Mechanistic Insights into How CMG Helicase Facilitates Replication Past DNA Roadblocks

Publication date: Available online 20 May 2017
Source:DNA Repair
Author(s): Michael A. Trakselis, Michael M. Seidman, Robert M. Brosh
Before leaving the house, it is a good idea to check for road closures that may affect the morning commute. Otherwise, one may encounter significant delays arriving at the destination. While this is commonly true, motorists may be able to consult a live interactive traffic map and pick an alternate route or detour to avoid being late. However, this is not the case if one needs to catch the train which follows a single track to the terminus; if something blocks the track, there is a delay. Such is the case for the DNA replisome responsible for copying the genetic information that provides the recipe of life. When the replication machinery encounters a DNA roadblock, the outcome can be devastating if the obstacle is not overcome in an efficient manner. Fortunately, the cell's DNA synthesis apparatus can bypass certain DNA obstructions, but the mechanism(s) are still poorly understood. Very recently, two papers from the O'Donnell lab, one structural (Georgescu et al., 2017 [1]) and the other biochemical (Langston and O'Donnell, 2017 [2]), have challenged the conventional thinking of how the replicative CMG helicase is arranged on DNA, unwinds double-stranded DNA, and handles barricades in its path. These new findings raise important questions in the search for mechanistic insights into how DNA is copied, particularly when the replication machinery encounters a roadblock.

Graphical abstract

http://ift.tt/2q5Apre

Interaction between the effects of the selective estrogen modulator femarelle and a vitamin D analog in human umbilical artery vascular smooth muscle cells

Publication date: Available online 20 May 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Dalia Somjen, Esther Knoll, Orli Sharon, Ariel Many, Naftali Stern
To further investigate the interaction between vitamin D system and estrogen-mimetic compounds in the human vasculature we studied the effect of the "less- calcemic" analog of 1,25(OH)2D3 (1,25D); JK 1624F2-2 (JKF) in the presence of selective estrogen modulator femarelle (F), the phytoestrogen daidzein (D) and estradiol-17b (E2) on ³[H] thymidine incorporation (DNA synthesis) and creatine kinase specific activity (CK) in human umbilical artery vascular smooth muscle cells (VSMC). F, D and E2, stimulated DNA synthesis at low concentrations, and inhibited it at high concentrations. All estrogen-related compounds increased CK dose- dependently. Daily treatment with JKF (1nM for 3 days) resulted in decreased DNA synthesis, increased CK and up- regulation of the stimulation of DNA synthesis by low estrogen-related hormones whereas D- and E2- mediated inhibition of cell proliferation was abolished by JKF. In contrast, inhibition of cell proliferation by F could not be blocked by JKF. JKF also up-regulated the stimulatory effects on CK by F, E2 and D. VSMC expressed Estrogen Receptor (ER)a and ERb mRNA at a relative ratio of 2.7:1.0, respectively. JKF pretreatment increased ERa (∼50%) and decreased ERb (∼25%) expression. E2 did not affect ERs whereas both D and F up-regulated ERb (∼100%) and ERa (∼50%). Additionally, JKF increased the intracellular competitive binding of F (from ∼70 to ∼310%), of D (from ∼60 to ∼250%) and of E2 from (from∼70 to ∼320%). F reciprocally modulated the vitamin D system by up-regulating VDR- and 25 hydroxyy vitamin D 1-a hydroxylase (1OHase) mRNA expression (∼120%). F also stimulated 1OHase activity as indicated by an increase in the production of 1, 25D (∼250%). A similar increase was elicited by D (∼90%) but not by E2. In conclusion, F has unique effects on human VSMC in that it can sustain inhibition of cell growth even in the presence of the vitamin D analog JKF. That JKF increases ER expression and F increased the endogenous production of 1, 25D and VDR expression offer new opportunities to modulate VSMC growth. Whether or not these mutual effects of F and JKF can be exploited to promote vascular health, particularly in estrogen-deficient states (e.g., menopause) is under investigation.



http://ift.tt/2qGHSQQ

Lactate induces osteoblast differentiation by stabilization of HIF1α

Publication date: Available online 20 May 2017
Source:Molecular and Cellular Endocrinology
Author(s): Yu Wu, Miaomiao Wang, Haihua Feng, Ying Peng, Jieyun Sun, Xiuxia Qu, Chunping Li
Aerobic glycolysis is involved in osteoblast differentiation induced by Wnt signaling or PTH treatment. However, it is still unclear whether lactate, the end product of aerobic glycolysis, plays any role in osteoblast differentiation. Herein we report that in cultures of osteoblast-lineage cells, lactate promoted alkaline phosphatase-positive cell formation, increased the activity of alkaline phosphatase, and induced the expression of osteocalcin. This osteoblast differentiation-inducing effect of lactate can be inhibited by blocking its entry into cells with MCT1 siRNA or inhibitors, and by interfering with its metabolism by using specific siRNAs for LDHB and PDH. Moreover, lactate stabilized HIF1α expression and inhibited HIF1α activity, with BAY87-2243 lowering the osteoblast differentiation-inducing effect of lactate. Thus, these findings reveal an unrecognized role for aerobic glycolysis in osteoblast differentiation via its end product, lactate.

Graphical abstract

http://ift.tt/2q8nOTj

Numerical investigation of the influence of process conditions on the temperature variation in fused deposition modeling

Publication date: 15 September 2017
Source:Materials & Design, Volume 130
Author(s): Jie Zhang, Xin Zhou Wang, Wang Wang Yu, Yu He Deng
An adaptable three-dimensional transient mathematical model of temperature variation with respect to space and time, during and after the fused deposition modeling (FDM), is proposed and applied with a boundary-adjusting finite difference method. This model enables researchers to study the influence of almost all other parameters on the temperature field and gradient variation when constructing any cuboid at fixed raster angle of 0(90)° and filling ratio of 100%. Some predicted but significant conclusions are reached: reheating of a deposited raster by a newly deposited one is universal and happens mainly in the layer thickness direction; temperature settings are the primary and direct factors determining temperature field variation, while layer thickness and printing speed can still exert their own influence; printing speed is predicted to be positively correlated to mechanical properties of FDM constructed components through the mechanism of thermal coalescence; strict energy management is required if a FDM printer of higher resolution is to be invented and applied. The technique of such mathematical model can provide immediate insights in the understanding of FDM process from the perspective of energy balance, many of which have never been revealed from previous reports yet.

Graphical abstract

http://ift.tt/2pXCfhK

Effect of thermal stability of γ′ phase on the recrystallization behaviors of Ni-based single crystal superalloys

Publication date: 15 September 2017
Source:Materials & Design, Volume 130
Author(s): Lu Qin, Yanling Pei, Shusuo Li, Xinbao Zhao, Shengkai Gong, Huibin Xu
The recrystallization may deteriorate the mechanical properties of single crystal superalloys greatly, which concerns the engineers and scientists in the aviation industry. Recrystallization behaviors after grit-blasting and annealing at different temperatures of a γ′-richen experimental single crystal alloy IC32 (the as-cast and heat-treated) were investigated. Samples of the as-cast ones are less prone to recrystallization than the heat-treated ones. In the as-cast state, the interdendritic regions show a stronger resistance to recrystallization than the dendritic regions. According to the results, we can conclude that the size characteristics and thermal stabilities of the γ′-phases play important roles in deciding the recrystallization resistances of the Ni-based single crystal superalloys.

Graphical abstract

http://ift.tt/2pXUcwM

The Tobacco Cembranoid (1S,2E,4S,7E,11E)-2,7,11-Cembratriene-4,6-diol as A Novel Angiogenesis Inhibitory Lead for The Control of Breast Malignancies

Publication date: Available online 20 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Mohammad M. Hailat, Hassan Y. Ebrahim, Mohamed M. Moheyldin, Amira A. Goda, Abu Bakar Siddique, Khalid A. El Sayed
(1S,2E,4S,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (1) and its 4-epi-analog (2) are diterpenes precursors of the key flavor components in most Nicotiana (tobacco) species that purposely degraded during commercial tobacco fermentation. Angiogenesis, recruitment of new blood vessels, is important for tumor growth, survival and metastasis that can be targeted to control cancer. This study shows evidences and potential of the cembranoid 1 as a potent angiogenesis modulator through targeting VEGFR2. In silico study suggested favorable docking scores and binding affinity of 1 at the ATP binding pocket of VEGFR2. The binding mode of 1 was parallel to the standard FDA-approved antiangiogenic drug sunitinib (4). In vitro, cembranoid 1 significantly reduced the activated VEGFR2 levels in multiple breast cancer cell lines. Intraperitoneal 40 mg/kg, 3X/week treatment of 1 significantly reduced the MDA-MB-231 cells breast tumor size in mice. Immunohistochemistry and Western blotting analysis of the treated mice tumors showed significant downregulation of the vasculogenesis marker CD31 and suppressed activated VEGFR2-paxillin-FAK pathway. Matrigel study in Swiss albino mice showed similar trend. The tobacco cembranoid 1 is a potential antiangiogenic lead useful for future use to control breast malignancies.

Graphical abstract

http://ift.tt/2q7PI1O

Synthesis and evaluation of c-di-4’-thioAMP as an artificial ligand for c-di-AMP riboswitch

Publication date: Available online 20 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Kazuto Shiraishi, Noriko Saito-Tarashima, Yosuke Igata, Keiji Murakami, Yasuko Okamoto, Yoichiro Miyake, Kazuhiro Furukawa, Noriaki Minakawa
Cyclic-di-adenosine monophosphate (c-di-AMP) is a bacterial second messenger that binds to an RNA receptor called riboswitch and regulates its downstream genes involving cell wall metabolism, ion transport, and spore germination. Therefore, the c-di-AMP riboswitch can be a novel target of antibiotics. In this study, we synthesized c-di-4'-thioAMP (1), which possesses a sulfur atom instead of an oxygen atom in the furanose ring, as a candidate of a bioisoster for natural c-di-AMP. The resulting 1 bound to the c-di-AMP riboswitch with a micromolar affinity (34.8 μM), and the phosphodiesterase resistance of 1 was >12-times higher than that of c-di-AMP. Thus, 1 can be considered to be a stable ligand against a c-di-AMP riboswitch.

Graphical abstract

http://ift.tt/2q83S32

Design, synthesis and biological evaluation of sulfonamide-substituted diphenylpyrimidine derivatives (Sul-DPPYs) as potent focal adhesion kinase (FAK) inhibitors with antitumor activity

Publication date: Available online 20 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Menghua Qu, Zhihao Liu, Dan Zhao, Changyuan Wang, Jianbin Zhang, Zeyao Tang, Kexin Liu, Xiaohong Shu, Hong Yuan, Xiaodong Ma
A class of sulfonamide-substituted diphenylpyrimidines (Sul-DPPYs) were synthesized to improve activity against the focal adhesion kinase (FAK). Most of these new Sul-DPPYs displayed moderate activity against the FAK enzyme with IC50 values of less than 100 nM; regardless, they could effectively inhibit several classes of refractory cancer cell lines with IC50 values of less than 10 µM, including the pancreatic cancer cell lines (AsPC-1, Panc-1 and BxPC-3), the NSCLC-resistant H1975 cell line, and the B lymphocyte cell line (Ramos cells). Results of flow cytometry indicated that inhibitor 7e promoted apoptosis of pancreatic cancer cells in a dose-dependent manner. In addition, it almost completely induced the apoptosis at a concentration of 10 µM. Compound 7e may be selected as a potent FAK inhibitor for the treatment of pancreatic cancer.

