Publication date: October 2017
Source:Neoplasia, Volume 19, Issue 10
Author(s): Jarmila Herůdková, Kamil Paruch, Prashant Khirsariya, Karel Souček, Martin Krkoška, Olga Vondálová Blanářová, Petr Sova, Alois Kozubík, Alena Hyršlová Vaculová
Although Chk1 kinase inhibitors are currently under clinical investigation as effective cancer cell sensitizers to the cytotoxic effects of numerous chemotherapeutics, there is still a considerable uncertainty regarding their role in modulation of anticancer potential of platinum-based drugs. Here we newly demonstrate the ability of one of the most specific Chk1 inhibitors, SCH900776 (MK-8776), to enhance human colon cancer cell sensitivity to the cytotoxic effects of platinum(II) cisplatin and platinum(IV)- LA-12 complexes. The combined treatment with SCH900776 and cisplatin or LA-12 results in apparent increase in G1/S phase–related apoptosis, stimulation of mitotic slippage, and senescence of HCT116 cells. We further show that the cancer cell response to the drug combinations is significantly affected by the p21, p53, and PTEN status. In contrast to their wt counterparts, the p53- or p21-deficient cells treated with SCH900776 and cisplatin or LA-12 enter mitosis and become polyploid, and the senescence phenotype is strongly suppressed. While the cell death induced by SCH900776 and cisplatin or LA-12 is significantly delayed in the absence of p53, the anticancer action of the drug combinations is significantly accelerated in p21-deficient cells, which is associated with stimulation of apoptosis beyond G2/M cell cycle phase. We also show that cooperative killing action of the drug combinations in HCT116 cells is facilitated in the absence of PTEN. Our results indicate that SCH900776 may act as an important modulator of cytotoxic response triggered by platinum-based drugs in colon cancer cells.
http://ift.tt/2f2Ezwz
Τετάρτη 6 Σεπτεμβρίου 2017
Chk1 Inhibitor SCH900776 Effectively Potentiates the Cytotoxic Effects of Platinum-Based Chemotherapeutic Drugs in Human Colon Cancer Cells
Tacrolimus Improves Symptoms of Children with Myasthenia Gravis Refractory to Prednisone
Source:Pediatric Neurology
Author(s): Chanchan Liu, Mengcui Gui, Yayun Cao, Jing Lin, Yue Li, Suqiong Ji, Bitao Bu
BackgroundMyasthenia gravis tends to affect children in China. Oral pyridostigmine and prednisone could effectively improve the symptoms, but multiple side effects constitute the major concern after long-term oral prednisone. Try to overcome the flaws of prednisone therapy and to obtain more satisfied improvement, we tested the efficacy and safety of tacrolimus in children.MethodsChildren with myasthenia gravis who had not achieved satisfactory improvement and suffered from severe side effects after prednisone therapy were recruited between January 2015 and December 2016 at Tongji Hospital. All the children were treated with tacrolimus 1-2 mg daily and adjusted based on the response and serum concentration. The dosage of prednisone, severity of symptoms, blood samples, serum concentration of tacrolimus and titers of anti-AChR antibodies were evaluated every 4 weeks.ResultsFourteen children were enrolled. One child withdrew in 2 weeks after the enrollment. Thirteen children have completed the therapy for 1 year. At the endpoint, dosage of prednisone were significantly decreased (p<0.05), the symptoms evaluated by quantitative myasthenia gravis score, myasthenia gravis-specific manual muscle testing and myasthenia gravis-activities of daily living score were significantly improved (p<0.05, p<0.05, p<0.01,respectively). More importantly, 10 (76.9%) patients had completely discontinued prednisone, and the major side effects were nearly reversed. The mean titer of anti-AChR antibodies significantly dropped from 1.96±2.62 nmol/L to 0.70±1.04 nmol/L (P<0.05). No severe adverse events were reported.ConclusionsOur result suggested that tacrolimus is a promising agent for children with refractory myasthenia gravis. Randomized clinical trials are needed to confirm the observation.
http://ift.tt/2eEYjWq
Scholar : These new articles for Voice and Speech Review are available online
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Increased expression of interleukin-21 along colorectal adenoma-carcinoma sequence and its predicating significance in patients with sporadic colorectal cancer
Source:Clinical Immunology
Author(s): Guanglin Cui, Aping Yuan, Li Zhu, Jon Florholmen, Rasmus Goll
The role and significance of interleukin (IL)-21 in the development of sporadic CRC have not been well defined. The aim of this study is therefore to investigate the dynamics of the IL-21 along colorectal adenoma-carcinoma sequence and to evaluate the impact of IL-21 on clinicopathological parameters and CRC prognosis. The real-time PCR results showed that the level of IL-21 in adenomas (n=50) and sporadic CRC (n=50) were significantly higher than that in normal controls (n=18), which were predominately observed in the adenoma/CRC stroma. Analysis revealed that IL-21 level was correlated with the overall survival time in CRC patients. Double immunofluorescence observations confirmed that IL-21 positive cells were mostly natural killer cells and T lymphocytes in the tumor stroma. These results indicate that significant increased IL-21 expression present within the adenoma/CRC microenvironment might have a potential predicating significance for survival time in patients with CRC.
http://ift.tt/2wGVrAz
Scholar : Communication Research and Practice, Volume 3, Issue 4, November 2017 is now available online on Taylor & Francis Online
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Scholar : Archives and Records, Volume 38, Issue 2, Autumn 2017 is now available online on Taylor & Francis Online
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A novel in vitro model for hematogenous spreading of S. aureus device biofilms demonstrating clumping dispersal as an advantageous dissemination mechanism.
A novel in vitro model for hematogenous spreading of S. aureus device biofilms demonstrating clumping dispersal as an advantageous dissemination mechanism.
