To the Editor: Alopecia areata (AA) is a polygenic, patchy nonscarring hair loss that presents on the scalp and body that drastically affects patients' quality of life.1 The pathogenesis of AA remains elusive, though T-lymphocyte–mediated inflammation and various environmental stressors play a role. The association between AA and various autoimmune diseases has been explored in several studies.1 Recently, studies found lower rates of nonmelanoma skin cancers and a trend toward decreased melanoma among AA patients.
http://ift.tt/2ycgNXc
Τρίτη 10 Οκτωβρίου 2017
Lack of an association between alopecia areata and visceral or hematopoietic cancers
Recurrence of genital aphthosis in girls: A retrospective analysis
To the Editor: Genital aphthosis in girls is a rare, underrecognized condition characterized by genital ulceration after an acute systemic illness.1,2 The aphthae often are associated with severe dysuria and emotional distress in this young, adolescent population. We sought to identify disease recurrence by reviewing clinical records from January 1997 through August 2015. Institutional review board approval was obtained (IRB# 15-008638, December 2015).
http://ift.tt/2wNkqSg
Prevalence of pediatric alopecia areata among 572,617 dermatology patients
To the Editor: The authors initiated this retrospective analysis to evaluate the prevalence, age, and sex of pediatric patients with alopecia areata (AA) and the impact that pediatric AA has on a typical dermatology practice. Billing data from Leavitt Medical Associates of Florida, doing business under the name Advanced Dermatology and Cosmetic Surgery, was collected from offices throughout Florida and Ohio, and 572,617 dermatology patients were identified. The study population included 71,951 pediatric patients (1-17 years of age): 33,800 boys and 37,791 girls.
http://ift.tt/2ycwpdA
Spectrum of orocutaneous disease associations
The oral cavity and cutaneous organ systems share a close embryologic origin. Therefore, there are numerous dermatologic conditions presenting with concomitant oral findings of which the dermatologist must be aware. The second article in this continuing medical education series reviews inflammatory orocutaneous conditions and a number of genodermatoses. It is essential for dermatologists to be familiar with oral cavity manifestations associated with dermatologic diseases for prompt diagnosis, management, and appropriate referral to stomatology and dentistry.
http://ift.tt/2wMV5Yi
Onychophagia and onychotillomania can be effectively managed
To the Editor: We greatly appreciate the commentary by Lipner and Scher.1 We agree that our patients would benefit from prompt treatment to reduce shame and prevent irreversible nail damage. Herein, we present our clinical pearls using pharmacotherapy, stimulus control, habit-reversal training (HRT), and cognitive behavioral and aversion therapy. We often combine psychotherapies such as HRT and stimulus control. Six or more sessions are typically required. We have treated several cases of onychophagia and onychotillomania with N-acetylcysteine 1200-2400 mg/day.
http://ift.tt/2ybJvro
Comment on “Psychocutaneous disease: Clinical perspectives”
To the Editor: Kuhn et al1 are to be commended for writing this informative review on psychocutaneous disease. In this manuscript, they delineate common psychiatric conditions with skin manifestations including delusional, factitious, obsessive-compulsive, and eating disorders; psychogenic pruritus; cutaneous sensory (pain) syndromes; posttraumatic stress disorder; and sleep-wake disorders. They appropriately describe the important role fingernails play in removing organisms during delusional infestations and describe patients with factitious skin disorder creating well-demarcated geometric erosions.
http://ift.tt/2yb9kaY
Smoke-evacuating cautery pencils for dermatologic surgery
Potential health risks may exist related to particulates and volatile chemicals in electrosurgical smoke.1 Although particulate matter is effectively filtered by specialized masks such as N-95 masks, volatile chemicals are not.1 Standard surgical masks provide no protection. Further, handheld smoke evacuation with stand-alone units requires an assistant to carefully follow the motions of the surgeon while reliably holding the evacuation tube at the correct distance from the cautery tip (≤2 in)2 without compromising the visual field.
http://ift.tt/2wMxiI0
Recurrence, evolution, and re-excision of moderately dysplastic nevi
To the Editor: I read with great interest the fascinating and valuable article by Hiscox et al on recurrence of moderately dysplastic nevi (MDN).1 The authors argue that their findings "support the conclusion of the Pigmented Lesion Subcommittee that incompletely excised MDN do not require re-excision." While the authors' study indeed adds to the literature, and supports the findings of another recent study2 assessing a similar clinical question, several important caveats should be noted.
http://ift.tt/2y9Y2ni
Approach to moderately dysplastic nevi with positive histologic margins
To the Editor: We are grateful to Dr Kantor for his thoughtful and detailed review of our paper.1 Our goal was to contribute to the literature regarding moderate dysplastic nevi (DN), and we showed that 147 such nevi with positive histologic margins showed a recurrence rate of only 4%.2 We agree that larger studies are needed and are grateful that they are underway. Dr Kantor is correct in pointing out that the majority of these moderate DNs were biopsied with the intent to excise, and we agree that our data are not applicable to partially sampled lesions because partial sampling was not the goal of our study.
http://ift.tt/2yblikY
Oral tofacitinib monotherapy in Korean patients with refractory moderate-to-severe alopecia areata: A case series
To the Editor: Recent reports document successful treatment of alopecia areata (AA) with tofacitinib.1-5 However, long-term data using tofacitinib monotherapy is still sparse, and we are unaware of the quality of treatment in persons of Asian decent. We report the results of extended tofacitinib monotherapy in adult Korean patients with moderate-to-severe AA.
http://ift.tt/2wNmXf6
Histopathologic features of melanoma in difficult-to-diagnose lesions: A case-control study; methodological issues
To the Editor: We read with great interest the article authored by Gonzalez et al that was published in the Journal of the American Academy of Dermatology in 2017.1 The authors aimed to measure the accuracy of histopathologic features in difficult-to diagnose melanocytic tumors and the interobserver agreement of those features. They constructed a prediction model and found that asymmetry, single-cell melanocytosis, solar elastosis, pagetoid melanocytosis, and broad surface diameter were the most predictive factors of outcome studied.
http://ift.tt/2yblele
Reply to: “Histopathologic features of melanoma in difficult-to-diagnose lesions: A case-control study; methodological issues”
To the Editor: I thank Drs Ayubi and Safiri1 for their comments regarding our recent article on the accuracy of different histopathologic features of melanoma in difficult-to-diagnose melanocytic neoplasms.2 I would like to emphasize that this was an exploratory hypothesis-generating research project designed to identify which histopathologic attributes were most likely to be of value in designing a diagnostic algorithm for the difficult melanocytic neoplasm. Ayubi and Safiri recommend (1) additional validation studies and (2) better demonstration of temporality between independent and dependent variables.
http://ift.tt/2ycgziO
Frequent skin examinations in patients with actinic keratoses: Ethical, financial, and moral implications
In many disputes, the 2 parties in disagreement can "meet each other halfway" and reach a pragmatic solution that may not be perfect but is acceptable to both. When disagreements occur in the context of the physician-patient relationship, there are inevitably ethical issues or principles to be considered in arriving at a solution. In addition, the competing interests of others may need to be considered.
http://ift.tt/2wMovpr
Mitigation or prevention of mild hair dye contact dermatitis after pretreatment with clobetasol foam
Nearly 40% of commercial hair dye users develop allergic contact dermatitis (ACD).1 Weak ACD reactions might be augmented with repeated exposure.2 Thus, stopping the cycle early might not only mitigate symptoms but also prevent progression.
http://ift.tt/2ycDlYc
Folate and phototherapy: What should we inform our patients?
Ultraviolet (UV) degradation of folate has been studied in vitro and in vivo, but comprehensive reviews of the subject and recommendations for supplementing folate are lacking, especially for women of childbearing age, in whom decreases in folate predisposes newborns to neural tube defects.
http://ift.tt/2wNwd2A
Comparative evaluation of electrospraying and lyophilization techniques on solid state properties of Erlotinib nanocrystals: Assessment of In-vitro cytotoxicity
Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Shreya Thakkar, Dilip Sharma, Manju Misra
IntroductionErlotinib is a well known FDA approved drug from category of tyrosine kinase inhibitors; used for the treatment of lung cancer. However its use is limited because of its poor water solubility.ObjectiveThe aim of present work was to improve solubility by developing a stable nanocrystal based drug delivery system of ERL with the aid of sodium lauryl sulfate as potential stabilizer and to carry out comparative evaluation of electrospraying and lyophilization as solidification techniques on its solid state properties.ExperimentalNanocrystal formulation was developed with antisolvent precipitation method having particle size, polydispersity index and zetapotential of 232.4±4.3nm, 0.162 and −9.82mV respectively. Further comparative evaluation of lyophilization and electrospraying was commenced as potential solidification techniques and solid powder matrix obtained from both the solidification techniques were compared in terms of size after re-dispersion (260±4.8 and 329±5.2nm respectively), particle morphology, surface area (0.984±0.11 and 0.341±0.05m2/g respectively), pore volume (0.0014 and 0.0009cc/g respectively), solid state of drug present and % drug release (~100% and ~78% respectively in 600min). In vitro cytotoxicity studies shared that obtained formulation was having reduced IC50 values in comparison to drug. Further intracellular reactive oxygen species production was found to be higher for formulation treated cells when compared to free drug. Overall developed formulation was found to be potential drug delivery system for lung cancer therapy.
Graphical abstract
http://ift.tt/2yfDmMQ
Statistical investigation of the full concentration range of fasted and fed simulated intestinal fluid on the equilibrium solubility of oral drugs
Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Jeremy Perrier, Zhou Zhou, Claire Dunn, Ibrahim Khadra, Clive G. Wilson, Gavin Halbert
Upon oral administration the solubility of a drug in intestinal fluid is a key property influencing bioavailability. It is also recognised that simple aqueous solubility does not reflect intestinal solubility and to optimise in vitro investigations simulated intestinal media systems have been developed. Simulated intestinal media which can mimic either the fasted or fed state consists of multiple components each of which either singly or in combination may influence drug solubility, a property that can be investigated by a statistical design of experiment technique. In this study a design of experiment covering the full range from the lower limit of fasted to the upper limit of fed parameters and using a small number of experiments has been performed. The measured equilibrium solubility values are comparable with literature values for simulated fasted and fed intestinal fluids as well as human fasted and fed intestinal fluids. The equilibrium solubility data range is statistically equivalent to a combination of published fasted and fed design of experiment data in six (indomethacin, phenytoin, zafirlukast, carvedilol, fenofibrate and probucol) drugs with three (aprepitant, tadalafil and felodipine) drugs not equivalent. In addition the measured equilibrium solubility data sets were not normally distributed. Further studies will be required to determine the reasons for these results however it implies that a single solubility measurement without knowledge of the solubility distribution will be of limited value. The statistically significant media factors which promote equilibrium solubility (pH, sodium oleate and bile salt) were in agreement with published results but the number of determined significant factors and factor interactions was fewer in this study, lecithin for example did not influence solubility. This may be due to the reduction in statistical sensitivity from the lower number of experimental data points or the fact that using the full range will examine media parameters ratios that are not biorelevant. Overall the approach will provide an estimate of the solubility range and the most important media factors but will not be equivalent to larger scale focussed studies. Further investigations will be required to determine why some drugs do not produce equivalent DoE solubility distributions, for example combined fasted and fed DoE, but this simply may be due to the complexity and individuality of the interactions between a drug and the media components.
