Extensive intraneural fascicular dissection of a lipofibromatous hamartoma of the ulnar digital nerve of the thumb

Abstract

Lipofibromatous hamartoma (LFH) is a rare, benign fibrofatty tumor of the peripheral nerves. Only a handful of cases have been reported in the literature, together with cases of LFH of the digital branches of the median nerve. The median nerve is the most commonly affected site. Different treatment approaches to LFH have been described according to the clinical presentation. A case of LFH of the ulnar digital nerve of the left thumb that underwent extensive intraneural fascicular dissection and mass excision is described in this paper. Good results were obtained, i.e., pain relief and good cosmesis. Extensive intraneural fascicular dissection and mass excision are considered to be a good management option for LFH of the digital branches of the median nerve, without the requirement of nerve excision or nerve grafting.

Level of evidence: Level V, therapeutic study.

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Activatable fluorescent probes in fluorescence-guided surgery: Practical considerations

Publication date: 15 February 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 4
Author(s): Ai Mochida, Fusa Ogata, Tadanobu Nagaya, Peter L. Choyke, Hisataka Kobayashi
Fluorescence-guided imaging during surgery is a promising technique that is increasingly used to aid surgeons in identifying sites of tumor and surgical margins. Of the two types of fluorescent probes, always-on and activatable, activatable probes are preferred because they produce higher target-to-background ratios, thus improving sensitivity compared with always-on probes that must contend with considerable background signal. There are two types of activatable probes: 1) enzyme-reactive probes that are normally quenched but can be activated after cleavage by cancer-specific enzymes (activity-based probes) and 2) molecular-binding probes which use cancer targeting moieties such as monoclonal antibodies to target receptors found in abundance on cancers and are activated after internalization and lysosomal processing (binding-based probes). For fluorescence-guided intraoperative surgery, enzyme-reactive probes are superior because they can react quickly, require smaller dosages especially for topical applications, have limited side effects, and have favorable pharmacokinetics. Enzyme-reactive probes are easier to use, fit better into existing work flows in the operating room and have minimal toxicity. Although difficult to prove, it is assumed that the guidance provided to surgeons by these probes results in more effective surgeries with better outcomes for patients. In this review, we compare these two types of activatable fluorescent probes for their ease of use and efficacy.

Graphical abstract

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Development of a stereoselective and scalable process for the preparation of a methylcyclobutanol-pyridyl ether

Publication date: 15 February 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 4
Author(s): Jeffrey T. Kuethe, Kallol Basu, Robert K. Orr, Eric Ashley, Marc Poirier, Lushi Tan
The evolution of a scalable process for the preparation of methylcyclobutanol-pyridyl ether 1 is described. Key aspects of this development including careful control of the stereochemistry, elimination of chromatography, and application to kilogram-scale synthesis are addressed.

Graphical abstract

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Unprecedented sugar bridged bisindoles selective inhibiting glioma stem cells

Publication date: Available online 16 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Xin Wei, Zhi Dai, Jing Yang, Afsar Khan, Hao-Fei Yu, Yun-Li Zhao, Yi-Fen Wang, Ya-Ping Liu, Zi-Feng Yang, Wan-Yi Huang, Xin-Hua Wang, Xu-Dong Zhao, Xiao-Dong Luo
Unlike reported bisindoles linked by single bond directly, alstoniasidines A (1) and B (2), from Alstonia scholaris featuring unprecedented skeleton with two indole moieties bridged by a sugar, represented a novel bisindole type having strictosamide-glucopyranose-picraline scafford. Both compounds exhibited selective cytotoxicity against human glioma stem cells (GSCs) and induced caspase-3 dependent extrinsic apoptosis by increasing the expression of interleukin 1 (IL-1), tumor necrosis factor (TNF-α), and the cleaved caspase-3, while damaged the unlimited proliferation and self-renewal capacity of GSCs. This finding might provide new type of leads for the selective killing of human glioma stem cells.

Graphical abstract

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Discovery of 18β-glycyrrhetinic acid conjugated aminobenzothiazole derivatives as Hsp90–Cdc37 interaction disruptors that inhibit cell migration and reverse drug resistance

Publication date: Available online 16 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Le Jin, Rizhen Huang, Xiaochao Huang, Bin Zhang, Min Ji, Hengshan Wang
A series of 18β-glycyrrhetinic acid (GA) conjugated aminobenzothiazole derivatives were designed, synthesized and evaluated for disruption activity of Hsp90-Cdc37 as well as the effects of in vitro cell migration. These compounds exhibited relatively good disruption activity against Hsp90-Cdc37 with IC50 values in low micromolar range. A docking study of the most active compound 11g revealed key interactions between 11g and Hsp90-Cdc37 complex in which the benzothiazole moiety and the amine chain group were important for improving activity. It is noteworthy that further antitumor activity screening revealed that some compounds exhibited better inhibitory activity than the commercial anticancer drug 5-FU and showed potent suppression activity against drug-resistant cancer cells. In particular, compound 11g appeared to be the most potent compound against the A549 cell line, at least partly, by inhibition of the activity of Hsp90 and apoptosis induction. The treatment of A549 cells with compound 11g resulted in inhibition of in vitro cell migration through wound healing assay and S phase of cell cycle arrested. In addition, 11g-induced apoptosis was significantly facilitated in A549 cells. Thus, we conclude that GA aminobenzothiazole derivatives may be the potential Hsp90-Cdc37 disruptors with the ability to suppress cells migration and reversed drug-resistant.

Graphical abstract

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Editorial Board

Publication date: 15 February 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 4





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Graphical Abstract TOC continued

Publication date: 15 February 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 4





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Optimization of antimalarial, and anticancer activities of (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate

Publication date: 15 February 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 4
Author(s): Jesús A. Romero, María E. Acosta, Neira D. Gamboa, Michael R. Mijares, Juan B. De Sanctis, Jaime E. Charris
Chemically modified versions of bioactive substances, are particularly useful in overcoming barriers associated with drug formulation, drug delivery and poor pharmacokinetic properties. In this study, a series of fourteen (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate (2–15) were prepared by using a one step synthesis from 1 previously described by us as potential antimalarial and antitumor agent. Molecules were evaluated as inhibitors of β-hematin formation, where most of them showed a significant inhibition value (% > 70). The best inhibitors were tested in vivo as potential antimalarials in mice infected with P. berghei ANKA, chloroquine susceptible strain. Three of them (5, 6, and 15) displayed antimalarial activity comparable to that of chloroquine. Also, molecules were evaluated for their cytotoxic activity against two human cancer cell lines (Jurkat E6.1 and HL60) and primary culture of human lymphocytes. Most of the synthesized compounds, except for analogs 2–6, 8, and 10–12, displayed cytotoxicity against cancer cell lines without affecting normal cells. The potency of the compounds was 15 ≫ 1, and 14 > 7, 9, and 13. Flow cytometry analysis demonstrated an increase in apoptotic cell death after 24 h. The compounds may affect tumor cell autophagy and consequently increase cell apoptosis.

Graphical abstract

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Post-Cardiac Arrest Management: Time to Cool It on Cooling?

No abstract available

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Targeted Temperature Management After Cardiac Arrest: Systematic Review and Meta-analyses

BACKGROUND: Targeted temperature management (TTM) with therapeutic hypothermia is an integral component of postarrest care for survivors. However, recent randomized controlled trials (RCTs) have failed to demonstrate the benefit of TTM on clinical outcomes. We sought to determine if the pooled data from available RCTs support the use of prehospital and/or in-hospital TTM after cardiac arrest. METHODS: A comprehensive search of SCOPUS, Elsevier's abstract and citation database of peer-reviewed literature, from 1966 to November 2016 was performed using predefined criteria. Therapeutic hypothermia was defined as any strategy that aimed to cool post–cardiac arrest survivors to a temperature ≤34°C. Normothermia was temperature of ≥36°C. We compared mortality and neurologic outcomes in patients by categorizing the studies into 2 groups: (1) hypothermia versus normothermia and (2) prehospital hypothermia versus in-hospital hypothermia using standard meta-analytic methods. A random effects modeling was utilized to estimate comparative risk ratios (RR) and 95% confidence intervals (CIs). RESULTS: The hypothermia and normothermia strategies were compared in 5 RCTs with 1389 patients, whereas prehospital hypothermia and in-hospital hypothermia were compared in 6 RCTs with 3393 patients. We observed no difference in mortality (RR, 0.88; 95% CI, 0.73–1.05) or neurologic outcomes (RR, 1.26; 95% CI, 0.92–1.72) between the hypothermia and normothermia strategies. Similarly, no difference was observed in mortality (RR, 1.00; 95% CI, 0.97–1.03) or neurologic outcome (RR, 0.96; 95% CI, 0.85–1.08) between the prehospital hypothermia versus in-hospital hypothermia strategies. CONCLUSIONS: Our results suggest that TTM with therapeutic hypothermia may not improve mortality or neurologic outcomes in postarrest survivors. Using therapeutic hypothermia as a standard of care strategy of postarrest care in survivors may need to be reevaluated.

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Perioperative Cardiac Arrest: Focus on Malignant Hyperthermia (MH)

No abstract available

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Perioperative Cardiac Arrest: Focus on Local Anesthetic Systemic Toxicity (LAST)

No abstract available

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Perioperative Cardiac Arrest: Focus on Anaphylaxis

No abstract available

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Cardiac Arrest in the Operating Room: Part 2—Special Situations in the Perioperative Period

As noted in part 1 of this series, periprocedural cardiac arrest (PPCA) can differ greatly in etiology and treatment from what is described by the American Heart Association advanced cardiac life support algorithms, which were largely developed for use in out-of-hospital cardiac arrest and in-hospital cardiac arrest outside of the perioperative space. Specifically, there are several life-threatening causes of PPCA of which the management should be within the skill set of all anesthesiologists. However, previous research has demonstrated that continued review and training in the management of these scenarios is greatly needed and is also associated with improved delivery of care and outcomes during PPCA. There is a growing body of literature describing the incidence, causes, treatment, and outcomes of common causes of PPCA (eg, malignant hyperthermia, massive trauma, and local anesthetic systemic toxicity) and the need for a better awareness of these topics within the anesthesiology community at large. As noted in part 1 of this series, these events are always witnessed by a member of the perioperative team, frequently anticipated, and involve rescuer–providers with knowledge of the patient and the procedure they are undergoing or have had. Formulation of an appropriate differential diagnosis and rapid application of targeted interventions are critical for good patient outcome. Resuscitation algorithms that include the evaluation and management of common causes leading to cardiac in the perioperative setting are presented. Practicing anesthesiologists need a working knowledge of these algorithms to maximize good outcomes.