Cell Microbiol. 2017 Sep 05;:
Authors: Grønnemose RB, Saederup KL, Kolmos HJ, Hansen SWK, Asferg CA, Rasmussen KJ, Palarasah Y, Andersen TE
Abstract
Staphylococcus aureus is able to disseminate from vascular device biofilms to the blood and organs, resulting in life-threatening infections such as endocarditis. The mechanisms behind spreading are largely unknown, especially how the bacterium escapes immune effectors and antibiotics in the process. Using an in vitro catheter infection model, we studied S. aureus biofilm growth, late-stage dispersal, and reattachment to downstream endothelial cell layers. The ability of the released biofilm material to resist host response and disseminate in vivo was furthermore studied in whole blood- and phagocyte survival assays, and in a short-term murine infection model. We found that S. aureus biofilms formed in flow of human plasma release biofilm thromboemboli with embedded bacteria and bacteria-secreted polysaccharides. The emboli disseminate as antibiotic and immune resistant vehicles that hold the ability to adhere to and initiate colonization of endothelial cell layers under flow. In vivo experiments showed that the released biofilm material reached the heart similarly as ordinary broth-grown bacteria, but also that clumps to some extend were trapped in the lungs. The clumping dispersal of S. aureus from in vivo-like vascular biofilms and their specific properties demonstrated here help explain the pathophysiology associated with S. aureus bloodstream infections.
PMID: 28873268 [PubMed - as supplied by publisher]
http://ift.tt/2vKEvvH
Examination of Nondesignated Preliminary Surgery Residents Recruited Since the Inception of Supplementary Offer and Acceptance Program: Lessons Learned From a Large Academic Program
Publication date: Available online 5 September 2017
Source:Journal of Surgical Education
Author(s): Maria Albuja-Cruz, Claire Travis, Michael Benge, Barbara Caufield, Mark Nehler
PurposeThe majority of surgery programs roster non-designated preliminary (NDP) residents. We and others have reported on the success of NDP resident mentoring with regard to categorical position placement. Lacking is a focus on the candidates themselves and differences based on initial career of choice.MethodsNDP residents' files since the institution of SOAP were reviewed for demographics, initial career choice, financial burden, region of medical school of origin, application and interview history, and pre-screen interview candidate score (high score of 22 – data includes USMLE scores, major clerkship grades, and AOA) used for categorical recruitment.ResultsFrom 2012-16 79 NDP residents have been recruited at UCDenver (82% via SOAP). Median age was 28 years, majority were single (73%), and male (82%). Thirty percent belonged to an under-represented minority group. Mean debt was $156,000 but 20% owe over $250,000. 90% attended US medical schools with 65% from the NRMP "South" region. 86% were recruited as fourth year students. NDPs were categorized as failing to match in general surgery (38%), surgical subspecialties (47%), or other (15%). NDPs applied to median of 68 programs (range 7-200) and granted a median of 8 interviews (range 0-24). NDPs had a mean pre-screening interview score of 13 out of 22 and only 9% would have met the standard threshold to obtain a categorical surgery interview. There were no differences in pre-screening scores in the three groups. 95% NDPs (excluding present year) successfully completed their R1 year (three resigned – one obtained a general surgery spot mid-year and two after matching in non-general surgery fields). 68% NDPs placed in categorical positions after the R1 year. The placement was better for the surgical subspecialty group compared to the other two.ConclusionsThe bias is that due to a more competitive applicant pool recruiting NDPs from surgical subspecialties would be optimal. However, those unmatched surgical subspecialty candidates are no better academically than the unmatched general surgery group, often have career interests that do not always align with scheduled rotations, and may not feel compelled to complete the year if they match. They place minimally better when accounting for those unmatched general surgery NDP R1s continuing as NDP R2s. Ultimately the success in a non-designated preliminary R1 surgery program is alignment of clinical educational opportunities with the needs of the trainee.
http://ift.tt/2w5LRFI
[The clinical characteristics of 346 patients with IgG4-related disease].
| Related Articles |
[The clinical characteristics of 346 patients with IgG4-related disease].
Zhonghua Nei Ke Za Zhi. 2017 Sep 01;56(9):644-649
Authors: Zhang PP, Zhao JZ, Wang M, Feng RE, Liu XW, Lai XM, Li XJ, Zeng JG, Shi HJ, Zhu HD, Xue W, Zhang H, Chen YY, Fei LY, Peng XF, Zeng FC, Zhang YM, Zhang W
Abstract
Objective: To analyze the clinical characteristics of IgG4-related disease (IgG4-RD)so as to improve the understanding of IgG4-RD in China. Methods: IgG4-RD patients were recruited from Peking Union Medical College Hospital between January 2011 and January 2016. All patients were followed-up for more than 6 months. The demographic characteristics, symptoms, organ involvements, laboratory examinations and treatment efficacy were evaluated and analyzed. Results: A total of 346 patients were finally enrolled, including 230 males (66.5%) and 116 females (33.5%). The mean age of disease onset was (53.8±14.2) years old. The mostly common involved organs were lymph nodes (56.4%) and submandibular glands (52.6%). Other affected organs and manifestations included: swelling of the lacrimal glands (46.5%), autoimmune pancreatitis (38.4%), pulmonary involvement (28.0%), sclerosing cholangitis (25.4%), naso-sinusitis (23.4%), parotid gland swelling (21.7%), retroperitoneal fibrosis (19.9%), large arteries involvement (9.5%), kidney involvement (obstructive nephropathy caused by retroperitoneal fibrosis was excluded) (6.9%), skin lesions (6.4%). Rare features consisted of thyroid glands, pituitary glands, gastrointestinal tract, pachymeningitis, pericardium, sclerosing mediastinitis and orchitis. The majority of patients had multi-organ involvement, such as 74.3% patients with 3 and more, 18.2% and 7.5% patients with 2 and single organ involvement respectively. The average IgG4-RD responder index (IgG4-RD RI) was 13.21±5.70. History of allergy was found in 172 (49.7%) patients. As to the laboratory tests, elevated serum IgG4 levels were confirmed in 285 (94.1%) patients, which was positively correlated with IgG4-RD RI. There were 33.5% patients receiving monotherapy of glucocorticoid, 52.6% treated with glucocorticoids combined with immunosuppressive agents, 4.9% patients with immunosuppressant only, and 9.0% patients with mild disease not receiving medication. The majority (336, 97.1%) patients improved the above regimens. Conclusion: IgG4-RD is a systemic fibro-inflammatory disease with multiple organ involvement. The mostly common involved organs include lymph node, submandibular glands, and pancreas. Glucocorticoids and immunosuppressive agents were effective for IgG4-RD.
