarian cancer cells, however this effect was effectively prevented by the cell protection against oxidative stress. Collectively, our findings indicate that ovarian cancer cells can elicit HGF-dependent senescence in HPMCs, which may contribute to the formation of a metastatic niche for these cells within the peritoneal cavity.

Graphical abstract

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Laser irradiation promotes the proliferation of mouse pre-osteoblast cell line MC3T3-E1 through hedgehog signaling pathway

Abstract

Low-level laser could promote osteoblast proliferation, and it has been applied in clinical practice to promote wound healing and tissue regeneration. However, the mechanism related to laser irradiation remains unclear. This study aimed to investigate the effects of low-level laser irradiation on the cell proliferation and the expressions of hedgehog signaling molecules Indian hedgehog (Ihh), Ptch, and Gli in vitro. In our present study, the MTT method was used to evaluate the effect on cell proliferation of laser irradiation on MC3T3-E1 cells. And cell cycle was examined by flow cytometry. Gene and protein expressions of hedgehog signaling molecules, including Ihh, Ptch, Smoothened (Smo), and Gli, were examined by qRT-PCR and western blot analysis. The results showed that laser irradiation at dosage of 3.75 J/cm² enhances the proliferation of MC3T3-E1 cells compared with control groups (p = 0.00). Moreover, laser irradiation (3.75 J/cm²) increased the cell amount at S phase (p = 0.00). In addition, the expressions of Ihh, Ptch, Smo, and Gli were significantly increased compared to the control during laser irradiation (3.75 J/cm²)-induced MC3T3-E1 osteoblast proliferation. After adding the hedgehog signaling inhibitor CY (cyclopamine), cell proliferation and Ihh, Ptch, Smo, and Gli expressions were inhibited (p = 0.00), and the cell amount at S phase was reduced compared with combination groups (p = 0.00). These results indicated that laser irradiation promotes proliferation of MC3T3-E1 cells through hedgehog signaling pathway. Our findings provide insights into the mechanistic link between laser irradiation-induced osteogenesis and hedgehog signaling pathway.

http://ift.tt/2sbnTHR

Effects of biotic and abiotic factors on the temporal dynamic of bat-fruit interactions

Publication date: August 2017
Source:Acta Oecologica, Volume 83
Author(s): Rafael de Souza Laurindo, Renato Gregorin, Davi Castro Tavares
Mutualistic interactions between animals and plants vary over time and space based on the abundance of fruits or animals and seasonality. Little is known about this temporal dynamic and the influence of biotic and abiotic factors on the structure of interaction networks. We evaluated changes in the structure of network interactions between bats and fruits in relation to variations in rainfall. Our results suggest that fruit abundance is the main variable responsible for temporal changes in network attributes, such as network size, connectance, and number of interactions. In the same way, temperature positively affected the abundance of fruits and bats. An increase in temperature and alterations in rainfall patterns, due to human induced climate change, can cause changes in phenological patterns and fruit production, with negative consequences to biodiversity maintenance, ecological interactions, and ecosystem functioning.



http://ift.tt/2sbhFYC

Evaluating the performance and intellectual structure of construction and demolition waste research during 2000–2016

Abstract

Construction and demolition (C&D) waste diminishes scarce land resources and endangers human health and the surrounding environment. Quantitative and visualized analysis was conducted to evaluate worldwide scientific research output on C&D waste from 2000 to 2016. The related information of 857 publications was collected from SCI-Expanded database and statistically analyzed. The number of documents about C&D waste presented a general growth during the last 17 years. Construction and Building Materials publication ranked first in the most productive journals. China and Spain acted as dominated roles comparing to other countries, and Hong Kong Polytechnic University was the institution with the largest amount of C&D waste research. Recycled aggregates, sustainable C&D waste management, and the rewarding program and commerce system were the hottest topics during 2000–2016 and in the near future according to the intellectual structure analysis.

http://ift.tt/2t1atkA

Occurrence, distribution, and risk assessment of antibiotics in the Songhua River in China

Abstract

The occurrence, distribution, and risk assessment of antibiotics in freshwater systems are receiving global attention, because of their impact on the environment and human health. However, few studies have focused on this topic in Northeast China and its Songhua River, the third-largest river in China. This study investigated the occurrence and distribution of 12 antibiotics, including three cephalosporins (cefazolin, cefmetazole, cefotaxime), three macrolides (azithromycin, clarithromycin, roxithromycin), three fluoroquinolones (ofloxacin, norfloxacin, flumequine), and three sulfonamides (sulfadiazine, sulfapyridine, sulfamethoxazole) in the mainstream and tributaries of the Songhua River. A total of 152 surface water samples were collected in January, May, July, and October 2016. These samples were analyzed using solid-phase extraction (SPE) and ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). The results indicated the wide use of all 12 antibiotics in the mainstream of the Songhua River. Sulfamethoxazole and cefazolin were the dominant antibiotics, with maximum concentrations of 73.1 and 65.4 ng L⁻¹, respectively. Other antibiotics were present at mean concentrations below 15 ng L⁻¹, except cefmetazole, present at a mean concentration of 35.6 ng L⁻¹. The spatial distribution of antibiotics showed that unbalanced regional development may lead to the distribution pattern of the antibiotics in the tributaries and the mainstream. Thus study also assessed the seasonal variation of antibiotics in urban surface water; cephalosporin, sulfonamide, fluoroquinolone, and macrolide concentrations were significantly higher during the icebound season than during non-icebound season. This may be due to the low temperature and water flow of the river in winter. Risk assessment showed that azithromycin, clarithromycin, roxithromycin, flumequine, and sulfamethoxazole posed a low or median risk to the aquatic organisms in the mainstream. The potential risks created by antibiotics to the aquatic environment should not be neglected in the Songhua River. The potential risks created by antibiotics to the aquatic environment should not be neglected in the Songhua River.

http://ift.tt/2swbiym

Phytoremediation of cadmium-polluted soil by Chlorophytum laxum combined with chitosan-immobilized cadmium-resistant bacteria

Abstract

This study examined the performance of the chitosan-immobilized cadmium-resistant bacteria Arthrobacter sp. and Micrococcus sp. on cadmium phytoremediation by Chlorophytum laxum in cadmium-polluted soil. These immobilized cadmium-resistant bacteria can survive in cadmium-contaminated soil and significantly increased soil cadmium solubility, but the ability of chitosan-immobilized cells to increase cadmium solubility was lower than that of free cells. A pot experiment demonstrated that chitosan-immobilized Micrococcus sp. promoted the growth of C. laxum planted in cadmium-contaminated soil. A significant increase in the cadmium concentration in the roots and aboveground parts of C. laxum was found in plants inoculated with free and chitosan-immobilized cells of these bacteria. The performance of Arthrobacter sp. free cells to augment cadmium accumulation in C. laxum was a little bit better than that of chitosan-immobilized Arthrobacter sp., except at 9 weeks after planting. The phytoextraction coefficient, bioaccumulation factor, and translocation factor of C. laxum inoculated with free and chitosan-immobilized cells of cadmium-resistant bacteria were higher than those of the uninoculated control and increased with time. Our findings suggest that chitosan-immobilized cells can be exploited to enhance the efficiency of cadmium phytoremediation by C. laxum.

http://ift.tt/2t0Kp94

Effects of low doses of glyphosate on DNA damage, cell proliferation and oxidative stress in the HepG2 cell line

Abstract

We studied the toxic effects of glyphosate in vitro on HepG2 cells exposed for 4 and 24 h to low glyphosate concentrations likely to be encountered in occupational and residential exposures [the acceptable daily intake (ADI; 0.5 μg/mL), residential exposure level (REL; 2.91 μg/mL) and occupational exposure level (OEL; 3.5 μg/mL)]. The assessments were performed using biomarkers of oxidative stress, CCK-8 colorimetric assay for cell proliferation, alkaline comet assay and cytokinesis-block micronucleus (CBMN) cytome assay. The results obtained indicated effects on cell proliferation, both at 4 and 24 h. The levels of primary DNA damage after 4-h exposure were lower in treated vs. control samples, but were not significantly changed after 24 h. Using the CBMN assay, we found a significantly higher number of MN and nuclear buds at ADI and REL after 4 h and a lower number of MN after 24 h. The obtained results revealed significant oxidative damage. Four-hour exposure resulted in significant decrease at ADI [lipid peroxidation and glutathione peroxidase (GSH-Px)] and OEL [lipid peroxidation and level of total antioxidant capacity (TAC)], and 24-h exposure in significant decrease at OEL (TAC and GSH-Px). No significant effects were observed for the level of reactive oxygen species (ROS) and glutathione (GSH) for both treatment, and for 24 h for lipid peroxidation. Taken together, the elevated levels of cytogenetic damage found by the CBMN assay and the mechanisms of primary DNA damage should be further clarified, considering that the comet assay results indicate possible cross-linking or DNA adduct formation.

http://ift.tt/2sw5EfG

Retrieval Practice Makes Procedure From Remembering: An Automatization Account of the Testing Effect.

Author: Racsmany, Mihaly; Szollosi, Agnes; Bencze, Dorottya

DOI: 10.1037/xlm0000423

Publication Date: POST AUTHOR CORRECTIONS, 29 June 2017

http://ift.tt/2sbyjXK

Can the First Letter Advantage Be Shaped by Script-Specific Characteristics?.