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Syndromic sebaceous nevus: current findings

Abstract

Background

Sebaceous nevus is a congenital malformation of the skin that usually occurs on the scalp or face. Syndromic forms do rarely exist with associated cerebral and ocular malformations. The skin lesions are pale at birth and become irregular by puberty. In the adult patient, tumors (usually benign) develop from sebaceous nevus. Their surgical excision during childhood can give a better result in terms of the definitive scar.

Objectives

The aim of this study is to analyze our cases of syndromic sebaceous hamartoma, perform a review of the existing literature, and propose guidelines for the therapeutic plan.

Methods

This is a retrospective study reviewing the cases of syndromic sebaceous nevus treated in the Department of Orthopedic Plastic Pediatric Surgery in Montpellier, France, and the Department of Pediatric Surgery in Lausanne, Switzerland, between 1994 and 2016.

Results

The files of six patients with syndromic sebaceous nevus were analyzed. The average age at the first consultation was 4 months. The location was craniofacial in all cases. Cerebral radiological imaging was performed on all patients; two showed abnormal findings. Four patients underwent ophthalmic examination, which all revealed abnormalities. Three patients had other associated malformations. Three patients presented with epilepsy or learning difficulties in the course of follow-up.

Conclusion

All patients presenting with extensive sebaceous nevus of the craniofacial region should benefit from cerebral imagery and ophthalmic examination since there is a very high probability of associated abnormalities. The developmental problems encountered could not be definitively associated with the skin malformations.

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Eosinophilic polymorphic and pruritic eruption associated with radiotherapy in a patient with primary nodal Merkel cell carcinoma

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Treatment optimization with secukinumab 150 mg for moderate-to-severe psoriasis in clinical practice: a single-center open-label 52-week study

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Photobiomodulation (PBM) therapy at 904 nm mitigates effects of exercise-induced skeletal muscle fatigue in young women

Abstract

Muscle fatigue is a process influenced by several mechanisms such as concentration of metabolic substrates, changes in blood flow, and increases in reactive oxygen species that impair contractile muscle function. In this context, photobiomodulation has been investigated for preventing muscle fatigue, with reports of positive effects on muscle performance. This study aimed to investigate the effects of 904-nm LASER photobiomodulation on rectus femoris muscle performance in young women. Eighteen young women participated in a randomized, participant and assessor-blinded crossover trial with placebo control. Active LASER (904 nm, 60 mW, 250 Hz, 3.6 J per diode, total dose of 129.6 J) intervention was applied prior to an isokinetic fatigue protocol consisting of a set of 60 concentric quadricep contractions at a constant dynamometer angular velocity of 180°/s. Compared to placebo, LASER photobiomodulation significantly reduced muscle fatigue across a range of indicators including reduced ratings of perceived exertion (P = 0.0139), and increased electromyographic fatigue index (EFI) (P = 0.005). The isokinetic dynamometer performance analysis demonstrated that LASER photobiomodulation increased peak torque (P = 0.04), time to peak torque (P = 0.042), total work (P = 0.032), average power (P = 0.0007), and average peak torque (P = 0.019) between both experimental conditions. No significant difference was observed for work fatigue index (P = 0.29) or for lactate concentration (P > 0.05). Photobiomodulation at 904 nm was effective in reducing fatigue levels and increasing muscle performance in young active women but had no effect on lactate levels.

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Targeted next-generation-sequencing for reliable detection of targetable rearrangements in lung adenocarcinoma—A single center retrospective study

Publication date: Available online 16 February 2018
Source:Pathology - Research and Practice
Author(s): Nadezda P. Velizheva, Markus P. Rechsteiner, Nadejda Valtcheva, Sandra Nicole Freiberger, Christine E. Wong, Bart Vrugt, Qing Zhong, Ulrich Wagner, Holger Moch, Sven Hillinger, Isabelle Schmitt-Opitz, Alex Soltermann, Peter J. Wild, Verena Tischler
Oncogenic rearrangements leading to targetable gene fusions are well-established cancer driver events in lung adenocarcinoma. Accurate and reliable detection of these gene fusions is crucial to select the appropriate targeted therapy for each patient. We compared the targeted next-generation-sequencing Oncomine Focus Assay (OFA; Thermo Fisher Scientific) with conventional ALK FISH and anti-Alk immunohistochemistry in a cohort of 52 lung adenocarcinomas (10 ALK rearranged, 18 non-ALK rearranged, and 24 untested cases). We found a sensitivity and specificity of 100% for detection of ALK rearrangements using the OFA panel. In addition, targeted NGS allowed us to analyze a set of 23 driver genes in a single assay. Besides EML4-ALK (11/52 cases), we detected EZR-ROS1 (1/52 cases), KIF5B-RET (1/52 cases) and MET-MET (4/52 cases) fusions. All EML4-ALK, EZR-ROS1 and KIF5B-RET fusions were confirmed by multiplexed targeted NGS assay (Oncomine Solid Tumor Fusion Transcript Kit, Thermo Fisher Scientific). All cases with EML4-ALK rearrangement were confirmed by Alk immunohistochemistry and all but one by ALK FISH. In our experience, targeted next-generation sequencing is a reliable and timesaving tool for multiplexed detection of targetable rearrangements. Therefore, targeted next-generation sequencing represents an efficient alternative to time-consuming single target assays currently used in molecular pathology.



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Determination of geographical origin of commercial tomato through analysis of stable isotopes, elemental composition and chemical markers

Publication date: July 2018
Source:Food Control, Volume 89
Author(s): Anja Mahne Opatić, Marijan Nečemer, Sonja Lojen, Jasmina Masten, Emil Zlatić, Helena Šircelj, David Stopar, Rajko Vidrih
In recent years, the geographical authentication of different agro-products, including vegetables, has gained an increasing amount of attention. This study investigated different approaches, both independently and in combination, to assign the country of origin to commercial tomato samples from Slovenia, Italy, Spain and Morocco. To create a model for their traceability, three sets of parameters were used: stable isotopes of the major bioelements (δ¹³C, δ¹⁵N, δ¹⁸O, δ³⁴S), macro and micro elements (P, K, Ca, S, Cl, Zn, Br, Rb, Sr), and chemical markers (total antioxidant potential, total phenolic compounds, ascorbic acid, lutein, nitrates and nitrites, ammonium). The data obtained were analysed using the supervised pattern-recognition technique of multivariate discriminant analysis. The statistical analysis based on leave-one-out cross-validation revealed that the best overall success rate was achieved when using either the combination of all three sets of parameters, or only the elemental content data. In both cases, correct classification was obtained for 80% of the samples. Moreover, the present study highlights the first characterisation and classification of commercial tomato samples using the combination of the methodologies proposed.



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Zinc oxide nanotetrapods with four different arm morphologies for versatile nanosensors

Publication date: 1 June 2018
Source:Sensors and Actuators B: Chemical, Volume 262
Author(s): Ingo Paulowicz, Vasile Postica, Oleg Lupan, Niklas Wolff, Sindu Shree, Ala Cojocaru, Mao Deng, Yogendra Kumar Mishra, Ion Tiginyanu, Lorenz Kienle, Rainer Adelung
The structural morphology of metal oxide nano- and microstructures plays a crucial role in the performances of sensors and especially of nanosensors. Here, a simple approach on the synthesis of three-dimensional (3D) highly porous ZnO nano- and microstructure networks with four different arm morphologies in the same process is reported. Systematic studies about the growth of micro- and nanotetrapods were performed and the corresponding mechanism has been discussed in detail. The difference in the morphologies of the obtained structures was understood on the basis of synthesis temperature variations, content of Zn vapor and oxygen in the furnace at different locations, which result in different growth rates along the ZnO c-axis. The approach developed in this work gives the possibility to simultaneously grow the interconnected networks of nano-ZnO-tetrapods (T), ZnO-T, with complex arm morphologies, ZnO-T-nanosheets, and ZnO nanowires (NW)-T. The obtained free-standing network material was integrated in an electronic device for gas/vapor sensing investigations. The individual structures with different morphologies (NW with a diameter down to 30 nm, two interconnected NWs, microsheets, and nanotetrapods with a diameter of the arms in the range of 40–80 nm) were integrated into nanosensor devices in order to investigate the influence of the morphology on the electrical and gas sensing properties. The results showed higher (S ≈ 510–2500 ppm) ammonia vapor sensing properties of ZnO-T compared to ZnO-T-nanosheets and ZnO-NW-T, revealing the importance of nano-junctions in nano-sensor devices. The presented approach offers the possibility to understand the importance of exposed facets and junctions on the sensing properties of such nanostructures. These results offer new opportunities for further experimental and fundamental studies of oxide morphologies in the context of nanosensor applications for environmental monitoring.

Graphical abstract

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Combined effect of water inundation and heavy metals on the photosynthesis and physiology of Spartina alterniflora

Publication date: 30 May 2018
Source:Ecotoxicology and Environmental Safety, Volume 153
Author(s): Xiangli Sun, Yan Xu, Qiqiong Zhang, Xiuzhen Li, Zhongzheng Yan
The frequency and duration of tidal flooding significantly influence the bioavailability of heavy metals (HMs) in sediment and hence exert toxicological effects on coastal wetland plants. In this study, the combined effects of different water inundation times (3, 6, 9, and 12 h) and HMs (Cu, Zn, Pb, and Cr) on the photosynthesis and physiology of Spartina alterniflora were investigated under greenhouse conditions. Results showed that S. alterniflora was somehow tolerant to the combined HMs treatments, and only the highest level of HM treatment decreased leaf chlorophyll content. Furthermore, the plants did not show any signs of victimization. Different times of water inundation with HMs did not exert any significant effect on the malonaldehyde (MDA) and chlorophyll contents in the leaves of S. alterniflora at day 20. Prolonged water inundation time at day 60 significantly reduced leaf chlorophyll content with the decrease in leaf photosynthetic rate, which was accompanied by a significant increase in the intercellular concentration of CO2. At day 60, abscisic acid dose-dependently increased along the different water inundation times, indicating that this phytohormone is involved in plant responses to flooding stress. Peroxidase (POD), superoxide dismutase (SOD), and ascorbate peroxidase (APX), showed different responses to the combined treatment of water inundation and HMs at different times. At day 20, the long duration of water inundation and HMs treatments (9 h+HMs and/or 12 h+HMs) significantly increased enzyme activity in the leaves compared with the control group (6 h). At day 60, the POD and SOD activities in the leaves of S. alterniflora decreased with prolonged water inundation time, and root APX activity significantly decreased compared with the 6 h water inundation treatment.