PMID: 28870031 [PubMed - in process]
http://ift.tt/2vLk2Hh
Scholar : Patterns of Prejudice, Volume 51, Issue 3-4, July - September 2017 is now available online on Taylor & Francis Online
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Scholar : These new articles for Museum Management and Curatorship are available online
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Source contributions to total concentrations and carcinogenic potencies of polychlorinated dibenzo- p -dioxins and polychlorinated dibenzofurans (PCDD/Fs) in ambient air: a case study in Suzhou City, China
Abstract
The potential source categories and source contributions of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) in ambient air from Suzhou City, China, were performed by principal component analysis-multiple linear regression (PCA-MLR) and positive matrix factorization (PMF). The carcinogenic potencies of PCDD/Fs were quantitatively apportioned based on the positive matrix factorization-toxic equivalent concentration (PMF-TEQ) method. The results of the present study were summarized as follows. (1) The total concentrations and toxic equivalent concentrations of PCDD/Fs (∑PCDD/Fs and TEQ) in ambient air from Suzhou City were 1.34–42.80 pg N m−3 and 0.081–1.22 pg I-TEQ N m−3, respectively. (2) PCA-MLR suggested that industrial combustion (IC), electric arc furnaces (EAFs) and secondary aluminum smelters (ALSs), unleaded gas-fueled vehicle sources (UGFVs), ALSs, and hazardous solid waste incinerators (HSWIs) could be the primary PCDD/F contributors, accounting for 13.2, 16.7, 35.5, 19.4, and 15.2% of ∑PCDD/Fs, respectively. (3) PMF and PMF-TEQ indicated that EAFs (carbon steel), UGFVs, IC, ALSs, municipal solid waste incinerators (MSWIs) and hospital waste incinerators (HWIs), and HSWIs contributed 10.9, 10.9, 42.8, 11.3, 10.7, and 13.4% to ∑PCDD/Fs, but contributed 8.3, 12.3, 50.3, 12.7, 6.0, and 10.4% to carcinogenic potencies of PCDD/Fs. This study was the first attempt to quantitatively apportion the source-specific carcinogenic potencies of PCDD/Fs in ambient air.
http://ift.tt/2gFYfX8
Carcinogenic Potential of Sanguinarine, a Phytochemical used in ‘Therapeutic’ Black Salve and Mouthwash
Publication date: Available online 6 September 2017
Source:Mutation Research/Reviews in Mutation Research
Author(s): Andrew Croaker, Graham J. King, John H. Pyne, Shailendra Anoopkumar-Dukie, Vilim Simanek, Lei Liu
Black salves are escharotic skin cancer therapies in clinical use since the mid 19th century. Sanguinaria canadensis, a major ingredient of black salve formulations, contains a number of bioactive phytochemicals including the alkaloid sanguinarine. Despite its prolonged history of clinical use, conflicting experimental results have prevented the carcinogenic potential of sanguinarine from being definitively determined.Sanguinarine has a molecular structure similar to known polyaromatic hydrocarbon carcinogens and is a DNA intercalator. Sanguinarine also generates oxidative and endoplasmic reticulum stress resulting in the unfolded protein response and the formation of 8-hydroxyguanine genetic lesions. Sanguinarine has been the subject of contradictory in vitro and in vivo genotoxicity and murine carcinogenesis test results that have delayed its carcinogenic classification. Despite this, epidemiological studies have linked mouthwash that contains sanguinarine with the development of oral leukoplakia, sanguinarine also proposed as an aetiological agent in gallbladder carcinoma.This literature review investigates the carcinogenic potential of sanguinarine. Reasons for contradictory genotoxicity and carcinogenesis results are explored, knowledge gaps identified and a strategy for determining the carcinogenic potential of sanguinarine especialy relating to black salve are discussed. As patients continue to apply black salve, especially to skin regions suffering from field cancerization and skin malignancies, an understanding of sanguinarines genotoxic and carcinogenic potential is of urgent clinical relevance.
http://ift.tt/2gFWDgc
Scholar : These new articles for Behavioral Sciences of Terrorism and Political Aggression are available online
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Scholar : These new articles for Asian Security are available online
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Can half-marathon affect overall health? The yin-yang of sport
Publication date: Available online 6 September 2017
Source:Journal of Proteomics
Author(s): Luca Dalle Carbonare, Marcello Manfredi, Giuseppe Caviglia, Eleonora Conte, Elisa Robotti, Emilio Marengo, Samuele Cheri, Francesco Zamboni, Daniele Gabbiani, Michela Deiana, Daniela Cecconi, Federico Schena, Monica Mottes, Maria Teresa Valenti
Physical activity improves overall health and counteracts metabolic pathologies. Adipose tissue and bone are important key targets of exercise; the prevalence of diseases associated with suboptimal physical activity levels has increased in recent times as a result of lifestyle changes. Mesenchymal stem cells (MSCs) differentiation in either osteogenic or adipogenic lineage is regulated by many factors. Particularly, the expression of master genes such as RUNX2 and PPARγ2 is essential for MSC commitment to osteogenic or adipogenic differentiation, respectively. Besides various positive effects on health, some authors have reported stressful outcomes as a consequence of endurance in physical activity. We looked for further clues about MSCs differentiation and serum proteins modulation studying the effects of half marathon in runners by means of gene expression analyses and a proteomic approach. Our results demonstrated an increase in osteogenic commitment and a reduction in adipogenic commitment of MSCs. In addition, for the first time we have analyzed the proteomic profile changes in runners after half-marathon activity in order to survey the related systemic adjustments. The shotgun proteomic approach, performed through the immuno-depletion of the 14 most abundant serum proteins, allowed the identification of 23 modulated proteins after the half marathon. Interestingly, proteomic data showed the activation of both inflammatory response and detoxification process. Moreover, the involvement of pathways associated to immune response, lipid transport and coagulation, was elicited. Notably, positive and negative effects may be strictly linked. Data are available via ProteomeXchange with identifier PXD006704.SignificanceWe describe gene expression and proteomic studies aiming to an in-depth understanding of half-marathon effects on bone and adipogenic differentiation as well as biological phenomena involved in sport activity.We believe that this novel approach suggests the physical effects on overall health and show the different pathways involved during half marathon.Contents of the paper have not been published or submitted for publication elsewhere. The authors declare no conflict of interest.