Graphical abstract

http://ift.tt/2q89N8i

Synthesis, molecular docking, and biological activity of polyfluoroalkyl dihydroazolo[5,1-c][1,2,4]triazines as selective carboxylesterase inhibitors

Publication date: Available online 20 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Evgeny V. Shchegol'kov, Galina F. Makhaeva, Natalia P. Boltneva, Sofya V. Lushchekina, Olga G. Serebryakova, Elena V. Rudakova, Nadezhda V. Kovaleva, Yanina V. Burgart, Viktor I. Saloutin, Oleg N.Chupakhin, Sergey O. Bachurin, Rudy J. Richardson
To search for effective and selective inhibitors of carboxylesterase (CaE), a series of 7-hydroxy-7-polyfluoroalkyl-4,7-dihydroazolo[5,1-c][1,2,4]triazines has been synthesized. Their inhibitory activity against acetylcholinesterase, butyrylcholinesterase, and CaE were investigated using the methods of enzyme kinetics and molecular docking. It was shown that the tested compounds are reversible selective CaE inhibitors of mixed type. Elongation of the polyfluoroalkyl substituent and the presence of an ester, preferably the ethoxycarbonyl group, enhance inhibitory activity toward CaE. Furthermore, the compounds with a tetrazole ring are more active against CaE than their triazole analogues. The obtained kinetic data are well explained by the results of molecular docking, according to which there is a similar orientation of triazolo- and tetrazolotriazines in the active site of CaE and the opposite one for pyrazolotriazines. In the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) assay, all of the studied tetrazolotriazines and some pyrazolotriazines demonstrrated good antiradical activity comparable with a standard antioxidant, Trolox. The leading compounds were nonafluorobutylsubstituted tetrazolo- and 7-phenylpyrazolotriazines, which possess effective and selective CaE inhibitory activity as well as additional useful radical-scavenging properties.

Graphical abstract

http://ift.tt/2q7UhJw

Social syntax: An approach to spatial modification through the reworking of space syntax for archaeological applications

Publication date: September 2017
Source:Journal of Anthropological Archaeology, Volume 47
Author(s): Samantha G. Fladd
Space syntax provides an approach to architecture that allows for the interpretation of social organization. However, many researchers who attempt archaeological applications have commented on the framework's inability to provide novel insights on spatial patterns, particularly in areas without an explicit and established social hierarchy. Many of the noted problems are tied to the absence of a consideration of the relationships among the intentions of builders, the lived experiences of occupants, and the impact of alterations to architecture. To address these issues, space syntax is reworked to focus on modifications to space through a combination of insights derived from practice theory and the life history/object biography approaches. Entitled social syntax, this framework integrates the useful graphic representations of space syntax with a focus on room life histories/biographies and a consideration of the dialectical interplay between architecture (structure) and occupants (agents). To illustrate the utility of this framework, it is applied to two room blocks from Homol'ovi I, an ancestral Hopi village in northeastern Arizona. This application highlights the strength and flexibility of social syntax as a framework for archaeological analyses focused on understanding how the use and meaning of architectural space develops throughout village occupation and depopulation.



http://ift.tt/2qD1F2Y

A double blind randomized prospective study comparing prilocaine versus ropivacaine in upper eyelid blepharoplasty

Dr. Ensat et al. [1] have to be eulogized for their aim to conduct their prospective randomized controlled trial. De facto, upper eyelid blepharoplasty is a very common surgical procedure which can be performed under local anaesthesia. Hence, we read this manuscript with extreme interest. In fact, we agree with the authors that one of the main elements to be considered during this procedure are bleeding and postoperative oedema. For this reason, any technical improvements in this particular field can potentially be a relevant step towards the achievement of better outcomes and post-operative quality of life.

http://ift.tt/2q54UNZ

Reconstruction of combined thumb amputation at metacarpal base level and index amputation at metacarpal level with pollicization and bilateral double toe composite transfer

The aim of this study is to describe the technique and report our experience with reconstruction of combined proximal thumb amputations at the metacarpal base and index finger amputation at metacarpal level with pollicization and bilateral double toe composite transfer.

http://ift.tt/2rpzx4O

Flowmetry evolution in microvascular surgery: A systematic review

This review aims to provide a summary of the flowmeter devices used in microvascular surgery, and assesses their contribution to improving the clinical outcomes of free-tissue transfer. Flowmeters are widely accepted as the standard method of intra-operative assessment of the patency of coronary vascular anastomoses, providing thresholds that predict outcome. There is limited evidence regarding the use of flow measurements in Plastic Surgery microvascular anastomoses; however, flowmetry appears to have some role in post-operative free flap monitoring and prevention of complications.

http://ift.tt/2q54Uxt

Commentary on “Does intramuscular gluteal augmentation using implants affect sensitivity in the buttocks?”

none.

http://ift.tt/2rpttJB

Post-reconstruction dermatitis of the breast

Approximately one-third of women diagnosed with breast cancer undergo mastectomy with subsequent implant-based or autogenous tissue-based reconstruction. Potential complications include infection, capsular contracture, and leak or rupture of implants with necessity for explantation. Skin rashes are infrequently described complications of patients who undergo mastectomy with or without reconstruction.

http://ift.tt/2q4JReJ

Body contouring after obesity surgery is associated with a weight loss benefit among patients

Patients who undergo obesity surgery often require body contouring procedures to eliminate excess skin. Recent studies suggest that body contouring surgery may provide psychological benefits to patients after obesity surgery. However, it is unclear how body contouring may impact weight loss maintenance after obesity surgery.

http://ift.tt/2rpHzKI

Endoscopic DIEP flap dissection (eDIEP): an experimental cadaveric study

Over the last decades, DIEP (deep inferior epigastric perforator) flap has gradually replaced the TRAM (transverse rectus muscle abdominis) as the gold standard in autologous breast reconstruction [1]. The DIEP flap has reduced the risk of postoperative abdominal wall complications (hernia and bulging) by half compared to the TRAM [2].

http://ift.tt/2q4XPgr

Measuring Satisfaction with Appearance: Validation of the FACE-Q Scales for double-eyelid blepharoplasty with minor incision in young Asians- Retrospective study of 200 cases

Double eye-lid surgery is one of the most popular performed aesthetic procedures in young Asians. Reliable measurement of patient reported outcomes is crucial for facial aesthetics. The FACE-Q is a new patient-reported outcome tool (PRO) composed of numerous independently functioning scales and checklists designed to measure outcomes. Here we described FACE-Q scales for double eye-lid surgery with minor incision in young Asians.

http://ift.tt/2rpIKdr

Two-artery replantation for digital tip amputation

In digital tip replantation, as the amputation level becomes more distal, venous repair becomes more challenging. Indeed, venous insufficiency has a significant impact on the failure rate of fingertip replantation1. To solve this problem, we attempted to anastomose two arteries whenever possible based on the brief that internal circulation is provided through arteriovenous communication and that a greater blood flow is necessary to restore the severely damaged tissue. From May 1998 to December 2015, 38 fingertip replantations with 2 arteries repair were performed in 38 patients.

http://ift.tt/2q4HhoU

Preventing the Complications of Tissue Expansion Using Fat Grafting Under Expanded Skin

Soft tissue expansion is a widely used technique for repairing soft tissue defects because of its multiple advantages. However, the limiting regenerative capacity of skin always leads to many complications with an occurrence rate of 3.65% for tissue necrosis and 1.68% for expander exposure(1, 2). Fortunately, we can observe several early signs before these complications, like skin thinning, telangiectasia, embolism and striae. Without timely and effective treatment, these early signs will turn into complications and the treatment will finally fail (Figure 1).

http://ift.tt/2rpO93X

Complications after prominent ear correction – A systematic review of the literature

There is great diversity in reported post-operative outcomes for otoplasty, with the incidence of haematoma or infection ranging from 0 percent to 15.6 percent and 0 percent to 10 percent respectively. With such variability it is difficult to determine an overall "average" incidence of common post-operative complications.

http://ift.tt/2q4YZZp

Cost Analysis of Percutaneous Fixation of Hand Fractures in the Main Operating Room Versus the Ambulatory Setting

To date, there have been no studies identifying the cost differential for performing closed reduction internal fixation (CRIF) of hand fractures in the operating room (OR) versus an ambulatory setting. Our goal was to analyze the cost and efficiency of performing CRIF in these two settings and to investigate current practice trends in Canada.

http://ift.tt/2rpOPX1

Hemodialysis does not impact axitinib exposure: clinical case of a patient with metastatic renal cell carcinoma

Abstract

Axitinib is approved with indication in patients with advanced renal cell carcinoma (RCC). Due to the localization of this cancer, physicians sometimes have to deal with hemodialyzed patients. Data exploring hemodialysis (HD) impact on axitinib pharmacokinetic (PK) or safety are lacking. To date, no data have been published on that problematic. This is the first publication discussing the assessment of axitinib PK for a patient undergoing HD. Our results suggest that there is no influence of HD on axitinib blood concentration. Interestingly, the membranes used are common and represent around 90% of the membranes used in routine for HD. Our data are also reassuring both from activity and from safety perspectives. In that case, axitinib administered at a dose of 6 mg twice a day was well tolerated and allowed 12 months of disease control. These results are in line with previous publications discussing other anti-angiogenic tyrosine kinase inhibitors pharmacokinetics, safety and activity among patients with metastatic RCC undergoing hemodialysis.

http://ift.tt/2qCWCQ1

The incidence and risk factors of febrile neutropenia in chemotherapy-naïve lung cancer patients receiving etoposide plus platinum

Abstract

Purpose

This study was to determine the incidence and risk factors of febrile neutropenia in chemotherapy-naïve Japanese patients treated systemically with etoposide plus platinum for lung cancer.

Methods

The study was a retrospective analysis of 244 patients who were monitored for febrile neutropenia through multiple cycles of the combination of etoposide with platinum, and the associations between incidence of febrile neutropenia and patient characteristics were evaluated.

Results

Eighty-eight patients were treated with etoposide plus cisplatin and 156 were treated with etoposide plus carboplatin. Of the 244 patients treated, 198 (81.1%) completed 4 cycles for chemotherapy. Febrile neutropenia was observed in 48 of 244 patients (19.7%), including 18 of 88 (20.5%) patients who received etoposide plus cisplatin and 30 of 156 (19.2%) patients who received etoposide plus carboplatin. Grade 3 or 4 of neutropenia was experienced by a total of 208 patients (85.2%); 79 of 88 (89.8%) receiving etoposide plus cisplatin and 129 of 156 (82.7%) receiving etoposide plus carboplatin. Male gender and previous radiotherapy were identified by multivariate analysis as independent risk factors for febrile neutropenia.

Conclusions

These results contrast with findings in Western patients and suggest that ethnic differences exist in the incidence of febrile neutropenia in patients receiving etoposide plus platinum chemotherapy. In addition, our results suggest that primary prophylaxis with granulocyte colony-stimulating factor should be considered for patients with these risk factors for febrile neutropenia prior to treatment with etoposide plus platinum.

http://ift.tt/2q898nd

Enhancing the therapeutic range of a targeted small-molecule tubulysin conjugate for folate receptor-based cancer therapy

Abstract

Purpose

EC0305 represents a folate-tubulysin B construct capable of specifically eradicating folate receptor (FR)-positive subcutaneous tumors from mice (Leamon et al., Cancer Res 68:9839–9844, 8). Herein we report on the use of multiple polar carbohydrate segments (e.g. 1-amino-1-deoxy-glucitolyl-γ-glutamate) placed in-between the folate and tubulysin B moieties of EC0305 creating a new conjugate, herein referred to as EC0531, with more desirable biological properties.