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Exploiting CdSe/ZnS core-shell photocatalyst modified with cytochrome c for epinephrine determination in drugs utilized in cardiopulmonary resuscitation

Publication date: June 2018
Source:Microchemical Journal, Volume 139
Author(s): André Silva Freires, Fernanda Maria dos Reis Lima, Sakae Yotsumoto-Neto, Saimon Moraes Silva, Flávio Santos Damos, Rita de Cássia Silva Luz
This work presents the development and application of a biosensor based on cadmium selenide/zinc sulphide core-shell quantum dot modified with the redox protein cytochrome c (CdSe/ZnS-Cytc) for the photoelectrochemical determination of epinephrine (EP). The photoactive biocomposite was immobilized on the surface of a glass substrate modified with indium doped tin oxide (CdSe/ZnS-Cytc/ITO). The photoactive film was characterized by electrochemical impedance spectroscopy and the photocurrent measurements were obtained by chronoamperometry using a LED light lamp as source of irradiation. After the experimental parameters optimization, the biosensor presented a good response for EP oxidation in a wide linear concentration range between 1μmolL⁻¹ and 1.2mmolL⁻¹ (with r=0.999; n=9). A detection limit of 2nmolL⁻¹ was obtained. The selectivity of the photosensor was evaluated against species such as uric acid, ascorbic acid, folic acid, barbital, glucose, and urea, and the results showed that the proposed biosensor has a good selectivity for the detection of EP. The CdSe/ZnS-Cytc/ITO photoelectrochemical biosensor was applied in injectable drug samples used in cardiopulmonary resuscitation. The recovery tests in the samples showed recovery values between 101 and 110% suggesting a good accuracy for the proposed method.



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Nivolumab-induced lichenoid dermatitis occurring in a patient with metastatic melanoma successfully treated with alitretinoin

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Rapid improvement of nail matrix psoriasis with apremilast: clinical and ultrasonographic assessment

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Nivolumab-induced lichenoid dermatitis occurring in a patient with metastatic melanoma successfully treated with alitretinoin

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Rapid improvement of nail matrix psoriasis with apremilast: clinical and ultrasonographic assessment

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Objective assessment of the degree of improvement or deterioration with patients by means of Ipsative Trend Analysis of resting electroencephalograms

Publication date: April 2018
Source:Medical Hypotheses, Volume 113
Author(s): Gerald Ulrich, Georg Juckel, Willi Schlösser
We report on a new quantitative EEG-approach, called Ipsative Trend Assessment which is based on the spatio-temporally defined patterns which are generated by the global interaction of cortical neurons.MethodsThe data were acquired from EEGs being recorded under resting conditions. Target variables are not the usually employed absolute values of the spectral parameters but rather their change being calculated from successive recordings with a single subjects design.RationaleSince the resting-EEG does not provide specific information, we had to decide what else might be addressed by that method.ConclusionsOur hypothesis according to which the SR-EEG indicates Selye's behaviorally non-specific General Adaptation Syndrome is based on good evidence.Main findingsDynamic pattern comparison between subsequent EEGs on the single case level is a hitherto neglected method, which may be utilize, for instance, with regard to objective therapeutic outcome assessment.SignificanceIn order to substantiate the clinical meaningfulness of our new approach we report two case vignettes of psychiatric impairments. Apart from that, our procedure should provide the desperately needed objective assessment of the therapeutic effect with any disease displaying a certain proportion of unspecific symptoms.



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It has not been proven why or that most research findings are false

Publication date: April 2018
Source:Medical Hypotheses, Volume 113
Author(s): John C. Ashton
The claim has been made that it can be proven that most published findings in medical, biological, and allied sciences are false and that the reason for this can be proven and explained with a mathematical model. It has not, however, been mathematically proven that most research findings are false, and this can be proven. The model used in the proof is incoherent and has been falsified. Furthermore, advice to researchers derived from the model is misleading and distracts from more important issues in experimental standards.



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Roles of the insulin signaling pathway in insect development and organ growth

Publication date: Available online 16 February 2018
Source:Peptides
Author(s): Xianyu Lin, Guy Smagghe
Organismal development is a complex process as it requires coordination of many aspects to grow into fit individuals, such as the control of body size and organ growth. Therefore, the mechanisms of precise control of growth are essential for ensuring the growth of organisms at a correct body size and proper organ proportions during development. The control of the growth rate and the duration of growth (or the cessation of growth) are required in size control. The insulin signaling pathway and the elements involved are essential in the control of growth. On the other hand, the ecdysteroid molting hormone determines the duration of growth. The secretion of these hormones is controlled by environmental factors such as nutrition. Moreover, the target of rapamycin (TOR) pathway is considered as a nutrient sensing pathway. Important cross-talks have been shown to exist among these pathways. In this review, we outline the control of body and organ growth by the insulin/TOR signaling pathway, and also the interaction between nutrition via insulin/TOR signaling and ecdysteroids at the coordination of organismal development and organ growth in insects, mainly focusing on the well-studied fruit fly Drosophila melanogaster.



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Subungual exostosis on index finger in a child

Piyush Kumar, Ghuncha Alam

Indian Journal of Dermatology, Venereology, and Leprology 2018 84(2):232-233



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Antihypertensives in dermatology Part II - Cutaneous adverse reactions to antihypertensives

P. S. S. Ranugha, Jayadev B Betkerur

Indian Journal of Dermatology, Venereology, and Leprology 2018 84(2):137-147

Antihypertensive drugs are prescribed frequently and can cause cutaneous adverse reactions. The exact incidence and frequency of these reactions are unknown. Multiple antihypertensive drug consumption has contributed to a substantial increase in the number of cutaneous adverse reactions to them. Thus, there is a need for dermatologists and physicians to be aware of the wide range of available antihypertensives and the type of reactions that can be expected. This review article focuses on the various clinical presentations that have been implicated or associated with them. The diagnosis and management have been discussed in brief.

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Total serum immunoglobulin E level and specific allergens in adults with skin diseases

Byung Gon Choi, Yang Won Lee, Yong Beom Choe, Kyu Joong Ahn

Indian Journal of Dermatology, Venereology, and Leprology 2018 84(2):148-152

Background: Immunoglobulin E (IgE) plays an important role in allergic diseases. Although several studies have shown the association of serum total IgE and allergen-specific IgE levels with allergic dermatological diseases such as atopic dermatitis, there are few studies addressing this association for skin diseases in general. Aims: We sought to evaluate IgE levels in skin diseases and investigate the differences based on the disease type and clinical factors such as gender and age. Methods: Data from 2836 patients who visited the dermatologic clinic of the Konkuk University Hospital, Seoul, Republic of Korea for 4 years were reviewed to document IgE levels and clinical information. IgE levels were collated with the type of skin disease, gender, and age. Results: Patients with atopic dermatitis had a much higher total IgE level and were more susceptible to allergens as compared to other disease groups. Patients in other disease groups showed no significant differences in IgE levels. Men showed higher total IgE levels but the gender differences decreased with increasing age. Limitations: The data were collected from patients at a referral centre and thus may not represent the general population of dermatologic patients. There was a lack of information regarding factors that could potentially influence IgE levels such as smoking history and disease severity. Conclusions: The results suggest that there are physiological or environmental differences in IgE-mediated immune responses between males and females. Also, except for atopic dermatitis, there were no clinical differences in the IgE levels among various skin diseases.

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Kumkum-induced allergic contact dermatitis: Are we missing the actual culprit?

Ashwini Annabathula, S Priya, CR Srinivas

Indian Journal of Dermatology, Venereology, and Leprology 2018 84(2):153-156

Background: Kumkum, made with turmeric and slaked lime along with colour enhancing dyes is known to cause allergic contact dermatitis. The possible contact allergens in kumkum include turmeric, Sudan-1, 4-aminoazobenzene, brilliant lake red R and cananga oil. We report patch test results among patients with suspected contact hypersensitivity to kumkum. Objective: To identify the allergen causing kumkum induced allergic contact dermatitis by patch testing and to advise patients about organic kumkum which doesnot contain colour enhancing dyes. Methods: Eighteen patients with suspected contact hypersensitivity to kumkum were patch tested with undiluted kumkum, undiluted turmeric, Sudan-1 (95%), 4-aminoazobenzene and allergens of the Indian Standard Series. Results: Of the 18 patients, 14 patients had patch test positivity to kumkum and 4 had a negative reaction to kumkum. Patch test with other suspected contact allergens showed positive reaction to turmeric in 4 patients, Sudan-1 in 3 patients and 4-aminoazobenzene in 2 patients. Among the allergens of the Indian Standard Series, positivity to nickel and fragrance mix was seen in 5 and 2 patients respectively. Positive reaction to PPD, chlorocresol and parthenium was seen in 1 patient each. Limitation: Small sample size. Conclusion: Allergic contact dermatitis to kumkum occurs both due to the dyes (added for enhancing the colour) and turmeric. All patients with suspected allergic contact dermatitis should be patch tested with kumkum, turmeric and dyes, based on which alternative non-allergic material could be advised. Kumkum dermatitis can also occur due to various other allergens, for which too patch testing should be done.

http://ift.tt/2Cqf3dt

Percutaneous ethanol injection as a promising and minimally invasive treatment for axillary osmidrosis: Double-blinded randomized controlled trial

Ali Asilian, Masoom Shahbazi, Bahareh Abtahi-Naeini, Nazila Poostiyan, Mohammad Ali Nilforoushzadeh

Indian Journal of Dermatology, Venereology, and Leprology 2018 84(2):157-162

Background: Axillary osmidrosis is a common problem with a strong negative impact on the professional and social quality of life. Several options are available for its treatment. But there are no treatment guidelines. The objective of this study was to evaluate efficacy and safety of percutaneous ethanol injection for treatment of axillary osmidrosis. Methods: A randomized, double-blind, placebo-controlled clinical trial to assess clinical efficacy and postoperative complications of percutaneous ethanol injection was performed among 60 patients (12–35 years of age) with axillary osmidrosis. The active agent used in the experimental group (n = 30) was sterile 90% ethanol and the placebo used in the control group (n = 30) was sterile normal saline administered in an identical syringe. The results of malodor elimination were graded by the patients as excellent, good, fair, and poor. All patients were followed-up for 10 months. Results: Malodor elimination was graded as good by 15 (50%) patients treated with percutaneous ethanol injection. A significant difference in the improvement of axillary osmidrosis was found between the experimental and control groups (P < 0.001). The most common post-procedure complication was transient subjective skin stiffness in the experimental group, which regressed spontaneously. There were no serious permanent side effects. Limitations: Relatively short duration of follow-up; and lack of histopathological evidence of destruction of the apocrine glands after treatment in most patients. Conclusions: Percutaneous ethanol injection is an effective and safe treatment method for axillary osmidrosis and does not have permanent side effects.

http://ift.tt/2CtMgoE

Clinical experience of adalimumab in the treatment of psoriasis - A 10-year journey in a tertiary dermatology centre

Wai Man Mandy Chan, Hazel Hweeboon Oon, Wei-Sheng Chong

Indian Journal of Dermatology, Venereology, and Leprology 2018 84(2):205-208



http://ift.tt/2Ew614J

Wolf's isotopic nonresponse in healed herpes zoster in erythroderma

Surabhi Sinha, Gunjan Verma, PK Sharma, Arvind Ahuja

Indian Journal of Dermatology, Venereology, and Leprology 2018 84(2):217-220



http://ift.tt/2EzZGp2

Granulomatous slack skin syndrome: Report of a unique case

S Uma Maheswari, V Sampath, A Ramesh

Indian Journal of Dermatology, Venereology, and Leprology 2018 84(2):169-173

Granulomatous slack skin syndrome is a rare variant of cutaneous T-cell lymphoma (mycosis fungoides). It is characterized clinically by redundant skin folds, which show a predilection towards flexural areas such as the axilla and the groin. Histologically, it shows a granulomatous T-cell infiltrate and loss of elastic tissue. It has an indolent but progressive course; and is usually refractory to treatment. We report a unique case of slack skin syndrome, sparing the classical sites with rapid and unusual involvement of non-intertriginous areas.

http://ift.tt/2CquDpH

Effect of intravenous pulse dexamethasone versus daily oral prednisolone on bone mineral density in dermatology patients: Is it a site-specific response?

