Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer

Abstract

Background

Selection of resistance mutations may play a major role in the development of endocrine resistance. ESR1 mutations are rare in primary breast cancer but have high prevalence in patients treated with aromatase inhibitors (AI) for advanced breast cancer. We investigated the evolution of genetic resistance to first line AI therapy using sequential ctDNA sampling in patients with advanced breast cancer.

Patients and Methods

83 patients on first line AI therapy for metastatic breast cancer were enrolled in a prospective study. Plasma samples were collected every 3 months to disease progression and ctDNA analysed by digital droplet PCR and enhanced tagged-amplicon sequencing (eTAm-Seq). Mutations identified in progression samples by sequencing were tracked back through samples prior to progression to study the evolution of mutations on therapy. The frequency of novel mutations were validated in an independent cohort of available baseline plasma samples in the SoFEA trial, which enrolled patients with prior sensitivity to AI.

Results

Of the 39 patients who progressed on first line AI, 56.4%(22/39) had ESR1 mutations detectable at progression, which were polyclonal in 40.9%(9/22) patients. In serial tracking, ESR1 mutations were detectable median 6.7 months (95%CI 3.7-NA) prior to clinical progression. Utilising eTAm-Seq ctDNA sequencing of progression plasma, ESR1 mutations were demonstrated to be sub-clonal in 72.2%(13/18) patients. Mutations in RAS genes were identified in 15.4%(6/39) of progressing patients (4 KRAS, 1 HRAS, 1 NRAS). In SoFEA, KRAS mutations were detected in 21.2%(24/113) patients, although there was no evidence that KRAS mutation status was prognostic for progression free or overall survival.

Conclusions

Cancers progressing on first line AI show high levels of genetic heterogeneity, with frequent sub-clonal mutations. Sub-clonal KRAS mutations are found at high frequency. The genetic diversity of AI resistant cancers may limit subsequent targeted therapy approaches.

http://ift.tt/2fLALzG

Multicenter clinical assessment of improved wearable multimodal convulsive seizure detectors

Summary

Objective

New devices are needed for monitoring seizures, especially those associated with sudden unexpected death in epilepsy (SUDEP). They must be unobtrusive and automated, and provide false alarm rates (FARs) bearable in everyday life. This study quantifies the performance of new multimodal wrist-worn convulsive seizure detectors.

Methods

Hand-annotated video-electroencephalographic seizure events were collected from 69 patients at six clinical sites. Three different wristbands were used to record electrodermal activity (EDA) and accelerometer (ACM) signals, obtaining 5,928 h of data, including 55 convulsive epileptic seizures (six focal tonic–clonic seizures and 49 focal to bilateral tonic–clonic seizures) from 22 patients. Recordings were analyzed offline to train and test two new machine learning classifiers and a published classifier based on EDA and ACM. Moreover, wristband data were analyzed to estimate seizure-motion duration and autonomic responses.

Results

The two novel classifiers consistently outperformed the previous detector. The most efficient (Classifier III) yielded sensitivity of 94.55%, and an FAR of 0.2 events/day. No nocturnal seizures were missed. Most patients had <1 false alarm every 4 days, with an FAR below their seizure frequency. When increasing the sensitivity to 100% (no missed seizures), the FAR is up to 13 times lower than with the previous detector. Furthermore, all detections occurred before the seizure ended, providing reasonable latency (median = 29.3 s, range = 14.8–151 s). Automatically estimated seizure durations were correlated with true durations, enabling reliable annotations. Finally, EDA measurements confirmed the presence of postictal autonomic dysfunction, exhibiting a significant rise in 73% of the convulsive seizures.

Significance

The proposed multimodal wrist-worn convulsive seizure detectors provide seizure counts that are more accurate than previous automated detectors and typical patient self-reports, while maintaining a tolerable FAR for ambulatory monitoring. Furthermore, the multimodal system provides an objective description of motor behavior and autonomic dysfunction, aimed at enriching seizure characterization, with potential utility for SUDEP warning.

http://ift.tt/2xhTcr2

Autovalidation and automation of the postanalytical phase of routine hematology and coagulation analyses in a university hospital laboratory

Authors: Mlinaric, Ana / Milos, Marija / Coen Herak, Désirée / Fucek, Mirjana / Rimac, Vladimira / Zadro, Renata / Rogic, Dunja


http://ift.tt/2hqYMN5

Hyperuricemia does not seem to be an independent risk factor for coronary heart disease