Graphical abstract
http://ift.tt/2j0BGAV
Proteomic comparison of three clinical diarrhoeagenic drug-resistant Escherichia coli isolates grown on CHROMagar™STEC media
Publication date: Available online 5 September 2017
Source:Journal of Proteomics
Author(s): John Bosco Kalule, Suereta Fortuin, Bridget Calder, Lourens Robberts, Karen H. Keddy, Andrew Nel, Shaun Garnett, Mark Nicol, Digby F. Warner, Nelson C. Soares, Jonathan M. Blackburn
Shiga-toxin-producing Escherichia coli (STEC) and enteropathogenic Escherichia coli (EPEC) are key diarrhoea-causing foodborne pathogens. We used proteomics to characterize the virulence and antimicrobial resistance protein profiles of three clinical pathogenic E. coli isolates (two EPEC [one resistant to ciprofloxacin] and one STEC) cultured on CHROMagar™STEC solid media after minimal laboratory passage. We identified 4767 unique peptides from 1630 protein group across all three clinical E. coli strains. Label-free proteomic analysis allowed the identification of virulence and drug resistance proteins that were unique to each of the clinical isolates compared in this study. The B subunit of Shiga toxin, ToxB, was uniquely detected in the STEC strain while several other virulence factors including SheA, OmpF, OmpC and OmpX were significantly more abundant in the STEC strain. The ciprofloxacin resistant EPEC isolate possessed reduced levels of key virulence proteins compared to the ciprofloxacin susceptible EPEC and STEC strains. Parallel reaction monitoring assays validated the presence of biologically relevant proteins across biologically-replicated cultures. Propagation of clinical isolates on a relevant solid medium followed by mass spectrometry analysis represents a convenient means to quantify virulence factors and drug resistance determinants that might otherwise be lost through extensive in vitro passage in enteropathogenic bacteria.SignificanceThrough the use of quantitative proteomics, we have characterized the virulence and antimicrobial resistance attributes of three clinically isolated, pathogenic E. coli strains cultured on solid media. Our results provide new, quantitative data on the expressed proteomes of these tellurite-resistant, diarrhoeagenic E. coli strains and reveal a subset of antimicrobial resistance and virulence proteins that are differentially abundant between these clinical strains. Our quantitative proteomics-based approach should thus have applicability in microbiological diagnostic labs for the identification of pathogenic/drug resistant E. coli in the future.
Graphical abstract
http://ift.tt/2j0B7qN
Auditory attention enhances processing of positive and negative words in inferior and superior prefrontal cortex
Source:Cortex
Author(s): Martin Wegrzyn, Cornelia Herbert, Thomas Ethofer, Tobias Flaisch, Johanna Kissler
Visually presented emotional words are processed preferentially and effects of emotional content are similar to those of explicit attention deployment in that both amplify visual processing. However, auditory processing of emotional words is less well characterized and interactions between emotional content and task-induced attention have not been fully understood. Here, we investigate auditory processing of emotional words, focussing on how auditory attention to positive and negative words impacts their cerebral processing.An fMRI study manipulating word valence and attention allocation was performed. Participants heard negative, positive and neutral words to which they either listened passively or attended by counting negative or positive words, respectively. Regardless of valence, active processing compared to passive listening increased activity in primary auditory cortex, left intraparietal sulcus, and right superior frontal gyrus. The attended valence elicited stronger activity in left inferior frontal gyrus (IFG) and left superior frontal gyrus (SFG), in line with these regions' role in semantic retrieval and evaluative processing. No evidence for valence-specific attentional modulation in auditory regions or distinct valence-specific regional activations (i.e. negative > positive or positive > negative) was obtained.Thus, allocation of auditory attention to positive and negative words can substantially increase their processing in higher-order language and evaluative brain areas without modulating early stages of auditory processing. Inferior and superior frontal brain structures mediate interactions between emotional content, attention, and working memory when prosodically neutral speech is processed.
http://ift.tt/2f2ZuzH
Visuo-spatial orienting during active exploratory behavior: processing of task-related and stimulus-related signals
Source:Cortex
Author(s): Emiliano Macaluso, Akitoshi Ogawa
Functional imaging studies have associated dorsal and ventral fronto-parietal regions with the control of visuo-spatial attention. Previous studies demonstrated that the activity of both the dorsal and the ventral attention systems can be modulated by many different factors, related both to the stimuli and the task. However, the vast majority of this work utilized stereotyped paradigms with simple and repeated stimuli. This is at odd with any real life situation that instead involve complex combinations of different types of co-occurring signals, thus raising the question of the ecological significance of the previous findings. Here we investigated how the brain responds to task-related and stimulus-related signals using an innovative approach that involved active exploration of a virtual environment. This enabled us to study visuo-spatial orienting in conditions entailing a dynamic and coherent flow of visual signals, to some extent analogous to real life situations. The environment comprised colored/textured spheres and cubes, which allowed us to implement a standard feature-conjunction search task (task-related signals), and included one physically salient object that served to track the processing of stimulus-related signals. The imaging analyses showed that the posterior parietal cortex activated when the participants' gaze was directed towards the salient-objects. By contrast, the right inferior partial cortex was associated with the processing of the target-objects and of distractors that shared the target-color and shape, consistent with goal-directed template-matching operations. The study highlights the possibility of combining measures of gaze orienting and functional imaging to investigate the processing of different types of signals during active behavior in complex environments.