Graphical abstract
http://ift.tt/2yfnD06
Studying of drug solubility in water and alcohols using drug-ammonium ionic liquid-compounds
Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Mohammad Halayqa, Aneta Pobudkowska, Urszula Domańska, Maciej Zawadzki
Synthesis of three mefenamic acid (MEF) derivatives - ionic liquid compounds composed of MEF in an anionic form and ammonium cation (choline, MEF1), or {di(2-hydroxyethyl)dimethyl ammonium (MEF2)}, or {tri(2-hydroxyethyl)methyl ammonium compound (MEF3)} is presented. The basic thermal properties of pure compounds i.e. fusion temperatures, and the enthalpy of fusion of these compounds have been measured with differential scanning microcalorimetry technique (DSC). Molar volumes have been calculated with the Barton group contribution method. The solubilities of MEF1, MEF2 and MEF3 using the dynamic method were measured at constant pH in a range of temperature from (290 to 370) K in three solvents: water, ethanol and 1-octanol. The experimental solubility data have been correlated by means of three commonly known GE equations: the Wilson, NRTL and UNIQUAC with the assumption that the systems studied here present simple eutectic behaviour. The activity coefficients of pharmaceuticals at saturated solutions in each binary mixture were calculated from the experimental data. The formation of MEF-ionic liquid compounds greatly increases the solubility in water in comparison with pure MEF or complexes with 2-hydroxypropyl-β-cyclodextrin. The development of these compounds formulations will assist in medication taking into account oral solid or gel medicines.
Graphical abstract
http://ift.tt/2yfBaoO
Binding affinity toward human prion protein of some anti-prion compounds — Assessment based on QSAR modeling, molecular docking and non-parametric ranking
Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Strahinja Kovačević, Milica Karadžić, Sanja Podunavac-Kuzmanović, Lidija Jevrić
The present study is based on the quantitative structure-activity relationship (QSAR) analysis of binding affinity toward human prion protein (huPrPC) of quinacrine, pyridine dicarbonitrile, diphenylthiazole and diphenyloxazole analogs applying different linear and non-linear chemometric regression techniques, including univariate linear regression, multiple linear regression, partial least squares regression and artificial neural networks. The QSAR analysis distinguished molecular lipophilicity as an important factor that contributes to the binding affinity. Principal component analysis was used in order to reveal similarities or dissimilarities among the studied compounds. The analysis of in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters was conducted. The ranking of the studied analogs on the basis of their ADMET parameters was done applying the sum of ranking differences, as a relatively new chemometric method. The main aim of the study was to reveal the most important molecular features whose changes lead to the changes in the binding affinities of the studied compounds. Another point of view on the binding affinity of the most promising analogs was established by application of molecular docking analysis. The results of the molecular docking were proven to be in agreement with the experimental outcome.
Graphical abstract
http://ift.tt/2yfB8NI
Insight into lipophilicity of deoxyribonucleoside‑boron cluster conjugates
Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Aneta Dąbrowska, Michał Matuszewski, Krzysztof Zwoliński, Anna Ignaczak, Agnieszka B. Olejniczak
Lipophilicity was investigated for 20 2′-deoxyribonucleoside derivatives modified with electron-neutral 1,2-dicarba-closo-dodecaborane, 1,12-dicarba-closo-dodecaborane, 7,8-dicarba-nido-undecaborate anion, and metallacarborane containing Co, Fe, or Cr. The partition coefficient (P) for neutral conjugates and the distribution coefficient (D7.4) for ionic compounds were determined as a lipophilicity descriptor using a shake-flask method. All modified nucleosides had P/D7.4 values higher than those of an appropriate unmodified 2′-closo-dodecaborane and metallacarborane was found to be three orders of magnitude higher than that of its unmodified counterpart. The lowest impact on the P/D7.4 values of the conjugates was observed for the 7,8-dicarba-nido-undecaborate anion. A preliminary molecular modeling study of a thymidine-carborane conjugate with β-cyclodextrin confirmed the ability of the components to form an inclusion complex.
Graphical abstract
http://ift.tt/2yfUxOv
Tuning the rheological properties of an ammonium methacrylate copolymer for the design of adhesives suitable for transdermal patches
Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Gaia M.G. Quaroni, Chiara G.M. Gennari, Francesco Cilurzo, Guylaine Ducouret, Costantino Creton, Paola Minghetti
Eudragit® RL (EuRL) matrices have been proposed to release a drug to the skin. However, no information is available on both viscoelastic and adhesive properties of such compositions. This work focuses on the evaluation of both rheological and texture properties of EuRL differently plasticized with tributyl citrate (TBC) or triacetin (TRI) in order to design a pressure sensitive adhesive suitable for transdermal patch preparation. The patch adhesive properties (i.e. tack, peel adhesion and shear adhesion) as well as its in vitro biopharmaceutical performances were determined after loading ibuprofen, ketoprofen or flurbiprofen. The addition of 40–60% w/w TBC or 40–50% w/w TRI to EuRL permitted to obtain matrices with the desired adhesive properties. Moreover, the increase of plasticizer content and loading of the drug reduced the relaxation time (τR). Consequently, the shear adhesion values decreased and the in vitro drug release constants (k) increased. Indeed, the k values from patches containing TBC were lower than the corresponding with TRI because of the lower fluidity of such matrices. In conclusion, the 60/40 EuRL/TBC binary blend is suitable for the design of transdermal patches since the in vitro permeability of the three selected drugs appeared comparable to those described in literature for marketed products.
Graphical abstract
http://ift.tt/2yedaSN
Effect of a high-cholesterol diet on lipoprotein metabolism and xanthoma formation in rabbits
Summary
Background
Xanthelasma is the most common type of cutaneous xanthoma and often occurs on the eyelids. Xanthoma has been reported to be highly correlated with abnormal lipoprotein metabolism.
Aims
In this study, we wanted to investigate the effects of a high-cholesterol diet on xanthoma formation and lipoprotein metabolism in rabbits.
Methods
In animals fed with high-cholesterol diet, deteced plasma lipid [ie, total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (L-DLC)] levels and pathology of xanthoma.
Results
Plasma lipid levels were dramatically elevated within 8 weeks. In addition, high dietary cholesterol promoted xanthoma formation on the napex. Microscopic examination showed that foam cells laden with cholesterol deposits accumulated around the dermal capillaries and cutaneous appendages within the skin of the napex.
Conclusion
These findings indicate a critical role for a high-cholesterol diet in the dysregulation of lipoprotein metabolism and the development of xanthoma in rabbits. The results suggest that abnormal lipid metabolism may increase the occurrence of xanthoma.
http://ift.tt/2kEvYW5
Effect of a high-cholesterol diet on lipoprotein metabolism and xanthoma formation in rabbits
Summary
Background
Xanthelasma is the most common type of cutaneous xanthoma and often occurs on the eyelids. Xanthoma has been reported to be highly correlated with abnormal lipoprotein metabolism.
Aims
In this study, we wanted to investigate the effects of a high-cholesterol diet on xanthoma formation and lipoprotein metabolism in rabbits.
Methods
In animals fed with high-cholesterol diet, deteced plasma lipid [ie, total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (L-DLC)] levels and pathology of xanthoma.
Results
Plasma lipid levels were dramatically elevated within 8 weeks. In addition, high dietary cholesterol promoted xanthoma formation on the napex. Microscopic examination showed that foam cells laden with cholesterol deposits accumulated around the dermal capillaries and cutaneous appendages within the skin of the napex.
Conclusion
These findings indicate a critical role for a high-cholesterol diet in the dysregulation of lipoprotein metabolism and the development of xanthoma in rabbits. The results suggest that abnormal lipid metabolism may increase the occurrence of xanthoma.
http://ift.tt/2kEvYW5
The preadolescent acne microbiome: A prospective, randomized, pilot study investigating characterization and effects of acne therapy
Abstract
Background/Objectives
Acne, a common pediatric disease, tends to be more comedonal in preadolescents, whereas older individuals are more likely to have inflammatory lesions in addition to comedones. Thus the microbiome of preadolescents may be different. In this pilot study we aimed to characterize the preadolescent acne microbiome, compare the microbiome in preadolescents with and without acne, and investigate changes in the microbiome after topical treatment with benzoyl peroxide or a retinoid in a small cohort of preadolescents.
Methods
Participants were 7-10 years of age with (intervention group) or without (control group) acne and were recruited during routine outpatient dermatology visits. Baseline questionnaires, physical examination, and pore strip application were performed for all participants. Intervention group participants were randomized to receive topical therapy with benzoyl peroxide 5% gel or cream or tretinoin 0.025% cream. Participants with acne were followed up 8-10 weeks later and pore strip application was repeated.
Results
Preadolescents with acne were colonized with a greater diversity of cutaneous bacteria than controls and the most commonly identified bacterium was Streptococcus. The number of bacterial species and phylogenetic diversity decreased after treatment with benzoyl peroxide and tretinoin.
Conclusion
The predominant bacteria in microbiome studies of adult acne is Propionibacterium, whereas in this pediatric population we saw a lot of Streptococcus bacteria. After treatment, the microbiomes of intervention group participants more closely resembled those of control group participants.
http://ift.tt/2yZoxuZ
Pediatric keloids: A 6-year retrospective review
Abstract
Background/Objectives
Keloids are reportedly rare at the extremes of life. We sought to describe the epidemiology of pediatric keloids seen at the plastic surgery outpatient department of the University College Hospital, Ibadan.
Methods
We retrospectively reviewed all children younger than 19 years who presented with nonburn keloids between 2008 and 2014. Data were obtained on age; duration, size, and location of the keloid; family history; mode of treatment; and outcome. Outcome variables were recurrence and wound complications. Data were analyzed using the Pearson chi-square test for discreet variables and the independent-sample t test for continuous variables. P < .05 was taken as statistically significant.
Results
Within the review period, 304 patients presented with keloids, of whom 40 (13.1%) were younger than 19 years. There was a female preponderance (n = 23, 57.5%). The mean age at onset of the keloid was 9.3 years (range 3 months-18 years). Thirty (75%) patients had keloids in the head and neck region. Keloids were sporadic in 31 (77.5%) patients. Nineteen (47.5%) patients had multimodal treatment for keloid. The recurrence rate was 20%. Recurrence was significantly associated with the size of the lesion (P = .003).
Conclusion
Keloids during childhood are not rare. More attention should be paid to the management of keloids in this age group.
http://ift.tt/2zfdNJV
Agminated segmental plaque-type blue nevus associated with hypertrichosis and soft tissue hypertrophy: Report of a case and review of the literature
Abstract
Blue nevi are common skin neoplasms that typically present as asymptomatic solitary papules, although they may rarely occur in an agminated configuration. We describe a case of agminated blue nevus in a segmental facial distribution associated with soft tissue hypertrophy and hypertrichosis in a 16-year-old boy and present a review of the literature. Although they are generally considered to be benign, concurrent soft tissue changes occurring within an agminated blue nevus should be investigated thoroughly to exclude alternate diagnoses.
http://ift.tt/2yZotLL
Perineal groove in female infants: A case series and literature review
Abstract
Background
Perineal groove is a rare congenital malformation that is unknown to many clinicians and is often misdiagnosed. Although it may be self-resolving during childhood, this nonepithelized mucous membrane can pose the risk of local irritation and infection, particularly urinary tract infection.