Sanjeev Handa, Gurjeet Singh, Amanjot Kaur Arora, Niranjan Khandelwal, Vivek Gupta

Indian Journal of Dermatology, Venereology, and Leprology 2018 84(2):174-178

Background: The use of glucocorticoids in various forms of administration is complicated by their systemic side effects. Although intravenous pulse therapy is considered to have lesser systemic side effects, there are few studies in literature comparing the effects of intravenous pulse glucocorticoids versus oral daily glucocorticoids on bone mineral density. Aim: To compare the effects of intravenous pulse glucocorticoids and oral daily glucocorticoids on bone mineral density with the aim of finding any site-specific osteopenic side effect. Methods: The study was conducted by the department of dermatology of Postgraduate Institute of Medical Education and Research, Chandigarh, India. The study comprised of two groups of patients. Group A consisted of 28 patients with pemphigus vulgaris who received intravenous pulses of dexamethasone at 4 weekly intervals. Group B consisted of 21 patients with airborne contact dermatitis who received oral daily prednisolone therapy. All the patients had a dual X-ray absorptiometry scan at baseline, and at 3 and 6 months of follow-up. The results were analyzed as changes in bone mineral density. Results: There was loss of bone mineral density at lumbar spine and the head of radius in both the groups. At the lumbar spine, Group B showed more reduction in bone mineral density at 3 months whereas in Group A it was more at the head of radius. In patients on oral steroids, the lumbar spine was significantly more affected than the head of radius at both 3 and 6 months of follow-up. However, in patients on intravenous pulse steroids, both the sites were equally affected at 3 and 6 months. Limitations: In our study, we used different glucocorticoids in the two groups: prednisolone in the oral daily group and dexamethasone in the intravenous pulse steroids group. A similar reduction in bone mineral density in both the groups may have been due to a longer half-life or more bone-directed side effects of dexamethasone as compared to prednisolone. Conclusion: Dermatologists need to be aware of the detrimental effects of high-dose intravenous pulsed glucocorticoids on bone mineral density and assessment of this parameter should be done before the initiation of therapy and also at regular intervals thereafter. During follow up, either the lumbar spine or the head of radius can be used to assess the osteopenic effect of intravenous pulse steroids, whereas the lumbar spine is a better site for this evaluation in patients on oral steroids.

http://ift.tt/2CtLZlC

Silymarin: An interesting modality in dermatological therapeutics

Konchok Dorjay, Tasleem Arif, Mohammad Adil

Indian Journal of Dermatology, Venereology, and Leprology 2018 84(2):238-243



http://ift.tt/2Ez3cj8

Music box spine keratoderma

Tasleem Arif, Mohammad Adil, Suhailur Rehman

Indian Journal of Dermatology, Venereology, and Leprology 2018 84(2):182-183



http://ift.tt/2CpdJYv

Elimination of leprosy in India: An analysis

Utpal Sengupta

Indian Journal of Dermatology, Venereology, and Leprology 2018 84(2):131-136

India attained the elimination figure of less than 1 case of leprosy per 10,000 people during December 2005. Despite this, India still accounts for the largest number of new leprosy cases in the world, maintaining more than 50 per cent of the leprosy burden of the world, notwithstanding over three decades of use of multidrug therapy. The present review analyzes the process of execution of the elimination program, identifies any lacunae therein and presents corrective measures that could be taken up for elimination of the disease from the country.

http://ift.tt/2HpI9gG

Operative Time and Flap Failure in Unilateral and Bilateral Free Flap Breast Reconstruction

J reconstr Microsurg
DOI: 10.1055/s-0038-1627445

Background There is an increasing trend toward bilateral breast reconstruction. Using the National Surgical Quality Improvement Program (NSQIP) database, we sought to understand the association between unilateral and bilateral free flap breast reconstruction and operative time and flap failure. Methods We selected a cohort of patients undergoing free flap breast reconstruction using the 2005 to 2010 NSQIP database. Cases were divided into unilateral and bilateral reconstruction. Subgroup analyses were performed dividing cases into delayed and immediate reconstruction. The effect of patient characteristics including age, body mass index (BMI), history of diabetes, and the American Society of Anesthesiologists' classification on operative time and flap failure was examined using univariable and multivariable regression models. Rates and odds ratios (OR) were reported using the multivariable gamma and logistic regression models, respectively. Results There were 691 free flap breast reconstructions performed in the cohort and 29.1% were bilateral cases. There was a 78-minute increase in the median operative time when comparing unilateral and bilateral reconstruction (p = 0.005). Patients undergoing bilateral reconstructions were generally younger and had fewer comorbidities compared with unilateral reconstructions. There was no significant association between bilateral reconstruction and flap failure. Immediate bilateral reconstructions had a significant increase in median operative time compared with immediate unilateral reconstructions (563 versus 480 minutes, p = 0.002) but no significant increase in operative time was noted when comparing delayed unilateral and delayed bilateral reconstructions. Prolonged operative time was associated with flap failure after adjusting for age and BMI (OR 1.17, p < 0.001). Conclusions Bilateral free flap breast reconstruction can be performed safely despite an increase in operative time when compared with unilateral reconstruction.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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Simplifying Arterial Coupling in Microsurgery—A Preclinical Assessment of an Everter Device to Aid with Arterial Anastomosis

J reconstr Microsurg
DOI: 10.1055/s-0038-1626691

Background A novel arterial everter device was engineered to simplify microvascular coupling of arteries by reliably securing the stiff, muscular wall of arteries over coupler pins. We compare microvascular coupling with the everter device to manual suturing for arterial anastomoses in a live large animal model. Methods In this preliminary study, bilateral external femoral arteries of five male swine were exposed and sharply divided. Arteries were anastomosed using either interrupted sutures (n = 5) or the everter device and Synovis Coupler (n = 5). The efficiency in engaging coupler pins, the time taken to perform the anastomosis, and vessel patency immediately post-op and at 1-week postanastomosis were evaluated. Vessel wall injury and luminal stenosis were compared between groups using histomorphometric analyses. Results On an average, 80% of coupler pins engaged the vessel walls after a single pass of the everter. The average time to perform the anastomosis was significantly less when using the everter/coupler compared with manual suturing (6:35 minute versus 25:09 minute, p < 0.001). Immediately post-op, 100% patency was observed in both groups. At 1 week post-op, four of five (80%) of coupled arteries and all five (100%) of hand-sewn arteries were patent. The degree of arterial wall injury, neointimal formation, and luminal stenosis for patent arteries were similar between groups. Conclusions Successful arterial anastomoses using the everter device with the Synovis Coupler was easier and significantly more efficient when compared with a standard hand-sewn technique. Both techniques had acceptable patency rates and similar effects on the vessel wall and intima.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
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Assessment of Function after Free Tissue Transfer to the Lower Extremity for Chronic Wounds Using the Lower Extremity Functional Scale

J reconstr Microsurg
DOI: 10.1055/s-0037-1621736

Background Free tissue transfer is one option for preservation of form and function in the native limb, in the setting of soft tissue paucity. However, the data on patient functionality after microvascular intervention is inconsistently reported. The Lower Extremity Function Scale (LEFS) measures patient-reported difficulty in carrying out 20 physical activities, on a Likert scale, the sum of which correlates with descriptive functional stages of 1–5. We assess limb functionality in this cohort of microvascular patients using the LEFS survey. Methods A retrospective chart review was conducted at a single academic medical center of 101 consecutive free flaps, from 2011 to 2016. Of the flaps that met inclusion criteria, 39 had completed LEFS surveys. Mean LEFS scores were calculated, and the effects of risk factors such as diabetes, age, and smoking status were analyzed. Results The mean LEFS score after free tissue transfer was 50.3 (SD ± 21.1), with a mean follow up survey time of 3.0 years (SD ± 1.3). The score correlated with Stage 4 function, or "independent community ambulation," and age was the only demographic factor associated with decreased functionality in this group. This is compared with mean LEFS score of 43.1 (SD ± 18.4) in cohort of 55 below knee amputations (BKAs), and 38.3 (SD ± 14.9) in 28 above knee amputations (AKAs), both correlating with Stage 3 function: "limited community ambulation." Conclusions Functional outcomes scores such as the LEFS demonstrate that patients can obtain an adequate level of functionality for independent community activity after free tissue transfer, although functional improvement diminishes with age.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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Gender Comparison of Medical Student Microsurgical Skills in a Laboratory Model

J reconstr Microsurg
DOI: 10.1055/s-0038-1626694

Background Perceived gender-related differences in surgical skills could limit opportunities available for any aspiring surgeon. There should be more available literature and logical analysis of these observations. The objective of this study is to evaluate the microsurgical skills of male and female medical students using a standard scale in the laboratory. Methods This study included medical students enrolled in the Kaohsiung Chang Gung Memorial Hospital from 2002 to 2015 who were evaluated by a senior consultant for their microsurgical skills. A standard numeric scale was used to evaluate their suturing technique after basic microsurgical training. Differences in the scores between male and female medical students were evaluated using statistical analysis. Results A total of 578 medical students were included in the study. There were 393 males (68%) and 185 females (32%). Using statistical analysis, there is no significant difference in the distribution of scores (P value = 0.78) and mean scores (P value = 0.75) between the two groups. Conclusions This study shows that microsurgical skills of male and female medical students are similar. Equal opportunities in the eventual pursuit of the surgical specialties should be available regardless of gender.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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Algorithmic Approach for Intraoperative Salvage of Venous Congestion in DIEP Flaps