Authors: Battaggia, Alessandro / Scalisi, Andrea / Puccetti, Luca


http://ift.tt/2xaHZH9

Insulin autoimmune syndrome (Hirata’s disease) in an Italian patient: a case report and review of the literature

Authors: Censi, Simona / Albergoni, Maria Paola / Gallo, Nicoletta / Plebani, Mario / Boscaro, Marco / Betterle, Corrado


http://ift.tt/2yfMAXd

Development of an internally controlled quantitative PCR to measure total cell-associated HIV-1 DNA in blood

Authors: Vicenti, Ilaria / Meini, Genny / Saladini, Francesco / Giannini, Alessia / Boccuto, Adele / Schiaroli, Elisabetta / Zazzi, Maurizio


http://ift.tt/2vYXkYo

Selective changes in cholesterol metabolite levels in plasma of breast cancer patients after tumor removal

Authors: Soucek, Pavel / Vrana, David / Ueng, Yune-Fang / Wei, Shouzou / Kozevnikovova, Renata / Guengerich, Frederick Peter


http://ift.tt/2vYhf9I

Analytical quality: an unfinished journey

Authors: Plebani, Mario


http://ift.tt/2w8bcna

High-sensitivity assays for cardiac troponins – continued

Authors: Lackner, Karl J.


http://ift.tt/2w7KMC6

Can a combination of average of normals and “real time” External Quality Assurance replace Internal Quality Control?

Authors: Badrick, Tony / Graham, Peter


http://ift.tt/2wZ4m0j

MEF2C loss-of-function mutation associated with familial dilated cardiomyopathy

Authors: Yuan, Fang / Qiu, Zhao-Hui / Wang, Xing-Hua / Sun, Yu-Min / Wang, Jun / Li, Ruo-Gu / Liu, Hua / Zhang, Min / Shi, Hong-Yu / Zhao, Liang / Jiang, Wei-Feng / Liu, Xu / Qiu, Xing-Biao / Qu, Xin-Kai / Yang, Yi-Qing


http://ift.tt/2w8gi2P

Irregular analytical errors in diagnostic testing – a novel concept

Authors: Vogeser, Michael / Seger, Christoph


http://ift.tt/2x0qoQA

Stability of routine biochemical analytes in whole blood and plasma/serum: focus on potassium stability from lithium heparin

Authors: Dupuy, Anne Marie / Cristol, Jean Paul / Vincent, Bruno / Bargnoux, Anne Sophie / Mendes, Mickael / Philibert, Pascal / Klouche, Kadda / Badiou, Stéphanie


http://ift.tt/2xu1gEK

Organotypic brain explant culture as a drug evaluation system for malignant brain tumors

Abstract

Therapeutic options for malignant brain tumors are limited, with new drugs being continuously evaluated. Organotypic brain slice culture has been adopted for neuroscience studies as a system that preserves brain architecture, cellular function, and the vascular network. However, the suitability of brain explants for anticancer drug evaluation has been unclear. We here adopted a mouse model of malignant glioma based on expression of H-Ras^V12 in Ink4a/Arf^−/− neural stem/progenitor cells to establish tumor-bearing brain explants from adult mice. We treated the slices with cisplatin, temozolomide, paclitaxel, or tranilast and investigated the minimal assays required to assess drug effects. Serial fluorescence-based tumor imaging was sufficient for evaluation of cisplatin, a drug with a pronounced cytotoxic action, whereas immunostaining of cleaved caspase 3 (a marker of apoptosis) and of Ki67 (a marker of cell proliferation) was necessary for the assessment of temozolomide action and immunostaining for phosphorylated histone H3 (a marker of mitosis) allowed visualization of paclitaxel-specific effects. Staining for cleaved caspase 3 was also informative in the assessment of drug toxicity for normal brain tissue. Incubation of explants with fluorescently labeled antibodies to CD31 allowed real-time imaging of the microvascular network and complemented time-lapse imaging of tumor cell invasion into surrounding tissue. Our results suggest that a combination of fluorescence imaging and immunohistological staining allows a unified assessment of the effects of various classes of drug on the survival, proliferation, and invasion of glioma cells, and that organotypic brain slice culture is therefore a useful tool for evaluation of antiglioma drugs.