Methods
A retrospective study of female infants diagnosed with a perineal groove was performed, demographic characteristics and clinical features were analyzed, and a photographic review was conducted.
Results
Five patients with perineal groove were observed in our clinic in 2015-16. The mean age was 14 months. None had symptoms, and no treatment was required. During follow-up of 1 year, all remained asymptomatic.
Conclusions
Our retrospective review suggests that perineal groove may be an underdiagnosed condition. Most cases resolve spontaneously, but confusion in diagnosis may lead to misdiagnosis or misinterpretation of sexual abuse and unnecessary treatments.
http://ift.tt/2i2Uv6y
Reconsidering the H&E stain as the gold standard in assessing the depth of burn wounds
While histological examination is considered by most as the gold standard for burn depth assessment, it has no practical use in the clinical setting. It has, however, been used in the research setting, as a mean for evaluating emerging techniques of depth measurement. Due to the limitations of the H&E stain, other stains have also been explored, such as lactate dehydrogenase (LDH), as presented in this issue, in "Improving the Histologic Characterization of Burn Depth." As the determination of burn depth is not a typical subject in dermatopathology, a summary of selected techniques and the possible role for the LDH stain in future research, is described herein.
http://ift.tt/2yfPT2D
Differential Processing of Isolated Object and Multi-item Pop-Out Displays in LIP and PFC
Abstract
Objects that are highly distinct from their surroundings appear to visually "pop-out." This effect is present for displays in which: (1) a single cue object is shown on a blank background, and (2) a single cue object is highly distinct from surrounding objects; it is generally assumed that these 2 display types are processed in the same way. To directly examine this, we applied a decoding analysis to neural activity recorded from the lateral intraparietal (LIP) area and the dorsolateral prefrontal cortex (dlPFC). Our analyses showed that for the single-object displays, cue location information appeared earlier in LIP than in dlPFC. However, for the display with distractors, location information was substantially delayed in both brain regions, and information first appeared in dlPFC. Additionally, we see that pattern of neural activity is similar for both types of displays and across different color transformations of the stimuli, indicating that location information is being coded in the same way regardless of display type. These results lead us to hypothesize that 2 different pathways are involved processing these 2 types of pop-out displays.http://ift.tt/2xyATZT
Missing ozone-induced potential aerosol formation in a suburban deciduous forest
Publication date: Available online 10 October 2017
Source:Atmospheric Environment
Author(s): T. Nakayama, Y. Kuruma, Y. Matsumi, Y. Morino, K. Sato, H. Tsurumaru, S. Ramasamy, Y. Sakamoto, S. Kato, Y. Miyazaki, T. Mochizuki, K. Kawamura, Y. Sadanaga, Y. Nakashima, K. Matsuda, Y. Kajii
As a new approach to investigating formation processes of secondary organic aerosol (SOA) in the atmosphere, ozone-induced potential aerosol formation was measured in summer at a suburban forest site surrounded by deciduous trees, near Tokyo, Japan. After passage through a reactor containing high concentrations of ozone, increases in total particle volume (average of 1.4 × 109 nm3/cm3, which corresponds to 17% that of pre-existing particles) were observed, especially during daytime. The observed aerosol formations were compared with the results of box model simulations using simultaneously measured concentrations of gaseous and particulate species. According to the model, the relative contributions of isoprene, monoterpene, and aromatic hydrocarbon oxidation to SOA formation in the reactor were 24, 21, and 55%, respectively. However, the model could explain, on average, only ∼40% of the observed particle formation, and large discrepancies between the observations and model were found, especially around noon and in the afternoon when the concentrations of isoprene and oxygenated volatile organic compounds were high. The results suggest a significant contribution of missing (unaccounted-for) SOA formation processes from identified and/or unidentified volatile organic compounds, especially those emitted during daytime. Further efforts should be made to explore and parameterize this missing SOA formation to assist in the improvement of atmospheric chemistry and climate models.
Graphical abstract
http://ift.tt/2hAYSl5
Lesions Responsible for Delayed Oral Transit Time in Post-stroke Dysphagia
Abstract
Introduction
Some stroke patients show oral phase dysphagia, characterized by a markedly prolonged oral transit time that hinders oral feeding. The aim of this study was to clarify the clinical characteristics and lesions responsible for delayed swallowing.
Methods
We reviewed 90 patients with stroke. The oral processing time plus the postfaucial aggregation time required to swallow semisolid food was assessed. The patients were divided into two groups according to oral transit time, and we analyzed the differences in characteristics such as demographic factors, lesion factors, and cognitive function. Logistic regression analyses were performed to examine the predictors of delayed oral transit time. Lesion location and volume were measured on brain magnetic resonance images. We generated statistic maps of lesions related to delayed oral phase in swallowing using voxel-based lesion symptom mapping (VLSM).
Results
The group of patients who showed delayed oral transit time had significantly low cognitive function. Also, in a regression model, delayed oral phase was predicted with low K-MMSE (Korean version of the Mini Mental Status Exam). Using VLSM, we found the lesion location to be associated with delayed oral phase after adjusting for K-MMSE score. Although these results did not reach statistical significance, they showed the lesion pattern with predominant distribution in the left frontal lobe.
Conclusion
Delayed oral phase in post-stroke patients was not negligible clinically. Patients' cognitive impairments affect the oral transit time. When adjusting it, we found a trend that the lesion responsible for delayed oral phase was located in the left frontal lobe, though the association did not reach significance. The delay might be related to praxis function.
http://ift.tt/2ybaK5m
A Significant Association of Malnutrition with Dysphagia in Acute Patients
Abstract
Dysphagia and malnutrition seem to be associated, but little research in detail has been reported. We aimed to clarify the association between dysphagia and malnutrition by adopting accurate diagnosis and mathematical evaluation of dysphagia using videofluorography and nutritional assessment calculated by a well-established nutritional risk index. We conducted a retrospective analysis of 165 enrolled patients who were admitted to our hospital for acute diseases and underwent videofluorography on suspicion of dysphagia in the year 2016. We diagnosed high-risk dysphagia in patients with 8-point penetration–aspiration scale (PAS) score over 4. We used the geriatric nutritional risk index (GNRI) as a nutritional assessment tool. A GNRI score less than 91.2 corresponds to malnutrition. The median age of 165 enrolled patients was 76.0, and the number of female patients was 53. The mean GNRI was 81.2, and 134 patients (81.2%) had malnutrition. The number of the patients with a diagnosis of high-risk dysphagia was 54 (32.7%). The GNRI of patients with high-risk dysphagia was significantly less than that of patients without (mean value 77.7 ± 10.5 vs. 83.0 ± 10.5, P = 0.003). GNRI < 91.2 was independently and significantly associated with high-risk dysphagia (OR 3.094; CI 1.057–9.058; P = 0.039). Based on the current study, the authors propose evaluating nutritional status to predict dysphagia risk of patients in the acute phase.
http://ift.tt/2wOcUq9
MTA promotes chemotaxis and chemokinesis of immune cells through distinct calcium-sensing receptor signaling pathways
Source:Biomaterials, Volume 150
Author(s): Fengjiao Chang, Jin Man Kim, Youngnim Choi, Kyungpyo Park
Mineral trioxide aggregate (MTA) has been introduced as a choice material for regenerative dentistry. To date, the diverse biological activities of MTA, including its anti-inflammatory effects, have been extensively discussed. However, there is limited insight into the link between MTA and immune cell migration. In this study, we report the role of MTA in enhancing both chemotactic and chemokinetic immune cell migration through distinct signaling pathways. By using versatile live imaging techniques, we demonstrated that MTA-mediated CaSR activation induced diverse downstream pathways to govern cell migratory capacity. In this context, Cdc42 generates cytoskeleton-driven cellular protrusions to steer directional cell migration (chemotaxis) whereas Ca2+-calmodulin dependent myosin light chain kinase induces cell contractility that plays an important role in speeding up the average migration speed (chemokinesis). Our findings illuminate an unrecognized role for MTA and the related CaSR signaling network in immune cell migration, providing evidence that can drive development of novel approaches to immunological therapy.
http://ift.tt/2i2XewL
Enhanced antitumor efficacy of arginine modified amphiphilic nanoparticles co-delivering doxorubicin and iSur-pDNA via the multiple synergistic effect
Source:Biomaterials, Volume 150
Author(s): Yudong Song, Cui Tang, Chunhua Yin
Arginine and α-tocopherol succinate (α-TOS) double grafted N-trimethyl chitosan chloride (TMC) nanoparticles (TAS NPs) were designed and developed for effective co-delivery of doxorubicin (DOX) and Survivin shRNA-expressing pDNA (iSur-pDNA). With DOX loading into the hydrophobic core and iSur-pDNA combining to the hydrophilic shell, TAS/DOX/pDNA NPs demonstrated favorable structural stability and sustained release properties in vitro. With the special non-clathrin-dependent endocytosis, TAS/DOX/pDNA NPs presented higher cellular uptake and mainly distributed in ER and Golgi rather than lysosomes following internalization. The in vitro nuclear localization, gene silencing efficiency, cell apoptosis, and growth inhibition of tumor cells were significantly promoted by arginine modification. In the tumor-bearing mice model, TAS/DOX/pDNA NPs possessed the maximum antitumor efficiency as compared with single delivery of DOX or iSur-pDNA. Particularly, blank TAS NPs were selectively be toxic to tumor cells as evidenced by their capabilities to inhibit proliferation and induce apoptosis of tumor cells. The promising tumor treatment of TAS/DOX/pDNA NPs via a multiple synergistic manner arising from DOX and pDNA as well as the vectors would provide a potential strategy for a dual-delivery system to improve their therapeutic efficacies.
http://ift.tt/2xxiEJm
Editorial board
Source:Biomaterials, Volume 148
http://ift.tt/2ze0J7A
Down-regulation of miR-26a-5p in hepatocellular carcinoma: a qRT-PCR and bioinformatics study
Publication date: Available online 10 October 2017
Source:Pathology - Research and Practice
Author(s): Liang Liang, Jiang-hui Zeng, Jie-yu Wang, Rong-quan He, Jie Ma, Gang Chen, Xiao-yong Cai, Xiao-hua Hu
BackgroundTo practically verify the clinical value of miR-26a-5p and thoroughly explore its target genes as well as its potential functions in hepatocellular carcinoma (HCC).MethodsHCC and adjacent non-cancerous hepatic tissues of 95 HCC patients were collected for analysis using reverse transcription quantitative real-time PCR (qRT-PCR). For the bioinformatics analysis, we identified potential target genes for miR-26a-5p from differentially expressed genes (DEGs) in Gene Expression Omnibus (GEO) data sets and miRWalk predicted database. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein-protein interaction (PPI) analyses were applied to analyze the prospective mechanisms of the predicted target genes.ResultsMiR-26a-5p showed a significantly lower expression level in HCC tissues (1.56±1.07) than adjacent benign liver tissues (2.28±1.06, P <0.001). The area under the curve (AUC) of the receiver operating characteristic (ROC) was 0.665 (95% CI: 0.588-0.743, P <0.001). Significant correlations between miR-26a-5p expression and clinicopathological features such as gender (r=0.275, P <0.01), clinical TNM stage (r=−0.306, P <0.01), and metastasis (r=−0.321, P <0.01) were observed. To examine potential target genes, we obtained 175 genes for further function analysis, by attaining the intersection of 2062 up-regulated DEGs and 1390 online-predicted target genes. The GO and KEGG pathway annotation indicated focal adhesion, regulation of actin cytoskeleton and the PI3K-Akt signaling pathway as significant prospective mechanisms. The PPI network indicated that NRAS was the most essential hub gene in the whole network.ConclusionDown-regulated miR-26a-5p was closely correlated with the status of metastasis and the progression of HCC. MiR-26a-5p might play protective roles by targeting diverse genes and pathways.