Methods

The synthesis of EC0531 and its tritium-labeled counterpart are described. EC0531's affinity for FR binding and specific cytotoxic activity was assessed using standard in vitro assays. Human tumor xenografts were used to directly compare EC0305 and EC0531's antitumor activity. Finally, bile duct cannulated, female Sprague–Dawley rats were used to compare hepatobiliary clearance of these two targeted chemotherapeutic agents.

Results

EC0531 tightly binds to the FR with an affinity about half that of folic acid. It was found to specifically inhibit the growth of FR⁺ cells (IC₅₀ of ~2 nM) in a dose-dependent manner. Using ³H-labeled compounds, more than a 12-fold higher amount of tubulysin was measured in a FR + human tumor xenograft compared to the unconjugated drug, a finding that explains, in part, why EC0531 displays curative activity, whereas the unconjugated tubulysin agent is essentially inactive. EC0531 was found to produce greater FR-specific anti-tumor activity at lower dose levels than EC0305; furthermore, EC0531's maximum tolerated dose level was significantly higher than that of EC0305, likely because EC0531's saccharopeptidic-based spacer allows for ~sixfold reduction in hepatic clearance.

Conclusions

These data provide additional evidence that the therapeutic range of targeted small-molecule drug conjugates can be favorably increased using molecular spacers constructed with 1-amino-1-deoxy-glucitolyl-γ-glutamate residues.

http://ift.tt/2qDjy1P

Paclitaxel-induced sensory peripheral neuropathy is associated with an ABCB1 single nucleotide polymorphism and older age in Japanese

Abstract

Purpose

Whether age and inter-individual variability of pharmacogenetics are risk factors for paclitaxel-induced peripheral neuropathy (PIPN) is inconclusive. This study was conducted to evaluate the influence of previously investigated single nucleotide polymorphisms (SNPs) and age, using genotype data from a prospective study of paclitaxel-related toxicity in Japanese patients with breast cancer.

Methods

Peripheral blood mononuclear cells from 127 Japanese women with breast cancer who received weekly adjuvant paclitaxel were used to genotypes SLCO1B3 T334G (rs4149117), CYP2C8 A1196G (rs10509681), ABCB1 C1236T (rs1128503), ABCB1 G2677T/A (rs2032582), and ABCB1 C3435T (rs1045642). Genotypic and clinical factors were investigated for associations with PIPN.

Results

Of the five SNPs evaluated, no SNPs were significantly associated with grade 2 or higher PIPN. However, ABCB1 1236 TT showed a trend to associate with grade 2 or higher PIPN compared to ABCB1 CT/CC (odds ratio 2.1, 95% CI 0.991–4.548, p = 0.051). In subgroup analysis, patients ≥60 years old with an ABCB1 1236 TT had a higher incidence of ≥grade 2 PIPN compared to patients with CT or CC genotype (p = 0.027). On multivariable analysis, age ≥60 years and the ABCB1 1236 TT showed a significant association with ≥grade 2 PIPN (p = 0.005 and p = 0.034, respectively).

Conclusions

ABCB1 1236 TT genotype and older age might be a predictor of PIPN, which diminishes quality of life of cancer survivors.

http://ift.tt/2q83VvP

Neurotoxicity after high-dose methotrexate (MTX) is adequately explained by insufficient folinic acid rescue

Abstract

Purpose

To challenge the view that the dose of folinic acid rescue after high-dose methotrexate (MTX) has no significance in the prevention of neurotoxicity and to present the minority view that neurotoxicity can be prevented by an adequate dose of folinic acid, without compromising treatment results. Several fallacies that led to the misunderstanding of post MTX neurotoxicity are presented.

Methods

Data mining using search engines was used to find relevant publications, and an e-mail survey of more than 60 authors of articles in this field was performed. All relevant articles identified were read in their entirety.

Results

Examples of clinical studies with neurotoxicity following inadequate rescue are given. Some studies demonstrated no neurotoxicity when adequate doses of folinic acid rescue were started 24–36 h after the start of HDMTX rescue even after mega doses of MTX. Rescue started after 42 h was associated with neurotoxicity except in patients with low serum MTX levels after 24 and 36 h. ALL protocols with neurotoxicity, especially BFM-like protocols, are presented. Protocol is reported in which single protocol changes prevented neurotoxicity.

Conclusions

From the published data, when folinic acid rescue is given in a sufficiently high enough dose and is started 24–36 h after the beginning of the methotrexate exposure, and virtually all forms of post MTX neurotoxicity can be prevented without compromising therapeutic results.

http://ift.tt/2qCZHj6

Phase II study of S-1 plus bevacizumab combination therapy for patients previously treated for non-squamous non-small cell lung cancer

Abstract

Purpose

To assess the efficacy and toxicity of S-1 and bevacizumab combination therapy for patients previously treated for advanced non-squamous non-small cell lung cancer (NSCLC).

Methods

This was a prospective, multi-center, single-arm phase II study. Patients with non-squamous NSCLC who had experienced progression after cytotoxic chemotherapy were enrolled. Oral S-1 was administered on days 1–14 of a 21-day cycle, and bevacizumab (15 mg/kg) was given intravenously on day 1. Patients received S-1 adjusted on the basis of their creatinine clearance and body surface area. The primary endpoint was response rate (RR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.

Results

We enrolled 30 patients. One patient had never received platinum-based therapy. Five patients had activating mutations of the epidermal growth factor receptor gene, of whom four had received tyrosine kinase inhibitors before this study. The RR was 6.7% [95% confidence interval (CI) 1.8–21.3%], and the disease control rate (DCR) was 80% (95% CI 62.7–90.5%). Median PFS was 4.8 months (95% CI 2.7–6.4 months], and median OS was 13.8 months (95% CI 8.4 months–not applicable). Patients did not experience any Grade 4 toxicity or treatment-related death. Grade 3 hematologic toxicity (anemia) occurred in one patient (3.3%). The main Grade 3 non-hematologic toxicities were anorexia (10%), infection (10%), and diarrhea (6.7%).

Conclusion

The addition of bevacizumab to S-1 was tolerable, but not beneficial for patients with previously treated non-squamous NSCLC. We do not recommend further study of this regimen.

http://ift.tt/2q80uFd

MITF suppression by CH5552074 inhibits cell growth in melanoma cells

Abstract

Purpose

Although treatment of melanoma with BRAF inhibitors and immune checkpoint inhibitors achieves a high response rate, a subset of melanoma patients with intrinsic and acquired resistance are insensitive to these therapeutics, so to improve melanoma therapy other target molecules need to be found. Here, we screened our chemical library to identify an anti-melanoma agent and examined its action mechanisms to show cell growth inhibition activity.

Methods

We screened a chemical library against multiple skin cancer cell lines and conducted ingenuity pathway analysis (IPA) to investigate the mechanisms of CH5552074 activity. Suppression of microphthalmia-associated transcription factor (MITF) expression levels was determined in melanoma cells treated with CH5552074. Cell growth inhibition activity of CH5552074 was evaluated in MITF-dependent melanoma cell lines.

Results

We identified an anti-melanoma compound, CH5552074, which showed remarkable cell growth inhibition activity in melanoma cell lines. The IPA results suggested that CH5552074-sensitive cell lines had activated MITF. In further in vitro studies in the melanoma cell lines, a knockdown of MITF with siRNA resulted in cell growth inhibition, which showed that CH5552074 inhibited cell growth by reducing the expression level of MITF protein.

Conclusions

These results suggest that CH5552074 can inhibit cell growth in melanoma cells by reducing the protein level of MITF. MITF inhibition by CH5552074 would be an attractive option for melanoma treatment.

http://ift.tt/2qDfTBd

In vitro and in vivo assessments of two novel hydrazide compounds against breast cancer as well as mammary tumor cells

Abstract

Purpose

The hydrazide backbone is a well-known structural core system found in a broad range of biologically activated compounds. Among which, the compounds with anticancer activity have been cited in a number of studies. With this object in mind, we focused on the in vitro and in vivo anticancer potential of two novel hydrazide derivatives bearing furan or thiophen substituents (compounds 1 and 2).

Methods

The cytotoxic property was evaluated using MTT assay against MCF-7 human breast adenocarcinoma cell line, while the in vivo antitumor activity was investigated in BALB/c mice bearing 4T1 mammary carcinoma cells. Flow cytometry was used for cell cycle analysis, and detection of apoptosis was examined by Annexin-V-FLUOS/PI assay. Protein expression of Bax, Bcl-2 and procaspase-3 was estimated by Western blotting.

Results

Compounds 1 and 2 were found to be cytotoxic towards breast cancer cells presenting IC₅₀ values of 0.7 and 0.18 µM, respectively, and selectivity over normal fibroblast cells. Our findings further indicated that 2 × IC₅₀ concentrations of both compounds induce early stage apoptosis and increase percentage of sub-G1 population in MCF-7 cells at 48 h. An elevation in Bax/Bcl-2 ratio and caspase-3 cleavage suggested that apoptosis induced by the two compounds is through a caspase- and mitochondrial-dependent pathway. In the in vivo study, compounds 1 and 2 at doses of 10 and 1 mg/Kg/day, respectively, significantly hindered the growth of tumor after 3 weeks of i.p. administration, when compared to vehicle-treated mice.

Conclusion

Collectively, the great potential exhibited by compound 2 could make it a promising chemotherapeutic candidate for human cancers, especially for breast cancer.

http://ift.tt/2qDeuKZ

Adjuvant concurrent chemoradiotherapy with low-dose daily cisplatin for extrahepatic bile duct cancer

Abstract

Purpose

We aimed to present the clinical outcomes of adjuvant concurrent chemoradiotherapy (CCRT) with low-dose daily cisplatin regimen compared to the conventional 5-fluorouracil (5-FU)-based regimen for extrahepatic bile duct cancer (EHBDC).

Methods

From October 1994 to April 2013, 41 patients received adjuvant CCRT with low-dose daily regimen or 5-FU-based regimens. Nineteen patients received low-dose of cisplatin just before every delivery of radiation therapy, and 21 patients received two cycles of 5-FU-based regimen during radiotherapy. We compared the clinical outcomes between two adjuvant CCRT regimens.

Results

Adjuvant CCRT with low-dose daily cisplatin showed comparable toxicity profiles compared with that of a 5-FU-based regimen. The median follow-up time was 33 months (range, 5–205), and the 5-year overall survival (OS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) were 34.2, 50.8, and 49.7%, respectively. Univariable analyses showed no significant differences in OS, LRRFS, and DMFS between the groups with two regimens. In multivariable analyses, chemotherapeutic regimen was a significant prognostic factor for OS, favoring the low-dose daily cisplatin regimen (HR = 2.491, p = 0.036) over 5-FU-based regimen, though not for LRRFS (p = 0.642) and DMFS (p = 0.756).