J reconstr Microsurg
DOI: 10.1055/s-0038-1626695

Background Flap congestion is a frequently described intraoperative complication during autologous breast reconstruction with abdominal perforator flaps, which, if not addressed, can lead to detrimental results such as flap failure. Here, we describe our institution's algorithm of intraoperative salvage of congested flaps and present their outcomes. Methods All patient charts from 2002 to 2016 of a single plastic surgeon were reviewed for patients who underwent deep inferior epigastric perforator flap breast reconstruction resulting in 602 patients and 831 flaps. Of those, 38 women (6.3%) with 40 congested flaps (4.8%) were included in this study. Based on the algorithm guiding the selection of additional venous anastomosis, the patients' surgical details, outcomes, as well as their demographic characteristics are evaluated. Results Average age and body mass index of our cohort were 47.0 ± 8.0 years and 26.1 ± 3.9, respectively. Ten patients (26.3%) were current or former smokers while 20 (52.6%) required external radiation. Thirty-two congested flaps (80.0%) were predominantly salvaged with a superficial inferior epigastric vein (SIEV)-to-deep inferior epigastric vein (comitante) anastomosis. An SIEV-to-internal mammary vein comitante anastomosis was the second favorite option (5 flaps, 12.5%). Five patients suffered minor complications within a mean follow-up of 18.8 ± 12.3 months without flap failure, bleeding, or infection. Conclusions Venous flap congestion is an uncommon intraoperative intricacy during free tissue transfer for autologous breast reconstruction. Our proposed algorithm primarily recommends adding an additional venous anastomosis between the superficial and deep drainage system and results and favorable outcomes without major complications.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
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Distribution and removal of organochlorine pesticides in waste clay bricks from an abandoned manufacturing plant using low-temperature thermal desorption technology

Abstract

The distribution of pollutants in waste clay bricks from an organochlorine pesticide-contaminated site was investigated, and removal of the pollutants using a thermal desorption technology was studied. The results showed that the contents of HCHs in both the surface and the inner layer of the bricks were slightly higher than those of DDTs. The total pore volume of the bricks was 37.7 to 41.6% with an increase from external to internal surfaces. The removal efficiency by thermal treatment was within 62 to 83% for HCHs and DDTs in bricks when the temperature was raised from 200 to 250 °C after 1 h. HCHs were more easily removed than DDTs with a higher temperature. Either intraparticle or surface diffusion controls the desorption processes of pollutants in bricks. It was feasible to use the polluted bricks after removal of the pollutants by low-temperature thermal desorption technology.

http://ift.tt/2BxSarL

A precision medicine approach to repetitive Transcranial Magnetic Stimulation (rTMS)

Publication date: Available online 16 February 2018
Source:Brain Stimulation
Author(s): Andrew F. Leuchter, Juliana Corlier




http://ift.tt/2ocTjg4

A statistical comparison of motion mitigation performances and robustness of various pencil beam scanned proton systems for liver tumour treatments

Publication date: Available online 16 February 2018
Source:Radiotherapy and Oncology
Author(s): Ye Zhang, Isabel Huth, Damien Charles Weber, Antony John Lomax
Background and purposeDifferent scanned proton therapy systems provide different scanning scenarios, directly changing the temporal interference between sequential beam delivery and tumour motion. We aim here to quantify the interplay effects and compare motion mitigation performance among different PBS scanning systems.Materials and methodsUsing 6 4DCT(MRI) datasets of liver tumours with irregular motions greater than 10 mm, 4D treatments with single- and double-field plans, and assuming various doses and motion mitigation approaches, were simulated for 8 PBS scenarios including spot or raster scanning, layered or volumetric rescanning, gating, constant or varying beam current and cyclotron or synchrotron beam sources. The resulting 4D plans were compared using the homogeneity index (D5-D95 in CTV) and treatment time.ResultsIndependent of scanning scenario and field dose, neither gating nor rescanning alone could mitigate motion effects completely. Re-gating (rescanning with gating) however was found to be similarly effective for all scanning scenarios, most field doses and both rescan modes, with the difference being mainly in the treatment efficiency. The advantage of cyclotron-based systems together with layer-by-layer beam current variation was demonstrated by the nearly constant treatment time as a function of increased field dose.ConclusionIndependently of PBS scanning dynamics, re-gating is sufficient to achieve acceptable 4D plan quality close to those of the static references.



http://ift.tt/2obR1hq

Cholesterol Esterification Enzyme Inhibition Enhances Antitumor Effects of Human Chimeric Antigen Receptors Modified T Cells

Chimeric antigen receptor-modified T cell (CART) therapy has been demonstrated to have significant effect on hematologic tumor in patients. However, many persistent obstacles and challenges still limit the application. It is known that CD8+ T cells are a key component of antitumor immunity. An avasimibe-induced inhibition of cholesterol esterification has been shown to improve the antitumor response of CD8+ T cells in mice. In this study, using human CD19-directed CART cells as effector cells and CD19-overexpressing K562 cells as target cells, we detected whether cholesterol acyltransferase inhibition by avasimibe can enhance the antitumor effect of human CART cells. After avasimibe treatment, the infection rate was dropped by up to 50% (P

http://ift.tt/2Byq7bK

Ex Vivo-expanded Natural Killer Cells Derived From Long-term Cryopreserved Cord Blood are Cytotoxic Against Primary Breast Cancer Cells

With over 600,000 units of umbilical cord blood (CB) stored on a global scale, it is important to elucidate the therapeutic abilities of this cryopreserved reservoir. In the advancing field of natural killer (NK) cell cancer immunotherapy, CB has proven to be a promising and noninvasive source of therapeutic NK cells. Although studies have proven the clinical efficacy of using long-term cryopreserved CB in the context of hematopoietic stem cell transplantations, little is known about its use for the ex vivo expansion of effector immune cells. Therefore, our group sought to derive ex vivo-expanded NK cells from long-term cryopreserved CB, using an artificial antigen presenting cell–mediated expansion technique. We compared the expansion potential and antitumor effector function of CB-derived NK (CB-NK) cells expanded from fresh (n=4), short-term cryopreserved (

http://ift.tt/2C4gi6E

Significance of Immune-related Lipase Increase Induced by Antiprogrammed Death-1 or Death Ligand-1 Antibodies: A Brief Communication

Antiprogrammed death-1 (anti-PD1) and antiprogrammed death ligand-1 (anti-PD-L1) antibodies are effective checkpoint inhibitors that stimulate the immune system against many types of cancers. The flip side of these immunotherapies is the generation of immune-related adverse events, which can theoretically affect all organs. Among these side effects, lipase increase is frequently observed; however the meaning of this biological abnormality remains poorly understood. We investigate in this case study all the lipase increases greater or equal to grade 2 that occurred in patients receiving anti-PD-1 or anti-PD-L1 treatments, to determine their biological and clinical significance. Twenty-one patients were retained with lipase increase related to the immune checkpoint inhibitor. Most of them (71%) were treated for a metastatic melanoma. The peak of lipase increase was observed at a median of 2.8 (range, 0.4–11.4) months after the initiation of the anti-PD1 or anti-PD-L1 treatment, which correlates with cycle 5 of treatment. Three of 21 patients (14%) had a clinical or radiologic immune-related pancreatitis that led to a permanent discontinuation of the treatment. In 15 of 21 (71%) patients, the lipase increase was not considered as clinically significant, and the treatment was continued without complications. The 3 remaining patients discontinued the treatment for progressive disease. These data indicate that lipase increase related to anti-PD1 or anti-PD-L1 is not associated with a significant clinical event in most cases. On the basis of these data, we propose that lipase increase in an asymptomatic patient and without radiographic abnormalities of the pancreas can be reasonably regarded as a not clinically significant event, allowing the continuation of the anti-PD-1 or anti-PD-L1 treatment.

http://ift.tt/2BynRBk

Pneumonitis in Irradiated Lungs After Nivolumab: A Brief Communication and Review of the Literature

Nivolumab is a feasible therapy option in patients with advanced non–small cell lung cancer (NSCLC) who progress on first-line treatment. However, there is limited information about an overlapping toxicity of PD-1 inhibitors when administered following thoracic radiotherapy (TRT). Three of 25 patients with advanced NSCLC were treated with palliative or curative intent. Nivolumab was initiated as second or third-line therapy after TRT for recurrent or progressive disease. All 3 patients developed grade 3 pneumonitis at some point during nivolumab therapy. Herein, we describe 3 cases of pneumonitis in patients with NSCLC started on nivolumab following TRT. Imaging analysis was strongly consistent with heterogenous lung parenchyma changes in the irradiated lung volume receiving a total dose of 15–20 Gy. Pulmonary toxicity was manageable; however, interruption of immunotherapy was necessary.