Author: Winskel, Heather; Ratitamkul, Theeraporn; Perea, Manuel

DOI: 10.1037/xlm0000434

Publication Date: POST AUTHOR CORRECTIONS, 29 June 2017

http://ift.tt/2tu8WEE

What Are the Costs of Degraded Parafoveal Previews During Silent Reading?.

Author: Vasilev, Martin R.; Slattery, Timothy J.; Kirkby, Julie A.; Angele, Bernhard

DOI: 10.1037/xlm0000433

Publication Date: POST AUTHOR CORRECTIONS, 29 June 2017

http://ift.tt/2sbwSsH

Attending Globally or Locally: Incidental Learning of Optimal Visual Attention Allocation.

Author: Beck, Melissa R.; Goldstein, Rebecca R.; van Lamsweerde, Amanda E.; Ericson, Justin M.

DOI: 10.1037/xlm0000428

Publication Date: POST AUTHOR CORRECTIONS, 29 June 2017

http://ift.tt/2tu8q9w

Primacy and Recency Effects for Taste.

Author: Daniel, Thomas A.; Katz, Jeffrey S.

DOI: 10.1037/xlm0000437

Publication Date: POST AUTHOR CORRECTIONS, 29 June 2017

http://ift.tt/2sbaEXJ

A new parameter for quantifying the variability of surface electromyographic signals during gait: the occurrence frequency

Publication date: Available online 30 June 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Francesco Di Nardo, Alessandro Mengarelli, Annachiara Strazza, Valentina Agostini, Marco Knaflitz, Laura Burattini, Sandro Fioretti
Natural variability of myoelectric activity during walking was recently analyzed considering hundreds of strides. This allowed assessing a parameter seldom considered in classic surface EMG (sEMG) studies: the occurrence frequency, defined as the frequency each muscle activation occurs with, quantified by the number of strides when a muscle is recruited with that specific activation modality. Aim of present study was to propose the occurrence frequency as a new parameter for assessing sEMG-signal variability during walking. Aim was addressed by processing sEMG signals acquired from Gastrocnemius Lateralis, Tibialis Anterior, Rectus Femoris and Biceps femoris in 40 healthy subjects in order to: 1) show that occurrence frequency is not correlated with ON/OFF instants (Rmean=0.11±0.07; P>0.05) and total time of activation (Rmean=0.15±0.08; P>0.05); 2) confirm the above results by two handy examples of application (analysis of gender and age) which highlighted that significant (P<0.05) gender-related and age-related differences within population were detected in occurrence frequency, but not in temporal sEMG parameters. In conclusion, present study demonstrated that occurrence frequency is able to provide further information, besides those supplied by classical temporal sEMG parameters and thus it is suitable to complement them in the evaluation of variability of myoelectric activity during walking.



http://ift.tt/2sbo6Le

Craniofacial features affecting mandibular asymmetries in skeletal Class II patients

Abstract

Objectives

The aim of this study was to evaluate the characteristics affecting different intensities of mandibular asymmetry in skeletal Class II adults using three-dimensional images. This study is clinically relevant since it allows professionals to evaluate the morphological components related to these deformities and more carefully obtain correct diagnosis and treatment plan for such patients.

Methods

Cone-beam computed tomography data of 120 Class II patients (40 with relative symmetry, 40 with moderate asymmetry, and 40 with severe asymmetry) were imported to SimPlant Ortho Pro^® 2.0 software (Dental Materialise, Leuven, Belgium). Three reference planes were established and linear measurements were performed from specific landmarks to these planes, comparing the deviated side and the contralateral side in each group, as well as the differences between groups. The correlation between midline mandibular asymmetry and other variables was also evaluated. Statistical analyses considered a significance level of 5%.

Results

Comparing the values obtained on the deviated side and on the contralateral side, there were significant differences for patients with moderate asymmetry and severe asymmetry. However, differences were seen more often in severe mandibular asymmetries. In those patients, there was a significant correlation of the gnathion deviation with lower dental midline deviation, difference in the lateral gonion positions, difference in the mandibular rami heights, and difference in the jugale vertical displacements.

Conclusions

For skeletal Class II patients with mandibular asymmetry, some craniofacial features are related to chin deviation and require proper evaluation, including the bilateral differences in the ramus height, mandibular body length, transverse and vertical positioning of the gonion and jugale points.

http://ift.tt/2utG4t5

Relevance of chromosomal band 11q13 in oral carcinogenesis: An update of current knowledge

Publication date: September 2017
Source:Oral Oncology, Volume 72
Author(s): Pablo Ramos-García, Isabel Ruiz-Ávila, José Antonio Gil-Montoya, Ángela Ayén, Lucía González-Ruiz, Francisco José Navarro-Triviño, Miguel Ángel González-Moles
An important event in oral carcinogenesis is the amplification of chromosomal band 11q13, in which numerous oncogenes and some tumor-suppressor genes are localized and frequently co-amplified during the malignant transformation of oral epithelium. The objectives of this study were to review published data on the involvement of 11q13 amplification in oral cancer, to provide an update on novel concepts and terminology related to gene amplification, and to explore the composition of the 11q13 amplicon in OSCC, including its most relevant amplicon cores and potential drivers. We report on the critical oncogenes and tumor-suppressor genes in 11q13 that may play a major role in oral cancer, focusing on their functions, on the characteristics acquired by their amplification, and on their clinicopathological implications. Finally, we discuss the possible usefulness of the 11q13 region as a therapeutic target in oral cancer.



http://ift.tt/2utCD5w

Craniofacial features affecting mandibular asymmetries in skeletal Class II patients

Abstract

Objectives

The aim of this study was to evaluate the characteristics affecting different intensities of mandibular asymmetry in skeletal Class II adults using three-dimensional images. This study is clinically relevant since it allows professionals to evaluate the morphological components related to these deformities and more carefully obtain correct diagnosis and treatment plan for such patients.

Methods

Cone-beam computed tomography data of 120 Class II patients (40 with relative symmetry, 40 with moderate asymmetry, and 40 with severe asymmetry) were imported to SimPlant Ortho Pro^® 2.0 software (Dental Materialise, Leuven, Belgium). Three reference planes were established and linear measurements were performed from specific landmarks to these planes, comparing the deviated side and the contralateral side in each group, as well as the differences between groups. The correlation between midline mandibular asymmetry and other variables was also evaluated. Statistical analyses considered a significance level of 5%.

Results

Comparing the values obtained on the deviated side and on the contralateral side, there were significant differences for patients with moderate asymmetry and severe asymmetry. However, differences were seen more often in severe mandibular asymmetries. In those patients, there was a significant correlation of the gnathion deviation with lower dental midline deviation, difference in the lateral gonion positions, difference in the mandibular rami heights, and difference in the jugale vertical displacements.

Conclusions

For skeletal Class II patients with mandibular asymmetry, some craniofacial features are related to chin deviation and require proper evaluation, including the bilateral differences in the ramus height, mandibular body length, transverse and vertical positioning of the gonion and jugale points.

http://ift.tt/2utG4t5

The selective cytotoxicity of new triazene compounds to human melanoma cells

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Ana Sousa, Fábio Santos, Maria Manuela Gaspar, Susana Calado, João D. Pereira, Eduarda Mendes, Ana Paula Francisco, Maria Jesus Perry
Metastatic melanoma still remains one the most difficult cancers to overcome. The aim of our research was the design of anti-tumour triazene compounds 3 for application to a melanoma-specific therapy. The strategy exploits the unique enzyme pathway of melanin biosynthesis for conversion of non-toxic prodrugs into toxic drugs in the melanoma cell. The compounds 3 were designed by coupling two active moieties, the alkylating triazenes and different tyrosinase substrates. All compounds 3 revealed to be chemically stable in isotonic phosphate buffer (PBS) at physiologic pH (t½≥48h), and most of them showed to be slowly hydrolysed in human plasma (1.5≤t½ (h)≤161). Compounds 3c–n revealed to be excellent tyrosinase substrates (0.74≤t½ (min)≤6) with the best tyrosinase substrate 3l releasing MMT 45s after tyrosinase activation. Structure-activity relationship studies allowed the identification of the better structural features for enzyme affinity. Furthermore, the derivatives 3l and 3m showed cell selectivity with significant cytotoxic effects (IC50 values of 46–65μM) against melanoma cell lines with tyrosinase overexpression MNT-1 and B16F10.

Graphical abstract

http://ift.tt/2ta03gJ

Synthesis and biological evaluation of JL-A7 derivatives as potent ABCB1 inhibitors

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Miaobo Pan, Jian Cui, Lei Jiao, Hesham Ghaleb, Chen Liao, Jiaqi Zhou, Mutta Kairuki, Haiyan Lin, Wenlong Huang, Hai Qian
Cancer chemotherapy failure is often due to the overexpression of ATP-binding cassette (ABC) transporters (particularly ABCB1), resulting in a variety of structurally and pharmacologically unrelated drugs efflux. The multidrug resistance (MDR) phenomenon could be reversed by ABCB1 inhibitors. Now, JL-A7 as the lead compound based on a triazol-N-ethyl-tetrahydroisoquinoline scaffold, 18 compounds were designed and synthesized. Substitution in para positions yielded high activities toward ABCB1. Moreover, compound 5 could effectively block the drug efflux function of ABCB1 and increase the accumulation of anti-cancer drugs to achieve effective treatment concentration in MDR cells.