Conclusions

Adjuvant CCRT with low-dose daily cisplatin regimen showed acceptable toxicities and survivals compared to those of the 5-FU-based regimen. Low-dose daily cisplatin can be one of the feasible regimens for adjuvant CCRT for EHBDC.

http://ift.tt/2q84Wns

Exposure of marine mussels to diclofenac: modulation of prostaglandin biosynthesis

Abstract

Human pharmaceuticals, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are an emerging threat to marine organisms. NSAIDs act through inhibition of cyclooxygenase (COX) conversion of arachidonic acid into prostaglandins. One experiment was carried out whereby marine mussels were exposed for 72 h to 1 and 100 μg/L diclofenac (DCF). A specific and sensitive method using liquid chromatography high-resolution tandem mass spectrometry was developed to quantify DCF in mussel tissues. The developed method could also clearly identify and quantify COX products, i.e., prostaglandin levels, and be used to assess their modulation following DCF exposure. Prostaglandin-D₂ (PGD₂) was always found below the detection limit (20 μg/kg dry weight (dw)). Basal prostaglandin-E₂ (PGE₂) concentrations ranged from below the detection limit to 202 μg/kg dw. Exposure of 100 μg/L resulted in a significant reduction in PGE₂ levels, whereas a downward trend was observed at 1 μg/L exposure. No difference was observed for prostaglandin-F₂α (PGF_2α) levels between controls and exposed organisms.

http://ift.tt/2r4zifv

Salicylic acid determination in estuarine and riverine waters using hollow fiber liquid-phase microextraction and capillary zone electrophoresis

Abstract

A low-cost methodology using hollow fiber liquid-phase microextraction (HF-LPME) and capillary zone electrophoresis (CZE) with UV-Vis detector was developed to analyze the salicylic acid (SA) in estuarine and riverine waters. The technique is easy-to-use and rapid, and demands little volume of organic solvent. The extraction was carried out using a polypropylene membrane supporting into octan-1-ol. HF-LPME under optimized conditions (donor solution sample pH 2, acceptor solution pH 14, sample volume 25 mL, fiber length 10 cm, acceptor volume 25 μL, extraction time 3 h and stirring speed 350 rpm) presented high enrichment factor (407 times) and good recovery in real water samples (from 88 to 110%). A limit of detection of 2.6 μg L⁻¹ was achieved using CZE with UV-Vis detector as quantification method. The method was applied to direct quantification of SA in environmental complex estuarine and riverine water matrices.

http://ift.tt/2pXgdfc

Influence of amendments on Cd and Zn uptake and accumulation in rice ( Oryza sativa L.) in contaminated soil

Abstract

Cadmium is a toxic metallic element that poses serious human health risks via consumption of contaminated agricultural products. The effect of mixtures of dicalcium phosphate and organic amendments, namely cow manure (MD) and leonardite (LD), on Cd and Zn uptake of three rice cultivars (KDML105, KD53, and PSL2) was examined in mesocosm experiments. Plant growth, Cd and Zn accumulation, and physicochemical properties of the test soils were investigated before and after plant harvest. Amendment application was found to improve soil physicochemical properties; in particular, soil organic matter content and nutrient (N, P, K, Ca, and Mg) concentrations increased significantly. The MD treatment was optimal in terms of increasing plant growth; the MD and LD treatments decreased soil Cd concentration by 3.3-fold and 1.6-fold, respectively. For all treatments, all rice cultivars accumulated greater quantities of Cd and Zn in roots compared with panicles and shoots. Among the three cultivars, RD53 accumulated the lowest quantity of Cd. Translocation factors (<0.28) and bioconcentration coefficients of roots (>1) indicate that the three rice cultivars are Cd excluders. Our results suggest that a mixture of organic and inorganic amendments can be used to enhance rice growth while reducing accumulation of heavy metals when grown in contaminated soil.

http://ift.tt/2pXwaSM

A flux-enhancing forward osmosis–nanofiltration integrated treatment system for the tannery wastewater reclamation

Abstract

Effective treatment of tannery wastewater prior to discharge to the environment as per environmental regulations remains a big challenge despite efforts to bring down the concentrations of the pollutants which are often quite high as measured in terms of chemical oxygen demand (7800 mg/L), total dissolved solids (5400 mg/L), chloride (4260 mg/L), sulphides (250 mg/L) and chromium. A pilot-scale forward osmosis and nanofiltration integrated closed loop system was developed for continuous reclamation of clean water from tannery wastewater at a rate of 52–55 L/m²/h at 1.6 bar pressure. The low-cost draw solution was 0.8 M NaCl solution. Continuous recovery for recycling the draw solute was done by nanofiltration of diluted draw solution at an operating pressure of 12 bar and volumetric cross-flow rate of 700 L/h. Fouling study revealed that the specific flat-sheet design of cross-flow forward osmosis module with counter current flow of feed and draw solution prevents the build-up of concentration polarization, thus enabling long-term filtration in continuous mode of operation without significant membrane fouling. This study culminates in the development of a compact, efficient and low-cost industrial wastewater treatment and reclamation technology.

http://ift.tt/2qJ9nHp

Assessment of trace metal accumulation in native mussels ( Brachidontes rodriguezii ) from a South American temperate estuary

Abstract

The present work provides the first results in heavy metal bioaccumulation in the autochthonous mussel Brachidontes rodriguezii from the Bahía Blanca Estuary (Argentina), one of the most important coastal environments of South America, subjected to different anthropogenic pressure. The study is based on the detection of Cd, Cu, Pb, Mn, and Fe in mussels' soft tissue and sediments' fine fraction by means of inductively coupled plasma atomic emission spectroscopy (ICP-OES), in order to analyze the potential relationship between both components of the aquatic system. Additionally, different indices are calculated with the purpose of obtaining detailed data. The heavy metal burden in mussels varied seasonally, showing a clearer pattern for the stations located in the internal area of the estuary. Metals exhibited maximum values in summer and to a lesser extent in winter, followed by a decrease during spring. Multiple international guideline assessment allowed classifying the area as moderately polluted, including a low range for Cd and medium for Cu and Pb. Moreover, the average detected levels were within the measured ranges in other coastal areas. Regarding human health, trace metal content in mussels met the national and international standards for safe consumption.

http://ift.tt/2pXtFQ6

Enhanced degradation of perfluorooctanoic acid using dielectric barrier discharge with La/Ce-doped TiO 2

Abstract

A synergistic system of dielectric barrier discharge (DBD) combined with La/Ce-TiO₂ was developed to investigate the decomposition performance of the environmentally persistent perfluorooctanoic acid (PFOA). The La/Ce-TiO₂ was modified by sol–gel method and characterized by XRD, SEM, and energy dispersive X-ray. The effects of PFOA concentration, applied voltage, initial pH, liquid conductivity, and additives on the removal rate of PFOA were explored. The results showed that the La/Ce-TiO₂ exhibited excellent catalytic effects on PFOA degradation in DBD system. When the applied voltage, PFOA concentration, pH value, and solution volume were 75 V, 100 mg/L, 3.63, and 1000 mL, respectively, the removal efficiency of PFOA was up to 97.5% by adding La₄Ce₁-TiO₂ in DBD. The corresponding defluorination ratio, TOC removal, and decomposition yield were 62.2%, 57.3%, and 37 g/kWh, respectively. Furthermore, five main intermediates including CF₃(CF₂)₆H, CF₃(CF₂)₅COOH, CF₃(CF₂)₅COH, CF₃(CF₂)₄COOH, and CF₃CF₂CF₃ were identified with LC–MS, and the degradation pathways of PFOA were proposed. The degradation mechanisms revealed that hydroxyl radicals play a significant role in the degradation of PFOA in the synergistic system.

http://ift.tt/2qJxQw9

Metal transport and remobilisation in a basin affected by acid mine drainage: the role of ochreous amorphous precipitates

Abstract

Metal-polluted mine waters represent a major threat to the quality of waters and sediments in a downstream basin. At the confluence between acidic mine waters and the unpolluted waters of the Gromolo Torrent (Liguria, North-West Italy), the massive formation of an ochreous amorphous precipitate takes place. This precipitate forms a soft blanket that covers the torrent bed and can be observed down to its mouth in the sea. The aim of this work is to evaluate the dispersion of metals in the Gromolo Torrent basin from the abandoned Cu-Fe sulphide mine of Libiola to the Ligurian Sea and to assess the metal remobilisation from the amorphous precipitates. The mineralogy of the superficial sediments collected in the torrent bed and the concentrations of different elements of environmental concern (Cu, Zn, Cd, Co, Cr, Mn, Ni, Pb, As, and Sb) were therefore analysed. The results showed that the precipitates contain high concentration of Fe, Al, Cu, and Zn, significantly modifying the bulk chemistry of the Gromolo Torrent sediments. In order to evaluate the possible remobilisation of ecotoxic elements from the amorphous precipitates, bulk leaching tests were performed with both deionised and seawater. Bulk leaching tests with deionised water mobilised primarily high Pb amounts, but also relatively high concentrations of Fe, Al, Cu, and Zn are released in the leachate. In seawater tests, Fe, Al, Cu, and Zn were released in smaller amounts, while other elements like Mn, Cd, Co, and Ni increased in the released fraction. Pb was still strongly released as in deionised water experiments. The results show that the interaction of precipitates and seawater can remobilise high concentrations of metals, thus affecting the surrounding environment.

http://ift.tt/2pXt7d1

Using poly-glutamic acid as soil-washing agent to remediate heavy metal-contaminated soils

Abstract

The extraction efficiency of heavy metals from soils using three forms of gamma poly-glutamic acid (γ-PGA) as the washing agents was investigated. Controlling factors including agent concentrations, extraction time, pH, and liquid to soil ratio were evaluated to determine the optimum operational conditions. The distribution of heavy metal species in soils before and after extraction processes was analyzed. Up to 46 and 74% of heavy metal removal efficiencies were achieved with one round and a sequential extraction process using H-bonding form of γ-PGA (200 mM) with washing time of 40 min, liquid to solid ratio of 10 to 1, and pH of 6. Major heavy metal removal mechanisms were (1) γ-PGA-promoted dissolution and (2) complexation of heavy metal with free carboxyl groups in γ-PGA, which resulted in heavy metal desorption from soils. Metal species on soils were redistributed after washing, and soils were remediated without destruction of soil structures and productivity.

http://ift.tt/2qJH1Nk

Lipopeptides produced by Bacillus subtilis as new biocontrol products against fusariosis in ornamental plants

Abstract

In this study, we have investigated the effects of three lipopeptides (fengycin, surfactin and mycosubtilin) produced by different strains of Bacillus subtilis against the phytopathogenic fungi Fusarium oxysporum f. sp. iridacearum, which affects the ornamental bulb plant populations of Iris sp. The antifungal effects were tested using minimum inhibitory concentration assay, determination of mycelium growth and spore germination inhibition rates. Also, in vivo tests on infected rhizomes and scanning electron microscopy were employed. Mycosubtilin alone and in combination with fengycin or/and surfactin showed potent inhibitory activity at concentrations as low as 5 μg ml⁻¹ which is 100 times lower compared to Topsin M, a common chemical fungicide frequently used against fusariosis in ornamental plants. An enhancement of mycosubtilin antifungal activity was observed when it was used in combination with surfactin due to a synergistic effect. At a concentration of 20 μg ml⁻¹, mycosubtilin inhibited the growth of the mycelium up to 49% and the spore germination ability up to 26% in comparison to control. In addition, significant changes on the macro- and micro-morphology have been observed. The antifungal activity is related to the inhibition of spore germination and the irreversible damage of the hyphae cell wall. To the best of our knowledge, this is the first attempt to propose the lipopeptides as biopesticides against the fusariosis of ornamental plants.