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A new procedure for processing extracted teeth for immediate grafting in post-extraction sockets. An experimental study in American Fox Hound dogs

Publication date: Available online 15 February 2018
Source:Annals of Anatomy - Anatomischer Anzeiger
Author(s): José Luis Calvo Guirado, Pilar Cegarra del Pino, Lari Sapoznikov, Rafael Arcesio Delgado Ruíz, Manuel Fernández Dominguez, Sérgio Alexandre Gehrke
ObjectivesTo investigate freshly extracted dental particulate used to graft post-extraction sockets in dogs, comparing new bone formation at experimental and control sites.Material and MethodsBilateral premolars P2, P3, P4 and first mandibular molars were extracted atraumatically from six American Fox Hound dogs. The teeth were ground immediately using a 'Smart Dentin Grinder.' The dentin particulate was sieved to ensure a grain size of 300-1200μm and immersed in an alcohol cleanser to dissolve organic debris and bacteria, followed by washing in sterile saline buffer solution.The animals were divided into two groups randomly: group 'A' (control) samples were left to heal without any extraction socket grafting procedure; group 'B' (experimental) sockets were filled with the autogenous dentin particulate graft. The rate of tissue healing and the quantity of bone formation were evaluated using histological and histomorphometric analyses at 60 and 90 days post-grafting. The type of bone generated was categorized as woven (immature bone) or lamellar bone (mature bone).ResultsSubstantially more bone formation was found in Group B (experimental) than Group A (control) at 60 and 90 days (p<0.05). Less immature bone was identified in the dentin grafted group (25.7%) than the control group (5.9%). Similar differences were also observed at 90 days post grafting.ConclusionAutogenous dentin particulate grafted immediately after extractions may be considered a useful biomaterial for socket preservation, protecting both buccal and lingual plates, generating large amounts of new woven bone formation after 60 days, and small amounts of lamellar bone after 90 days healing.



http://ift.tt/2oatxcm

Laser-induced plasma spectroscopy (LIPS): use of a geological tool in assessing bone mineral content

Abstract

Bone may be similar to geological formulations in many ways. Therefore, it may be logical to apply laser-based geological techniques in bone research. The mineral and element oxide composition of bioapatite can be estimated by mathematical models. Laser-induced plasma spectrometry (LIPS) has long been used in geology. This method may provide a possibility to determine the composition and concentration of element oxides forming the inorganic part of bones. In this study, we wished to standardize the LIPS technique and use mathematical calculations and models in order to determine CaO distribution and bone homogeneity using bovine shin bone samples. We used polished slices of five bovine shin bones. A portable LIPS instrument using high-power Nd++YAG laser pulses has been developed (OpLab, Budapest). Analysis of CaO distribution was carried out in a 10 × 10 sampling matrix applying 300-μm sampling intervals. We assessed both cortical and trabecular bone areas. Regions of interest (ROI) were determined under microscope. CaO peaks were identified in the 200–500 nm wavelength range. A mathematical formula was used to calculate the element oxide composition (wt%) of inorganic bone. We also applied two accepted mathematical approaches, the Bartlett's test and frequency distribution curve-based analysis, to determine the homogeneity of CaO distribution in bones. We were able to standardize the LIPS technique for bone research. CaO concentrations in the cortical and trabecular regions of B1–5 bones were 33.11 ± 3.99% (range 24.02–40.43%) and 27.60 ± 7.44% (range 3.58–39.51%), respectively. CaO concentrations highly corresponded to those routinely determined by ICP-OES. We were able to graphically demonstrate CaO distribution in both 2D and 3D. We also determined possible interrelations between laser-induced craters and bone structure units, which may reflect the bone structure and may influence the heterogeneity of CaO distributions. By using two different statistical methods, we could confirm if bone samples were homogeneous or not with respect to CaO concentration distribution. LIPS, a technique previously used in geology, may be included in bone research. Assessment of element oxide concentrations in the inorganic part of bone, as well as mathematical calculations may be useful to determine the content of CaO and other element oxides in bone, further analyze bone structure and homogeneity and possibly apply this research to normal, as well as diseased bones.

http://ift.tt/2sBDKUI

SPC25 upregulation increases cancer stem cell properties in non-small cell lung adenocarcinoma cells and independently predicts poor survival

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Jingxia Chen, Hongfen Chen, Hanbing Yang, Huizhen Dai
In this study, we investigated the functional role and prognostic value of spindle pole body component 25 (SPC25) in non-small cell lung cancer (NSCLC). SPC25 expression profile in lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC) and normal lung tissues was examined by using data from the Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA). LUAD A549 cells and LUSC H520 cells were used to investigate the influence of SPC25 on cancer stem cell (CSC) properties in terms of the proportion of CD133⁺ cells, tumorsphere formation and CSC markers, including CD133, ALDH1 and Sox2. Data mining was also performed in the Kaplan-Meier plotter and TCGA-NSCLC to assess the independent prognostic value of SPC25. Results showed SPC25 was significantly upregulated in LUAD and LUSC tissues compared with normal lung tissues. SPC25 overexpression significantly increased the CSC properties and invasion of A549 cells, but not H520 cells. In comparison, SPC25 knockdown impaired the CSC properties and invasion of A549 cells, but not H520 cells. Univariate and multivariate analysis confirmed that high SPC25 expression was an independent prognostic factor for poor overall survival (OS) (HR: 1.622, 95%CI: 1.207–2.178, p = .001) and recurrence-free survival (RFS) (HR: 1.726, 95%CI: 1.242–2.399, p = .001) in LUAD patients. However, no independent prognostic value of SPC25 was observed in LUSC patients even under the best cut-off model. Based on these findings, we infer that SPC25 upregulation can increase CSC properties in LUAD and independently predict poor survival in this histological subtype.

Graphical abstract

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The sedative activity of flavonoids from Passiflora quadrangularis is mediated through the GABAergic pathway

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Andressa Corneo Gazola, Geison Modesti Costa, Silvana Maria Zucolotto, Leonardo Castellanos, Freddy Alejandro Ramos, Thereza Christina Monteiro de Lima, Eloir Paulo Schenkel
The aim of this study was to investigate the sedative activity of the aqueous leaf extract of Passiflora quadrangularis, a species that is widely cultivated and consumed in South America, and to identify its main constituents and elucidate the involvement of the GABAergic pathway in its mechanism of action. The bioguided fractionation of the crude extract showed a positive relationship between the sedative activity of the extract and its flavonoids. The methods employed to identify and isolate its main flavonoids resulted in the identification of vitexin-2''-O-xyloside, vitexin-2''-O-glucoside, orientin-2''-O-xyloside and orientin-2''-O-glucoside. Vitexin-2"-O-xyloside, the major flavonoid of the extract, showed sedative activity after oral administration in mice.

Graphical abstract

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Ferulic acid protects lipopolysaccharide-induced acute kidney injury by suppressing inflammatory events and upregulating antioxidant defenses in Balb/c mice

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Salma Mukhtar Mir, Halley Gora Ravuri, Raj Kumar Pradhan, Sairam Narra, Jerald Mahesh Kumar, Madhusudana Kuncha, Sanjit Kanjilal, Ramakrishna Sistla
Sepsis-induced acute kidney injury (AKI) is responsible for 70–80% mortality in intensive care patients due to elevated levels of endotoxin, Lipopolysaccharide (LPS) caused by gram-negative infections. Ferulic acid (FA), a phenolic phytochemical is known for its renal protection on various induced models of nephrotoxicity. However, the curative effect of FA in LPS-induced AKI is not well studied. This study aimed to investigate the effect of FA on LPS-induced AKI in mice model and to understand the protective mechanisms involved, to provide evidence for FA in the treatment of AKI. Balb/c mice were treated with FA at 50 mg/kg and 100 mg/kg dosages after LPS stimulation (10 mg/kg). At the end of the intervention, we determined the concentrations of serum creatinine and blood urea nitrogen, inflammatory cytokines and histopathological changes in animals. Also, the relative protein expression level of TLR4 mediated NF-κB signaling pathway were studied in kidney tissues. FA treated animals showed upregulation of antioxidant defenses and suppression of inflammatory events by inhibiting TLR-4 mediated NFκB activation. However, LPS alone administered group, resulted in rapid renal damage with increased levels of blood urea nitrogen and modest increase in creatinine; decreased antioxidant defenses and release of inflammatory cytokines. The histopathological analysis also revealed the protective action of the FA against sepsis induced fibrosis and renal damage. Our findings demonstrated that FA exhibits marked protective effects on LPS-induced AKI in mice suggesting its chemopotential role for treating AKI in humans.

Graphical abstract

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Silybum marianum oil attenuates hepatic steatosis and oxidative stress in high fat diet-fed mice

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Shu Yun Zhu, Ning Jiang, Jing Yang, Jie Tu, Yue Zhou, Xiang Xiao, Ying Dong
In the present study, the effects of Silybum marianum oil (SMO) on hepatic steatosis and oxidative stress were investigated during the development of nonalcoholic fatty liver disease (NAFLD) in high fat diet (HFD)-fed mice. The results showed that body weight, fat mass, and serum biochemical parameters such as triglyceride, free fatty acid, glucose and insulin were reduced by SMO treatment. Meanwhile, SMO decreased the histological injury of liver and the levels of hepatic triglyceride, cholesterol and free fatty acid in HFD-fed mice. SMO administration elevated the activities of superoxide dismutase (SOD) and catalase (CAT) and reduced the level of malondialdehyde (MDA) in the liver. Enzyme linked immunosorbent assay showed that SMO significantly decreased the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in HFD mice. Furthermore, the mRNA levels of sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthase (FAS) and liver X receptor α (LXRα) were lower, but peroxisome proliferator-activated receptor α (PPARα) was higher in mice treated with SMO compared with the HFD group. The results indicated that SMO could play a certain protective role against HFD-induced NAFLD, and the protective effects might be associated with attenuating lipid accumulation, oxidative stress and inflammation, improving lipid metabolism.



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Immune cells involved in the pathogenesis of ankylosing spondylitis

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Alireza Rezaiemanesh, Mohsen Abdolmaleki, Kamal Abdolmohammadi, Hamideh Aghaei, Fatemeh Dadgar Pakdel, Yousef Fatahi, Narjes Soleimanifar, Mahdi Zavvar, Mohammad Hossein Nicknam
Ankylosing spondylitis (AS) is an inflammatory autoimmune disease. AS is a prototype form of spondyloarthropathies (SpA). The precise etiology of AS has not been fully understood. But Inflammation has a critical role in the pathogenesis of the disease. The immune system by various cells, secreted-mediators and markers manage and regulate the immune responses and inflammation. Every factor which disturbed this regulation and hemostasis can cause chronic inflammation. In this review, we discussed the role of several innate and adaptive immune cells involved in the triggering, initiation, development, and regulation of AS.



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Efficacy and safety of combined low doses of either diclofenac or celecoxib with gabapentin versus their single high dose in treatment of neuropathic pain in rats

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Mohamed A. Ibrahim, Walaa Yehia Abdelzaher, Remon R. Rofaeil, Soha Abdelwahab
Neuropathic pain is a worldwide health problem with no consensus regarding its optimal therapy. This study compared the analgesic effect and gastric, hepatic, and renal safety of combined low doses of diclofenac and celecoxib with gabapentin versus their individual high doses in the treatment of neuropathic pain in rats. Left sciatic nerve ligation was used as neuropathic pain model. Rats were allocated into 7 groups (7 rats for each): sham control; model group (received vehicle); Gaba-group (received gabapentin (100 mg/kg /day); Diclo 10-group (received diclofenac (10 mg/kg); Cele 10-group (received celecoxib (10 mg/kg/day); Gaba + Diclo 5 (receivedgabapentin(100 mg/kg /day) plus diclofenac (5 mg/kg); Gaba + Cele 5 (received gabapentin (100 mg/kg/day) plus celecoxib (5 mg/kg)). The analgesic effect was assessed using both hot plate and acetone tests. The impact of the used drugs on peptic ulcer index, liver enzymes, and serum urea and creatinine was evaluated, along with histopathological examination and oxidative stress parameters. Combination therapy of low dose of either diclofenac or celecoxib, with gabapentin showed higher analgesic effect compared with their individual high doses as indicated by prolonged response time in hot plate test and decreased frequency of paw withdrawal in acetone test. Their effect was associated with gentle effect on gastric mucosa, renal and hepatic integrity and oxidative stress parameters. In conclusion, the use of combined low doses of either diclofenac or celecoxib with gabapentin is better than high dose monotherapy regarding both the efficacy and safety.