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Aberrant promoter methylation of the PAQR3 gene is associated with prostate cancer
Publication date: Available online 10 October 2017
Source:Pathology - Research and Practice
Author(s): Kowit Lounglaithong, Andrey Bychkov, Pichet Sampatanukul
Methylation markers are promising tools for diagnosis, prognosis and targeted treatment of cancer. In prostate carcinoma, aberrant promoter hypermethylation occurs earlier in the disease course and more consistently than recurrent somatic mutations. PAQR3, a tumor suppressor gene, was recently found to be downregulated in prostate cancer cell lines. We hypothesized that promoter methylation could be responsible for PAQR3 silencing in prostate cancer tissues. We aimed to investigate PAQR3 promoter methylation in prostate cancer by comparing it to benign prostatic hyperplasia (BPH). A total of 154 human prostate tissue samples, including 92 cases with prostate cancer and 62 cases with BPH, were examined by methylation-specific PCR. Clinicopathological correlation between PAQR3 promoter methylation and prognostically relevant variables was studied by statistical analysis. Promoter methylation of PAQR3 was significantly more frequent in prostate carcinoma compared to BPH (73.9% vs. 25.8%, p <0.01). The high prevalence of PAQR3 methylation in cancer foci was also confirmed with microdissection technique in 12 samples of prostate adenocarcinoma. PAQR3 hypermethylation was associated with perineural invasion (p=0.03), an adverse clinicopathological feature of prostate cancer. We concluded that PAQR3 can be a promising methylation marker candidate for the detection and monitoring of prostate cancer.
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Over expression of HIF1α is associated with inactivation of both LimD1 and VHL in renal cell carcinoma: clinical importance
Publication date: Available online 10 October 2017
Source:Pathology - Research and Practice
Author(s): Subhayan Sur, Arun Kumar Maurya, Anup Roy, Tyson V. Sharp, Dilip Kumar Pal, Chinmay Kumar Panda
It is evident that the association of LimD1 and VHL could regulate stabilization of HIF1α protein. In this study, the expression of LimD1, VHL and HIF1α was analyzed in primary renal cell carcinoma (RCC) samples to understand their association with development of the disease. For this purpose, immunohistochemical expression analysis of LimD1, VHL and HIF1α was performed along with proliferation marker PCNA in 32 primary RCC samples in different subtypes at different clinical stages of Indian patients (year: 2014–2016). Significant decrease (P<0.05) in LimD1 and VHL expression was observed in different subtypes of RCC and in early invasive lesions. High nuclear expression of HIF1α was seen in different subtypes as well as in early invasive lesions. The LimD1 and VHL expression strongly correlated with each other, while inversely correlated with HIF1α. On the other hand, increased expression of PCNA was seen in different sub types and in early invasive lesions. The PCNA expression was negatively correlated with LimD1 and VHL expression and positively correlated with HIF1α. Thus, our data indicates that the reduced expression of LimD1 and VHL might have synergistic effect on induction of HIF1α resulting increased cellular proliferation and progression of the disease.
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Oceanic dispersion of Fukushima-derived Cs-137 simulated by multiple oceanic general circulation models
Source:Journal of Environmental Radioactivity, Volume 180
Author(s): Hideyuki Kawamura, Akiko Furuno, Takuya Kobayashi, Teiji In, Tomoharu Nakayama, Yoichi Ishikawa, Yasumasa Miyazawa, Norihisa Usui
To understand the concentration and amount of Fukushima-derived Cs-137 in the ocean, this study simulated the oceanic dispersion of Cs-137 by atmospheric and oceanic dispersion simulations. The oceanic dispersion simulations were carried out with an oceanic dispersion model and multiple oceanic general circulation models. The Cs-137 concentrations were sensitive to ocean currents in the coastal, offshore, and open oceans. The mean Cs-137 concentrations of the multiple models relatively well agreed with the observed concentrations in the coastal and offshore oceans during the first few months after the Fukushima disaster, and in the open ocean during the first year after the disaster. The Cs-137 amounts were quantified in the coastal, offshore, and open oceans during the first year after the disaster. It was suggested that Cs-137 actively dispersed from the coastal and offshore oceans to the open ocean, and from the surface layer to the deeper layers in the North Pacific.
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Application of ISOCS system in the laboratory efficiency calibration
Source:Journal of Environmental Radioactivity
Author(s): Dominik Grządziel, Krzysztof Kozak, Jadwiga Mazur, Mariusz Mroczek
ISOCS (In Situ Counting Object System) from Canberra is applied in laboratory for creating efficiency calibrations of good quality without using radioactive standards. Besides of typical sample containers used in laboratory, ISOSC system also allows modelling containers and objects of almost any shape and elemental composition.The study was based on gamma spectrometry with HPGe semiconductor detector with electronics and software spectrum analysis GENIE 2000 + ISOCS. Measuring set is equipped with portable shield system with set of collimators ISOCS Shield Systems Model ISOXSHLD from Canberra. This shielding system provides attenuation of gamma background radiation with average value 33 (for gamma energies from 186 keV to 2615.5 keV).The portable shield system can be used for low-background laboratory measurements. For this purpose a measuring vessel of new geometry was constructed: the polystyrene cylinder with a height of 40 mm and a diameter of 70 mm. The efficiency calibration for this container was performed using both ISOCS system and classical calibration standard in the same geometry. In order to verify the correctness of performed calibration procedures, the measurements of radioactive standard CBSS 2 were made. The results of both calibrations were compared with the data from the standard certificate. Satisfactory agreement was achieved. Mean percentage difference between results from ISOCS calibration compared to reference values is 6% for all isotopes activities in CBSS 2 standard.The set of collimators was used to develop efficiency calibration for in situ measurements of the soil surface. Test measurements were carried out at the area of the Institute of Nuclear Physics Polish Academy of Sciences in Kraków, Poland (IFJ PAN). Two measurement methods were compared: in situ and laboratory gamma spectroscopy. The obtained average results (from all 10 measuring points) are consistent within the range of measurement uncertainty.
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Cold agglutinins in a patient undergoing normothermic cardiac operation with warm cardioplegia
Cold agglutinins are autoantibodies that agglutinate red blood cells at low temperatures, leading to haemagglutination and haemolysis. They are generally of no clinical significance. However, when people with cold agglutinins undergo cardiac operation with hypothermia and cold cardioplegia, they can experience complications. Thus, different perioperative management is required for such patients. We describe a 74-year-old man with cold agglutinins incidentally detected on the preoperative screening test. He had never experienced any complications or developed a haematological disease. Since cold agglutinins were incidentally detected on the preoperative test, a special strategy was used to manage the temperature of cardiopulmonary bypass (CPB) and cardioplegia. He successfully underwent normothermic cardiac operation with warm cardioplegia. A continuous retrograde hyperkalaemic infusion and intermittent antegrade infusion of warm cardioplegia with normothermic CPB is one of the best methods to avoid hypothermia and excessive activity and metabolism of the heart, and to provide a suitable operative field.
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Use of a dynamic gait trainer for a child with thoracic level spinal cord injury
Paediatric spinal cord injury (SCI) can result in permanent mobility impairment with consequences for activity, participation and quality of life. This case documents the effect of an overground supported stepping intervention using a dynamic gait trainer. To our knowledge, there are no published studies on this intervention for children with SCI and similar interventions have only been reported in children at American Spinal Injury Association Impairment Scale (AIS) levels B and C.
A child with a T10 (thoracic level, vertebra 10), AIS level A injury, sustained at 2 years of age, continued to make gains in all areas including participation, activity, body structure and function over the following 4 years. Use of a dynamic gait trainer improved the participant's ability to be active and participate despite lack of further neuromuscular recovery. This novel approach with a commonly available device allowed the child to be active and participate in the absence of neural recovery.
http://ift.tt/2yfAI9N
Early sonographic detection of a succenturiate placenta after IVF in a 42-year-old woman with multiple comorbidities
We present a case of a 42-year-old woman with a pregnancy resulting from in vitro fertilisation and a medical history including two spontaneous abortions, hypercoagulable state and other comorbidities. At 13 4/7 weeks' gestation, during research ultrasonography, the patient was noted to have an anterior succenturiate placental lobe. Following an episode of vaginal bleeding at 21 6/7 weeks, she was diagnosed with a low-lying posterior placental lobe. Velamentous cord insertion, placenta previa and vasa previa were excluded at that time. After elective induction for advanced maternal age at 39 0/7 weeks, arrest of labour and chorioamnionitis resulted in a primary low transverse caesarean section and delivery of a healthy girl at 39 3/7 weeks. Gross examination of the placenta showed an irregular, singleton placenta with an attached succenturiate lobe and a marginally inserting umbilical cord. Both lobes were connected by two vessels.
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Knotted urethral catheter: an unusual complication in adults
Knotting of feeding tubes or urinary catheters has been reported as a rare complication in paediatrics when draining the bladder. This is caused by inserting thin flexible tubes too far in, allowing it to coil. We present a case of a 70-year-old woman who was catheterised during a routine spinal surgery, and the catheter coiled and balloon failed to deflate requiring a cystostopic approach to puncture the balloon and remove it. Awareness of this complication in female catheterisation and education on length of catheter insertion is important to avoid this.
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Metastatic primary seminal vesicle adenocarcinoma: management of a rare tumour with multiagent chemotherapy and hormonal therapy
Primary seminal vesicle adenocarcinoma is one of the rarest genitourinary cancers. The pathogenesis is unknown and clinical manifestations are protean. There is no defined treatment for this disease and various combinations of surgery, chemotherapy, radiation therapy and hormonal therapy have been used in the past. Here, we have reported a primary seminal vesicle adenocarcinoma with hepatic metastases, managed with multiagent chemotherapy (oxaliplatin and 5-fluorouracil based) and androgen ablation (with triptorelin). The key to management of such a case is early diagnosis and multimodal treatment. The reported survival rate continues to be poor even for a localised disease. A consolidated follow-up protocol ensures early diagnosis of recurrent or metastatic disease so that second-line therapy can be started.