http://ift.tt/2qJpfJW

Editorial Board

Publication date: April 2017
Source:Journal of Bodywork and Movement Therapies, Volume 21, Issue 2





http://ift.tt/2rDGVGg

The role of timing in the treatment of spinal cord injury

Publication date: August 2017
Source:Biomedicine & Pharmacotherapy, Volume 92
Author(s): Amene Saghazadeh, Nima Rezaei
Regeneration failure after primary spinal cord injury (SCI) leads to diverse clinical complications in a severity- and level of SCI-dependent manner. The cost of treating both of them (initial regeneration failure and following complications) would be prohibitive, particularly in less developed nations. The well-recognized circumstances arose from primary SCI include excitotoxicity and inflammation. SCI increases concentrations of extracellular amino acids (EAAs) in the severity-dependent manner and the maximum level of EAAs at the injury site will be reduced by distance from the injury site. Increased concentrations of EAAs and their signaling result in energy and metabolic changes and eventually neurotoxicity. Therefore EAAs play a crucial role in moving towards secondary stage of SCI. There is a close correspondence between severity of SCI and intensity of acute inflammatory response, which includes proinflammatory cytokines (IL-1β, TNF-α, and IL-6) and immune cells (neutrophils, microglia, and mast cells). The communication between microglia and astrocytes mediate formation of astroglial scar. The scar is thought to diminish the spread of inflammation and lesion volume, and on the other side poses an obstacle to achieving axon regeneration. Moreover, mast cells exert an anti-inflammatory role in the ground of injured spinal cord by degradation of proinflammatory mediators, while mast cells-derived histamine may cause excitotoxicity. Therefore research suggests a very double-sword remark about the work of inflammatory mediators in the injured spinal cord. Myelin associated inhibitors (MAIs) are among the growing list of extrinsic inhibitors of neuroregeneration in the injured-CNS. They function via NgR-dependent mechanisms. The time for intervention by NgR antagonists must be fixed according to the expression pattern of this receptor and its dependent MAIs after SCI. Altogether, experimental studies suggest potential benefits of combating EAAs, inflammatory mediators, and MAIs during the first minutes, hours and weeks after SCI, respectively. However, acute inflammation initially induced by SCI tends to be permanent, even at several years after SCI. This supports the notion that paying attention to inflammation must persist through time. The consideration of seconds-dependent state of spinal cord after primary injury is a very therapeutic and also preventive approach against future possible complications. It is thereby possible to propose "timing", which is perfectly practicable throughout the world, as an effective campaign against the final failure of SCI.



http://ift.tt/2qJB02Z

Protective effect and mechanism of lycopene on endothelial progenitor cells (EPCs) from type 2 diabetes mellitus rats

Publication date: August 2017
Source:Biomedicine & Pharmacotherapy, Volume 92
Author(s): Yao-Chi Zeng, Li-Sheng Peng, Liyuan Zou, Shu-Fen Huang, Yi Xie, Gui-Ping Mu, Xue-Hui Zeng, Xi-Lin Zhou, Ya-Chi Zeng
Endothelial progenitor cells (EPCs), widely existing in bone marrow and peripheral blood, are involved in the repair of injured vascular endothelium and angiogenesis which are important to diabetic mellitus (DM) patients with vascular complications. The number and the function of EPCs are related to the advanced glycation end products (AGEs) generated in DM patients. Lycopene (Lyc) is an identified natural antioxidant that protects EPCs under the microenvironment of AGEs from damage. However, the underlying mechanism remains unclear. To investigate the effect of Lyc on EPCs, we isolated EPCs from DM rat bone marrow and determined cell proliferation, cell cycle,apoptosis and autophagy of EPCs. The present study showed that 10μg/mL Lyc improved cell proliferation and had low cytotoxicity in the presence of AGEs. In addition, Lyc rescued S phase of the cell cycle arrest, reduced apoptosis rate and decreased autophagic reaction including ROS and mitochondrial membrane potential (MMP) of EPCs. Moreover, Lyc combined use of autophagy inhibitors, 3-MA, had better protective effects. Taken together, our data suggests that Lyc promotes EPCs survival and protect EPCs from apoptosis and oxidative autophagy induced by AGEs, further remaining the number and function of EPCs. This study provides new insights into Lyc protective mechanism of AGEs-induced oxidative autophagy in EPCs from DM patients and offers a new therapy for DM vascular complications.



http://ift.tt/2pXjgUG

Troxerutin (TXN) potentiated 5-Fluorouracil (5-Fu) treatment of human gastric cancer through suppressing STAT3/NF-κB and Bcl-2 signaling pathways

Publication date: August 2017
Source:Biomedicine & Pharmacotherapy, Volume 92
Author(s): Gui-yun Xu, Xiao-jun Tang
Gastric cancer still presents a significant problem for public health worldwide. Troxerutin (TXN), a flavonoid present in tea, coffee, cereal grains, and a variety of fruits and vegetables, exhibits various pharmacological and biological activities in vitro and in vivo. We investigated the ability of TXN to reverse the in vitro and in vivo drug resistance of human gastric cancer cells, which were resistant to treatment of 5-Fluorouracil (5-FU). 5-Fu is a pyrimidine analog, which is widely used in the treatment of cancers. Here, we found the growth inhibitory effects of TXN on human gastric cancer cell, resistant to 5-FU. TXN and 5-FU co-treatment resulted in a dose-dependent suppression of the cell proliferation. Decreasing of phosphorylated signal transducers and activation of transcription 3 (STAT3) was included in suppression of p65 by TXN with 5-FU in combination. Additionally, the presence of TXN sensitized gastric cancer cells resistant to 5-FU to 5-FU-induced apoptosis by suppressing Bcl-2. The pro-apoptotic proteins of Bax and Bid were up-regulated, accompanied with Caspase cleavage, leading to apoptosis. Moreover, in mice xenograft models, the combined therapy inhibited tumor growth compared to the TXN or 5-FU treatment alone. Our data indicated a novel therapeutic strategy to potentiate 5-FU-induced anti-tumor effect in gastric cancer cells with resistance to 5-FU by TXN through suppression of p-STAT3/NF-κB (p65 and p50) and Bcl-2.



http://ift.tt/2qJv2PE

Numb had anti-tumor effects in prostatic cancer

Publication date: August 2017
Source:Biomedicine & Pharmacotherapy, Volume 92
Author(s): Ji Sun, Kai Wang, Jingfei Teng, Yufu Yu, Runmiao Hua, Haiyong Zhou, Dachuan Zhong, Yi Fan
AimThe aim of this study was to explain the Numb anti-cancer effects in the prostatic cancer.MethodsCollecting the 20 prostatic cancer patients and analyzing the correlation between Numb and Glease score. Transfection Numb into DU-145 and PC-3 cells, measuring the proliferation rate of difference groups by MTT assay, evaluating the cell apoptosis and cell cycle of difference group by Flow cytometry; measuring the invasion and migration abilities by transwell and wound healing assays. In the nude mice experiment, establish prostatic cancer nude mouse subcutaneous planting tumor model by DU-145 cells, Injection the Numb from tail vein. Evaluating the tumor volume and weight.ResultsThe Numb protein expression was decreased with Glease score increasing. The proliferation rate of Numb groups were significantly decreased compared with NC groups (P<0.05, respectively). The apoptosis and G1 phase rates of Numb groups were significantly enhanced compared with NC groups (P<0.05, respectively). The invasion and migration abilities of Numb group cells were significantly weaken compared with NC groups (P<0.05, respectively). In the WB assay, The relative proteins (Numb, P53, Cyclin D1, Rac1, MMP-2 and MMP-9) expression were significantly differences between NC and Numb groups (P<0.05, respectively). In the vivo experiment, the tumor volume and weight of Numb group was significantly lighter than NC group (P<0.05, respectively).ConclusionOverexpression Numb had anti-cancer effects to prostatic cancer in vitro and vivo experiments, the mechanism might be P53/Cyclin D1 and Rac1/MMP-2/-9 signaling pathway.



http://ift.tt/2pXI92z

Restoration of Arpin suppresses aggressive phenotype of breast cancer cells

Publication date: August 2017
Source:Biomedicine & Pharmacotherapy, Volume 92
Author(s): Yi Li, Jiliang Qiu, Ting Pang, Zhixing Guo, Yonghui Su, Qingan Zeng, Xuexia Zhang
Arpin, a negative regulator of the actin-related protein-2/3 (Arp2/3) complex, is downregulated and predicts poor prognosis in breast cancer patients. However, its biological relevance in breast cancer is still unclear. This study was conducted to investigate the roles of Arpin in breast cancer growth and invasion. We overexpressed Arpin expression in MCF-7 and MDA-MB-231 breast cancer cells and examined the effects of restoration of Arpin on cell proliferation, colony formation, cell cycle distribution, invasion in vitro and tumorigenesis in vivo. The related molecular mechanism(s) was determined. It was found that ectopic expression of Arpin significantly decreased cell proliferation, colony formation, and tumorigenicity. Flow cytometric analysis showed that overexpression of Arpin significantly increased the percentage of G0/G1-phase cells and decreased the percentage of S-phase cells. Moreover, restoration of Arpin impaired the invasiveness of breast cancer cells, as determined by Transwell invasion assays. Mechanistically, overexpression of Arpin inhibited the phosphorylation of Akt in breast cancer cells. Co-expression of a constitutively active form of Akt blunted the suppression of cell proliferation and invasion by Arpin. Taken together, we provide evidence that Arpin acts as a tumor suppressor in breast cancer, which is associated with inhibition of Akt signaling. Restoration of Arpin may represent a promising therapeutic strategy against breast cancer progression.



http://ift.tt/2qJv0Y2

Dual hypopigmentary effects of punicalagin via the ERK and Akt pathways

Publication date: August 2017
Source:Biomedicine & Pharmacotherapy, Volume 92
Author(s): Jun Seob Shin, Jun Hee Cho, Hana Lee, Hyo-Soon Jeong, Myo-Kyoung Kim, Hye-Young Yun, Nyoun Soo Kwon, Dong-Seok Kim
Punicalagin is a phenolic compound with antioxidant properties. However, the effects of punicalagin on melanin synthesis have been poorly evaluated. Therefore, we investigated the effects of punicalagin on melanogenesis in Mel-Ab cells. Punicalagin significantly inhibited melanin synthesis in a dose-dependent manner. In accordance with the melanin content, punicalagin also dose-dependently decreased tyrosinase activity. Punicalagin did not directly inhibit tyrosinase in a cell-free system but did downregulate the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase. Therefore, we examined the effects of punicalagin on melanogenesis-related signaling pathways. Punicalagin induced extracellular signal-regulated kinase (ERK) and Akt phosphorylation but had no effect on β-catenin level. We measured melanin content and MITF expression in the presence of the ERK pathway inhibitor PD98059 and/or the Akt pathway inhibitor LY294002. Cotreatment with PD98059 and LY294002 almost completely restored punicalagin-induced hypopigmentation. These data indicate that punicalagin inhibits melanin synthesis through ERK and Akt phosphorylation, with subsequent downregulation of MITF and tyrosinase.



http://ift.tt/2pXjhYK

Ezrin/NF-kB activation regulates epithelial- mesenchymal transition induced by EGF and promotes metastasis of colorectal cancer

Publication date: August 2017
Source:Biomedicine & Pharmacotherapy, Volume 92
Author(s): Yingru Li, Zhaoyu Lin, Bin Chen, Shuang Chen, Zhipeng Jiang, Taicheng Zhou, Zehui Hou, Youyuan Wang
There is growing evidence that epithelial mesenchymal-transition (EMT) plays significant roles in terms of tumor metastasis. There are a lot of cytokines inducing EMT of tumor cells, EGF is one of the important cytokines.Ezrin is a connexin between the cytoskeleton and the cell membrane, which is closely related to the morphological movement and metastasis of tumor cells.EGF can activate Ezrin and affects cell motility. In recent years, many studies have shown that NF-kB acts as an important transcription factor, involving in the process of EMT. However, does Ezrin participate in the regulation of EGF-induced EMT through the NF-kB pathway? This question needs us to discuss.In the present study, we found that EGF could induce colorectal cancer cells to develop EMT,enhance their ability to invade and migrate and promotes phosphorylation of Ezrin Tyr353.On the other hand, inhibition of Ezrin could reverse EGF-induced EMT and inhibit NF-kB P65 translocating into the nucleus. Finally, knockout of Ezrin inhibited EGF-induced lung metastasis of colorectal cancer xenografts and abnormal activation of Ezrin and NF-kB were related with colorectal cancer metastasis and poor prognosis. Our present results suggest that Ezrin/NF-kB pathway may provide experimental evidence for new targeted drugs for colorectal cancer metastasis.



http://ift.tt/2qJAW3f

A study of peritoneal metastatic xenograft model of colorectal cancer in the treatment of hyperthermic intraperitoneal chemotherapy with Raltitrexed

Publication date: August 2017
Source:Biomedicine & Pharmacotherapy, Volume 92
Author(s): Cen Qiu, Yueqi Li, Xin Liang, Yingxue Qi, Yiyang Chen, Xianke Meng, Hongtu Zheng, Ye Xu, Sanjun Cai, Guoxiang Cai, Jianwen Liu
Peritoneal metastasis of colorectal cancer is one of the most incident and fateful diseases among relapse cases. It shows a certain resistance to systemic chemotherapy. The perfusion system in clinic is complex and hard to be used in fundamental researches. This study aims at evaluating the effect of an improved hyperthermic intraperitoneal chemotherapy with Raltitrexed used in tumor-bearing mice with peritoneal metastatic colorectal carcinoma. The results showed that no severe adverse effect was observed. All control animals developed extensive peritoneal and mesenteric metastatic nodes. Tumor sites in the treatment groups were reduced significantly. The administration dose of Raltitrexed influenced concentration in systemic blood and peritoneal tissues. Temperature promoted the intracellular absorption of Raltitrexed significantly. Our findings reveal that hyperthermic intraperitoneal chemotherapy is an efficient therapy in treating peritoneal metastatic carcinoma in nude mice. It can effectively reduce the extension of carcinoma cells from macro and micro examination. The combination of hyperthermia and Raltitrexed resulted in an improved therapeutic effect on animal models.