http://ift.tt/2gFZwNT
Linking left hemispheric tissue preservation to fMRI language task activation in chronic stroke patients
Source:Cortex
Author(s): Joseph C. Griffis, Rodolphe Nenert, Jane B. Allendorfer, Jerzy P. Szaflarski
The preservation of near-typical function in distributed brain networks is associated with less severe deficits in chronic stroke patients. However, it remains unclear how task-evoked responses in networks that support complex cognitive functions such as semantic processing relate to the post-stroke brain anatomy. Here, we used recently developed methods for the analysis of multimodal MRI data to investigate the relationship between regional tissue concentration and functional MRI activation evoked during auditory semantic decisions in a sample of 43 chronic left hemispheric stroke patients and 43 age, handedness, and sex-matched controls. Our analyses revealed that closer-to-normal levels of tissue concentration in left temporo-parietal cortex and the underlying white matter correlated with the level of task-evoked activation in distributed regions associated with the semantic network. This association was not attributable to the effects of left hemispheric lesion or brain volumes, and similar results were obtained when using explicit lesion data. Left temporo-parietal tissue concentration and the associated task-evoked activations predicted patient performance on the in-scanner task, and also predicted patient performance on out-of-scanner naming and verbal fluency tasks. Exploratory analyses using the average HCP-842 tractography dataset revealed the presence of fronto-temporal, fronto-parietal, and temporo-parietal semantic network connections in the locations where tissue concentration was found to correlate with task-evoked activation in the semantic network. In summary, our results link the preservation of left posterior temporo-parietal structures with the preservation of task-evoked semantic network function in chronic left hemispheric stroke patients. Speculatively, this relationship may reflect the status of posterior temporo-parietal areas as cortical and white matter convergence zones that support coordinated processing in the distributed semantic network. Damage to these regions may contribute to atypical task-evoked responses during semantic processing in chronic stroke patients.
http://ift.tt/2f22e0b
Phase I study of axitinib and everolimus in metastatic solid tumours and extension to metastatic renal cell carcinoma: Results of EVAX study
Source:European Journal of Cancer, Volume 85
Author(s): Alain Ravaud, Carlos Gomez-Roca, Marie-Quitterie Picat, Laurence Digue, Christine Chevreau, Anne Gimbert, Emmanuelle Chauzit, Rémi Sitta, François Cornelis, Julien Asselineau, Richard Aziza, Amaury Daste, Cathy Quemener, Jessica Baud, Andréas Bikfalvi, Delphine Pedenon–Périchout, Adelaïde Doussau, Mathieu Molimard, Jean-Pierre Delord
PurposeAnti-angiogenic and mammalian target of rapamycin inhibitors have shown efficacy in solid tumours. Reported combination of both drugs was deemed to be too toxic. Due to a potential favourable safety profile of axitinib (AX), a phase I study combining everolimus (EV) and AX for solid tumours was explored.Experimental designPatients (pts) with advanced cancers were enrolled in an escalation phase I study to investigate the safety of the combination. Pharmacokinetic profile and functional vascular imaging were performed. An extension to pts with naive metastatic renal cell carcinoma (MRCC) was explored.Results15 pts were included over three different dose levels (DLs); DL 0: AX 3 mg BID (twice daily)/EV 5 mg OD (once daily); DL 1: AX 5 mg BID/EV 5 mg OD and DL 2: AX 5 mg BID/EV 10 mg OD for 28 d. One dose-limiting toxicity (DLT) was reported at DL 0: grade (Gr) III diarrhoea and one DLT at DL 2: Gr III asthenia. Three severe adverse events (AEs) in two pts were unexpected: jaw osteonecrosis, recurrent renal failure and cardiomyopathy. Maximum tolerated dose (MTD) was level 2. After 1st cycle, Gr III or Gr II AEs of interest were mainly asthenia, diarrhoea and anorexia. All pts but one showed tumour shrinkage. Partial responses (PRs) were seen in one pt with bladder carcinoma and in one pt in 1st line MRCC in the escalating phase. In the extension phase in naive MRCC treated at MTD, five pts had a PR and one pt had a prolonged stable disease.ConclusionThe recommended dose for phase II is AX 5 mg BID/EV 10 mg OD.
http://ift.tt/2j25c9j
Effects of spatial fMRI resolution on the classification of naturalistic movies
Source:NeuroImage, Volume 162
Author(s): H. Mandelkow, J.A. de Zwart, J.H. Duyn
Studies involving multivariate pattern analysis (MVPA) of BOLD fMRI data generally attribute the success of the information-theoretic approach to BOLD signal contrast on the fine spatial scale of millimeters facilitating the classification or decoding of perceptual stimuli. However, to date MVPA studies that have actually explored fMRI resolutions at less than 2 mm voxel size are rare and limited to small sets of unnatural stimuli (like visual gratings) as well as specific sub-regions of the brain, notably the primary somatosensory cortices. To investigate what spatial scale best supports high information extraction under more general conditions this study combined naturalistic movie stimuli with high-resolution fMRI at 7 T and linear discriminant analysis (LDA) of global and local BOLD signal patterns.Contrary to predictions, LDA and similar classifiers reached a maximum in classification accuracy (CA) at a smoothed resolution close to 3 mm, well above the 1.2 mm voxel size of the fMRI acquisition. Maximal CAs around 90% were contingent upon global fMRI signal patterns comprising 4 k–16 k of the most reactive voxels distributed sparsely throughout the occipital and ventro-temporal cortices. A Searchlight analysis of local fMRI patterns largely confirmed the global results, but also revealed a small subset of brain regions in early visual cortex showing limited increases in CA with higher resolution. Principal component analysis of the global and local fMRI signal patterns suggested that reproducible neuronal contributions were spatially auto-correlated and smooth, while other components of higher spatial frequency were likely related to physiological noise and responsible for the reduced CA at higher resolution. Systematic differences between experiments and subjects suggested that higher CA was significantly correlated with more consistent behavior revealed by eye tracking. Thus, the optimal resolution of fMRI data for MVPA was mainly limited by physiological noise of high spatial frequency as well as behavioral (in-)consistency.