Establishment, culture, and analysis of tumor-bearing brain explants as a drug evaluation system for malignant brain tumors.

http://ift.tt/2xiIsJa

Development and validation of a nomogram predicting the overall survival of stage IV breast cancer patients

Abstract

This study aimed to develop a nomogram to predict the overall survival (OS) of stage IV breast cancer patients. We searched the National Cancer Database (NCDB) for stage IV breast cancer patients diagnosed between 2010 and 2013. Predictors of OS were identified and a nomogram was developed and validated using concordance index (C-index), calibration plots, and risk group stratifications. A total of 7199 patients from the NCDB were included in the study. With a median follow-up of 25.7 months, the 1-year and 3-year OS rates were 80.6% and 52.5%, respectively. Race, age, comorbidity status, T-stage, grade, ER/PR/Her2 status, the presence of lung/liver/brain metastasis, surgery, radiotherapy, and chemotherapy were significantly associated with OS. The developed nomogram had a C-index of 0.722 (95% CI 0.710–0.734) and 0.725 (95% CI 0.713–0.736) in the training and the validation cohorts, respectively. The predicted survival using the nomogram is well correlated with actual OS. The nomogram was able to stratify patients into different risk groups, among which the survival benefit of local therapy varied. We developed a nomogram to predict the overall survival of stage IV breast cancer patients. Prospectively designed studies with international collaborations are needed to further validate our nomogram.

Nomogram to predict the overall survival stage IV breast cancer patients. This would be helpful to clinical decision-making.

http://ift.tt/2xiLJDj

Medulloblastoma in children and adolescents: a systematic review of contemporary phase I and II clinical trials and biology update

Abstract

Survival rates for patients with medulloblastoma have improved in the last decades but for those who relapse outcome is dismal and new approaches are needed. Emerging drugs have been tested in the last two decades within the context of phase I/II trials. In parallel, advances in genetic profiling have permitted to identify key molecular alterations for which new strategies are being developed. We performed a systematic review focused on the design and outcome of early-phase trials evaluating new agents in patients with relapsed medulloblastoma. PubMed, clinicaltrials.gov, and references from selected studies were screened to identify phase I/II studies with reported results between 2000 and 2015 including patients with medulloblastoma aged <18 years. A total of 718 studies were reviewed and 78 satisfied eligibility criteria. Of those, 69% were phase I; 31% phase II. Half evaluated conventional chemotherapeutics and 35% targeted agents. Overall, 662 patients with medulloblastoma/primitive neuroectodermal tumors were included. The study designs and the response assessments were heterogeneous, limiting the comparisons among trials and the correct identification of active drugs. Median (range) objective response rate (ORR) for patients with medulloblastoma in phase I/II studies was 0% (0–100) and 6.5% (0–50), respectively. Temozolomide containing regimens had a median ORR of 16.5% (0–100). Smoothened inhibitors trials had a median ORR of 8% (3–8). Novel drugs have shown limited activity against relapsed medulloblastoma. Temozolomide might serve as backbone for new combinations. Novel and more homogenous trial designs might facilitate the development of new drugs.

This systematic review in early-phase trials in patients with medulloblastoma summarizes the recent experience in therapeutic strategies in patients with relapsed and refractory medulloblastoma and highlights the strengths and pitfalls of current trials.

http://ift.tt/2xhoxdm

Dynamic changes of urine proteome in a Walker 256 tumor-bearing rat model

Abstract

Despite advances in cancer treatments, early diagnosis of cancer is still the most promising way to improve outcomes. Without homeostatic control, urine reflects systemic changes in the body and can potentially be used for early detection of cancer. In this study, a tumor-bearing rat model was established by subcutaneous injection of Walker 256 cells. Urine samples from tumor-bearing rats were collected at five time points during cancer development. Dynamic urine proteomes were profiled using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Several urine proteins that changed at multiple time points were selected as candidate cancer biomarkers and were further validated by multiple reaction monitoring (MRM) analysis. It was found that the urinary protein patterns changed significantly with cancer development in a tumor-bearing rat model. A total of 10 urinary proteins (HPT, APOA4, CO4, B2MG, A1AG, CATC, VCAM1, CALB1, CSPG4, and VTDB) changed significantly even before a tumor mass was palpable, and these early changes in urine could also be identified with differential abundance at late stages of cancer. Our results indicate that urine proteins could enable early detection of cancer at an early onset of tumor growth and monitoring of cancer progression.