Graphical abstract

http://ift.tt/2pXoakp

The Individual and Population Genetics of Antibody Immunity

Publication date: Available online 20 May 2017
Source:Trends in Immunology
Author(s): Corey T. Watson, Jacob Glanville, Wayne A. Marasco
Antibodies (Abs) produced by immunoglobulin (IG) genes are the most diverse proteins expressed in humans. While part of this diversity is generated by recombination during B-cell development and mutations during affinity maturation, the germ-line IG loci are also diverse across human populations and ethnicities. Recently, proof-of-concept studies have demonstrated genotype–phenotype correlations between specific IG germ-line variants and the quality of Ab responses during vaccination and disease. However, the functional consequences of IG genetic variation in Ab function and immunological outcomes remain underexplored. In this opinion article, we outline interconnections between IG genomic diversity and Ab-expressed repertoires and structure. We further propose a strategy for integrating IG genotyping with functional Ab profiling data as a means to better predict and optimize humoral responses in genetically diverse human populations, with immediate implications for personalized medicine.



http://ift.tt/2qJqmcJ

The effectiveness of the computerized visual perceptual training program on individuals with Down syndrome: An fMRI study

Publication date: July 2017
Source:Research in Developmental Disabilities, Volume 66
Author(s): Yi-Ting Wan, Ching-Sui Chiang, Sharon Chia-Ju Chen, Yee-Pay Wuang
This study investigated the effectiveness of the Computerized Visual Perception Training (CVPT) program on individuals with Down syndrome (DS, mean age=13.17±4.35years, age range: 6.54–20.75 years). All participants have mild intellectual disability classified by the standard IQ measures (mean=61.2, ranges from 55 to 68). Both the Test of Visual Perceptual Skill- Third Edition (TVPS-3) and functional magnetic resonance imaging (fMRI) were used to evaluate the training outcomes. Results of TVPS-3 and fMRI showed that DS group had visual perceptual deficits and abnormal neural networks related to visual organization. The results showed that DS intervention group had significant improvements on TVPS-3 after intervention. The fMRI results indicated more activation in superior and inferior parietal lobes (spatial manipulation), as well as precentral gyrus and dorsal premotor cortex (motor imagery) in DS intervention group. The CVPT program was effective in improving visual perceptual functions and enhancing associated cortical activations in DS.



http://ift.tt/2qJB6rv

Long-term outcomes in ypT0 rectal cancers: an international multi-centric investigation on behalf of Italian Society of Surgical Oncology Young Board (YSICO)

Publication date: Available online 19 May 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Laura Lorenzon, Dario Parini, Daniela Rega, Alfredo Mellano, Vincenzo Vigorita, Alberto Biondi, Raquel Jaminez-Rosellon, Maximilian Scheiterle, Ivana Giannini, Gaetano Gallo, Graziella Marino, Luca Turati, Patrizia Marsanic, Lorenzo De Franco, Luigi Marano
AimTo investigate the outcome and pattern of survivals of rectal cancer patients presenting a complete or nearly complete tumor response after neo-adjuvant treatment.MethodsYoung surgeons <40years old affiliated to the Italian Society of Surgical Oncology (YSICO) from 13 referral centers for colorectal cancer treatment, were invited to participate a retrospective study. Records from patients treated from 2005 to 2015 with a pathological diagnosis of ypT0/ypTis were retrieved and pooled in a common data-base for statistical purposes. All clinical and pathological variables were reviewed. Univariate and multivariate analyses were conducted with the end-point of survivals.ResultsTwo hundreds and sixty-one patients were analyzed including 237 ypT0 and 24 ypTis. Nodal positive patients were 8.7%. More than sixty-six percent of the patients did not perform adjuvant chemotherapy, with a statistical difference comparing N0 versus N+ patients (66.8% vs 40.9%, p 0.02). Mean follow-up was of 47.6 months. Twenty-two relapses were observed, 91.6% at a distant site. The mean time to recurrence was of 35.3 months. On univariate analysis, the use of adjuvant chemotherapy correlated with better OS exclusively in ypT0N+ patients and not in ypT0N0. Univariate and multivariate analyses documented nodal positivity as the only prognostic factor correlated with a worse OS.ConclusionRecurrences were mostly diagnosed at a distant site and within the third year of follow-up. Nodal positivity was the only variable independently correlated with a worse OS. Univariate analysis documented a benefit for the use of adjuvant chemotherapy treatment exclusively in ypT0N+ rectal cancers.



http://ift.tt/2rEbvj4

Segmentation of Lumen and Outer wall of Abdominal Aortic Aneurysms from 3D Black-Blood MRI with a Registration Based Geodesic Active Contour Model

Publication date: Available online 19 May 2017
Source:Medical Image Analysis
Author(s): Yan Wang, Florent Seguro, Evan Kao, Yue Zhang, Farshid Faraji, Chengcheng Zhu, Henrik Haraldsson, Michael Hope, David Saloner, Jing Liu
Segmentation of the geometric morphology of abdominal aortic aneurysm is important for interventional planning. However, the segmentation of both the lumen and the outer wall of aneurysm in magnetic resonance (MR) image remains challenging. This study proposes a registration based segmentation methodology for efficiently segmenting MR images of abdominal aortic aneurysms. The proposed methodology first registers the contrast enhanced MR angiography (CE-MRA) and black-blood MR images, and then uses the Hough transform and geometric active contours to extract the vessel lumen by delineating the inner vessel wall directly from the CE-MRA. The proposed registration based geometric active contour is applied to black-blood MR images to generate the outer wall contour. The inner and outer vessel wall are then fused presenting the complete vessel lumen and wall segmentation. The results obtained from 19 cases showed that the proposed registration based geometric active contour model was efficient and comparable to manual segmentation and provided a high segmentation accuracy with an average Dice value reaching 89.79%.



http://ift.tt/2pXenLu

The unresolved riddle of glucocorticoid withdrawal

Abstract

Glucocorticoid (GC) therapy is the most common cause of adrenal insufficiency (AI). The real prevalence of AI after GC is unknown but it could involve more than 30% of patients. Some gene variation has been associated with the variability of hypothalamic-pituitary-adrenal (HPA) axis and this issue could contribute to the individual variation of adrenal function after GC treatment. Symptoms and signs of AI are nonspecific and frequently the diagnosis is delayed. Dosage, duration of treatment, administration route and serum cortisol value are not completely useful to predict AI. Clinical estimation of HPA suppression is difficult and biochemical testing is needed to confirm the diagnosis of AI. The different tapering regimens are based on a very low quality of evidence and considering the sizable individual variation, it is improbable that future research will find a secure GC tapering schedule for all patients. The aim of this review is to address the most important aspects in management of GC withdrawal in light of current knowledge.

http://ift.tt/2rD3trc

Tall cell and diffuse sclerosing variants of papillary thyroid cancer: outcome and predicting value of risk stratification methods

Abstract

Purpose

Tall cell (TCV) and diffuse sclerosing (DSV) variants are aggressive variants of papillary thyroid cancer (PTC). We compared the risk of recurrent/persistent disease in patients with TCV, DSV and classical PTC (cPTC) and evaluated the prognostic accuracy of initial vs. ongoing risk stratification.

Methods

A consecutive series of DSV (n = 54), TCV (n = 72) and cPTC (n = 184) patients was retrospectively analyzed. TCV and DSV patients were first risk stratified for recurrent/persistent disease without considering the histotype as a risk factor and subsequently, 6–24 months after initial treatment, re-classified on the basis of the response to therapy (ongoing risk stratification).

Results

Extrathyroidal extension was more frequent in DSV than in TCV and cPTC patients (p < 0.05); moreover, only DSV tumors had a higher rate of recurrent/persistent disease when compared to cPTC treated with the same protocol (total thyroidectomy followed by ¹³¹I treatment) (p < 0.01). After initial treatment, 54.2% of TCV and 20.4% of DSV patients were classified at low risk, while at ongoing risk stratification, the excellent response (low risk) was higher for both TCV (77.8%) and DSV (50.0%) patients relative to initial stratification (both p < 0.01). Using ongoing risk classification, positive predictive value (PPV) for persistent/recurrent disease was higher relative to initial risk stratification for both TCV (PPV = 93.8 vs. 39.4%) and DSV (PPV = 63.0 vs. 34.9%), p < 0.05 for both.

Conclusions

In our series DSV, but not TCV patients, had poorer outcome than cPTC treated with the same protocol. Moreover, the ongoing risk stratification predicted outcome better than the initial classification in both TCV and DSV patients.

http://ift.tt/2r48qwd

Benefits of a regular vs irregular rhythm-based training programme on physical fitness and motor skills in obese girls

Abstract

Purpose

The aim of the current study was to examine the impact of a physical exercise programme including rhythmic elements (regular and irregular tempos) on physiological variables, motor skills (MS), and jump performances in obese girls.

Methods

Thirty-six obese girls (age: 10.4 ± 0.9 years, body mass: 58.7 ± 4.0 kg, height: 1.37 ± 0.04 m, body mass index: 31.2 ± 2.1) participated in three weekly physical exercise sessions for 6 weeks, with each session consisting of basic fundamental locomotor movements. The participants were divided into two groups: a control group (CG) and an experimental group (EG). CG performed the exercise in a quiet setting (i.e., without rhythmic accompaniment), whereas regular and irregular rhythmic accompaniments were prescribed in EG. The physical exercise programme included three sessions per week for 6 weeks. Each session was composed of three parts: 15 min of warm-up, followed by 40 min of exercises based on basic locomotor movements (i.e., running, hopping, skipping, jumping, leaping, sliding, galloping, throwing, catching, kicking, dribbling, and striking) and then 5 min of stretching. Each exercise was demonstrated by the teacher. Before and after the intervention period, cardiovascular measures (i.e., resting blood pressures, recovery for heart rate and systolic blood pressure, and recovery rate-pressure product) were made and five MS (i.e., running, hopping, leaping, jumping and dribbling) were evaluated in two conditions (i.e., during exercise with regular and irregular tempos). Moreover, performances on vertical jump tests (squat and countermovement jump tests) were measured.