Graphical abstract

http://ift.tt/2taqbZf

Editorial board

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15





http://ift.tt/2ta0Der

Ultrasound-dependent cytoplasmic internalization of a peptide-sonosensitizer conjugate

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Yuki Inaba, Kazunori Watanabe, Mizuki Kitamatsu, Eiji Nakata, Atsushi Harada, Takashi Ohtsuki
A method to induce cytoplasmic peptide delivery, using ultrasound, was demonstrated using a molecular conjugate of a cell-penetrating peptide (CPP), a functional peptide, and a sonosensitizer. As a model of such molecular conjugates, TatBim-RB, consisting of the Tat CPP, the Bim apoptosis inducing peptide, and the sonosensitizer rose bengal was synthesized. CPPs have been widely used for intracellular delivery of various cargos; however, CPP-fused molecules tend to become entrapped in endosomes, as was observed for TatBim-RB molecules applied to cells. To promote escape of the entrapped TatBim-RB molecules, cells were irradiated with ultrasound, which successfully induced endosomal escape and cytoplasmic dispersion of TatBim-RB, and subsequently apoptosis. Our results suggest that this peptide-sonosensitizer conjugate strategy may facilitate numerous kinds of medicinal chemistry studies, and furthermore, this specific conjugate may exhibit potential as a novel therapeutic agent for the promotion of apoptosis.

Graphical abstract

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Synthesis and biological activity of peptide proline-boronic acids as proteasome inhibitors

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Liqiang Han, Yanzhao Wen, Ridong Li, Bo Xu, Zemei Ge, Xin Wang, Tieming Cheng, Jingrong Cui, Runtao Li
On the basis of the application of proline-boronic acid as pharmacophore in the kinase inhibitors and our previous research results, using proline-boronic acid as warhead, two series of peptide proline-boronic acids, dipeptide proline-boronic acids (I) and tripeptide proline-boronic acids (II), were designed and synthesized. All the synthesized compounds were first evaluated for their biological activity against MGC803 cell, and then, the best compound II-7 was selected to test its anti-tumor spectrum on six human tumor cell lines and proteasome inhibition against three subunits. The results indicated that series II have much better biological activities than series I. The compound II-7 exhibited not only excellent biological activities with IC50 values of nM level in both cell and proteasome models, but also much better subunit selectivity. Thus, proline-boronic acid as warhead is reasonable in the design of proteasome inhibitors.

Graphical abstract

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Discovery of novel 5-oxa-2,6-diazaspiro[3.4]oct-6-ene derivatives as potent, selective, and orally available somatostatin receptor subtype 5 (SSTR5) antagonists for treatment of type 2 diabetes mellitus

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Hideki Hirose, Takeshi Yamasaki, Masaki Ogino, Ryo Mizojiri, Yumiko Tamura-Okano, Hiroaki Yashiro, Yo Muraki, Yoshihide Nakano, Jun Sugama, Akito Hata, Shinji Iwasaki, Masanori Watanabe, Tsuyoshi Maekawa, Shizuo Kasai
Somatostatin receptor subtype 5 (SSTR5) has emerged as a novel attractive drug target for type 2 diabetes mellitus. Starting from N-benzyl azetidine derivatives 1 and 2 as in-house hit compounds, we explored the introduction of a carboxyl group into the terminal benzene of 1 to enhance SSTR5 antagonistic activity by the combination of the substituents at the 3-position of the isoxazoline. Incorporation of a carboxyl group at the 4-position of the benzene ring resulted in a significant enhancement in potency, however, the 4-benzoic acid derivative 10c exhibited moderate human ether-a-go-go related gene (hERG) inhibitory activity. A subsequent optimization study revealed that replacement of the 4-benzoic acid with an isonipecotic acid dramatically reduced hERG inhibition (5.6% inhibition at 30μM) by eliminating π-related interaction with hERG K⁺ channel, which resulted in the identification of 1-(2-((2,6-diethoxy-4′-fluorobiphenyl-4-yl)methyl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)piperidin-4-carboxylic acid 25a (hSSTR5/mSSTR5 IC50=9.6/57nM). Oral administration of 25a in high-fat diet fed C57BL/6J mice augmented insulin secretion in a glucose-dependent manner and lowered blood glucose concentration.

Graphical abstract

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Discovery of novel quinazoline-2,4(1H,3H)-dione derivatives as potent PARP-2 selective inhibitors

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Hailong Zhao, Ming Ji, Guonan Cui, Jie Zhou, Fangfang Lai, Xiaoguang Chen, Bailing Xu
The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC50=467nM, PARP-2 IC50=11.5nM, selectivity PARP-1/PARP-2=40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program.

Graphical abstract

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Isolation, structure elucidation, and synthesis of antiplasmodial quinolones from Crinum firmifolium

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Christopher C. Presley, Yongle Du, Seema Dalal, Emilio F. Merino, Joshua H. Butler, Stéphan Rakotonandrasana, Vincent E. Rasamison, Maria B. Cassera, David G.I. Kingston
Antiplasmodial bioassay guided fractionation of a Madagascar collection of Crinum firmifolium led to the isolation of seven compounds. Five of the seven compounds were determined to be 2-alkylquinolin-4(1H)-ones with varying side chains. Compounds 1 and 4 were determined to be known compounds with reported antiplasmodial activities, while 5 was believed to be a new branched 2-alkylquinolin-4(1H)-one, however, it was isolated in limited quantities and in admixture and therefore was synthesized to confirm its structure as a new antiplasmodial compound. Along with 5, two other new and branched compounds 6 and 7 were synthesized as well. Accompanying the five quinolones were two known compounds 2 and 3 which are inactive against Plasmodium falciparum. The isolation, structure elucidation, total synthesis, and biological evaluation of these compounds are discussed in this article.

Graphical abstract

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Synthesis, antiviral evaluation and molecular docking studies of N4-aryl substituted/unsubstituted thiosemicarbazones derived from 1-indanones as potent anti-bovine viral diarrhea virus agents

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): María C. Soraires Santacruz, Matías Fabiani, Eliana F. Castro, Lucía V. Cavallaro, Liliana M. Finkielsztein
A series of N⁴-arylsubstituted thiosemicarbazones derived from 1-indanones and a set of compounds lacking such substitution in the N⁴ position of the thiosemicarbazone moiety were synthesized and evaluated for their anti-bovine viral diarrhea virus (BVDV) activity. Among these, derivatives 2 and 15 displayed high activity (EC50=2.7±0.4 and 0.7±0.1µM, respectively) as inhibitors of BVDV replication. Novel key structural features related to the anti-BVDV activity were identified by structure-activity relationship (SAR) analysis. In a previous study, the thiosemicarbazone of 5,6-dimethoxy-1-indanone (5,6-TSC) was characterized as a non-nucleoside inhibitor (NNI) of the BVDV RNA-dependent RNA polymerase. In the present work, cross-resistance assays were performed with the most active compounds. Such studies were carried out on 5,6-TSC resistant BVDV (BVDV-TSC^r T1) carrying mutations in the viral polymerase. This BVDV mutant was also resistant to compound 15. Molecular docking studies and MM/PBSA calculations were performed to assess the most active derivatives at the 5,6-TSC viral polymerase binding site. The differences in the interaction pattern and the binding affinity of derivative 15 either to the wild type or BVDV-TSC^r T1 polymerase were key factors to define the mode of action of this compound.

Graphical abstract

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Design, synthesis and tumor cell growth inhibitory activity of 3-nitro-2H-cheromene derivatives as histone deacetylaes inhibitors

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Shuai Tan, Feng He, Tingting Kong, Jingde Wu, Zhaopeng Liu
As a continuous research for the discovery of coumarin-based targeted anticancer agents, we designed and synthesized a series of novel histone deacetylases (HDAC) inhibitors using the 8-ethoxy-3-nitro-2H-chromene as the surface binding or cap group, linear dicarboxylic acid or ω-amino acid moiety with different length as the linking motif, ortho-aminoanilides, amides or α-aminoamides as the zinc binding group and the internal cavity motifs. Most of these 3-nitro-2H-chromene derivatives exhibited good growth inhibitory activity against K562, A549, MCF-7, PC3 and Hela cells and were more potent than the reference drug SAHA and MS-275. At the concentration of 10µM, the ortho-aminoanilide series and the d-Phe derived α-aminoamide derivatives 16a and 16b displayed more potent activity toward HADC1 over HADC2, and only moderate to weak activity over HADC6. In contrast, the amide ZBG analogues, 12a and 12b, 14 and 15, were only moderate HDAC6 inhibitors, but more selective over HDAC1 and HDAC2. The ortho-aminoanilides 9b, 9c, 10b, 10c, 11b, and the α-aminoamides 16a and 16b were potent HADC1 inhibitors with the IC50 values in the nanomolar ranges. The ortho-aminoanilides 10b and10c with a phenyl internal cavity motif were more potent than MS-275 as HADC1 inhibitors and more selective over HADC2.

Graphical abstract

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1,2,4-Triazole and 1,3,4-oxadiazole analogues: Synthesis, MO studies, in silico molecular docking studies, antimalarial as DHFR inhibitor and antimicrobial activities

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Sampark S. Thakkar, Parth Thakor, Hiren Doshi, Arabinda Ray
1,2,4-Triazole and 1,3,4-oxadiazole analogues are of interest due to their potential activity against microbial and malarial infections. In search of suitable antimicrobial and antimalarial compounds, we report here the synthesis, characterization and biological activities of 1,2,4-triazole and 1,3,4-oxadiazole analogues (SS 1-SS 10). The molecules were characterized by IR, mass, ¹H NMR, ¹³C NMR and elemental analysis. The in vitro antimicrobial activity was investigated against pathogenic strains, the results were explained with the help of DFT and PM6 molecular orbital calculations. In vitro cytotoxicity and genotoxicity of the molecules were studied against S. pombe cells. In vitro antimalarial activity was studied. The active compounds were further evaluated for enzyme inhibition efficacy against the receptor Pf-DHFR computationally as well as in vitro to prove their candidature as lead dihydrofolate reductase inhibitors.