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Double PCL sign on sagittal MRI of the knee
Description
A 24-year-old male presented with left knee pain and swelling after a fall six weeks earlier playing football. Clinical examination revealed an antalgic gait and a moderate left knee effusion with tenderness along the medial joint line. Anterior drawer and Lachman tests were positive, suggesting an anterior cruciate ligament (ACL) injury. An MRI scan performed shortly after the injury revealed a large joint effusion and significant acute bone oedema involving the medial tibial condyle. While the posterior cruciate ligament (PCL) was intact, the ACL was elongated and suspicious for an intrasubstance tear. A bucket-handle tear of the medial meniscus was observed with the free fragment seen within the intercondylar notch. This gave rise to the double PCL sign on sagittal view. The patient underwent arthroscopic ACL reconstruction with a hamstring graft, and the medial meniscus was excised as it was unrepairable.
The 'double PCL' sign refers to the...
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Fulminant Bacillus cereus septicaemia with multiple organ ischaemic/haemorrhagic complications in a patient undergoing chemotherapy for acute myelogenous leukaemia
Bacillus cereus is a Gram-positive spore-forming rod widely found in the environment and is thought to be a frequent source of contamination. This micro-organism is reportedly a significant pathogenic agent among immunocompromised individuals. Furthermore, multiple cases of fulminant septicaemia have been reported among individuals receiving chemotherapy for acute myelogenous leukaemia. In some cases, B. cereus septicaemia was associated with multiple haemorrhages. We, herein, describe a patient with an extremely acute course of B. cereus septicaemia characterised by haemorrhage and infarction of multiple organs, which led to his death. Our findings suggest that delayed treatment of B. cereus in patients with haematologic malignancies undergoing chemotherapy may result in extremely poor outcomes; thus, immediate empirical treatment with vancomycin should be considered.
http://ift.tt/2gaY9L9
Juvenile elastoma without germline mutations in LEMD3 gene: A case of Buschke-Ollendorff syndrome?
Abstract
We report the case of a 6-year-old Caucasian girl with clinical and histopathologic features of Buschke-Ollendorff syndrome. Histologic examination of skin lesions showed thick, curly, elastic fibers in the derma. Bone lesions compatible with Buschke-Ollendorff syndrome were found in the girl's mother. Mutations in LEMD3 are pathogenic for Buschke-Ollendorff syndrome. Analysis of all exons and exon-intron junctions of LEMD3 did not reveal any germline mutations.
http://ift.tt/2y9AMsg
High glucose impaired estrogen receptor alpha signaling via β-catenin in osteoblastic MC3T3-E1
Publication date: Available online 10 October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Rui Wang, Dong Gao, Yin Zhou, Lu Chen, Bin Luo, Yanrong Yu, Hao Li, Jiawei Hu, Qiren Huang, Ming He, Weijie Peng, Dan Luo
Diabetic Mellitus is a risk factor for osteoporosis. It has been suggested that altered estrogen or estrogen receptor α/β (ERα/β) signaling may be involved in diabetic osteoporosis. The present study is to investigate the effects of high glucose on ERα/β signaling in osteoblastic MC3T3-E1 and how the altered signaling of ERα/β affect osteoblastic bone formation. ERα/β signaling was demonstrated as ERα/β protein expression (Western Blotting) and ER transcription activity (Luciferase Reporter assays). Proliferation (WSK-1 assaying), differentiation (ALP staining) and mineralization (Alizalard Red staining) of MC3T3-E1 were examined to evaluate bone formation function. It has been found that high glucose increased ERα/β expression dose-dependently and time-dependently, but high glucose (33mM) decreased ERα transcription activity. 17β-estradiol increased the ERα/β expression dose-dependently in normal medium, but decreased the ERα/β expression dose-dependently in medium with high glucose (33mM). High glucose decreased bone formation and also decreased the osteogenic effects of 17β-estradiol (10−8M). High glucose decreased β-catenin expression dose-dependently and time-dependently. LiCl, an inhibitor of β-catenin degradation, decreased ERα expression but increased ERα transcription activity. When compared with high glucose treatment, LiCl (5mM) increased ALP activity and calcified nodes. Besides, high glucose also decreased the protein expression PI–3K, pAKT/AKT, GSK-3β. In conclusion, the present study suggested that high glucose may impair ERα transcription activity by inhibiting β-catenin signaling in osteoblastic MC3T3-E1, leading decreased bone formation ligand-dependently or ligand-independently.
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Simultaneous profiles of sulfonated androgens, sulfonated estrogens and sulfonated progestogens in postpubertal boars (sus scrofa domestica) measured by LC-MS/MS
Publication date: Available online 10 October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): G. Schuler, A. Sánchez-Guijo, M.F. Hartmann, S.A. Wudy
1 Sulfonated steroids (s-St) have been usually regarded as inactive metabolites but are progressively considered as precursors for the intra-tissue formation of bioactive steroids. Moreover, independent effects without preceding removal of the sulfate group have been observed. We use the porcine testicular-epididymal compartment as a model to investigate the still largely unknown s-St physiology as the boar exhibits an intriguingly broad s-St spectrum predominantly originating from the testis. The application of LC-MS/MS in steroidomics enables the determination of unconjugated and intact sulfonated steroids with currently highest specificity and good sensitivity, allowing the concurrent measuring of numerous analytes in larger quantities of samples. Profiles (6hours, 20min intervals) were generated for sulfonated 5-androstene-3ß,17ß-diol (Adiol-S), androsterone (A-S), dehydroepiandrosterone (DHEA-S), epiandrosterone (EA-S), epitestosterone (ET-S), estrone (E1-S), estradiol-17β (E2-S), pregnenolone (P5-S), 17αOH-pregnenolone (OHP5-S) and unconjugated testosterone (T) in four unstimulated and four hCG-stimulated boars. Moreover, concentrations were measured in individual samples collected from testicular afferent and efferent blood to differentiate between testicular vs. extratesticular origin. Highest concentrations were found for EA-S, followed by ET-S, Adiol-S and DHEA-S, which mostly exceeded the levels of E1-S and A-S. Lowest concentrations were obtained for E2-S, P5-S and OHP5-S. The analytical profile also included sulfonated T, 5α-dihydrotestosterone and cholesterol. However, their concentrations were below the limit of quantification. Profiles of quantifiable s-St were consistent with a wave-like pattern associated with T pulses. In postpartal females (n=5) concentrations of all analytes assessed were undetectable, suggesting that in pigs the adrenals are not a quantitatively significant source of s-St.
http://ift.tt/2gtWaOB
Antimicrobial Peptides, Nanotechnology, and Natural Metabolites as Novel Approaches for Cancer Treatment
Publication date: Available online 10 October 2017
Source:Pharmacology & Therapeutics
Author(s): Michel L. Leite, Nicolau B. da Cunha, Fabricio F. Costa
Despite the advances in tumor identification and treatment, cancer remains the primary driver of death around the world. Also, regular treatments for the disease are incapable of targeting particular cancer types at different stages since they are not specifically focused on harmful cells since they influence both solid and tumor cells, causing side effects and undesirable symptoms. Therefore, novel strategies should be developed to treat this disease. Several efforts have been made in this direction to find more effective alternatives to cancer treatment, such as the use of antimicrobial peptides (AMPs) with antitumoral activity, nanocarriers and natural compounds from a variety of sources. AMPs are more specific to their targets because of electrostatic interaction between AMPs and the cancer cells' plasma membrane. Nanocarriers may be used for the delivery of non-soluble drugs, which are poorly stable or require a controlled release. In addition, natural compounds have been a rich source of anti-cancer agents for decades. In this review, these three approaches will be discussed, showing recent advances and advantages of using these strategies to treat cancer as well as the combination of these approaches increasing anticancer activity.
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Targeting Aging with Functional Food: Pasta with Opuntia Single-Arm Pilot Study
Rejuvenation Research , Vol. 0, No. 0.
http://ift.tt/2zeV9ll
Attenuation of Oxidative Damage by Coenzyme Q10 Loaded Nanoemulsion Through Oral Route for the Management of Parkinson's Disease
Rejuvenation Research , Vol. 0, No. 0.
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Hotspots of De Novo Point Mutations in Induced Pluripotent Stem Cells
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Masahito Yoshihara, Ryoko Araki, Yasuji Kasama, Misato Sunayama, Masumi Abe, Kohji Nishida, Hideya Kawaji, Yoshihide Hayashizaki, Yasuhiro Murakawa
Induced pluripotent stem cells (iPSCs) are generated by direct reprogramming of somatic cells and hold great promise for novel therapies. However, several studies have reported genetic variations in iPSC genomes. Here, we investigated point mutations identified by whole-genome sequencing in mouse and human iPSCs in the context of epigenetic status. In contrast to disease-causing single-nucleotide polymorphisms, de novo point mutations introduced during reprogramming were underrepresented in protein-coding genes and in open chromatin regions, including transcription factor binding sites. Instead, these mutations occurred preferentially in structurally condensed lamina-associated heterochromatic domains, suggesting that chromatin organization is a factor that can bias the regional mutation rate in iPSC genomes. Mutation signature analysis implicated oxidative stress associated with reprogramming as a likely cause of point mutations. Altogether, our study provides deeper understanding of the mutational landscape of iPSC genomes, paving an important way toward the translation of iPSC-based cell therapy.
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Teaser
Yoshihara et al. show that de novo point mutations introduced during iPSC reprogramming preferentially occur in structurally condensed lamina-associated heterochromatic domains and exhibit an oxidative stress-induced DNA damage mutation signature. This study provides better characterization of iPSC mutations at the whole-genome level and accelerates the translation of iPSC-based cell therapies.http://ift.tt/2yb4Zoh
Remarkable Stability of Myelinating Oligodendrocytes in Mice
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Richa B. Tripathi, Martyna Jackiewicz, Ian A. McKenzie, Eleni Kougioumtzidou, Matthew Grist, William D. Richardson
New myelin-forming oligodendrocytes (OLs) are generated in the mouse central nervous system during adulthood. These adult-born OLs might augment the existing population, contributing to neural plasticity, or else replace OLs that die in use (turnover). To distinguish between these alternatives, we induced genetic labeling of mature myelinating OLs in young adult mice and tracked their subsequent survival. OL survival rates were region dependent, being higher in corpus callosum (∼90% survival over 20 months) and motor cortex (∼70% survival) than in corticospinal tract or optic nerve (50%–60% survival). Survival rates over the first 8 months were 90%–100% in all regions except the optic nerve. In the corpus callosum, new OLs accumulate during young adulthood and are therefore likely to participate in adaptive myelination. We also found that the number of myelin internodes maintained by individual cortical OLs is stable for at least 8 months but declines ∼12% in the following year.