http://ift.tt/2x9YKn8
Independent circuits in basal ganglia and cortex for the processing of reward and precision feedback
Source:NeuroImage, Volume 162
Author(s): David Pascucci, Clayton Hickey, Jorge Jovicich, Massimo Turatto
In order to understand human decision making it is necessary to understand how the brain uses feedback to guide goal-directed behavior. The ventral striatum (VS) appears to be a key structure in this function, responding strongly to explicit reward feedback. However, recent results have also shown striatal activity following correct task performance even in the absence of feedback. This raises the possibility that, in addition to processing external feedback, the dopamine-centered "reward circuit" might regulate endogenous reinforcement signals, like those triggered by satisfaction in accurate task performance. Here we use functional magnetic resonance imaging (fMRI) to test this idea. Participants completed a simple task that garnered both reward feedback and feedback about the precision of performance. Importantly, the design was such that we could manipulate information about the precision of performance within different levels of reward magnitude. Using parametric modulation and functional connectivity analysis we identified brain regions sensitive to each of these signals. Our results show a double dissociation: frontal and posterior cingulate regions responded to explicit reward but were insensitive to task precision, whereas the dorsal striatum - and putamen in particular - was insensitive to reward but responded strongly to precision feedback in reward-present trials. Both types of feedback activated the VS, and sensitivity in this structure to precision feedback was predicted by personality traits related to approach behavior and reward responsiveness. Our findings shed new light on the role of specific brain regions in integrating different sources of feedback to guide goal-directed behavior.
http://ift.tt/2wGL7bW
Investigating the maturation of microstructure and radial orientation in the preterm human cortex with diffusion MRI
Publication date: 15 November 2017
Source:NeuroImage, Volume 162
Author(s): Zach Eaton-Rosen, Benoit Scherrer, Andrew Melbourne, Sebastien Ourselin, Jeffrey J. Neil, Simon K. Warfield
Preterm birth disrupts and alters the complex developmental processes in the cerebral cortex. This disruption may be a contributing factor to widespread delay and cognitive difficulties in the preterm population. Diffusion-weighted magnetic resonance imaging (DW MRI) is a noninvasive imaging technique that makes inferences about cellular structures, at scales smaller than the imaging resolution. One established finding is that DW MRI shows a transient radial alignment in the preterm cortex. In this study, we quantify this maturational process with the "radiality index", a parameter that measures directional coherence, which we expect to change rapidly in the perinatal period. To measure this index, we used structural T2-weighted MRI to segment the cortex and generate cortical meshes. We obtained normal vectors for each face of the mesh and compared them to the principal diffusion direction, calculated by both the DTI and DIAMOND models, to generate the radiality index. The subjects included in this study were 89 infants born at fewer than 34 weeks completed gestation, each imaged at up to four timepoints between 27 and 42 weeks gestational age. In this manuscript, we quantify the longitudinal trajectory of radiality, fractional anisotropy and mean diffusivity from the DTI and DIAMOND models. For the radiality index and fractional anisotropy, the DIAMOND model offers improved sensitivity over the DTI model. The radiality index has a consistent progression across time, with the rate of change depending on the cortical lobe. The occipital lobe changes most rapidly, and the frontal and temporal least: this is commensurate with known developmental anatomy. Analysing the radiality index offers information complementary to other diffusion parameters.
http://ift.tt/2x9YBA6
On the contribution of motor planning to the retroactive cuing benefit in working memory: Evidence by mu and beta oscillatory activity in the EEG
Source:NeuroImage, Volume 162
Author(s): Daniel Schneider, Anna Barth, Edmund Wascher
Attention can be allocated toward mental representations in working memory also after the initial encoding of information has been completed. It was shown that focusing on only one item within working memory transfers this representation into a protected state, reducing its susceptibility to interference by incoming signals. The present study investigated the nature of this retroactive cue (retro-cue) benefit by means of oscillatory activity in the EEG. In a working memory task with a retro-cue indicating one, two or three memory representations as relevant and a block-wise distractor display presented after the retro-cue, participants had to remember the orientation of a colored bar. On behavioral level, we found that the interfering effect of the distractor display on memory performance could be prevented when a retro-cue reduced the number of attended representations in working memory. However, only the one-item retro-cue led to an overall increase in task performance compared to a condition without a retro-cue. The neural basis of this special representational status was investigated by means of oscillatory parameters in the EEG and a clustering approach on level of the independent components (ICs) in the signal. The retroactive reduction of attended working memory representations was reflected in a suppression of alpha power over right parietal and parieto-occipital sites. In addition, we found that an IC cluster representing oscillatory activity in the mu/beta range (10–12 Hz and 20–24 Hz) with a source in sensorimotor cortex revealed a power suppression already prior to the memory probe following the one-item retro-cue. This suggests that the retro-cue benefit results in large parts from the possibility to focus attention on one particular item in working memory and initiate motor planning processes already ahead of the probe stimulus indicating the respective response.
http://ift.tt/2wGM5oJ
Functional magnetic resonance imaging of auditory cortical fields in awake marmosets
Publication date: 15 November 2017
Source:NeuroImage, Volume 162
Author(s): Camille R. Toarmino, Cecil C.C. Yen, Daniel Papoti, Nicholas A. Bock, David A. Leopold, Cory T. Miller, Afonso C. Silva
The primate auditory cortex is organized into a network of anatomically and functionally distinct processing fields. Because of its tonotopic properties, the auditory core has been the main target of neurophysiological studies ranging from sensory encoding to perceptual decision-making. By comparison, the auditory belt has been less extensively studied, in part due to the fact that neurons in the belt areas prefer more complex stimuli and integrate over a wider frequency range than neurons in the core, which prefer pure tones of a single frequency. Complementary approaches, such as functional magnetic resonance imaging (fMRI), allow the anatomical identification of both the auditory core and belt and facilitate their functional characterization by rapidly testing a range of stimuli across multiple brain areas simultaneously that can be used to guide subsequent neural recordings. Bridging these technologies in primates will serve to further expand our understanding of primate audition. Here, we developed a novel preparation to test whether different areas of the auditory cortex could be identified using fMRI in common marmosets (Callithrix jacchus), a powerful model of the primate auditory system. We used two types of stimulation, band pass noise and pure tones, to parse apart the auditory core from surrounding secondary belt fields. In contrast to most auditory fMRI experiments in primates, we employed a continuous sampling paradigm to rapidly collect data with little deleterious effects. Here we found robust bilateral auditory cortex activation in two marmosets and unilateral activation in a third utilizing this preparation. Furthermore, we confirmed results previously reported in electrophysiology experiments, such as the tonotopic organization of the auditory core and regions activating preferentially to complex over simple stimuli. Overall, these data establish a key preparation for future research to investigate various functional properties of marmoset auditory cortex.