Graphical abstract

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Synthesis, molecular modelling and CYP24A1 inhibitory activity of novel of (E)-N-(2-(1H-imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Ismail M. Taban, Jinge Zhu, Hector F. DeLuca, Claire Simons
CYP24A1 (25-hydroxyvitamin D-24-hydroxylase) is a useful enzyme target for a range of medical conditions including cancer, cardiovascular and autoimmune disease, which show elevated CYP24A1 levels and corresponding reduction of calcitriol (the biologically active form of vitamin D). A series of (E)-N-(2-(1H-imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides have been synthesised using an efficient synthetic route and shown to be potent inhibitors of CYP24A1 (IC50 0.11–0.35μM) compared with the standard ketoconazole. Molecular modelling using our CYP24A1 homology model showed the inhibitors to fill the hydrophobic binding site, forming key transition metal interaction between the imidazole nitrogen and the haem Fe³⁺ and multiple interactions with the active site amino acid residues.

Graphical abstract

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Synthesis, biological evaluation and molecular modeling of imidazo[1,2-a]pyridine derivatives as potent antitubulin agents

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Jin Liu, Daiying Zuo, Tongfei Jing, Ming Guo, Lingyun Xing, Wenyu Zhang, Jianwen Zhao, Jiwei Shen, Ping Gong, Dajun Zhang, Xin Zhai
Two series of novel 5,7-diarylimidazo[1,2-a]pyridine-8-carbonitrile derivatives (3a–3q and 7a–7n) were designed by modification of CA-4 pharmacophore to develop colchicine targeted antitubulin agents. All compounds were efficiently synthesized and evaluated for their cytotoxicity against five selected cancer cell lines (HT-29, H460, A549, MKN-45 and SMMC-7721) which got an insight in structure and activity relationships (SARs). Several molecules (7e, 7f, 7h–7j and 7m) were disclosed to exhibit promising antiproliferative activity with IC50 values in double-digit nanomolar degree. Optimization toward these compounds led to the discovery of a promising lead 7e, which showed noteworthy potency with IC50 value ranging from 0.01 to 3.2µM superior to CA-4 and Crolibulin. Importantly, immunofluorescence staining and colchcine competitive binding assay revealed that microtubule dynamics was disrupted by 7e by binding at the colchicine site of tubulin. Moreover, molecular docking studies suggested the binding of this mimic at colchcine-binding site is similar to Crolibulin, as was in conformity with the observed SARs for these compounds.

Graphical abstract

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Olaparib hydroxamic acid derivatives as dual PARP and HDAC inhibitors for cancer therapy

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Zigao Yuan, Shaopeng Chen, Qinsheng Sun, Ning Wang, Dan Li, Shuangshuang Miao, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang
Olaparib was the first PARP inhibitor approved by the FDA for patients with BRCA-mutated ovarian cancer. Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of olaparib and HDAC inhibitors. Herein, based on rational drug design strategy, hydroxamic acid derivatives of olaparib were constructed as dual PARP and HDAC inhibitors. These hybrid compounds showed potent inhibitory activities against PARP1/2 and HDAC1/6 with IC50 values in the nanomolar range. Furthermore, compound P1 exhibited broad-spectrum antiproliferative activities in selected human cancer cell lines. Specially, P1 showed more potent activity than olaparib and SAHA in cancer cells MDA-MB-231, HCC1937 and Raji, and 4.1-fold less cytotoxicity compared with SAHA to normal cells MCF-10A. Further mechanism study indicated that P1 could induce the cleavage of PARP and the hyperacetylation of histones, increase the expression of DNA damage biomarker γ-H2AX, decrease the level of BRCA1 and RAD51, and regulate tumor cell growth and apoptosis through modulating both mitochondrial- and death receptor-mediated pathways. Therefore, our study suggested that compounds targeting PARP and HDAC concurrently might be a practical approach for cancer therapy.

Graphical abstract

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Synthesis and pharmacological evaluation of glycine amide derivatives as novel vascular adhesion protein-1 inhibitors without CYP3A4 and CYP2C19 inhibition

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Susumu Yamaki, Yuji Koga, Akira Nagashima, Mitsuhiro Kondo, Yoshiaki Shimada, Keitaro Kadono, Ayako Moritomo, Kosei Yoshihara
Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted optimization studies of our lead compound 1, which we previously reported as a novel VAP-1 inhibitor, to enhance the inhibition of human VAP-1 and to reduce CYP3A4 and CYP2C19 inhibition. As a result, we identified 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (17h) as a novel orally active VAP-1 inhibitor, with 14-fold increased human VAP-1 inhibitory activity compared to 1, without CYP3A4 and CYP2C19 inhibition. Oral administration of 17h significantly inhibited the progression of proteinuria in streptozotocin (STZ) induced diabetic rats at 0.3 and 1mg/kg, suggesting that this compound has potential to be a therapeutic agent for the treatment of diabetic nephropathy.

Graphical abstract

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Design, synthesis, and evaluation of DNA topoisomerase II-targeted nucleosides

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Hironobu Matsumoto, Mitsuaki Yamashita, Teruyuki Tahara, Shinya Hayakawa, Shun-ichi Wada, Kiyoshi Tomioka, Akira Iida
We developed novel nucleoside-based topoisomerase II selective inhibitors and showed that small structural units, such as catechols, are essential for DNA topoisomerase II inhibitory activity. Moreover, nucleoside analogues containing TBS and 1,3-dithian moieties had potent and selective DNA topoisomerase II inhibitory activities. In further experiments, compound 25b having a beta configuration of the thymine moiety showed relatively strong growth inhibitory activity against cancer cell lines, and was more potent against all cancer cell lines than compound 26b, which carries a thymine moiety in the alpha configuration.

Graphical abstract

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Discovery of simplified leucyladenylate sulfamates as novel leucyl-tRNA synthetase (LRS)-targeted mammalian target of rapamycin complex 1 (mTORC1) inhibitors

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Suyoung Yoon, Jong Hyun Kim, Yura Koh, Phuong-Thao Tran, Jihyae Ann, Ina Yoon, Jayun Jang, Won Kyung Kim, Sangkook Lee, Jiyoun Lee, Sunghoon Kim, Jeewoo Lee
Leucyl-tRNA synthetase (LRS) has been reported to be a possible mediator of intracellular amino acids signaling to mTORC1. Given that mTORC1 is associated with cell proliferation and tumorigenesis, the LRS-mediated mTORC1 pathway may offer an alternative strategy in anticancer therapy. In this study, we developed a series of simplified analogues of leucyladenylate sulfamate (1) as LRS-targeted mTORC1 inhibitors. We replaced the adenylate group with a N-(3,4-dimethoxybenzyl)benzenesulfonamide (2a) or a N-(2-phenoxyethyl)benzenesulfonamide groups (2b) that can maintain specific binding, but has more favorable physicochemical properties such as reduced polarity and asymmetric centers. Among these simplified analogues, compound 16 and its constrained analogue 22 effectively inhibited S6K phosphorylation in a dose-dependent manner and exhibited cancer cell specific cytotoxicity against six different types of cancer cells. This result supports that LRS is a viable target for novel anticancer therapy.

Graphical abstract

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Discovery of novel somatostatin receptor subtype 5 (SSTR5) antagonists: Pharmacological studies and design to improve pharmacokinetic profiles and human Ether-a-go-go-related gene (hERG) inhibition

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Takeshi Yamasaki, Hideki Hirose, Tohru Yamashita, Nobuyuki Takakura, Sachie Morimoto, Takashi Nakahata, Asato Kina, Yoshihide Nakano, Yumiko Okano Tamura, Jun Sugama, Tomoyuki Odani, Yuji Shimizu, Shinji Iwasaki, Masanori Watanabe, Tsuyoshi Maekawa, Shizuo Kasai
Somatostatin (SST) is a peptide hormone comprising 14 or 28 amino acids that inhibits endocrine and exocrine secretion via five distinct G-protein-coupled receptors (SSTR1–5). SSTR5 has an important role in inhibiting the secretion of pancreatic and gastrointestinal hormones (e.g., insulin, GLP-1, PYY) through the binding of SSTs; hence, SSTR5 antagonists are expected to be novel anti-diabetic drugs. In the course of our lead generation program of SSTR5 antagonists, we have discovered a novel spiroazetidine derivative 3a. However, pharmacological evaluation of 3a revealed that it had to be administered at a high dose (100mg/kg) to show a persistent glucose-lowering effect in an oral glucose tolerance test (OGTT). We therefore initiated an optimization study based on 3a aimed at improving the antagonistic activity and mean residence time (MRT), resulting in the identification of 2-cyclopropyl-5-methoxybiphenyl derivative 3k. However, 3k did not show a sufficient persistent glucose-lowering effect in an OGTT; moreover, hERG inhibition was observed. Hence, further optimization study of the biphenyl moiety of compound 3k, focused on improving the pharmacokinetic (PK) profile and hERG inhibition, was conducted. Consequently, the introduction of a chlorine atom at the 6-position on the biphenyl moiety addressed a putative metabolic soft spot and increased the dihedral angle of the biphenyl moiety, leading to the discovery of 3p with an improved PK profile and hERG inhibition. Furthermore, 3p successfully exhibited a persistent glucose-lowering effect in an OGTT at a dose of 3mg/kg.