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Teaser
Tripathi et al. estimate the lifetime of myelinating oligodendrocytes (OLs) by fate-mapping in Opalin-CreERT2: Tau-mGFP mice. In the corpus callosum, >90% of OLs survived for >1.5 years and probably outlive the mouse. Therefore, adult-born OLs are not needed for myelin homeostasis but potentially contribute to experience-dependent, adaptive myelination.http://ift.tt/2ybqZzo
Enhancement of BLM-DNA2-Mediated Long-Range DNA End Resection by CtIP
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): James M. Daley, Judit Jimenez-Sainz, Weibin Wang, Adam S. Miller, Xiaoyu Xue, Kevin A. Nguyen, Ryan B. Jensen, Patrick Sung
DNA double-strand break repair by homologous recombination entails the resection of DNA ends to reveal ssDNA tails, which are used to invade a homologous DNA template. CtIP and its yeast ortholog Sae2 regulate the nuclease activity of MRE11 in the initial stage of resection. Deletion of CtIP in the mouse or SAE2 in yeast engenders a more severe phenotype than MRE11 nuclease inactivation, indicative of a broader role of CtIP/Sae2. Here, we provide biochemical evidence that CtIP promotes long-range resection via the BLM-DNA2 pathway. Specifically, CtIP interacts with BLM and enhances its helicase activity, and it enhances DNA cleavage by DNA2. Thus, CtIP influences multiple aspects of end resection beyond MRE11 regulation.
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Teaser
Biochemical analysis by Daley et al. shows that CtIP not only functions as a cofactor for the MRN complex but also stimulates long-range resection by BLM-DNA2-RPA. CtIP interacts with BLM and enhances its helicase activity, and it upregulates the DNA flap cleavage activity of DNA2.http://ift.tt/2yapCAN
Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Karina Zadorozhny, Vincenzo Sannino, Ondrej Beláň, Jarmila Mlčoušková, Mário Špírek, Vincenzo Costanzo, Lumír Krejčí
Fanconi anemia (FA) is a genetic disorder characterized by a defect in DNA interstrand crosslink (ICL) repair, chromosomal instability, and a predisposition to cancer. Recently, two RAD51 mutations were reported to cause an FA-like phenotype. Despite the tight association of FA/HR proteins with replication fork (RF) stabilization during normal replication, it remains unknown how FA-associated RAD51 mutations affect replication beyond ICL lesions. Here, we report that these mutations fail to protect nascent DNA from MRE11-mediated degradation during RF stalling in Xenopus laevis egg extracts. Reconstitution of DNA protection in vitro revealed that the defect arises directly due to altered RAD51 properties. Both mutations induce pronounced structural changes and RAD51 filament destabilization that is not rescued by prevention of ATP hydrolysis due to aberrant ATP binding. Our results further interconnect the FA pathway with DNA replication and provide mechanistic insight into the role of RAD51 in recombination-independent mechanisms of genome maintenance.
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Teaser
Zadorozhny et al. find that RAD51 mutations associated with Fanconi anemia not only impair DNA crosslink repair but also affect DNA replication during fork stalling. The mutant proteins cause RAD51 filament destabilization and induce pronounced structural changes resulting from aberrant ATP binding and hydrolysis.http://ift.tt/2yaiHrl
Homeostatic Presynaptic Plasticity Is Specifically Regulated by P/Q-type Ca2+ Channels at Mammalian Hippocampal Synapses
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Alexander F. Jeans, Fran C. van Heusden, Bashayer Al-Mubarak, Zahid Padamsey, Nigel J. Emptage
Voltage-dependent Ca2+ channels (VGCC) represent the principal source of Ca2+ ions driving evoked neurotransmitter release at presynaptic boutons. In mammals, presynaptic Ca2+ influx is mediated mainly via P/Q-type and N-type VGCC, which differ in their properties. Changes in their relative contributions tune neurotransmission both during development and in Hebbian plasticity. However, whether this represents a functional motif also present in other forms of activity-dependent regulation is unknown. Here, we study the role of VGCC in homeostatic plasticity (HSP) in mammalian hippocampal neurons using optical techniques. We find that changes in evoked Ca2+ currents specifically through P/Q-type, but not N-type, VGCC mediate bidirectional homeostatic regulation of both neurotransmitter release efficacy and the size of the major synaptic vesicle pools. Selective dependence of HSP on P/Q-type VGCC in mammalian terminals has important implications for phenotypes associated with P/Q-type channelopathies, including migraine and epilepsy.
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Jeans at al. show that both basal neurotransmission and synaptic vesicle pool sizes are specifically regulated by the presynaptic P/Q-type voltage-gated Ca2+ channel during HSP at mammalian hippocampal synapses. This may shed light on mechanisms underlying phenotypes associated with P/Q-type channelopathies, including migraine and epilepsy.http://ift.tt/2yccknx
Live Imaging Reveals that the First Division of Differentiating Human Embryonic Stem Cells Often Yields Asymmetric Fates
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Katharine Brown, Kyle M. Loh, Roel Nusse
How do stem cells respond to signals to initiate differentiation? Here, we show that, despite uniform exposure to differentiation-inducing extracellular signals, individual human embryonic stem cells (hESCs) respond heterogeneously. To track how hESCs incipiently exit pluripotency, we established a system to differentiate hESCs as single cells and conducted live imaging to track their very first cell division. We followed the fate of their earliest daughters as they remained undifferentiated or differentiated toward the primitive streak (the earliest descendants of pluripotent cells). About 30%–50% of the time, hESCs divided to yield one primitive streak and one undifferentiated daughter. The undifferentiated daughter cell was innately resistant to WNT signaling and could not respond to this primitive-streak-specifying differentiation signal. Hence, the first division of differentiating hESCs sometimes yields daughters with diverging fates, with implications for the efficiency of directed differentiation protocols and the underlying rules of lineage commitment.
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Teaser
Brown et al. show that 30%–50% of the time, the first division of differentiating human embryonic stem cells generates one differentiated and one undifferentiated daughter cell. These asymmetric fate outcomes have implications for the efficiency of stem cell differentiation protocols and the mechanisms underlying lineage commitment.http://ift.tt/2yb5E9b
Functional Plasticity of Odor Representations during Motherhood
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Amit Vinograd, Yael Fuchs-Shlomai, Merav Stern, Diptendu Mukherjee, Yuan Gao, Ami Citri, Ian Davison, Adi Mizrahi
Motherhood is accompanied by new behaviors aimed at ensuring the wellbeing of the offspring. Olfaction plays a key role in guiding maternal behaviors during this transition. We studied functional changes in the main olfactory bulb (OB) of mothers in mice. Using in vivo two-photon calcium imaging, we studied the sensory representation of odors by mitral cells (MCs). We show that MC responses to monomolecular odors become sparser and weaker in mothers. In contrast, responses to biologically relevant odors are spared from sparsening or strengthen. MC responses to mixtures and to a range of concentrations suggest that these differences between odor responses cannot be accounted for by mixture suppressive effects or gain control mechanisms. In vitro whole-cell recordings show an increase in inhibitory synaptic drive onto MCs. The increase of inhibitory tone may contribute to the general decrease in responsiveness and concomitant enhanced representation of specific odors.
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Teaser
Motherhood is associated with changes in neural circuits that affect how the mother senses her surroundings. Vinograd et al. show that the olfactory bulb is a locus of plasticity. Output neurons of the bulb have elevated inhibition, and odor coding of natural odors is improved.http://ift.tt/2yccmMb
Temporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Hansruedi Mathys, Chinnakkaruppan Adaikkan, Fan Gao, Jennie Z. Young, Elodie Manet, Martin Hemberg, Philip L. De Jager, Richard M. Ransohoff, Aviv Regev, Li-Huei Tsai
Microglia, the tissue-resident macrophages in the brain, are damage sensors that react to nearly any perturbation, including neurodegenerative diseases such as Alzheimer's disease (AD). Here, using single-cell RNA sequencing, we determined the transcriptome of more than 1,600 individual microglia cells isolated from the hippocampus of a mouse model of severe neurodegeneration with AD-like phenotypes and of control mice at multiple time points during progression of neurodegeneration. In this neurodegeneration model, we discovered two molecularly distinct reactive microglia phenotypes that are typified by modules of co-regulated type I and type II interferon response genes, respectively. Furthermore, our work identified previously unobserved heterogeneity in the response of microglia to neurodegeneration, discovered disease stage-specific microglia cell states, revealed the trajectory of cellular reprogramming of microglia in response to neurodegeneration, and uncovered the underlying transcriptional programs.
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Mathys et al. use single-cell RNA sequencing to determine the phenotypic heterogeneity of microglia during the progression of neurodegeneration. They identify multiple disease stage-specific cell states, including two molecularly distinct reactive microglia phenotypes that are typified by modules of co-regulated type I and type II interferon response genes, respectively.http://ift.tt/2yb5FtL
Overproduction of Neurons Is Correlated with Enhanced Cortical Ensembles and Increased Perceptual Discrimination
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Wei-Qun Fang, Rafael Yuste
Brains vary greatly in neuronal number and density, even across individuals within the same species, yet it remains unclear whether such variation leads to differences in brain function or behavior. By imaging cortical activity of a mouse model in which neuronal production is moderately enhanced in utero, we find that animals with more cortical neurons also develop enhanced functional correlations and more distinct neuronal ensembles in primary visual cortex. These mice also have sharper orientation discrimination in their visual behavior. These results unveil a correlation between neuronal ensembles and behavior and suggest that neuronal number is linked to functional modularity and perceptual discrimination of visual cortex. By experimentally linking differences in neuronal number and behavior, our findings could help explain how evolutionary and developmental variability of individual and species brain size may lead to perceptual and cognitive differences.
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Fang et al. report that mice engineered to have more cortical neurons also have more neuronal ensembles and improved visual discrimination compared to wild-type mice. These findings suggest that neuronal production is linked to functional modularity and perceptual discrimination in the visual cortex.http://ift.tt/2ybqYvk
Uncoupling of Metabolic Health from Longevity through Genetic Alteration of Adipose Tissue Lipid-Binding Proteins
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Khanichi N. Charles, Min-Dian Li, Feyza Engin, Ana Paula Arruda, Karen Inouye, Gökhan S. Hotamisligil
Deterioration of metabolic health is a hallmark of aging and generally assumed to be detrimental to longevity. Exposure to a high-calorie diet impairs metabolism and accelerates aging; conversely, calorie restriction (CR) prevents age-related metabolic diseases and extends lifespan. However, it is unclear whether preservation of metabolic health is sufficient to extend lifespan. We utilized a genetic mouse model lacking Fabp4/5 that confers protection against metabolic diseases and shares molecular and lipidomic features with CR to address this question. Fabp-deficient mice exhibit extended metabolic healthspan, with protection against insulin resistance and glucose intolerance, inflammation, deterioration of adipose tissue integrity, and fatty liver disease. Surprisingly, however, Fabp-deficient mice did not exhibit any extension of lifespan. These data indicate that extension of metabolic healthspan in the absence of CR can be uncoupled from lifespan, indicating the potential for independent drivers of these pathways, at least in laboratory mice.