http://ift.tt/2x9pUuf
Cardiac cycle-induced EPI time series fluctuations in the brain: Their temporal shifts, inflow effects and T2∗ fluctuations
Source:NeuroImage, Volume 162
Author(s): Olivia Viessmann, Harald E. Möller, Peter Jezzard
The cardiac-induced arterial pressure wave causes changes in cerebral blood flow velocities and volumes that affect the signals in echo-planar imaging (EPI). Using single-echo EPI time series data, acquired fast enough to unalias the cardiac frequency, we found that the cardiac cycle-induced signal fluctuations are delayed differentially in different brain regions. When referenced to the time series in larger arterial structures, the cortical voxels are only minimally shifted but significant shifts are observed in subcortical areas. Using double-echo EPI data we mapped the voxels' "signal at zero echo time", S0, and apparent T2∗ over the cardiac cycle. S0 pulsatility was maximised for voxels with a cardiac cycle-induced timing that was close to the arterial structures and is likely explained by enhanced inflow effects in the cortical areas compared to subcortical areas. Interestingly a consistent T2∗ waveform over the cardiac cycle was observed in all voxels with average amplitude ranges between 0.3-0.55% in grey matter and 0.15–0.22% in white matter. The timing of the T2∗ waveforms suggests a partial volume fluctuation where arteriolar blood volume changes are counterbalanced by changes in CSF volumes.
http://ift.tt/2w5pyjp
Neural overlap of L1 and L2 semantic representations in speech: A decoding approach
Source:NeuroImage, Volume 162
Author(s): Eowyn Van de Putte, Wouter De Baene, Marcel Brass, Wouter Duyck
Although research has now converged towards a consensus that both languages of a bilingual are represented in at least partly shared systems for language comprehension, it remains unclear whether both languages are represented in the same neural populations for production. We investigated the neural overlap between L1 and L2 semantic representations of translation equivalents using a production task in which the participants had to name pictures in L1 and L2.Using a decoding approach, we tested whether brain activity during the production of individual nouns in one language allowed predicting the production of the same concepts in the other language. Because both languages only share the underlying semantic representation (sensory and lexical overlap was maximally avoided), this would offer very strong evidence for neural overlap in semantic representations of bilinguals. Based on the brain activation for the individual concepts in one language in the bilateral occipito-temporal cortex and the inferior and the middle temporal gyrus, we could accurately predict the equivalent individual concepts in the other language. This indicates that these regions share semantic representations across L1 and L2 word production.
http://ift.tt/2wFgmG5
Validation of radial artery-based uncalibrated pulse contour method (PulsioFlex) in an unselected cohort of critically ill patients.
http://ift.tt/2eKoChD
A critique of the revised conflict tactics scales-2 (CTS-2)
Source:Aggression and Violent Behavior
Author(s): Richard Toby Jones, Shihning Chou, Kevin Browne
The purpose of this review is to critically evaluate the Conflict Tactics Scales-2, a measure used worldwide for research and clinical practices. The reliability, validity and normative samples of the CTS-2 are considered and compared with similar psychometric measures. The limitations of the original CTS have been discussed alongside the CTS-2. Reliability is considered to be good to excellent by alpha coefficient and the variance explained by differing samples or methods of administration. Caution is recommended when interpreting the CTS-2 in clinical settings. Researchers point toward a five-factor structure to the CTS-2. The importance of appropriate norms is discussed and considered crucial when using the tool in settings where reporting patterns may differ. Difficulties in comparing CTS-2 scores across samples, cultures and countries are highlighted. Overall, the CTS-2 is a robust psychometric measure, although it holds limited clinical utility if it is used separately from other sources of information gathering (i.e. psychometric measures or interview). In order to enhance clinical utility, it should be administered alongside measures or clinical interviews that can provide added context regarding violence in the family. More research is required in diverse population samples, cultures/countries and languages.
http://ift.tt/2xa4PzX
Impaired insulin signaling upon loss of ovarian function is associated with a reduction of tristetraprolin and an increased stabilization of chemokine in adipose tissue
Publication date: Available online 5 September 2017
Source:Molecular and Cellular Endocrinology
Author(s): Eun-Kyung Choi, Monisha Rajasekaran, Ok-Joo Sul, Yeonsoo Joe, Hyun-Taeg Chung, Rina Yu, Hye-Seon Choi
Loss of ovarian function can activate inflammation and lead to insulin resistance (IR). IR is also a core feature of obesity and obesity-associated metabolic dysfunction. Tristetraprolin/zinc finger protein 36 (TTP) interferes with TNF-α production by destabilizing TNF-α mRNA, and mice deficient in TTP develop a complex syndrome of inflammatory disease (Carballo et al., 1998; Taylor et al., 1999). We hypothesized that ovariectomy (OVX) might also prime inflammation by reducing tristetraprolin/zinc finger protein 36 (TTP) levels. We used a mouse OVX model to study impaired insulin signaling due to loss of ovarian function by evaluating Akt activity upon insulin stimulus. Impaired insulin signaling was initially detected in adipose tissue (AT) at 4 weeks after OVX, and then spread to liver and muscle, finally resulting in systemic IR at 12 weeks after OVX. OVX decreased TTP protein levels and increased adipocyte size, oxidative stress, chemokine expression and fat mass in AT by 4 weeks after surgery. TTP deficiency due to TTP gene deletion induced aberrant insulin signaling and increased chemokine expression and macrophage numbers in AT but did not increase adipocyte size, oxidative stress, or fat mass, suggesting that it promotes insulin signaling by decreasing AT inflammation independent of oxidative stress and adiposity. OVX, like TTP deficiency, increased the stability of chemokine transcripts as assessed from their half-lives. Our data indicate that the impaired insulin signaling resulting from OVX is due to an OVX-induced reduction of TTP and the resulting stabilization of inflammatory chemokines.