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Understanding of human ATP binding cassette superfamily and novel multidrug resistance modulators to overcome MDR

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Imran Shair Mohammad, Wei He, Lifang Yin
Indeed, multi-drug resistance (MDR) is a significant obstacle to effective chemotherapy. The overexpression of ATP-binding cassette (ABC) membrane transporters is a principal cause of enhanced cytotoxic drug efflux and treatment failure in various types of cancers. At cellular level, the pumps of ABC family regulate the transportation of numerous substances including drugs in and out of the cells. In past, the overexpression of ABC pumps suggested a well-known mechanism of drug resistance in cancers as well as infectious diseases. In oncology, the search for new compounds for the inhibition of these hyperactive ABC pumps either genetically or functionally, growing interest to reverse multi-drug resistance and increase chemotherapeutic effects. Several ABC pump inhibitor/modulators has been explored to address the cancer associated MDR. However, the clinical results are still disappointing and conventional chemotherapies are constantly failed in successful eradication of MDR tumors. In this context, the structural and functional understanding of different ATP pumps is most important. In this concise review, we elaborated basic crystal structure of ABC transporter proteins as well as its critical elements such as different domains, motifs as well as some important amino acids which are responsible for ATP binding and drug efflux as well as demonstrated an ATP-switch model employed by various ABC membrane transporters. Furthermore, we briefly summarized different newly identified MDR inhibitors/modulators, deployed alone or in combination with cytotoxic agents to deal with MDR in different types of cancers.



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Activation of PPARγ mediates icaritin-induced cell cycle arrest and apoptosis in glioblastoma multiforme

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Yongji Liu, Ling Shi, Yuan Liu, Peng Li, Guoping Jiang, Xiaoning Gao, Yongbin Zhang, Chuanwu Jiang, Weiping Zhu, Hongxing Han, Fang Ju
BackgroundGlioblastoma multiforme (GBM) is the most prevalent primary malignancy of the brain. This study was designed to investigate whether icaritin exerts anti-neoplastic activity against GBM in vitro.Materials and methodsCell Counting Kit-8 (CCK-8) assay was utilized to examine the viability of GBM cells. The apoptotic cell population was measured by flow cytometry analysis. Cell cycle distribution was detected by flow cytometry as well. Western blot analysis was performed to examine the level of biomarker proteins in GBM cells. Levels of PPARγ mRNA and protein were detected by qPCR and western blot analysis, respectively. To examine the role of PPARγ in the anti-neoplastic activity of icaritin, PPARγ antagonist GW9662 or PPARγ siRNA was used. The activity of PPARγ was determined by DNA binding and luciferase assays.ResultsOur findings revealed that icaritin markedly suppresses cell growth in a dose-dependent and time-dependent fashion. The cell population at the G0/G1 phase of the cell cycle was significantly increased following icaritin treatment. Meanwhile, icaritin promoted apoptotic cell death in T98G and U87MG cells. Further investigation showed upregulation of PPARγ played a key role in the anti-neoplastic activities of icaritin. Moreover, our result demonstrated activation of AMPK signaling by icaritin mediated the modulatory effect of icaritin on PPARγ.ConclusionOur results suggest the PPARγ may mediate anti-neoplastic activities against GBM.

Graphical abstract

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Bryophyllum pinnatum inhibits arginase II activity and prevents oxidative damage occasioned by carbon tetrachloride (CCl4) in rats

Publication date: May 2018
Source:Biomedicine & Pharmacotherapy, Volume 101
Author(s): Scholastica Onyebuchi Anadozie, Jacob Ayodele Akinyemi, Shadrach Agunbiade, Basiru Olaitan Ajiboye, Olusola Bolaji Adewale
Bryophyllum pinnatum (B. pinnatum) (Lam.) Oken is used in tropical Africa for the treatment of several diseases such as kidney and urinary disorders. This study was aimed to evaluate the effect of B. pinnatum on arginase II activity and its prevention against renal oxidative damage occasioned by CCl4 in rats. Rats were randomly divided into six groups; group I served as the control, group II served as carbon tetrachloride (CCl4) intoxicated group, group III–V animals were pre-treated with silymarin (25 mg/kg body weight), 25 mg/kg body weight aqueous extracts of Bryophyllum pinnatum (AEBP) and 50 mg/kg body weight AEBP, respectively, for 14 days, followed by a single injection of CCl4. Group VI rats received AEBP only (50 mg/kg body weight). Results obtained revealed that CCl4 intoxication significantly increased (p < 0.05) the levels of renal markers (serum urea, creatinine and arginase II) in rats when compared to the control group. Further, oxidative stress status appeared in CCl4-intoxicated rats, as evidence by significant elevation in malondialdehyde (MDA), with concomitant decrease in levels of functional sulfhydryl groups (SH), antioxidant enzymes and nitric oxide in rats' kidney. These adverse changes, due to CCl4 intoxication in rats, were however, prevented by pre-treatment with AEBP leaves (25 and 50 mg/kg body weight). The inhibition of arginase II, as well as increased antioxidant status by AEBP in CCl4-intoxicated rats suggests that B. pinnatum can protect kidney against CCl4-induced oxidative damage.

Graphical abstract

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LncRNA-LET inhibits cell viability, migration and EMT while induces apoptosis by up-regulation of TIMP2 in human granulosa-like tumor cell line KGN

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Qingfang Han, Wenke Zhang, Jinlai Meng, Li Ma, Aihua Li
BackgroundPolycystic ovary syndrome (PCOS) is a common endocrine disease characterized by hyperandrogenism, irregular menses, and polycystic ovaries. Several long non-coding RNAs (lncRNAs) are aberrantly expressed in PCOS patients; however, little is known about the effects of the lncRNA-low expression in tumor (lncRNA-LET) on PCOS. We aimed to explore the effects of lncRNA-LET on human granulosa-like tumor cell line, KGN.MethodsExpression of lncRNA-LET in normal IOSE80 cells and granulosa cells was determined by qRT-PCR. KGN cell viability, apoptosis and migration were measured by trypan blue exclusion method, flow cytometry assay and wound healing assay, respectively. TGF-β1 was used to induce epithelial-mesenchymal transition (EMT) process. LncRNA-LET expression and mRNA expressions of TIMP2 and EMT-related proteins were measured by qRT-PCR. Western blot analysis was used to measure the protein expression of apoptosis-related proteins, EMT-related proteins, TIMP2, and the proteins in the Wnt/β-catenin and Notch signaling pathways.ResultslncRNA-LET was down-regulated in KGN cells, and its overexpression inhibited cell viability and migration, and promoted apoptosis in KGN cells. Overexpression of lncRNA-LET increased the expression of E-cadherin and decreased the expressions of N-cadherin and vimentin in KGN cells. These effects of lncRNA-LET on KGN cells were reversed by TIMP2 suppression. Overexpression of TIMP2 inhibited cell viability, migration and EMT process, and increased apoptosis by activating the Wnt/β-catenin and Notch pathways.ConclusionOverexpression of lncRNA-LET inhibits cell viability, migration and EMT process, and increases apoptosis in KGN cells by up-regulating the expression of TIMP2 and activating the Wnt/β-catenin and notch signaling pathways.



http://ift.tt/2EMpxJj

Evaluation of the anti-hypertensive effect of Tengfu Jiangya tablet by combination of UPLC-Q-exactive-MS-based metabolomics and iTRAQ-based proteomics technology

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Yanpeng Tian, Feng Jiang, Yunlun Li, Haiqiang Jiang, Yanjun Chu, Lijuan Zhu, Weixing Guo
ObjectiveTengfu Jiangya tablet (TJT) is a traditional Chinese medicine formulation composed of Uncaria rhynchophylla and Semen raphani. It is a hospital preparation that is widely used in clinics for treating hypertension. A previous metabolomics study reported that TJT exerted a protective effect on hypertension by restoring impaired NO production, ameliorating the inflammatory state, and vascular remodeling. A clinical proteomics study also revealed five key target proteins during TJT intervention. This study aimed to integrate proteome and metabolome data sets for a holistic view of the molecular mechanisms of TJT in treating hypertension.MethodsSerum samples from spontaneously hypertensive rats and Wistar Kyoto rats were analyzed using ultra-high performance liquid chromatography coupled to Q Exactive hybrid quadrupole-Orbitrap mass spectrometry (UPLC-Q-Exactive-MS)-based metabolomics technology and isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics technology. Moreover, we selected two candidate proteins and determined their expression levels in rat serum using an enzyme-linked immunosorbent assay (ELISA).ResultsA total of 20 potential biomarkers and 14 differential proteins in rat serum were identified. These substances were mainly involved in three biological pathways: the kallikrein–kinin pathway, the lipid metabolism pathway, and the PPARγ signaling pathway.ConclusionsThe results suggested that TJT could effectively treat hypertension, partially by regulating the above three metabolic pathways. The combination of proteomics and metabolomics provided a feasible method to uncover the underlying interventional effect and therapeutic mechanism of TJT on spontaneously hypertensive rats.



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POU5F1B promotes hepatocellular carcinoma proliferation by activating AKT

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Yaozhen Pan, Lei Zhan, Ling Chen, Hong Zhang, Chengyi Sun, Chungen Xing
Hepatocellular carcinoma (HCC) is one of the most common tumors, so far, there still aren't good therapeutic methods. Looking for new targets makes a top priority. In this study, we found a OCT4 pseudogene, POU5F1B was significantly upregulated in HCC cells and tissues, patients with high POU5F1B had shorter survival time compared to patients with low POU5F1B expression. POU5F1B overexpression promoted HCC proliferation, while its knockdown inhibited HCC proliferation determined by MTT assay, soft agar growth assay, BrdU incorporation assay, and cell cycle assay. Mechanism analysis suggested POU5F1B could activate AKT, AKT inhibition in HCC cells with POU5F1B overexpression significantly inhibited cell proliferation compared to cells only with POU5F1B overexpression, suggesting POU5F1B promoted HCC proliferation by activating AKT. Finally, we analyzed the relationship between POU5F1B expression and AKT activity in HCC tissues, and found POU5F1B expression was positive correlated with activated AKT. Taken together, our findings suggested POU5F1B promoted HCC proliferation by activating AKT, and provided a new target for HCC therapy.