Urine is a noninvasive and attractive biofluid for biomarker research, and has the potential to reflect early and small pathological changes in the body. Urine proteins changed significantly with cancer development in a tumor-bearing rat model. Our results indicate that urine proteins could enable early detection of cancer at an early onset of tumor growth and monitoring of cancer progression.

http://ift.tt/2xins51

Incidence, risk factors, and outcomes of central venous catheter-related thromboembolism in breast cancer patients: the CAVECCAS study

Abstract

Previous epidemiologic studies investigating central venous catheter (CVC)-related venous thromboembolism (CRT) were conducted in heterogenous cancer populations and data in breast cancer (BC) remain limited. To investigate the Doppler ultrasound (DUS)-CRT incidence, risk factors and outcomes in BC, we designed a prospective, multicenter cohort of nonmetastatic invasive BC patients undergoing insertion of a CVC for chemotherapy. All patients underwent double-blind DUS before, 7, 30, and 90 days after CVC insertion and a 6 months clinical follow-up. Symptomatic DUS-CRT were treated by anticoagulants. D-Dimers, thrombin generation, and platelet-derived microparticles were measured before and 2 days after CVC placement. In DUS-CRT patients, a nested case–control study analyzed the role of thrombophilia. Among 524 patients, the DUS-CRT (14 symptomatic, 46 asymptomatic) cumulative probability was 9.6% at 3 months and 11.5% at 6 months (overall incidence rate: 2.18/100 patient-months). Ten/14 symptomatic DUS-CRT were detected on double-blind DUS before the clinical symptoms, and 3/14 had a simultaneous pulmonary embolism. No clinical thrombotic event subsequently occurred in untreated asymptomatic DUS-CRT. Age >50 years (OR, 1.80; 95% CI, 1.01–3.22), BMI >30 kg/m² (OR, 2.64; 95% CI, 1.46–4.76) and comorbidities (OR, 2.05; 95% CI, 1.18–3.56) were associated with DUS-CRT. No biomarkers was found to predict DUS-CRT. In multivariate analysis, BMI >30 kg/m² (OR, 2.66; 95%CI, 1.46–4.84) and lobular carcinoma histology (OR, 2.56; 95%CI, 1.32–4.96) remained the only significant DUS-CRT risk factors. Thrombophilia did not account for DUS-CRT. Only clinical parameters identified high risk DUS-CRT patients who may be considered for thromboprophylaxis.

Data regarding central venous catheter-related thrombosis (CRT) in breast cancer (BC) patients are limited, although CVC placement for chemotherapy is common in this population and BC is the first cause of cancer in women worldwide. We conducted a large prospective multicentre study (9 cancer hospitals, 524 patients). The 6-months cumulative probability of symptomatic and asymptomatic CRT was 11.5%. BMI >30 kg/m² and lobular carcinoma histology were the main risk factors for CRT.

http://ift.tt/2ximlh1

Safety and Immunogenicity of an Anti–Zika Virus DNA Vaccine — Preliminary Report

Zika virus (ZIKV) is a flavivirus that was originally discovered in a sentinel rhesus macaque in Uganda in 1947 and is endemic in Africa and Asia. After outbreaks in Yap Island and French Polynesia, ZIKV infection was identified in Brazil in 2015 and has spread rapidly throughout the Americas. ZIKV…

http://ift.tt/2xiAj2g

After the Mass Shooting in Las Vegas — Finding Common Ground on Gun Control

We've seen so many mass shootings — in theaters, in churches, in nightclubs, in schools — that each new episode of the mass slaughter of Americans induces a weary sense of déjà vu. But some realities of the recent mass shooting in Las Vegas, the largest in modern history, might help produce action,…

http://ift.tt/2y1pdCP

Genetic Screening for EMS-Induced Maize Embryo-Specific Mutants Altered in Embryo Morphogenesis