Graphical abstract

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Cyclic MOG35–55 ameliorates clinical and neuropathological features of experimental autoimmune encephalomyelitis

Publication date: 1 August 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 15
Author(s): Athanasios Lourbopoulos, George Deraos, Minos-Timotheos Matsoukas, Olga Touloumi, Aggeliki Giannakopoulou, Hubert Kalbacher, Nikolaos Grigoriadis, Vasso Apostolopoulos, John Matsoukas
EAE is induced to susceptible mice using linear peptides of myelin proteins of the central nervous system. Specific peptide motifs within the peptide-binding groove of the MHC peptide-complex determines the affinity of the peptide in each animal and the consequent T-cell receptor recognition and activation of the cell. Altered peptide ligand (APL) vaccination is a novel approach based on an effort to induce T-cell tolerance or alter cytokine profile from pro-inflammatory to anti-inflammatory. In the present study we synthesized the MOG35–55 peptide and altered its 3-dimensional conformation to make it a cyclic one (c-MOG35–55). EAE was induced in C57BL/6 mice and pathology was studied on acute and chronic phase of the disease. Our data indicates that c-MOG35–55 peptide alone induces a mild transient acute phase without chronic axonopathy. Administration of the c-MOG35–55 peptide at a 1:1 ratio during disease induction significantly ameliorates clinical disease and underlying pathology, such as demyelination and axonopathy in the acute and chronic phases. Binding and structural studies revealed milder interactions between the c-MOG35–55 and mouse or human MHC class II alleles (H2-IA^b and HLA-DR2). Collectively, we provide data supporting for the first time the concept that the cyclic modification of an established encephalitogenic peptide ameliorates the clinical outcomes and underlying pathological processes of EAE. Such a cyclic modification of linear peptides could provide a novel treatment approach for future, patient-selective, immunomodulative treatments of multiple sclerosis.

Graphical abstract

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Gene Therapy Approaches to Immunodeficiency

Publication date: Available online 29 June 2017
Source:Hematology/Oncology Clinics of North America
Author(s): Sujal Ghosh, H. Bobby Gaspar

Teaser

Transfer of gene-corrected autologous hematopoietic stem cells in patients with primary immunodeficiencies has emerged as a new therapeutic approach. Patients with various conditions lacking a suitable donor have been treated with retroviral vectors and a gene-addition strategy. Initial promising results were shadowed by the occurrence of malignancies in some of these patients. Current trials, developed in the last decade, use safer viral vectors to overcome the risk of genotoxicity and have led to improved clinical outcomes. This review reflects the progresses made in specific disorders, including adenosine deaminase deficiency, X-linked severe combined immunodeficiency, chronic granulomatous disease, and Wiskott-Aldrich syndrome.


http://ift.tt/2u8s4p1

Therapeutic Gene Editing Safety and Specificity

Publication date: Available online 29 June 2017
Source:Hematology/Oncology Clinics of North America
Author(s): Christopher T. Lux, Andrew M. Scharenberg

Teaser

Therapeutic gene editing is significant for medical advancement. Safety is intricately linked to the specificity of the editing tools used to cut at precise genomic targets. Improvements can be achieved by thoughtful design of nucleases and repair templates, analysis of off-target editing, and careful utilization of viral vectors. Advancements in DNA repair mechanisms and development of new generations of tools improve targeting of specific sequences while minimizing risks. It is important to plot a safe course for future clinical trials. This article reviews safety and specificity for therapeutic gene editing to spur dialogue and advancement.


http://ift.tt/2tyYhJh

CT-guided percutaneous radiofrequency ablation of osteoid osteoma: Our experience in 87 patients

Anurag Chahal, Prathiba Rajalakshmi, Shah A Khan, Shishir Rastogi, Deep N Srivastava, Shivanand Gamanagatti

Indian Journal of Radiology and Imaging 2017 27(2):207-215

Purpose: To evaluate the technical and clinical success of radiofrequency ablation of osteoid osteoma and analyze the factors responsible for clinical success. We also tried to investigate the role of follow-up computed tomography (CT) imaging. Materials and Methods: This is a prospective study approved by the institute's ethics committee involving 87 patients with appendicular osteoid osteoma. CT-guided radio frequency ablation was performed using a bipolar ablation system. Patients were followed up over 15.4 (4–24) months for pain, and clinical success/failure was determined using established criteria. Patients with clinical failure were taken for repeat ablation. Follow-up CT was obtained at 6 months and correlated with clinical success. Procedural scans were later reviewed for technical success in a blinded manner and correlated with clinical success along with other imaging and patient characteristics. Results: Mean pre-procedure visual analog scale (VAS) score was 7.0 ± 0.8. Primary success rate after single session was 86.2%(75/87 patients), and overall success rate after one/two sessions was 96.6%(84/87). No major complications were noted. Technical success rate was 89.7%(78/87). All 9 patients who had a suboptimal needle positioning had recurrence where as three patients had recurrence despite technical success. None of the imaging characteristics or history of prior intervention was significantly associated with clinical success. Follow-up CT showed advanced bone healing in 48 lesions, and was confined to the treatment success group. Alternately, minimal/absent bone healing was seen in all (12) patients of primary treatment failure and 27 patients with treatment success. Conclusions: CT-guided percutaneous radio frequency ablation is a safe and highly effective treatment for osteoid osteomas even in recurrent and residual cases. Technical success is the most important parameter affecting the outcome. Post radio frequency ablation CT findings have a good positive but a poor negative predictive value in prognostication.

http://ift.tt/2sqh1dK

Hard metal lung disease: Unexpected CT findings

P Sergio, M Ceruti, L Manotti, R Manuguerra, P Ceruti, A Dell'Osso

Indian Journal of Radiology and Imaging 2017 27(2):256-259



http://ift.tt/2taeGRu

Alteration in the number and integrity of white matter tracts in the preterm: A quantitative diffusion tensor imaging and diffusion fibre tractography in children

Ruma M Sreedharan, Subramonium Aiyappan, N Roy

Indian Journal of Radiology and Imaging 2017 27(2):119-124

Purpose: Periventricular white matter is most commonly injured in preterm babies with hypoxia. To assess white matter damage, we decided to perform diffusion tensor imaging (DTI) in preterm children with history of hypoxia and magnetic resonance imaging (MRI) features of periventricular leukomalacia (PVL) (PTH). We hypothesized that the PTH have reduced number of white matter fibres compared to age matched pre term children without hypoxia (PTHO), and also depending on the severity of PVL, there could be reduction in the number of fibres as well. Materials and Methods: The present study was carried out at the Government Medical College, Thiruvananthapuram. DTI was performed on 15 PTH and 15 PTHO. We measured number of fibres and fractional anisotropy of corpus callosum (CC) and optic radiations (OR). Results: There was significant difference between two groups with regard OR (P < 0.001).The mean number of OR fibres in cases and control was 104 ± 28.44 (mean ± SD) and 578 ± 286 (mean ± SD), respectively.The mean number of CC in cases was 953 ± 429 and in controls was 1625 ± 116 with a P value <0.56. No significant difference in FA was seen between cases and controls (P = 0.94). Conclusions: Preterm children with history of hypoxia and MRI features of PVL show reduced number of CC and OR compared to preterm children without hypoxia. There was significant correlation between PVL severity and number of OR fibres which could be due to the preferential involvement of periventricular white matter, in which OR has a major contribution.

http://ift.tt/2t9Cll6

Differentiation of secondary involvement of the breast by lymphoreticular malignancy from fibroadenoma using ultrasound elastography: A report of two cases

Eren Abdulkadir, Ertan Gulhan, Sila Ulus

Indian Journal of Radiology and Imaging 2017 27(2):237-240

Extramedullary lymphoma infiltration of the breast by lymphoblastic lymphoma is very rare and most cases are of B-cell lineage; T-cell neoplasms represent less than 10% of all breast lymphomas. Here, we report one patient with lymphoblastic lymphoma and one patient with leukemia, who have similar lesions in breasts with different ultrasound elastography findings. Ultrasound-guided tru-cut biopsies were performed and the first lesion was confirmed as lymphoma infiltration and the second as fibroadenoma. In cases of breast mass presence in patients with a history of hematologic malignancies such as lymphoma or leukemia, breast infiltration should be kept in mind. Elastography findings can assist in the differentiation of these lesions and further investigations or biopsies can be avoided.

http://ift.tt/2spVW3e

MRI features in dengue encephalitis: A case series in South Indian tertiary care hospital

Brijesh K Soni, Debasheesh S R Das, RA George, R Aggarwal, R Sivasankar

Indian Journal of Radiology and Imaging 2017 27(2):125-128

Dengue virus, a RNA virus of family Flaviviradae is considered non-neurotropic. Increasing studies and case reports reveal neurological manifestations of dengue virus. In our case series, we have evaluated magnetic resonance imaging (MRI) findings of 3 patients with dengue fever diagnosed by positive dengue NS1 antigen with neurological symptoms, which revealed nonspecific imaging features of dengue encephalitis in two cases and dengue meningoencephalitis in one case. Autopsy findings are also correlated in 2 patients who succumbed to their disease. This case series underlines the consideration of dengue encephalitis in patients of dengue fever with neurological symptoms and relevant imaging findings.