Graphical abstract
http://ift.tt/2wGF72M
The herbicides trifluralin and tebuthiuron have no genotoxic or mutagenic potential as evidenced by genetic tests
Abstract
Brazil has been the largest world consumer of pesticides since 2008, followed by the USA. The herbicides trifluralin and tebuthiuron have been widely applied in agriculture. These herbicides are selective for some plant species, and their use brings various benefits. However, the genotoxic and mutagenic effects of tebuthiuron on non-target organisms are poorly known, and in addition, the effects of trifluralin must be better investigated. Therefore, this study employed genetic tests including the comet assay and micronucleus test to evaluate the genotoxic effects of trifluralin and tebuthiuron on HepG2 cells. In addition, we have used the Ames test to assess the mutagenic effects of the herbicides on the TA97a, TA98, TA100, and TA1535 strains of Salmonella typhimurium. On the basis of the comet assay and the micronucleus test, trifluralin did not cause genetic damage to HepG2 cells. In addition, trifluralin did not impact the tested S. typhimurium strains. Regarding tebuthiuron, literature has shown that this herbicide damaged DNA in Oreochromis niloticus. Nevertheless, we have found that tebuthiuron was not genotoxic to either HepG2 cells or the S. typhimurium strains. Therefore, neither trifluralin nor tebuthiuron exerted genotoxic or mutagenic potential at the tested conditions.
http://ift.tt/2w5SEPA
Patterns of Intraosseous Recurrence following Stereotactic Body Radiotherapy for Coxal Bone Metastasis
Publication date: Available online 5 September 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Kei Ito, Takuya Shimizuguchi, Keiji Nihei, Tomohisa Furuya, Hiroaki Ogawa, Hiroshi Tanaka, Keisuke Sasai, Katsuyuki Karasawa
PurposeThis study aimed to analyze the detailed pattern of intraosseous failure after stereotactic body radiotherapy (SBRT) for coxal bone metastasis.MethodsPatients treated with SBRT to coxal bone metastasis were identified by retrospective chart review. SBRT doses were 30 Gy or 35 Gy in 5 fractions. A margin of 5-10 mm was added to the gross tumor volume to create the clinical target volume. We evaluated the presence or absence of intraosseous recurrence using magnetic resonance imaging. Intraosseous recurrences were assessed as "in-field" or "marginal/out-of-field". In addition, we measured the distance between the center of the recurrent tumor and the nearest edge of the initial bone metastasis in cases of marginal/out-of-field recurrence.ResultsSeventeen patients treated for 17 coxal bone metastases were included. Median age was 64 years (range, 48-79 years). Coxal lesions involved the ilium in 14 cases, pubis in 3 and ischium in 4 (3 lesions crossed over multiple regions). Patients most commonly had renal cell carcinoma (29.4%), followed by lung, hepatic cell and colorectal cancers (23.5%, 11.8% and 11.8%, respectively). Median follow-up after SBRT was 13 months (range, 2-44 months). Among all 17 cases, 7 cases developed 8 intraosseous recurrences, including in-field recurrence in 1 case and marginal/out-of-field recurrences in 7 cases. Median time to intraosseous recurrence was 10 months (range, 2-35 months). Among 7 cases with marginal/out-of-field recurrence, mean distance to the center of the recurrent tumor from the nearest edge of the initial bone metastasis was 34 mm (range, 15-55 mm).ConclusionsMost recurrences were observed out-of-field in the same coxal bone. These results suggest that defining the optimal clinical target volume in SBRT for coxal bone metastasis to obtain sufficient local tumor control is difficult.
Teaser
Patterns of intraosseous failure in 17 patients treated with stereotactic body radiation therapy (SBRT) for coxal bone metastases were analyzed retrospectively. Although SBRT achieved good local control at the target, marginal/out-of-field recurrences in the coxal bone were observed in 7 cases. Tumor recurrence occurred at an average distance of more than 30 mm from the initial metastasis.http://ift.tt/2j10HvN
Τρίτη 5 Σεπτεμβρίου 2017
A novel class of Plasmodial ClpP protease inhibitors as potential antimalarial agents
Publication date: Available online 5 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Sourabh Mundra, Vandana Thakur, Angelica M. Bello, Sumit Rathore, Mohd Asad, Lianhu Wei, Jane Yang, Sai Kumar Chakka, Radhakrishnan Mahesh, Pawan Malhotra, Asif Mohmmed, Lakshmi P. Kotra
The prokaryotic ATP-dependent ClpP protease, localized in the relict plastid of malaria parasite, represents a potential drug target. In the present study, we utilized in silico structure-based screening and medicinal chemistry approaches to identify a novel pyrimidine series of compounds inhibiting P. falciparum ClpP protease activity and evaluated their antiparasitic activities. Structure-activity relationship indicated that morpholine moiety at C2, an aromatic substitution at N3 and a 4-oxo moiety on the pyrimidine are important for potent inhibition of ClpP enzyme along with antiparasiticidal activity. Compound 33 exhibited potent antiparasitic activity (EC₅₀ 9.0 ± 0.2 μM), a 9-fold improvement over the antiparasitic activity of the hit molecule 6. Treatment of blood stage P. falciparum cultures with compound 33 caused morphological and developmental abnormalities in the parasites; further, compound 33 treatment hindered apicoplast development indicating the targeting of apicoplast.
Graphical abstract
http://ift.tt/2wGilIl
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Publication date: September 2017 Source: Free Radical Biology and Medicine, Volume 110 Author(s): Lucía Fernández-del-Río, Anish Nag, Elen...
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Abstract Noise pollution is a major factor of environmental complaints in many cities, which has significant impacts on human health. As a...