We have previously identified embryo-specific (emb) mutations that resulted in maize kernels containing abnormal embryos with normal appearing endosperm among the progeny of active Robertson's Mutator stocks.  Our rationale for the mutant screen described here is that it should be possible to produce ethyl methane sulfonate (EMS)-induced embryo-specific mutations at a frequency higher than that obtained by transposon mutagenesis and with greater ease. This proved to be the case when we screened for mutations that are embryo-specific among progeny of materials generated with EMS-treated pollen. The EMS-induced emb mutation frequency reported here is nearly three times the 4.5% we obtained with the transposable element stocks. The 45 mutants reported here were all tested for germination capacity and nearly all were lethal. The embryo phenotypes of 34 mutations were examined by dissection of mature embryos. All were found to be retarded in development and morphologically abnormal. Half of this group of mutants is blocked in the proembryo and transition stages. They likely include mutations in nuclear genes coding for plastid proteins. The other 17 are mainly blocked in the coleoptilar stage, or in later stages with a low frequency. This group likely includes mutations in genes regulating the completion of shoot apical meristem development and accompanying morphogenetic events. Most of the complementation tests using 19 of the mutations in 35 unique combinations complimented each other except for two pairs of mutations with similar phenotypes. Our results provide additional evidence for the presence of many emb loci in the maize genome.

http://ift.tt/2fT7qqW

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma [Research Briefs]

Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such therapies is that genomic profiling results could commonly differ between the primary and metastatic tumor. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multi-region sequencing showed significant discrepancy within the primary tumor and between the primary tumor and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, pilot analysis of cfDNA sequencing demonstrated the feasibility of detecting genomic amplifications not detected in primary tumor sampling. Lastly, we profiled paired primary, metastatic tumors and cfDNA from patients enrolled in the PANGEA trial of targeted therapies in GEA, and found that genomic biomarkers were recurrently discrepant between the primary tumor and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy.

http://ift.tt/2y0qdqh

Music Perception Training for Pediatric Cochlear Implant Recipients Ages 3 to 5 Years: A Pilot Study

Abstract

This study examined the potential effectiveness of music perception training program for pediatric cochlear implant recipients. A pilot study was conducted with six young CI recipients with a mean age of 4.4 years to investigate the applicability of the systematic training program targeting discrimination and identification of rhythm, pitch, and timbre, and singing skills. Participants received a total of 24 training sessions and their music perception task performance on seven subtests was measured before and after the program. The results showed that task performance rates of participants increased for all subtests, with significant improvement in rhythm discrimination and identification. This indicates that this structured training could be applied to this population in order to facilitate them to effectively process temporal and spectral features of music.

http://ift.tt/2xVquJD

Exploring the Meaning of a Performance in Music Therapy for Children and Their Families Experiencing Homelessness and Family Violence

Abstract

This qualitative project explored the experience and meaning of a supported group performance held at the conclusion of a music therapy program for children and their families who were receiving support for homelessness and family violence. Interviews were conducted with three preadolescent girls who had participated in the group performance, as well as four parents who were audience members. An interpretative phenomenological analysis explored some of the similarities and differences experienced by participants. The performance was a multifaceted experience, with both positive and challenging aspects described. Three recurrent themes were identified: the children experienced intense, but mixed, emotions; the performance connected the children to their family and peers; and the audience played an active role in the performance. The findings emphasize the ways performance provides opportunities for families to positively engage with one another, and support each other, during times of crisis.

http://ift.tt/2wzcCDa

Evaluating a Pilot Improvisational Drumming Curriculum: Implications for Improving Confidence and Skills among Music Therapy Students

Abstract

Presented here are performance results of music therapy students in a college course that was designed to prepare them to use percussion interventions in therapy. After discussing the purpose and teaching methods used, self-reported confidence levels were examined to determine the effects of training in the use of common drum circle instruments and experience facilitating drum circles in a small-group setting. Data consisted of results from surveys regarding confidence and perceived skills. Mean confidence scores data were analyzed through graphical presentation. Mean self-reported skill-level scores were also compared to the mean scores given by the instructor for each question on the skills survey. Examination of the data indicated a positive trend for self-reported confidence and drumming-skill levels. Comparison of instructor scores and student scores indicated strong agreement between teacher and student assessment of skills. In addition, skill-level trends supported the idea that student confidence increased as skill level increased.

http://ift.tt/2xUFojd

Surgical Music Therapy: The Significance and Implementation of Music Therapy in the Operating Arena