http://ift.tt/2t9Jvpb

Pelvic radiograph in skeletal dysplasias: An approach

Manisha Jana, Nikhil Nair, Arun K Gupta, Madhulika Kabra, Neerja Gupta

Indian Journal of Radiology and Imaging 2017 27(2):187-199

The bony pelvis is constituted by the ilium, ischium, pubis, and sacrum. The pelvic radiograph is an important component of the skeletal survey performed in suspected skeletal dysplasia. Most of the common skeletal dysplasias have either minor or major radiological abnormalities; hence, knowledge of the normal radiological appearance of bony pelvis is vital for recognizing the early signs of various skeletal dysplasias. This article discusses many common and some uncommon radiological findings on pelvic radiographs along with the specific dysplasia in which they are seen; common differential diagnostic considerations are also discussed.

http://ift.tt/2sqmrWe

Sequential MR imaging (with diffusion-weighted imaging) changes in metronidazole-induced encephalopathy

Rupinder Singh, Ramanjeet Kaur, Pawan Pokhariyal, Rajul Aggarwal

Indian Journal of Radiology and Imaging 2017 27(2):129-132

Metronidazole-induced neuro-toxicity, though rare, is known. A characteristic spatial distribution of lesions in cerebellar dentate nuclei and dorsal pons is known. However, temporal progression of lesions on magnetic resonance imaging (MRI) has not been described previously. We describe two such cases which presented initially with splenial hyperintesity and showed progression to characterstic lesions. Both cases improved with stoppage of metronidazole.

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Singular observation of a desirable change after bronchial artery embolization for hemoptysis in intracavitary aspergilloma

B P K Prasad, Brijesh Ray

Indian Journal of Radiology and Imaging 2017 27(2):225-228

Aspergillomas are fungal balls developing in pre-existing lung cavities, which are most commonly secondary to tuberculosis. Aspergillomas can cause hemoptysis due to erosion of the blood vessels in cavity walls, which can often be recurrent, massive, and life-threatening. Bronchial artery embolization is considered to be the treatment of choice for short-term control of hemoptysis, and lobectomy as the definitive treatment for aspergilloma. We present a unique observation in two cases of aspergilloma where the fungal balls disappeared radiologically after bronchial artery embolization performed for massive hemoptysis.

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Multimodality imaging spectrum of complications of horseshoe kidney

Hardik U Shah, Vijayanadh Ojili

Indian Journal of Radiology and Imaging 2017 27(2):133-140

Horseshoe kidney is the most common congenital renal fusion anomaly with an incidence of 1 in 400–600 individuals. The most common type is fusion at the lower poles seen in greater than 90% of the cases, with the rest depicting fusion at the upper poles, resulting in an inverted horseshoe kidney. Embryologically, there are two theories hypothesizing the genesis of horseshoe kidney – mechanical fusion theory and teratogenic event theory. As an entity, horseshoe kidney is an association of two anatomic anomalies, namely, ectopia and malrotation. It is also associated with other anomalies including vascular, calyceal, and ureteral anomalies. Horseshoe kidney is prone to a number of complications due to its abnormal position as well as due to associated vascular and ureteral anomalies. Complications associated with horseshoe kidney include pelviureteric junction obstruction, renal stones, infection, tumors, and trauma. It can also be associated with abnormalities of cardiovascular, central nervous, musculoskeletal and genitourinary systems, as well as chromosomal abnormalities. Conventional imaging modalities (plain films, intravenous urogram) as well as advanced cross-sectional imaging modalities (ultrasound, computed tomography, and magnetic resonance imaging) play an important role in the evaluation of horseshoe kidney. This article briefly describes the embryology and anatomy of the horseshoe kidney, enumerates appropriate imaging modalities used for its evaluation, and reviews cross-sectional imaging features of associated complications.

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IgG4-Related disease simulating paraneoplastic syndrome: Role of 18FDG PET/CT imaging

Madhuri S Mahajan, Sudeshna Maitra, Natasha Singh, Melvika Pereira

Indian Journal of Radiology and Imaging 2017 27(2):249-253

Immunoglobulin G4 (IgG4)-related systemic disease (IgG4-RSD) is a new systemic entity associated with autoimmune pancreatitis (AIP). Other organ involvements take the form of sclerosing cholangitis, sclerosing cholecystitis, sclerosing sialadenitis, retroperitoneal fibrosis, and interstitial nephritis. Recently, lung diseases related to IgG4 have been described to occur with or without other organ involvement. These diseases include interstitial lung disease (ILD), pulmonary inflammatory pseudotumor, and lymphomatoid granulomatosis. Most of these cases occur in combination with AIP, which also appears to have a general preponderance for males. The true incidence of IgG4-related ILD and the incidence of AIP are unknown. Here, we describe a case of a 53-year-old gentleman who presented with weight loss, fever, loose motions, altered sensorium, and persistent low hemoglobin, for which he was referred for 18-fluorodeoxyglucose positron emission tomography/computed tomography scan to diagnose probable underlying occult malignancy/paraneoplastic syndrome. It revealed features suggestive of IgG4 disease involving the pancreas and lungs, which was confirmed subsequently.

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Gadolinium based contrast agents in current practice: Risks of accumulation and toxicity in patients with normal renal function

Anju Ranga, Yatish Agarwal, Kanika J Garg

Indian Journal of Radiology and Imaging 2017 27(2):141-147

Despite being decked as the most prized compounds in the nugget box of contrast agents for clinical radiologists, and carrying an indisputable tag of safety of the US Food and Drug Administration for close to three decades, all may not be seemingly well with the family of gadolinium compounds. If the first signs of violations of primum non nocere in relation to gadolinium-based contrast agents (GBCAs) appeared in the millennium year with the first published report of skin fibrosis in patients with compromised renal function, the causal relationship between the development of nephrogenic systemic fibrosis (NSF) and GBCAs, first proposed by two European groups in 2006, further precluded their use in renocompromised patients. The toxicity, pharmacokinetics, and pharmacodynamics of GBCAs, however, has come under hawk-eyed scrutiny with recent reports that gadolinium tends to deposit cumulatively in the brain of patients with normal hepatobiliary function and intact blood–brain barrier. While the jury on the long-term hazard significance of this critical scientific finding is still out, the use of GBCAs must be guided by due clinical diligence, avoidance of repeated doses, and preferring GBCAs with the best safety profiles.

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Subtle versus the obvious – “Is it time for the Smart Radiologist?”

Chander Mohan

Indian Journal of Radiology and Imaging 2017 27(2):117-118



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Multimodality imaging of vaginal rhabdomyosarcoma

Richa S Chauhan, Dheeraj K Singh, Bishwarup Guha, Ishan Kumar, Ashish Verma

Indian Journal of Radiology and Imaging 2017 27(2):148-151

Rhabdomyosarcoma (RMS) is a malignant mesenchymal tumor arising from the embryonal muscle cells (rhabdomyoblasts), and is the most common soft tissue sarcoma in children and young adults accounting for 4–6% of all malignancies in this age group. Though rare overall, embryonal rhabdomyosarcoma is the most common malignancy arising in the pediatric female genitourinary tract with sarcoma botryoides being the most common variant of the tumor. In young and adolescent individuals, the cervix and uterus are affected; whereas in infants, vaginal lesions are more common. Imaging plays a crucial role not only in the initial diagnosis but also in long-term follow-up of genital RMS. We describe a rare case of embryonal rhabdomyosarcoma of the vagina occurring in a 23-year-old female who presented with abnormal vaginal bleeding ever since she was a child.

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Early outcomes of radiofrequency ablation in unresectable metastatic colorectal cancer from a tertiary cancer hospital in India

Suyash Kulkarni, Nitin S Shetty, Ashwin M Polnaya, Sushil Patil, Kunal Gala, Rahul Chivate, Vikas Ostwal, Anant Ramaswamy, Shailesh V Shrikhande, Mahesh Goel, Shraddha Patkar, Manish Bhandare, Venkatesh Rangarajan, Purandare Nilendu

Indian Journal of Radiology and Imaging 2017 27(2):200-206

Aims: The study was carried out to evaluate the early outcomes using Radiofrequency Ablation (RFA) for unresectable liver metastases in the management of metastatic colorectal cancer (mCRC) from an area of low endemicity. Material and Methods: 60 Patients with unresectable colorectal liver metastases had undergone 88 sessions of RFA from January 2007 till December 2013. The results were retrospectively analysed to evaluate the outcomes in terms of efficacy and survival rates. Results: The median follow up of patients in our series was 24.8months. 35/52 (67.3%) patients had complete response at 3 months while 8 patients were lost to follow up. Of the 17 patients who had recurrence, 4 (23.5%) were at the ablated site while 13 patients (76.4%) progressed elsewhere. Abdominal pain was commonest post procedural symptom (20%). There was no procedure related mortality or any major complications. Mean disease free interval and Progression free survival was 6.7 and 13.1 months. Estimated median survival in patients with liver limited disease and those with small lesion (<3cm) was 3.79 years and 3.45 years respectively. Median survival in patients with lesion size 3–5 cms was 1.5 years. Annual survival rates would be 94.5%, 55.2% and 26.2% for 1, 3 and 5 years. Conclusion: Radiofrequency ablation of unresectable liver metastases is effective in treatment of mCRC. Estimated survival rates and Annual survival rates at our institute from the low endemic region also follow the global trend. Size of the lesion was an important predictor of efficacy of RFA. Presence of extrahepatic disease and lesion size >3 cm was associated with decreased survival.