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Deterioration of metabolic health is a hallmark of aging and generally thought to be detrimental to longevity. Charles et al. utilize FABP-deficient mice as a model to demonstrate that the preservation of metabolic health in this model persists throughout life, even under metabolic stress, but does not increase longevity.http://ift.tt/2ybPa0y
A Specific ChREBP and PPARα Cross-Talk Is Required for the Glucose-Mediated FGF21 Response
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Alison Iroz, Alexandra Montagner, Fadila Benhamed, Françoise Levavasseur, Arnaud Polizzi, Elodie Anthony, Marion Régnier, Edwin Fouché, Céline Lukowicz, Michèle Cauzac, Emilie Tournier, Marcio Do-Cruzeiro, Martine Daujat-Chavanieu, Sabine Gerbal-Chalouin, Véronique Fauveau, Solenne Marmier, Anne-Françoise Burnol, Sandra Guilmeau, Yannick Lippi, Jean Girard, Walter Wahli, Renaud Dentin, Hervé Guillou, Catherine Postic
While the physiological benefits of the fibroblast growth factor 21 (FGF21) hepatokine are documented in response to fasting, little information is available on Fgf21 regulation in a glucose-overload context. We report that peroxisome-proliferator-activated receptor α (PPARα), a nuclear receptor of the fasting response, is required with the carbohydrate-sensitive transcription factor carbohydrate-responsive element-binding protein (ChREBP) to balance FGF21 glucose response. Microarray analysis indicated that only a few hepatic genes respond to fasting and glucose similarly to Fgf21. Glucose-challenged Chrebp−/− mice exhibit a marked reduction in FGF21 production, a decrease that was rescued by re-expression of an active ChREBP isoform in the liver of Chrebp−/− mice. Unexpectedly, carbohydrate challenge of hepatic Pparα knockout mice also demonstrated a PPARα-dependent glucose response for Fgf21 that was associated with an increased sucrose preference. This blunted response was due to decreased Fgf21 promoter accessibility and diminished ChREBP binding onto Fgf21 carbohydrate-responsive element (ChoRE) in hepatocytes lacking PPARα. Our study reports that PPARα is required for the ChREBP-induced glucose response of FGF21.
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FGF21 is a hepatokine with beneficial metabolic effects, including control of sucrose preference. Iroz et al. demonstrate that Fgf21 is a unique hepatic gene inducible by both fasting and glucose signals and that the transcription factors PPARα and ChREBP both regulate the endocrine control of sugar intake by hepatic FGF21.http://ift.tt/2yal7pY
Molecular Mechanism by which Prominent Human Gut Bacteroidetes Utilize Mixed-Linkage Beta-Glucans, Major Health-Promoting Cereal Polysaccharides
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Kazune Tamura, Glyn R. Hemsworth, Guillaume Déjean, Theresa E. Rogers, Nicholas A. Pudlo, Karthik Urs, Namrata Jain, Gideon J. Davies, Eric C. Martens, Harry Brumer
Microbial utilization of complex polysaccharides is a major driving force in shaping the composition of the human gut microbiota. There is a growing appreciation that finely tuned polysaccharide utilization loci enable ubiquitous gut Bacteroidetes to thrive on the plethora of complex polysaccharides that constitute "dietary fiber." Mixed-linkage β(1,3)/β(1,4)-glucans (MLGs) are a key family of plant cell wall polysaccharides with recognized health benefits but whose mechanism of utilization has remained unclear. Here, we provide molecular insight into the function of an archetypal MLG utilization locus (MLGUL) through a combination of biochemistry, enzymology, structural biology, and microbiology. Comparative genomics coupled with growth studies demonstrated further that syntenic MLGULs serve as genetic markers for MLG catabolism across commensal gut bacteria. In turn, we surveyed human gut metagenomes to reveal that MLGULs are ubiquitous in human populations globally, which underscores the importance of gut microbial metabolism of MLG as a common cereal polysaccharide.
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Mixed-linkage β(1,3)/β(1,4)-glucan (MLG) is an important complex dietary polysaccharide (dietary fiber), the degradation of which in the human gut depends on the resident microbiota. Tamura et al. outline the molecular mechanism of MLG utilization by Bacteroides ovatus and reveal that the majority of surveyed humans possess MLG-utilizing Bacteroidetes.http://ift.tt/2yc3PsI
Differential Regulation of Lipoprotein and Hepatitis C Virus Secretion by Rab1b
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Constantin N. Takacs, Ursula Andreo, Viet Loan Dao Thi, Xianfang Wu, Caroline E. Gleason, Michelle S. Itano, Gabriella S. Spitz-Becker, Rachel L. Belote, Brenna R. Hedin, Margaret A. Scull, Charles M. Rice, Sanford M. Simon
Secretory cells produce diverse cargoes, yet how they regulate concomitant secretory traffic remains insufficiently explored. Rab GTPases control intracellular vesicular transport. To map secretion pathways, we generated a library of lentivirus-expressed dominant-negative Rab mutants and used it in a large-scale screen to identify regulators of hepatic lipoprotein secretion. We identified several candidate pathways, including those mediated by Rab11 and Rab8. Surprisingly, inhibition of Rab1b, the major regulator of transport from the endoplasmic reticulum to the Golgi, differently affected the secretion of the very-low-density lipoprotein components ApoE and ApoB100, despite their final association on mature secreted lipoprotein particles. Since hepatitis C virus (HCV) incorporates ApoE and ApoB100 into its virus particle, we also investigated infectious HCV secretion and show that its regulation by Rab1b mirrors that of ApoB100. These observations reveal differential regulation of hepatocyte secretion by Rab1b and advance our understanding of lipoprotein assembly and lipoprotein and HCV secretion.
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Takacs et al. show that Rab1b, a major regulator of transport from the endoplasmic reticulum to the Golgi, differentially controls the secretion of lipoprotein components ApoE and ApoB100 and infectious hepatitis C virus particles.http://ift.tt/2yaZEgR
Degradation of Bcl-2 by XIAP and ARTS Promotes Apoptosis
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Natalia Edison, Yael Curtz, Nicole Paland, Dana Mamriev, Nicolas Chorubczyk, Tali Haviv-Reingewertz, Nir Kfir, David Morgenstern, Meital Kupervaser, Juliana Kagan, Hyoung Tae Kim, Sarit Larisch
We describe a mechanism by which the anti-apoptotic B cell lymphoma 2 (Bcl-2) protein is downregulated to induce apoptosis. ARTS (Sept4_i2) is a tumor suppressor protein that promotes cell death through specifically antagonizing XIAP (X-linked inhibitor of apoptosis). ARTS and Bcl-2 reside at the outer mitochondrial membrane in living cells. Upon apoptotic induction, ARTS brings XIAP and Bcl-2 into a ternary complex, allowing XIAP to promote ubiquitylation and degradation of Bcl-2. ARTS binding to Bcl-2 involves the BH3 domain of Bcl-2. Lysine 17 in Bcl-2 serves as the main acceptor for ubiquitylation, and a Bcl-2 K17A mutant has increased stability and is more potent in protection against apoptosis. Bcl-2 ubiquitylation is reduced in both XIAP- and Sept4/ARTS-deficient MEFs, demonstrating that XIAP serves as an E3 ligase for Bcl-2 and that ARTS is essential for this process. Collectively, these results suggest a distinct model for the regulation of Bcl-2 by ARTS-mediated degradation.
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Many cancers avoid cell death (apoptosis) by expressing high levels of apoptosis inhibitors, such as Bcl-2. Thus, Bcl-2 is a major target for cancer therapy. Edison et al. describe a mechanism by which the ARTS protein promotes proteasome-mediated degradation of Bcl-2 and thereby stimulates cell death.http://ift.tt/2yb10bi
Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Sampada Kalan, Ramon Amat, Miriam Merzel Schachter, Nicholas Kwiatkowski, Brian J. Abraham, Yanke Liang, Tinghu Zhang, Calla M. Olson, Stéphane Larochelle, Richard A. Young, Nathanael S. Gray, Robert P. Fisher
Cdk7, the CDK-activating kinase and transcription factor IIH component, is a target of inhibitors that kill cancer cells by exploiting tumor-specific transcriptional dependencies. However, whereas selective inhibition of analog-sensitive (AS) Cdk7 in colon cancer-derived cells arrests division and disrupts transcription, it does not by itself trigger apoptosis efficiently. Here, we show that p53 activation by 5-fluorouracil or nutlin-3 synergizes with a reversible Cdk7as inhibitor to induce cell death. Synthetic lethality was recapitulated with covalent inhibitors of wild-type Cdk7, THZ1, or the more selective YKL-1-116. The effects were allele specific; a CDK7as mutation conferred both sensitivity to bulky adenine analogs and resistance to covalent inhibitors. Non-transformed colon epithelial cells were resistant to these combinations, as were cancer-derived cells with p53-inactivating mutations. Apoptosis was dependent on death receptor DR5, a p53 transcriptional target whose expression was refractory to Cdk7 inhibition. Therefore, p53 activation induces transcriptional dependency to sensitize cancer cells to Cdk7 inhibition.
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Kalan et al. find that activation of the p53 tumor suppressor protein in human colon cancer-derived cells can induce transcriptional dependency on Cdk7, analogous to constitutive dependencies described in other tumors driven by oncogenic transcription factors. This work provides a proof of concept for combining p53-activating agents with Cdk7 inhibitors to elicit synthetic lethality.http://ift.tt/2ycck71
Covalent Modifications of Histone H3K9 Promote Binding of CHD3
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Adam H. Tencer, Khan L. Cox, Luo Di, Joseph B. Bridgers, Jie Lyu, Xiaodong Wang, Jennifer K. Sims, Tyler M. Weaver, Hillary F. Allen, Yi Zhang, Jovylyn Gatchalian, Michael A. Darcy, Matthew D. Gibson, Jinzen Ikebe, Wei Li, Paul A. Wade, Jeffrey J. Hayes, Brian D. Strahl, Hidetoshi Kono, Michael G. Poirier, Catherine A. Musselman, Tatiana G. Kutateladze
Chromatin remodeling is required for genome function and is facilitated by ATP-dependent complexes, such as nucleosome remodeling and deacetylase (NuRD). Among its core components is the chromodomain helicase DNA binding protein 3 (CHD3) whose functional significance is not well established. Here, we show that CHD3 co-localizes with the other NuRD subunits, including HDAC1, near the H3K9ac-enriched promoters of the NuRD target genes. The tandem PHD fingers of CHD3 bind histone H3 tails and posttranslational modifications that increase hydrophobicity of H3K9—methylation or acetylation (H3K9me3 or H3K9ac)—enhance this interaction. Binding of CHD3 PHDs promotes H3K9Cme3-nucleosome unwrapping in vitro and perturbs the pericentric heterochromatin structure in vivo. Methylation or acetylation of H3K9 uniquely alleviates the intra-nucleosomal interaction of histone H3 tails, increasing H3K9 accessibility. Collectively, our data suggest that the targeting of covalently modified H3K9 by CHD3 might be essential in diverse functions of NuRD.