Graphical abstract

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EFLDO induces apoptosis in hepatic cancer cells by caspase activation in vitro and suppresses tumor growth in vivo

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Yan-bo Qu, Zhi-xin Liao, Chao Liu, Xin-zhu Wang, Jing Zhang
To study the apoptosis induced by EFLDO (ent-3α-formylabieta-8(14), 13(15)-dien-16,12β-olide), extracted from the Euphorbia lunulata Bge, in the HepG2 cell line and to study the antitumor activity of this compound in vivo, Cell viability and migration were evaluated with CCK-8 (2-(2-methoxy-4-nitrophenyl)-3- (4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt) and wound healing assays, respectively. In addition, the cell cycle was examined using flow cytometry after propidium iodide (PI) staining. Apoptosis was analyzed by using the Annexin V/PI staining assay. Pro-caspase activation and apoptosis protein expression were evaluated by western blotting. A HepG2 xenograft model in nude mice was also established to study the antitumor activity of EFLDO in vivo. Immunohistochemical analysis was used to detect the expression of Ki67 in the tumors in situ. EFLDO could induce dose- and time-dependent apoptosis in HepG2 human hepatic cancer cells. Activation of caspases 3, 8, and 9 played an important role in EFLDO-induced apoptosis in vitro. Decreased levels of Bcl-2 and Survivin and increased level of BAX were also involved in this process. Furthermore, EFLDO could inhibit HepG2 tumor growth in nude mice, and the proliferation characteristics, reflected by the Ki67 index, were suppressed significantly. The results indicated that EFLDO could induce apoptosis in hepatic cancer cells by caspase activation in vitro and suppress tumor growth in vivo.



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MicroRNA-519d inhibits proliferation and induces apoptosis of human hypertrophic scar fibroblasts through targeting Sirtuin 7

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Xiaoqian Zhou, Yidun Xie, Houan Xiao, Xudong Deng, Yu Wang, Liyuan Jiang, Chen Liu, Rui Zhou
MicroRNAs (miRNAs) play critical roles in various pathological processes, including hypertrophic scar (HS) formation. However, the precise role of miRNAs in HS formation remains largely unknown. In this study, we aimed to investigate the role of miR-519d in HS formation. We found that miR-519d expression was significantly downregulated in HS tissues and fibroblasts. Overexpression of miR-519d inhibited the expression of type I collagen (Col I), type III collagen (Col III) and α-smooth muscle actin (α-SMA) in HS fibroblasts. Moreover, overexpression of miR-519d reduced the proliferation and induced the apoptosis of HS fibroblasts. In contrast, suppression of miR-519d showed the opposite effects. Interestingly, Sirtuin 7 (SIRT7) was identified as a target gene of miR-519d. The results showed that miR-519d directly targeted the 3′-untranslated region of SIRT7 and negatively regulated its expression. Furthermore, miR-519d regulated the expression of TGF-β type I receptor (TGFBRI) and the phosphorylation of Smad2. Knockdown of SIRT7 by siRNA inhibited the expression of Col I, Col III and α-SMA, and reduced the proliferation and induced the apoptosis of HS fibroblasts. Overexpression of SIRT7 abrogated the effects mediated by miR-519d overexpression in HS fibroblasts. Overall, these results suggest that miR-519d inhibits the expression of extracellular matrix-associated genes, reduces the proliferation and induces the apoptosis of HS fibroblasts by targeting SIRT7, implying a suppressive role of miR-519d in HS formation. This study suggests that miR-519d may serve as a promising therapeutic target for treatment of human HS.



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Oridonin inhibits oral cancer growth and PI3K/Akt signaling pathway

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Jing Yang, Xianyue Ren, Liping Zhang, Yuanyuan Li, Bin Cheng, Juan Xia
Oridonin, a bioactive diterpenoid purified from Rabdosia rubescens, has been shown to possess anticancer capacity in several cancer types. However, its effects on oral squamous cell carcinoma (OSCC) cells remain unclear. This study aimed to investigate the anticancer ability of oridonin in OSCC cells, including proliferation, apoptosis and underlying mechanisms using the OSCC cell lines, UM1 and SCC25. The results showed that oridonin not only inhibited proliferation and clonal formation but also induced G2/M cell cycle arrest and apoptosis in UM1 and SCC25 cells in a dose-dependent manner. Western blot revealed that oridonin treatment increased the ratio of Bax/Bcl-2, and activated the cleavage of caspase-3, caspase-9 and PARP-1. Oridonin also induced G2/M phase arrest in OSCC cells via down-regulating the G2/M transition-related proteins such as cyclin B1 or up-regulating cyclin D1, cyclin D3, P21, p-CDK1 and cyclin A2. In addition, oridonin treatment significantly inhibited the phosphorylation of PI3K and Akt and inhibited tumor growth of OSCC xenograft in nude mice. Taken together, these results suggested that oridonin possesses anti-oral cancer capacity via inhibiting the PI3K/Akt signaling and induce apoptosis and G2/M-phase arrest. Therefore, oridonin may be a potential anticancer drug for the treatment of oral cancer.

Graphical abstract

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Long noncoding RNA maternally expressed gene 3 knockdown alleviates lipopolysaccharide-induced inflammatory injury by up-regulation of miR-203 in ATDC5 cells

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Zhaolin Wang, Xiaohua Chi, Liping Liu, Yaqun Wang, Xiaoyan Mei, Yan Yang, Tanghong Jia
BackgroundOsteoarthritis (OA) is a common degenerative joint disease, which seriously impacts the health of elderly. However, there is no effective treatment for curing this disease until now. Numerous studies reported that long noncoding RNAs (lncRNAs) are closely related to the pathogenesis of OA. Therefore, the study aims to investigate the effect of maternally expressed gene 3 (MEG3) on lipopolysaccharide (LPS)-induced inflammatory injury of ATDC5 cells.MethodsDifferent concentrations (0, 1, 5, and 10 μg/ml) of LPS were used to induce ATDC5 cells injury. The specific expressing vectors were then transfected into ATDC5 cells to alter MEG3, Sirt1 and miR-203 expressions. Flow cytometry, luciferase reporter, qRT-PCR and western blot assays were used to detect cell viability, apoptosis, and the expressions of apoptosis-related proteins and pro-inflammatory factors (IL-1β, IL-6, IL-8 and TNF-α). Meanwhile, ELISA was used for analyzing the concentrations of inflammatory cytokines in culture supernatant. Besides, the key pathways of PI3K/AKT and NF-κB were examined by western blot.ResultsLPS decreased cell viability, increased cell apoptosis, promoted the release of pro-inflammatory factors, and down-regulated MEG3 expression, Moreover, MEG3 knockdown alleviated LPS-induced inflammatory injury. MEG3 acted as a competing endogenous RNAs (ceRNA) for miR-203, and MEG3 knockdown reduced inflammatory injury by regulating miR-203. Furthermore, miR-203 positively regulated Sirt1 expression, and Sirt1 alleviated LPS-induced inflammatory injury via mediating PI3K/AKT and NF-κB pathways.ConclusionThis study showed that MEG3 knockdown alleviated LPS-induced inflammatory injury in ATDC5 cells by regulating miR-203 expression. Hence, the findings may offer a potential treatment perspective of OA.



http://ift.tt/2sysw3j

Sirtuin7 has an oncogenic potential via promoting the growth of cholangiocarcinoma cells

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Wenzhi Li, Zhe Sun, Chen Chen, Lin Wang, Zhimin Geng, Jie Tao
Accumulating evidence indicates that sirtuin7 (SIRT7) plays an oncogenic role in the main types of liver cancer, hepatocellular carcinoma (HCC). Nevertheless, the clinical significance of SIRT7 and its role in cholangiocarcinoma (CCA) is largely undiscovered. Here, we found that SIRT7 displayed higher expression in CCA tissues compared to intrahepatic normal bile duct and surrounding liver tissues based on The Cancer Genome Atlas (TCGA) data. Our data further confirmed that SIRT7 was overexpressed in CCA patient tissues and cell lines. Clinical analysis revealed that high SIRT7 expression was correlated with large tumor size and advanced tumor-node-metastasis (TNM) stage. Furthermore, SIRT7 overexpression independently predicted poor prognosis of CCA patients. Functionally, we demonstrated that SIRT7 knockdown suppressed proliferation and cell cycle progression of HUCCT1 cells in vitro and in vivo. SIRT7 restoration promoted the growth of QBC-939 cells. Mechanistically, SIRT7 reduced p21 expression and increased the levels of Cyclin D1 and cyclin dependent kinase 2 (CDK2) in CCA cells. Furthermore, microRNA-125b-5p (miR-125b-5p) was recognized as a direct negative regulator of SIRT7 and reduced SIRT7 abundance in CCA cells. Notably, miR-125b-5p restoration showed similar effects to SIRT7 knockdown on the growth of CCA cells. Taken together, we demonstrate for the first time that miR-125b-5p regulation of SIRT7 functions as an oncogene and a potential prognostic biomarker in CCA.

Graphical abstract

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Psychotomimetic-like behavioral effects of memantine in the mouse

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100
Author(s): Nobue Kitanaka, Junichi Kitanaka, F. Scott Hall, Yoshiro Kubota, Yumi Mimura, Sayaka Ogura, Yukiya Okada, George R. Uhl, Motohiko Takemura
A single administration of mice with memantine (1-amino-3,5-dimethyladamantane), a glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, induced stereotyped behaviors in dose- and time-dependent manners. The predominant behavioral component of the stereotypy was a continuous, exaggerated sniffing which was accompanied by persistent locomotion. In contrast, a psychostimulant methamphetamine (METH) predominantly induced a stereotyped biting and other forms of intense stationary stereotypical behaviors. Memantine-induced stereotyped sniffing was attenuated by pretreatment with haloperidol, a dopamine D2 receptor antagonist, in a dose-dependent manner. The memantine-induced stereotyped sniffing was also attenuated by pretreatment with betahistine (2-[2-(methylamino)ethyl]pyridine), an agent which increases histamine turnover and releases histamine in the brain. These observations suggest that memantine might induce stereotypies through neuronal mechanisms that are somewhat different from those of METH, but still overlap to a certain extent, since memantine-induced stereotypies can be attenuated by the mechanisms that also suppress METH-induced stereotypy. Importantly, these data suggests that the effects of memantine may be more limited to the ventral striatum including nucleus accumbens than those of METH, which is associated with dorsal striatal stimulation at high doses. In this respect memantine may also have pharmacological properties such as compartmentation (i.e. brain distribution) and neuronal mechanisms different from those of other NMDA receptor antagonists, such as ketamine, which may have important implications for therapeutic uses of these drugs.



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