Results

EG exhibited greater improvement in MS with a regular tempo (and sometimes an irregular tempo), cardiovascular components, and jump performances.

Conclusion

These findings demonstrate that physical exercise at various tempos is useful for improving physical fitness, developing MS, and thus probably preventing obesity complications.

http://ift.tt/2rD6YOu

A novel dual-wavelength laser stimulator to elicit transient and tonic nociceptive stimulation

Abstract

This study aimed to develop a new laser stimulator to elicit both transient and sustained heat stimulation with a dual-wavelength laser system as a tool for the investigation of both transient and tonic experimental models of pain. The laser stimulator used a 980-nm pulsed laser to generate transient heat stimulation and a 1940-nm continuous-wave (CW) laser to provide sustained heat stimulation. The laser with 980-nm wavelength can elicit transient pain with less thermal injury, while the 1940-nm CW laser can effectively stimulate both superficial and deep nociceptors to elicit tonic pain. A proportional integral-derivative (PID) temperature feedback control system was implemented to ensure constancy of temperature during heat stimulation. The performance of this stimulator was evaluated by in vitro and in vivo animal experiments. In vitro experiments on totally 120 specimens fresh pig skin included transient heat stimulation by 980-nm laser (1.5 J, 10 ms), sustained heat stimulation by 1940-nm laser (50–55 °C temperature control mode or 1.5 W, 5 min continuous power supply), and the combination of transient/sustained heat stimulation by dual lasers (1.5 J, 10 ms, 980-nm pulse laser, and 1940-nm laser with 50–55 °C temperature control mode). Hemoglobin brushing and wind-cooling methods were tested to find better stimulation model. A classic tail-flick latency (TFL) experiment with 20 Wistar rats was used to evaluate the in vivo efficacy of transient and tonic pain stimulation with 15 J, 100 ms 980-nm single laser pulse, and 1.5 W constant 1940-nm laser power. Ideal stimulation parameters to generate transient pain were found to be a 26.6 °C peak temperature rise and 0.67 s pain duration. In our model of tonic pain, 5 min of tonic stimulation produced a temperature change of 53.7 ± 1.3 °C with 1.6 ± 0.2% variation. When the transient and tonic stimulation protocols were combined, no significant difference was observed depending on the order of stimuli. Obvious tail-flick movements were observed. The TFL value of transient pain was 3.0 ± 0.8 s, and it was 4.4 ± 1.8 s for tonic pain stimulation. This study shows that our novel design can provide effective stimulation of transient pain and stable tonic pain. Furthermore, it can also provide a reliable combination of transient and consistent stimulations for basic studies of pain perception.

http://ift.tt/2r3M3qC

Correlates of khat use during pregnancy: A cross-sectional study

Publication date: October 2017
Source:Addictive Behaviors, Volume 73
Author(s): Motohiro Nakajima, Mulusew G. Jebena, Mohammed Taha, Markos Tesfaye, Esayas Gudina, Andrine Lemieux, Richard Hoffman, Mustafa al'Absi
ObjectivesKhat is widely used in East African countries including Ethiopia. A growing body of evidence indicates that long-term khat use is associated with various health consequences. The aim of this study was to examine the magnitude and correlates of khat use in pregnant women.MethodsThis study used a cross-sectional, face-to-face interview design that included 642 pregnant women receiving antenatal care services at primary care centers in Ethiopia. A series of chi-square tests and regression models were conducted to examine whether khat use status (i.e., 123 current khat users, 41 former khat users, and 478 non-users) was associated with socio-demographic, mental distress, and substance use measures.ResultsAs compared with non-users, current and former khat users had higher levels of depressive symptoms and distress. Khat users minimized potential health risks associated with khat use. Social and motivational factors related to khat use were different between current and former khat users.ConclusionsFindings of this study suggest a substantial prevalence of khat use among pregnant women in Ethiopia and highlight the role of socio-demographic and cultural influences on khat use during pregnancy. Health care professionals in the region where khat is available are encouraged to ask their female patients about khat use and encourage them to refrain from use while they are pregnant. The positive link between khat and mental distress warrants further research focusing on biological, psychological, and social mechanisms of this relationship.



http://ift.tt/2pX15ON

Is subclinical gambling really subclinical?

Publication date: October 2017
Source:Addictive Behaviors, Volume 73
Author(s): Jeremiah Weinstock, Laura M. April, Selmi Kallmi
Gambling disorder and substance use disorders (SUD) overlap in terms of etiology and diagnostic constructs (e.g., preoccupation, loss of control), yet diagnostic thresholds for the disorders are different. Currently, endorsing 2–3 gambling disorder criteria does not warrant a diagnosis while endorsing 2–3 SUD criteria does. The aim of this study was to examine whether subclinical gamblers (i.e., endorsing 2–3 gambling disorder criteria) experience psychosocial dysfunction equivalent to individuals who are diagnosed with mild severity SUD (i.e., 2–3 SUD criteria) and whether this level of dysfunction is significantly different from individuals with no psychopathology. Data are from the first wave of Quinte Longitudinal Study, a large epidemiological sample (N=4121). Psychometrically supported measures assessed for psychosocial functioning and the presence of Axis-I psychiatric disorders. Cross-sectional analysis examined 7 domains of psychosocial functioning using ANCOVA, which allowed for the inclusion of covariates, to test for difference between subclinical gamblers and individuals with no psychopathology and individuals with mild severity SUD. Equivalency testing compared subclinical gamblers in relation to mild severity SUD. Subclinical gamblers reported significantly poorer psychosocial functioning in relation to individuals endorsing no current psychopathology. Subclinical gamblers were also equivalent to and not significantly different from individuals with mild severity SUD. Subclinical gamblers experience similar psychosocial impairment to those individuals who endorse mild severity SUD, and this significantly differed from healthy individuals. The threshold for diagnosis of gambling disorder therefore warrants re-examination.



http://ift.tt/2qJwlOI

Academy of Nutrition and Dietetics Nutrition Practice Guideline for Type 1 and Type 2 Diabetes in Adults: Systematic Review of Evidence for Medical Nutrition Therapy Effectiveness and Recommendations for Integration into the Nutrition Care Process

Publication date: Available online 19 May 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Marion J. Franz, Janice MacLeod, Alison Evert, Catherine Brown, Erica Gradwell, Deepa Handu, Adam Reppert, Megan Robinson




http://ift.tt/2q7B5vD

Multi-Institutional Development of a Mastoidectomy Performance Evaluation Instrument

Publication date: Available online 20 May 2017
Source:Journal of Surgical Education
Author(s): Thomas Kerwin, Brad Hittle, Don Stredney, Paul De Boeck, Gregory Wiet
ObjectiveA method for rating surgical performance of a mastoidectomy procedure that is shown to apply universally across teaching institutions has not yet been devised. This work describes the development of a rating instrument created from a multi-institutional consortium.DesignUsing a participatory design and a modified Delphi approach, a multi-institutional group of expert otologists constructed a 15-element task-based checklist for evaluating mastoidectomy performance. This instrument was further refined into a 14-element checklist focusing on the concept of safety after using it to rate a large and varied population of performances.SettingTwelve otolaryngological surgical training programs in the United States.ParticipantsA total of 14 surgeons from 12 different institutions took part in the construction of the instrument.ResultsBy using 14 experts from 12 different institutions and a literature review, individual metrics were identified, rated as to the level of importance and operationally defined to create a rating scale for mastoidectomy performance. Initial use of the rating scale showed modest rater agreement. The operational definitions of individual metrics were modified to emphasize "safe" as opposed to "proper" technique. A second rating instrument was developed based on this feedback.ConclusionsUsing a consensus-building approach with multiple rounds of communication between experts is a feasible way to construct a rating instrument for mastoidectomy. Expert opinion alone using a Delphi method provides face and content validity evidence, however, this is not sufficient to develop a universally acceptable rating instrument. A continued process of development and experimentation to demonstrate evidence for reliability and validity making use of a large population of raters and performances is necessary to achieve universal acceptance.



http://ift.tt/2r40MSG

Special Issue: Progress in Biological Understanding of Cancer Metastasis

Publication date: Available online 20 May 2017
Source:Seminars in Cancer Biology
Author(s): Ira-Ida Skvortsova




http://ift.tt/2pX4MnU

Carbon nanomaterials as versatile platforms for theranostic applications

Publication date: Available online 19 May 2017
Source:Drug Discovery Today
Author(s): Mirae Kim, Jinhyeong Jang, Chaenyung Cha
Theranostic nanomedicine, utilizing state-of-the-art, multifaceted nanomaterials and devices with therapeutic and diagnostic dual functions, has emerged as a highly attractive and promising new field of medicine. The theory behind the use of nanomaterials for theranostic applications is to impart multifunctionality by applying various engineering strategies to combine different modalities on a nanoscale. Carbon nanomaterials, which have been a subject of intense scientific research and industrial applications in recent years, have also found their way into theranostic nanomedicine owing to their innate multifunctionality. In this review, we outline recent research progress and trends in utilizing various types of carbon nanomaterial for theranostic applications.



http://ift.tt/2rDECCO

Targeting EGFR/HER2 heterodimerization with a novel anti-HER2 domain II/III antibody

Publication date: July 2017
Source:Molecular Immunology, Volume 87
Author(s): Xiaojie Yu, Lingfei Wang, Yafeng Shen, Chao Wang, Yajun Zhang, Yanchun Meng, Yang Yang, Beibei Liang, Bo Zhou, Huajing Wang, Huafeng Wei, Changhai Lei, Shi Hu, Bohua Li
HER2, a ligand-free tyrosine kinase receptor of the HER family, is frequently overexpressed in breast cancer. The anti-HER2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer. Despite the effectiveness of trastuzumab, its efficacy remains variable and often modest. Thus, there is an urgent need to improve ErbB2-targeting therapy. Here, we describe a novel anti-HER2 antibody, 7C3, which was developed using hybridoma technique. Structural analysis confirms that the epitope of this antibody is in domain II/III of HER2. Moreover, a structural conformation change was observed in HER2 in complex with 7C3. Interestingly, this novel anti-HER2 antibody exhibits efficacy in blocking HER2/EGFR heterodimerization and signaling. The results highlight the different function role of HER2 domains and the unique potential of 7C3 to inhibit the HER2/EGFR heterodimer, which may complement current anti-HER2 treatments.



http://ift.tt/2q7bYc5

Immunomodulatory function of whole human umbilical cord derived mesenchymal stem cells

Publication date: July 2017
Source:Molecular Immunology, Volume 87
Author(s): Hao Zhang, Yanling Tao, Haihui Liu, Saisai Ren, Bin Zhang, Hu Chen
Bone marrow derived mesenchymal stem cells (MSCs) play a critical role in immune modulation. However, immunomodulatory function of whole human umbilical cord derived mesenchymal stem cells (UC-MSCs) remains unclear. In this study, UC-MSCs were separated from whole umbilical cord using a single enzyme digestion. UC-MSCs (CD73⁺, CD90⁺, CD105⁺, and CD34⁻, CD45⁻, HLA-DR⁻) were differentiated into adipocytes, osteocytes and chondrocytes in vitro under specific stimulatory environments. UC-MSCs suppressed umbilical cord blood lymphocyte proliferation stimulated by mitogen, and ELISA showed that the secretion of INF-γ was downregulated, and the secretion of IL-4 was upregulated, with CD8⁺ T cells markedly decreased and CD4⁺ T cells changed lightly. Moreover, the infusion of UC-MSCs in recipient mice transplanted with donor bone marrow cells ameliorated acute graft-versus host disease (aGVHD) and extended survival. In conclusion, UC-MSCs might negatively modulate immunoreactions, and have application potential in the treatment of aGVHD caused by allogeneic stem cells transplantation.