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Severity assessment of acute pancreatitis using CT severity index and modified CT severity index: Correlation with clinical outcomes and severity grading as per the Revised Atlanta Classification

Biswanath Sahu, Pooja Abbey, Rama Anand, Ashok Kumar, Shaili Tomer, Ekta Malik

Indian Journal of Radiology and Imaging 2017 27(2):152-160

Aims: To assess the severity of acute pancreatitis (AP) using computed tomography (CT) severity index (CTSI) and modified CT severity index (MCTSI), to correlate with clinical outcome measures, and to assess concordance with severity grading, as per the revised Atlanta classification (RAC). Materials and Methods: In this prospective study approved by the Institutional Review Board (November 2014 to March 2016), sixty patients with AP (as per the RAC definition) underwent contrast-enhanced computed tomography (CECT) 5–11 days (median 6 days) after symptom onset. Two radiologists, blinded to clinical parameters, independently assessed CTSI and MCTSI (differences were resolved by consensus). Clinical outcome parameters included duration of stay in the hospital and intensive care unit (ICU), presence of persistent organ failure (OF), evidence of infection, need for intervention, and mortality. Results: We included 60 cases [36 males, age range 19–65 (mean 37) years]. As per the RAC, 26 patients had mild AP, 12 moderately severe, and 22 severe AP. According to CTSI and MCTSI, mild, moderate, and severe cases were 27 (45%), 19 (31.7%), 14 (23.3%) and 24 (40%), 10 (16.7%), 26 (43.3%), respectively. MCTSI was concordant with the RAC grading in 54 (90.0%), CTSI was concordant in 47 (78.3%), and both were concordant in 43 (71.7%) cases. Area under the receiver-operating characteristic (ROC) curves (AUROC) was compared by the Hanley and McNeil method. Both CTSI and MCTSI were significantly associated with outcome parameters (P < 0.001), except duration of ICU stay. Sensitivity, specificity, positive predictive value (PPV), and accuracy of CTSI for detecting moderate/severe disease were 97.1%, 100%, 100%, and 98.3% respectively, and of MCTSI were 100%, 92.3%, 94.4%, and 96.7% respectively. Conclusion: Both CTSI and MCTSI showed significant correlation with clinical outcome parameters, and good concordance with RAC grading of severity. MCTSI showed a higher sensitivity but lower specificity than CTSI in differentiating mild from moderate/severe AP.

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Imaging features of vascular compression in abdomen: Fantasy, phenomenon, or true syndrome

Sitthipong Srisajjakul, Patcharin Prapaisilp, Sirikan Bangchokdee

Indian Journal of Radiology and Imaging 2017 27(2):216-224

Vascular structures in the abdomen can compress or be compressed by adjacent structures. Classic imaging findings of vascular compressions, including median arcuate ligament syndrome, superior mesenteric artery syndrome, nutcracker syndrome, portal biliopathy, May-Thurner syndrome, and ureteropelvic junction obstruction will be discussed here. It is important to correlate imaging findings and clinical data to identify asymptomatic vascular compression which requires no treatment, intermittent vascular compression with nonspecific or vague clinical manifestation, and the subset of patients with true syndromes who will benefit from treatment.

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MR fistulography with percutaneous instillation of aqueous jelly: A cost effective technique innovation

Rohit Aggarwal, Brijesh K Soni, Joish U Kumar, Raju A George, Rajeev Sivasankar

Indian Journal of Radiology and Imaging 2017 27(2):161-166

Background: Perianal fistula is a commonly encountered condition in routine surgical practice. Accurate presurgical mapping of these tracts is vital to prevent recurrence. We have assessed the effectiveness of percutaneous instillation of aqueous jelly prior to magnetic resonance (MR) fistulography. Aims and Objectives: To study the role of percutaneous instillation of aqueous jelly in fistulous tracts prior to MR fistulography. Materials and Methods: All patients with active discharge, referred for MR fistulography between January 2014 and April 2016, were included in this study. Approximately 3–5 ml of sterile aqueous jelly was percutaneously instilled into the external openings prior to MR fistulography. Post MR fistulography, patients were monitored till surgery for pain, fever, or bleeding.The type of fistulae, location of internal openings, lateral ramifications, and presence of abscess were compared with per operative findings for diagnostic accuracy. Results: Sixty-four patients enrolled in our study had undergone preoperative MR fistulography with aqueous jelly instillation. MR fistulography revealed a total of 77 tracts and showed a sensitivity and specificity of 100% in delineation of type of tract. Forty-nine internal openings were identified with 94.2% sensitivity, 100% specificity, and 95.3% accuracy. 90.5% sensitivity, 100% specificity, and accuracy of 97% were observed in delineation of lateral ramifications. None of the patients reported pain, fever, or bleeding post procedure till surgery. Conclusion: Percutaneous instillation of aqueous jelly prior to MR fistulography is a safe, cost effective, and accurate technique to provide a comprehensive delineation of the complex anatomy of perianal fistulae.

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Role of exponential apparent diffusion coefficient in characterizing breast lesions by 3.0 Tesla diffusion-weighted magnetic resonance imaging

Shweta Kothari, Archana Singh, Utpalendu Das, Diptendra K Sarkar, Chhanda Datta, Avijit Hazra

Indian Journal of Radiology and Imaging 2017 27(2):229-236

Objective: To evaluate the role of exponential apparent diffusion coefficient (ADC) as a tool for differentiating benign and malignant breast lesions. Patients and Methods: This prospective observational study included 88 breast lesions in 77 patients (between 18 and 85 years of age) who underwent 3T breast magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI) using b-values of 0 and 800 s/mm2 before biopsy. Mean exponential ADC and ADC of benign and malignant lesions obtained from DWI were compared. Receiver operating characteristics (ROC) curve analysis was undertaken to identify any cut-off for exponential ADC and ADC to predict malignancy. P value of <0.05 was considered statistically significant. Histopathology was taken as the gold standard. Results: According to histopathology, 65 lesions were malignant and 23 were benign. The mean ADC and exponential ADC values of malignant lesions were 0.9526 ± 0.203 × 10−3 mm2/s and 0.4774 ± 0.071, respectively, and for benign lesions were 1.48 ± 0.4903 × 10−3 mm2/s and 0.317 ± 0.1152, respectively. For both the parameters, differences were highly significant (P < 0.001). Cut-off value of ≤0.0011 mm2/s (P < 0.0001) for ADC provided 92.3% sensitivity and 73.9% specificity, whereas with an exponential ADC cut-off value of >0.4 (P < 0.0001) for malignant lesions, 93.9% sensitivity and 82.6% specificity was obtained. The performance of ADC and exponential ADC in distinguishing benign and malignant breast lesions based on respective cut-offs was comparable (P = 0.109). Conclusion: Exponential ADC can be used as a quantitative adjunct tool for characterizing breast lesions with comparable sensitivity and specificity as that of ADC.

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Cystic lesions of the pancreatico-biliary tree: A schematic MRI approach

Jaydeep Halankar, Kartik Jhaveri, Ur Metser

Indian Journal of Radiology and Imaging 2017 27(2):167-176

Although a common occurrence, cystic lesions of the pancreatico-biliary tree (PBT) may pose a diagnostic dilemma because they encompass a large number of neoplastic and benign processes with varied clinical symptoms. Knowledge of lesion classification and characterization are essential in making an accurate prospective diagnosis. This is necessary for identifying clinically significant cystic masses, which at times may require invasive intervention from indolent, nonneoplastic lesions, for which surveillance may suffice. Today, there is an arsenal of modalities for assessing the PBT, however, magnetic resonance imaging (MRI) remains at the forefront for characterizing cystic morphology and fluid content, internal septations, solid component, enhancement patterns, as well as assessing the surrounding normal structures. This pictorial review aims to review the spectrum of MRI features, which will aid in the differential diagnoses of cystic lesions of the PBT and mimickers, enabling the radiologist to reach a more confident diagnosis.

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A peek into the future of radiology using big data applications

Amit T Kharat, Shubham Singhal

Indian Journal of Radiology and Imaging 2017 27(2):241-248

Big data is extremely large amount of data which is available in the radiology department. Big data is identified by four Vs – Volume, Velocity, Variety, and Veracity. By applying different algorithmic tools and converting raw data to transformed data in such large datasets, there is a possibility of understanding and using radiology data for gaining new knowledge and insights. Big data analytics consists of 6Cs – Connection, Cloud, Cyber, Content, Community, and Customization. The global technological prowess and per-capita capacity to save digital information has roughly doubled every 40 months since the 1980's. By using big data, the planning and implementation of radiological procedures in radiology departments can be given a great boost. Potential applications of big data in the future are scheduling of scans, creating patient-specific personalized scanning protocols, radiologist decision support, emergency reporting, virtual quality assurance for the radiologist, etc. Targeted use of big data applications can be done for images by supporting the analytic process. Screening software tools designed on big data can be used to highlight a region of interest, such as subtle changes in parenchymal density, solitary pulmonary nodule, or focal hepatic lesions, by plotting its multidimensional anatomy. Following this, we can run more complex applications such as three-dimensional multi planar reconstructions (MPR), volumetric rendering (VR), and curved planar reconstruction, which consume higher system resources on targeted data subsets rather than querying the complete cross-sectional imaging dataset. This pre-emptive selection of dataset can substantially reduce the system requirements such as system memory, server load and provide prompt results. However, a word of caution, "big data should not become "dump data" due to inadequate and poor analysis and non-structured improperly stored data. In the near future, big data can ring in the era of personalized and individualized healthcare.