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Tencer et al. find that CHD3 co-localizes with the other subunits of the NuRD complex and H3K9ac at NuRD target genes. The authors further demonstrate that the PHD fingers of CHD3 associate with histone H3 tails, and this association is augmented through methylation or acetylation of H3K9.http://ift.tt/2yccmvF
Erasure of Tet-Oxidized 5-Methylcytosine by a SRAP Nuclease
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Soo-Mi Kweon, Bing Zhu, Yibu Chen, L. Aravind, Shuang-Yong Xu, Douglas E. Feldman
Enzymatic oxidation of 5-methylcytosine (5mC) in DNA by the Tet dioxygenases reprograms genome function in embryogenesis and postnatal development. Tet-oxidized derivatives of 5mC such as 5-hydroxymethylcytosine (5hmC) act as transient intermediates in DNA demethylation or persist as durable marks, yet how these alternative fates are specified at individual CpGs is not understood. Here, we report that the SOS response-associated peptidase (SRAP) domain protein Srap1, the mammalian ortholog of an ancient protein superfamily associated with DNA damage response operons in bacteria, binds to Tet-oxidized forms of 5mC in DNA and catalyzes turnover of these bases to unmodified cytosine by an autopeptidase-coupled nuclease. Biallelic inactivation of murine Srap1 causes embryonic sublethality associated with widespread accumulation of ectopic 5hmC. These findings establish a function for a class of DNA base modification-selective nucleases and position Srap1 as a determinant of 5mC demethylation trajectories during mammalian embryonic development.
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Kweon et al. uncover a function for the SRAP domain, which couples autoproteolytic cleavage to activation of a nuclease selective for DNA containing Tet-oxidized derivatives of 5-methylcytosine. These findings reveal a mechanism for targeted erasure of DNA methylation via the stepwise enzymatic actions of Tet and SRAP.http://ift.tt/2yccmf9
Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Sagar R. Shah, Justin M. David, Nathaniel D. Tippens, Ahmed Mohyeldin, Juan C. Martinez-Gutierrez, Sara Ganaha, Paula Schiapparelli, Duane H. Hamilton, Claudia Palena, Andre Levchenko, Alfredo Quiñones-Hinojosa
Molecular factors that define stem cell identity have recently emerged as oncogenic drivers. For instance, brachyury, a key developmental transcriptional factor, is also implicated in carcinogenesis, most notably of chordoma, through mechanisms that remain elusive. Here, we show that brachyury is a crucial regulator of stemness in chordoma and in more common aggressive cancers. Furthermore, this effect of brachyury is mediated by control of synthesis and stability of Yes-associated protein (YAP), a key regulator of tissue growth and homeostasis, providing an unexpected mechanism of control of YAP expression. We further demonstrate that the brachyury-YAP regulatory pathway is associated with tumor aggressiveness. These results elucidate a mechanism of controlling both tumor stemness and aggressiveness through regulatory coupling of two developmental factors.
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Malignant neoplasms exhibit uninhibited and dysregulated growth coupled with acquisition of stem-like properties that are integral to the development and progression of disease. Shah et al. demonstrate a critical role of brachyury in regulating stemness and growth by activating YAP through direct transcriptional and post-transcriptional mechanisms in various cancers.http://ift.tt/2yc1BJE
Human Organ Chip Models Recapitulate Orthotopic Lung Cancer Growth, Therapeutic Responses, and Tumor Dormancy In Vitro
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Bryan A. Hassell, Girija Goyal, Esak Lee, Alexandra Sontheimer-Phelps, Oren Levy, Christopher S. Chen, Donald E. Ingber
Here, we show that microfluidic organ-on-a-chip (organ chip) cell culture technology can be used to create in vitro human orthotopic models of non-small-cell lung cancer (NSCLC) that recapitulate organ microenvironment-specific cancer growth, tumor dormancy, and responses to tyrosine kinase inhibitor (TKI) therapy observed in human patients in vivo. Use of the mechanical actuation functionalities of this technology revealed a previously unknown sensitivity of lung cancer cell growth, invasion, and TKI therapeutic responses to physical cues associated with breathing motions, which appear to be mediated by changes in signaling through epidermal growth factor receptor (EGFR) and MET protein kinase. These findings might help to explain the high level of resistance to therapy in cancer patients with minimal residual disease in regions of the lung that remain functionally aerated and mobile, in addition to providing an experimental model to study cancer persister cells and mechanisms of tumor dormancy in vitro.
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Hassell et al. demonstrate that, when human lung cancer cells are grown within organ-on-a-chip culture devices that mimic lung structure and function, tumor cells recapitulate tumor growth and invasion patterns, as well as responses to therapy, observed in human patients. They also discover that breathing motions influence these responses.http://ift.tt/2yaBGSP
Self-Organized Cerebral Organoids with Human-Specific Features Predict Effective Drugs to Combat Zika Virus Infection
Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Momoko Watanabe, Jessie E. Buth, Neda Vishlaghi, Luis de la Torre-Ubieta, Jiannis Taxidis, Baljit S. Khakh, Giovanni Coppola, Caroline A. Pearson, Ken Yamauchi, Danyang Gong, Xinghong Dai, Robert Damoiseaux, Roghiyh Aliyari, Simone Liebscher, Katja Schenke-Layland, Christine Caneda, Eric J. Huang, Ye Zhang, Genhong Cheng, Daniel H. Geschwind, Peyman Golshani, Ren Sun, Bennett G. Novitch
The human cerebral cortex possesses distinct structural and functional features that are not found in the lower species traditionally used to model brain development and disease. Accordingly, considerable attention has been placed on the development of methods to direct pluripotent stem cells to form human brain-like structures termed organoids. However, many organoid differentiation protocols are inefficient and display marked variability in their ability to recapitulate the three-dimensional architecture and course of neurogenesis in the developing human brain. Here, we describe optimized organoid culture methods that efficiently and reliably produce cortical and basal ganglia structures similar to those in the human fetal brain in vivo. Neurons within the organoids are functional and exhibit network-like activities. We further demonstrate the utility of this organoid system for modeling the teratogenic effects of Zika virus on the developing brain and identifying more susceptibility receptors and therapeutic compounds that can mitigate its destructive actions.
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Cerebral organoids recapitulate many aspects of human corticogenesis and are a useful platform for modeling neurodevelopmental mechanisms and diseases. Watanabe et al. describe enhanced organoid methods and model ZIKV pathology. More susceptibility receptors for ZIKV are identified, and differential effects of various compounds to mitigate ZIKV-induced cytopathy are demonstrated.http://ift.tt/2ycb5oy
Biodegradable zwitterionic sulfobetaine polymer and its conjugate with paclitaxel for sustained drug delivery
Publication date: Available online 10 October 2017
Source:Acta Biomaterialia
Author(s): Haotian Sun, Michael Yu Zarng Chang, Wei-I Cheng, Qing Wang, Alex Commisso, Meghan Capeling, Yun Wu, Chong Cheng
A fully biodegradable zwitterionic polymer and the corresponding conjugate with paclitaxel (PTX) were synthesized as promising biomaterials. Allyl-functionalized polylactide (PLA) was employed as the precursor of polymer backbones. UV-induced thiol-ene reaction was conducted to conjugate thiol-functionalized sulfobetaine (SB) with the PLA-based backbone. The resulting zwitterionic polymer did not exhibit considerable cytotoxicity. A polymer-drug conjugate was also obtained by thiol-ene reaction of both thiol-functionalized SB and PTX with allyl-functionalized PLA. The conjugate could readily form narrowly-dispersed nanoparticles in aqueous solutions with a volume-average hydrodynamic diameter (Dh,V) of 19.3 ± 0.2 nm. Such a polymer-drug conjugate-based drug delivery system showed full degradability, well-suppressed non-specific interaction with biomolecules, and sustained drug release. In vitro assessments also confirmed the significant anti-cancer efficacy of the conjugate. After 72 h incubation with PLA-SB/PTX containing 10 µg/mL of PTX, the cell viabilities of A549, MCF7, and PaCa-2 cells were as low as 20.0 ± 2.5%, 1.7 ± 1.7%, and 14.8 ± 0.9%, respectively. Both flow cytometry and confocal microscopy suggested that the conjugates could be easily uptaken by A549 cells before the major release of PTX moieties. Overall, this work elucidates promising potentials of biodegradable zwitterionic polymer-based materials in biomedical applications.Statement of SignificanceThe applicability of FDA-approved biodegradable aliphatic polyesters has been significantly restricted because they are hydrophobic and lack functionalities. Recently zwitterionic polymers have emerged as promising hydrophilic biomaterials, but most of the reported zwitterionic polymers are non-biodegradable. This study reports a novel aliphatic polyester-based zwitterionic polymer and the corresponding polymer-drug conjugate. Their aliphatic polyester and zwitterionic components provide them with high enzymatic degradability and low nonspecific interactions with biomolecules, respectively. While the zwitterionic polymer did not show noticeable cytotoxicity, the corresponding polymer-anticancer drug conjugate exhibited acid-sensitive sustained drug release, remarkable effectiveness in killing cancer cells, as well as the ready cellular internalization. This work lays a foundation for the further development of synthetic biodegradable zwitterionic polymer-based materials which potentially may have broad and significant biomedical applications.
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http://ift.tt/2wN6Oq8
Engineering intranasal mRNA vaccines to enhance lymph node trafficking and immune responses
Publication date: Available online 10 October 2017
Source:Acta Biomaterialia
Author(s): Man Li, You Li, Ke Peng, Ying Wang, Tao Gong, Zhirong Zhang, Qin He, Xun Sun
Intranasal mRNA vaccination provides immediate immune protection against pandemic diseases. Recent studies have shown that diverse forms of polyethyleneimine (PEI) have potent mucosal adjuvant activity, which could significantly facilitate the delivery of intranasal mRNA vaccines. Nevertheless, optimizing the chemical structure of PEI to maximize its adjuvanticity and decrease its toxicity remains a challenge. Here we show that the chemical structure of PEI strongly influences how well nanocomplexes of PEI and mRNA migrate to the lymph nodes and elicit immune responses. Conjugating cyclodextrin (CD) with PEI600 or PEI2k yielded CP (CD-PEI) polymers with different CD/PEI ratios. We analyzed the delivery efficacy of CP600, CP2k, and PEI25k as intranasal mRNA vaccine carriers by evaluating the lymph nodes migration and immune responses. Among these polymers, CP2k/mRNA showed significantly higher in vitro transfection efficiency, stronger abilities to migrate to lymph nodes and stimulate dendritic cells maturation in vivo, which further led to potent humoral and cellular immune responses, and showed lower local and systemic toxicity than PEI25k/mRNA. These results demonstrate the potential of CD-PEI2k/mRNA nanocomplex as a self-adjuvanting vaccine delivery vehicle that traffics to lymph nodes with high efficiency.SignificanceAs we face outbreaks of pandemic diseases such as Zika virus, intranasal mRNA vaccination provides instant massive protection against highly variant viruses. Various polymer-based delivery systems have been successfully applied in intranasal vaccine delivery. However, the influence of molecular structure of the polymeric carriers on the lymph node trafficking and dendritic cell maturation is seldom studied for intranasal vaccination. Therefore, engineering polymer-based vaccine delivery system and elucidating the relationship between molecular structure and the intranasal delivery efficiency are essential for maximizing the immune responses. We hereby construct self-adjuvanting polymer-based intranasal mRNA vaccines to enhance lymph node trafficking and further improve immune responses.
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http://ift.tt/2wMjqgX
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