http://ift.tt/2qCoOm9

Chicken interleukin-1β mutants are effective single-dose vaccine adjuvants that enhance mucosal immune response

Publication date: July 2017
Source:Molecular Immunology, Volume 87
Author(s): Wen-Ting Chen, Hao-Kai Chang, Cheng-Chung Lin, Shan-Min Yang, Hsien-Sheng Yin
The use of cytokines as adjuvants in poultry is promising because they may enhance immune responses to antigens. In this study, we created two mutants, chicken interleukin-1 beta (ChIL-1β) Q19A and R140A, which exhibited significantly increased in vivo biological activity compared with wild-type ChIL-1β. The potential mucosal adjuvant activity of the mutants Q19A and R140A was evaluated in chickens through the intranasal coadministration of a single dose of the Newcastle disease virus (NDV) vaccine with Q19A or R140A. Compared with chickens vaccinated with only the NDV vaccine or the NDV vaccine plus wild-type recombinant ChIL-1β, chickens vaccinated with Q19A or R140A had significantly increased serum hemagglutination-inhibition antibody titers and anti-NDV-specific IgA antibody levels 1 week later, a high amount of interferon-γ secretion from splenocytes, and increased secretory IgA accumulated in nasal tissues. In addition, molecular dynamics simulations of the mutant R140A bound to its receptor (IL-1RI) and receptor accessory protein (IL-1RAcP) were more energetically favorable than the analogous wild-type ternary complex resulting in a decreased energy, which may stabilize the R140A/IL-1RI/IL-1RAcP complex. In conclusion, the mutants Q19A and R140A are effective adjuvants that accelerate and enhance chicken mucosal immunity when co-administered with one dose of the NDV vaccine.



http://ift.tt/2q77Bhp

Letter to the editor: “A case of Guillain-Barré syndrome with meningeal irritation”

Publication date: Available online 19 May 2017
Source:Brain and Development
Author(s): Ibtihel Rebai, Nedia Ben Achour, Emna El Mabrouk, Ichraf Kraoua, Ilhem Ben Youssef-Turki




http://ift.tt/2rD15RA

Genotoxic potential of dental bulk-fill resin composites

Publication date: Available online 20 May 2017
Source:Dental Materials
Author(s): Tobias T. Tauböck, Danijela Marovic, Davor Zeljezic, Andrea D. Steingruber, Thomas Attin, Zrinka Tarle
ObjectiveTo investigate both genotoxicity and hardening of bulk-fill composite materials applied in 4-mm layer thickness and photo-activated for different exposure times.MethodsThree flowable bulk-fill materials and one conventional flowable composite were filled in molds (height: 4mm) and irradiated for 20 or 30s. The top (0mm) and bottom (4mm) specimen surface were mechanically scraped, and eluates (0.01g composite in 1.5ml RPMI 1640 cell culture media) prepared for each material, surface level and irradiation time. Genotoxicity was assessed in human leukocytes using both the alkaline comet assay and cytokinesis-blocked micronucleus assay, and Knoop hardness (KHN) was measured at the top and bottom specimen surface (n=8).ResultsAt both irradiation times, none of the bulk-fill composites significantly affected comet assay parameters used in primary DNA damage assessment or induced significant formation of any of the scored chromatin abnormalities (number of micronuclei, nuclear buds, nucleoplasmic bridges), whether eluates were obtained from the top or bottom surface. Furthermore, no decrease in KHN from the top to the bottom surface of the bulk-fill materials was observed. On the other hand, the conventional composite irradiated for 20s showed at 4-mm depth a significant increase in the percentage of DNA that migrated in the tail and a significant increase in the number of nuclear buds, as well as a significant decrease in KHN relative to the top surface.SignificanceBulk-fill resin composites, in contrast to conventional composite, applied in 4-mm thickness and photo-activated for at least 20s do not induce relevant genotoxic effects or mechanical instability.



http://ift.tt/2r3DA78

Fracture resistance of molar teeth with mesial-occlusal-distal (MOD) restorations

Publication date: Available online 20 May 2017
Source:Dental Materials
Author(s): Herzl Chai, Brian R. Lawn
ObjectiveFilled MOD restorations show near-complete recovery of tooth strength relative to the newly prepared, unfilled state. The present study examines the underlying mechanics of this recovery by more closely quantifying the mode of splitting fracture from the cavity base. By understanding the role of specific cavity dimensions on fracture resistance, useful clinical guidelines concerning MOD morphologies are formulated.MethodsA systematic in vitro study is made of the load-bearing capacity of filled and unfilled MOD cavities by axially loading extracted molar teeth with a hard metal ball. Filled and unfilled cavities are considered as bounding cases. Focus is placed on drillings with rectangular or rounded tips, covering a range of cavity widths and depths. The failure process is monitored during loading by a video camera, enabling the entire damage evolution from first contact to ultimate failure to be recorded.SignificanceWhile respecting the widely accepted clinical practice of drilling cavities with internal widths less than one third that of the entire tooth, a stronger correlation is obtained between critical splitting load PC and ratio of cavity wall thickness h (distance between cavity wall and outer tooth surface) to cavity depth D. Imposing a conservative upper limit on PC for tooth survival, the study recommends that MOD cavities be prepared such that the ratio remains in the region h>D, regardless of the tooth size.



http://ift.tt/2rCHhgW

Experimental hydrophilic vinyl polysiloxane (VPS) impression materials incorporating a novel surfactant compared with commercial VPS

Publication date: Available online 20 May 2017
Source:Dental Materials
Author(s): Shahab Ud Din, Sandra Parker, Michael Braden, Pete Tomlins, Mangala Patel
ObjectivesTo formulate experimental hydrophilic (Exp) VPS impression materials incorporating a novel surfactant (Rhodasurf CET-2), and to compare their contact angles (CAs) with commercial materials, before/after disinfection.MethodsCAs were measured immediately after setting and after disinfection (1% NaOCl; 30min and 24h), together with their change whilst a droplet remained on the materials surface (over 10, 20, 30 60 and 120s), on three commercial (Aquasil Ultra-Monophase [Aq M], Elite HD-Monophase [Elt M], Extrude Medium-bodied [Extr M]) and four experimental (Exp I–IV) materials, using the Drop Shape Analysis 100 technique. The results were compared statistically.ResultsCAs of all experimental materials were within the range of those obtained for the commercial materials, with the exception of Exp-IV, which presented with the lowest CAs at the three time points. The control Exp-I was hydrophobic at all three time points (CAs ∼100+), as was Elite. Immediately after setting, Aq M had low CAs but these increased significantly after 30min of disinfection. After twenty four hours' disinfection CAs of all Exp/commercial VPS increased significantly compared to immediately after setting. The CAs of droplets left on the material (120s) decreased with time, even after disinfection, except for Exp-I.SignificanceThe novel surfactant Rhodasurf CET-2 in Exp-III and IV, is an effective surfactant, retaining a low CA after disinfection, compared with Igepal CO-530 in Aq M. Disinfecting VPS impression materials for more than 30min increases their surface CAs, and therefore prolonged disinfection periods should be avoided.



http://ift.tt/2r3q0QX

Clinical Thyroidology High-Impact Articles

FREE ACCESS through May 30, 2017
Read Now:

Surgery for Neck Recurrence of Thyroid Cancer Can Achieve Complete Remission in a Majority of Patients
Jerome M. Hershman, Masha J. Livhits

How Often Does a Thyroid Cancer Patient Need to Undergo Surveillance with Cervical Ultrasound?
Martin Biermann

A New Assessment of the Prevalence and Risk Factors of Liver Abnormalities in Hyperthyroidism
Jacques Orgiazzi

Higher Preconception TSH Values Are Associated With Adverse Obstetric Outcomes
Elizabeth N. Pearce

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

http://ift.tt/2pWIbHT

Which patients with inoperable vulvar cancer may benefit from brachytherapy in addition to external beam radiation? A Surveillance, Epidemiology, and End Results analysis

Publication date: Available online 19 May 2017
Source:Brachytherapy
Author(s): Yuan James Rao, Caressa Hui, Anupama Chundury, Julie K. Schwarz, Todd DeWees, Matthew A. Powell, David G. Mutch, Perry W. Grigsby
PurposeIt is unknown whether brachytherapy after external beam radiation (EBRT + BT) results in improved outcomes compared with EBRT alone for patients with inoperable vulvar cancer. The purpose of this study was to compare survival outcomes for patients who received these treatment modalities.Methods and MaterialsData between 1973 and 2011 from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database were analyzed. Patients with Federation of International Gynecologists and Obstetricians stage I-IVA vulvar cancer treated with definitive EBRT + BT or EBRT alone were included. Patients with prior surgical resection were excluded. Disease-specific survival (DSS) and overall survival were compared using the Kaplan–Meier method and Cox proportional hazard models.ResultsA total of 649 patients were analyzed, of which 617 received EBRT alone and 32 received EBRT + BT. Median follow-up was 33 months in surviving patients. The use of brachytherapy declined from 16% of cases treated in 1973–1980 to 4% in 2001–2011 (p = 0.04). EBRT + BT vs. EBRT alone was not significantly associated with improved DSS (45% vs. 33% at 5 years) or overall survival (34% vs. 24% at 5 years) on univariate or multivariate analyses. On post hoc subgroup analyses, brachytherapy consolidation was associated with higher 5-year DSS in a composite subgroup that included patients with stage IVA disease, tumor >4 cm, or node-positive disease (52% vs. 27%, p = 0.02).ConclusionsUtilization of BT consolidation with EBRT for vulvar cancer is declining in the United States. EBRT + BT is not associated with improved survival compared with EBRT alone in the overall group of patients. Certain subgroups of patients might benefit from brachytherapy, but this hypothesis requires validation in future studies.



http://ift.tt/2roSy7h

Comparison of implant stability measurement devices for bone-anchored hearing aid systems

Publication date: Available online 20 May 2017
Source:The Journal of Prosthetic Dentistry
Author(s): Lindsey Westover, Gary Faulkner, William Hodgetts, Don Raboud
Statement of problemThe success of implants for bone-anchored hearing aids (BAHA) relies on proper osseointegration at the bone-implant interface. Clinical evaluation of implant stability is important in prescribing loading, identifying the risk of failure, and monitoring the long-term health of the implant.PurposeThe purpose of this in vitro study was to evaluate 2 measurement systems for BAHA implant stability: the most commonly used, Osstell implant stability quotient (ISQ), and a newly developed advance system for implant stability testing (ASIST).Material and methodsBAHA implants (Oticon Medical Ponto and Cochlear BAHA Connect systems) were installed in plastic materials with adhesive to simulate implants integrated in bone with varying levels of interface stiffness. Different lengths of BAHA abutments were used with each implant specimen, and stability measurements were obtained with both the Osstell ISQ and the ASIST systems. The measurement systems were evaluated in terms of sensitivity to differences in interface stiffness and the effect of abutment length on the stability measurement. Repeated measures ANOVA followed by post hoc t tests were used for the comparisons with a Bonferroni adjusted alpha value of .05/15 = .003 to control for potential type 1 errors.ResultsChanging the abutment length of a single implant installation had minimal effect on the ASIST stability coefficient, whereas large variations were observed in the Osstell implant stability quotient (ISQ). The Osstell showed a clear relationship of decreasing ISQ with increasing abutment length for both the Oticon Medical and the Cochlear implant systems. Both the ASIST and the Osstell were found to be sensitive to changes in interface properties, with the ASIST being more sensitive to these changes.ConclusionsThe ASIST system is more sensitive to changes in interface properties and shows smaller variation because of changes in abutment length than the Osstell ISQ system.



http://ift.tt/2rDsD8z