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ESCMID Postgraduate Education Course: Applications of MALDI-TOF Mass Spectrometry in Clinical Microbiology

Publication date: Available online 30 June 2017
Source:Microbes and Infection
Author(s): Gilbert Greub, Jacob Moran-Gilad, John Rossen, Adrian Egli




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Endocrine functions of vitamin D

Publication date: Available online 29 June 2017
Source:Molecular and Cellular Endocrinology
Author(s): Carsten Carlberg




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The relation between social anxiety and biased interpretations in adolescents with mild intellectual disabilities

Publication date: August 2017
Source:Research in Developmental Disabilities, Volume 67
Author(s): Esther O. Houtkamp, Mariët J. van der Molen, E. Leone de Voogd, Elske Salemink, Anke M. Klein
BackgroundCognitive theories of anxiety emphasize the importance of cognitive processes in the onset and maintenance of anxiety disorders. However, little is known about these processes in children and adolescents with Mild Intellectual Disabilities (MID).AimsThe aim of this study was to investigate interpretation bias and its content-specificity in adolescents with MID who varied in their levels of social anxiety.Method and proceduresIn total, 631 adolescents from seven special secondary schools for MID filled in questionnaires to measure their levels of social anxiety. They also completed the Interpretation Recognition Task to measure how they interpret ambiguous situations.Outcomes and resultsAdolescents with higher self-reported levels of social anxiety interpreted ambiguous scenarios as more negative than adolescents with lower self-reported social anxiety. Furthermore, this negative interpretation was specific for social situations; social anxiety was only associated with ambiguous social anxiety-related scenarios, but not with other anxiety-related scenarios.Conclusions and implicationsThese findings support the hypothesis that socially anxious adolescents with MID display an interpretation bias that is specific for stimuli that are relevant for their own anxiety. This insight is useful for improving treatments for anxious adolescents with MID by targeting content-specific interpretation biases.



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Nutritional strategies and gut microbiota composition as risk factors for necrotizing enterocolitis in very-preterm infants.

Related Articles

Nutritional strategies and gut microbiota composition as risk factors for necrotizing enterocolitis in very-preterm infants.

Am J Clin Nutr. 2017 Jun 28;:

Authors: Rozé JC, Ancel PY, Lepage P, Martin-Marchand L, Al Nabhani Z, Delannoy J, Picaud JC, Lapillonne A, Aires J, Durox M, Darmaun D, Neu J, Butel MJ, Nutrition EPIPAGE 2 study group and the EPIFLORE Study Group

Abstract
Background: The pathophysiology of necrotizing enterocolitis (NEC) remains poorly understood.Objective: We assessed the relation between feeding strategies, intestinal microbiota composition, and the development of NEC.Design: We performed a prospective nationwide population-based study, EPIPAGE 2 (Etude Epidémiologique sur les Petits Ages Gestationnels), including preterm infants born at <32 wk of gestation in France in 2011. From individual characteristics observed during the first week of life, we calculated a propensity score for the risk of NEC (Bell's stage 2 or 3) after day 7 of life. We analyzed the relation between neonatal intensive care unit (NICU) strategies concerning the rate of progression of enteral feeding, the direct-breastfeeding policy, and the onset of NEC using general linear mixed models to account for clustering by the NICU. An ancillary propensity-matched case-control study, EPIFLORE (Etude Epidémiologique de la flore), in 20 of the 64 NICUs, analyzed the intestinal microbiota by culture and 16S ribosomal RNA gene sequencing.Results: Among the 3161 enrolled preterm infants, 106 (3.4%; 95% CI: 2.8%, 4.0%) developed NEC. Individual characteristics were significantly associated with NEC. Slower and intermediate rates of progression of enteral feeding strategies were associated with a higher risk of NEC, with an adjusted OR of 2.3 (95% CI: 1.2, 4.5; P = 0.01) and 2.0 (95% CI: 1.1, 3.5; P = 0.02), respectively. Less favorable and intermediate direct-breastfeeding policies were associated with higher NEC risk as well, with an adjusted OR of 2.5 (95% CI: 1.1, 5.8; P = 0.03) and 2.3 (95% CI: 1.1, 4.8; P = 0.02), respectively. Microbiota analysis performed in 16 cases and 78 controls showed an association between Clostridium neonatale and Staphylococcus aureus with NEC (P = 0.001 and P = 0.002).Conclusions: A slow rate of progression of enteral feeding and a less favorable direct-breastfeeding policy are associated with an increased risk of developing NEC. For a given level of risk assessed by propensity score, colonization by C. neonatale and/or S. aureus is significantly associated with NEC. This trial (EPIFLORE study) was registered at clinicaltrials.gov as NCT01127698.

PMID: 28659297 [PubMed - as supplied by publisher]

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Animal-assisted interventions: A national survey of health and safety policies in hospitals, eldercare facilities, and therapy animal organizations

Publication date: Available online 30 June 2017
Source:American Journal of Infection Control
Author(s): Deborah E. Linder, Hannah C. Siebens, Megan K. Mueller, Debra M. Gibbs, Lisa M. Freeman
BackgroundAnimal-assisted intervention (AAI) programs are increasing in popularity, but it is unknown to what extent therapy animal organizations that provide AAI and the hospitals and eldercare facilities they work with implement effective animal health and safety policies to ensure safety of both animals and humans. Our study objective was to survey hospitals, eldercare facilities, and therapy animal organizations on their AAI policies and procedures.MethodsA survey of United States hospitals, eldercare facilities, and therapy animal organizations was administered to assess existing health and safety policies related to AAI programs.ResultsForty-five eldercare facilities, 45 hospitals, and 27 therapy animal organizations were surveyed. Health and safety policies varied widely and potentially compromised human and animal safety. For example, 70% of therapy animal organizations potentially put patients at risk by allowing therapy animals eating raw meat diets to visit facilities. In general, hospitals had stricter requirements than eldercare facilities.DiscussionThis information suggests that there are gaps between the policies of facilities and therapy animal organizations compared with recent guidelines for animal visitation in hospitals.ConclusionsFacilities with AAI programs need to review their policies to address recent AAI guidelines to ensure the safety of animals and humans involved.



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CD61+ and CAF+ were found to be good prognosis factors for invasive breast cancer patients

Publication date: Available online 30 June 2017
Source:Pathology - Research and Practice
Author(s): Dongyan Cai, Xiaohong Wu, Tingting Hong, Yong Mao, Xiaosong Ge, Dong Hua
BackgroundDuring the epithelial tumor development process, changes in tumor cell genes are an important driving factor for tumorigenesis. Recently, however, studies have shown that the tumor microenvironment, especially for cancer-associated fibroblasts (CAFs) and the infiltration of platelets into tumors, plays an essential role in the progression of human malignant disease.MethodsIn this study, we investigated the presence and prognostic role of podoplanin-expressing CAFs (CAF+), the infiltration of platelets into tumors (CD61+) and platelet count before surgery in a large sample of patients with breast cancer. Podoplanin expression and platelet infiltration were evaluated by immunohistochemistry in 164 patients with breast cancer.ResultsSeventy-two patients (44%) showed CAF+, while fifty-seven patients (35%) showed CD61+. Several strong positive correlations were found, including CD61+ with blood platelet count before surgery (P=0.004), and CAF+ with CD61+ (P=0.048). Patients with CAF+, CD61+ or platelet count >280×10⁹/L before surgery had a significantly shorter disease-free survival according to univariate analysis. Multivariable analysis showed that CAF+ was an independent prognostic factor (Hazard ratio=3.928; p=0.005).ConclusionsCAF+ and CD61+ were found to be good negative prognosis factors for invasive breast cancer patients. CD61+ also had strong positive correlation with blood platelet count before surgery. These targets may be used as strategies for the treatment of breast cancer in the future.



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Prognostic implication of BRAF and TERT promoter mutation combination in papillary thyroid carcinoma – a meta-analysis

Abstract

Introduction

he use of molecular markers, especially BRAF and TERT promoter mutations, for risk stratification in papillary thyroid carcinoma (PTC) is subject to continuing debate. In this study, we aimed to investigate the clinicopathological implication of each genotype when combining BRAF and TERT promoter mutations in PTCs.

Methods

We searched four electronic databases including PubMed, Scopus, Web of Science and Virtual Health Library for relevant studies. Pooled estimates of odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated using random-effect model.

Results

From 111 results, we finally included 11 studies with 3911 PTC patients for meta-analyses. Our results demonstrated that PTCs with concurrent BRAF and TERT promoter mutations were associated with increased tumor aggressiveness in comparison with PTCs harboring BRAF or TERT promoter mutation alone. The combination of BRAF and TERT promoter mutations could classify PTCs into four distinct risk groups with decreasing aggressiveness as follow: coexisting BRAF and TERT >> TERT alone = BRAF alone >> no mutations.

Conclusion

The risk stratification of PTC based on these four genotypes can help improve the clinical management of PTCs by identifying the group of PTCs with the highest aggressiveness.

This article is protected by copyright. All rights reserved.

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