Abstract

While music therapy is rarely practiced perioperatively, an extensive body of research confirms the efficacy of music therapy with comparable medical populations. Numerous music-in-medicine and music therapy studies suggest that surgical music therapy (SMT) may in fact be beneficial in the perioperative realm. In this article, SMT experiences are relayed, offering goals, suggestions, and challenges in its facilitation. Methods, practices, and professional issues related to expediting music therapy in the surgical arena are discussed, with the objective of inspiring real-world applications and further research in this area. In so doing, this article articulates the potential of SMT to serve as an adjunct to standard surgical care and illustrates how music therapists might introduce and expand SMT practices at hospitals and surgery centers nationwide.

http://ift.tt/2xVqRUk

Musical Mnemonics Training: Proposed Mechanisms and Case Example with Acquired Brain Injury

Abstract

After an acquired brain injury, simple semantic, declarative memory tasks such as knowing one's address can be difficult to complete. Music's ability to extend and optimize shared neurologic pathways responsible for music perception, production, and memory processes makes rhythmic-melodic templates uniquely suited for declarative memorization tasks. Rhythm and melody have long been used to memorize information, and many have direct experience learning the letters of their alphabet using the familiar childhood song "Twinkle Twinkle." Therapeutic applications for musical mnemonics exist in both child and adult populations. Typically developing children, children with special needs, and those who have sustained neurologic injury or disease processes affecting memory may benefit from training using musical mnemonics. The purposes of this paper are to provide an overview of memory processing, review the research literature on music-mediated memory tasks in clinical populations experiencing impairments in memory, and describe suggested mechanisms for their action using the Rational-Scientific Mediating Model (Thaut, 2005). An intervention example utilizing the Transformational Design Model (TDM) will demonstrate how this technique can be implemented in a clinical setting.

http://ift.tt/2xUKJHd

The power of music: Pioneering discoveries in the new science of song The music instinct: Science & song

Mannes, E. (2011). The Power of Music: Pioneering Discoveries in the New Science of Song. New York: Walker & Company. 263 pages. ISBN: 978-0-8027-1996-6. $11.95/$19.60.

http://ift.tt/2xUKH23

Music therapy in schools: Working with children of all ages in mainstream and special education

Tomlinson, Jo, Derrington, Philippa, and Oldfield, Amelia (Eds.). (2012). Music therapy in schools: Working with children of all ages in mainstream and special education. Jessica Kingsley Publishers. 227 pages. $39.95. ISBN 987-1-84905-000-5, ebook ISBN 9780857004741.

http://ift.tt/2wyk01S

I Will Follow You: The Combined Use of Songwriting and Art to Promote Healing in a Child Who Has Been Traumatized

Abstract

This article describes music therapy services provided to a six-year-old child who had been physically and sexually abused. While the music therapist had been meeting with the child for over a year at the time of this writing, this report focuses on an intervention implemented over the course of approximately six months. It presents a new way of combining songwriting and visual art to facilitate emotional expression, specifically, the use of therapist-composed songs in response to the child's drawings. The drawings and therapist-composed songs are related to emotions that the child chose as being important for her healing. Several processes are explained, including (a) how the child was encouraged to use visual art, (b) how the therapist composed each song, and (c) how the child responded to the therapist-composed songs. The paper further summarizes the essential elements of this approach, including giving the child control of the process, providing validation and acceptance for the child and where she is in the healing process, increasing her self-esteem, and providing a healthy emotional outlet. Three audio examples are included with their corresponding drawings. The clinical considerations of establishing sufficient rapport with the child, already having a strong songwriting background, flexibility with the various ways a song can be written and the client's chosen level of involvement, and collaborating with an art therapist are included in the discussion of this paper.

http://ift.tt/2xUKtrJ

Countertransference in End-of-Life Music Therapy

Abstract

Countertransference is a complex and important issue for end-of-life music therapists. However, limited literature is available on the subject of end-of-life music therapy and countertransference to guide professionals as we encounter the effects of countertransference inside and outside sessions. There are circumstances associated with end-of-life music therapy that require a closer look, that demand recognition, and that may result in better music experiences for our clients. The purpose of this article is to explore the experiences and influences of countertransference in the unique situations presented by end-of-life music therapy, thus increasing readers' awareness of the potential impact of countertransference upon their clinical practices.

http://ift.tt/2xUKdZN

Metabolic characteristics of programmed cell death-ligand 1-expressing lung cancer on 18F-fluorodeoxyglucose positron emission tomography/computed tomography

Abstract

Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have been identified as novel targets of immunotherapy of lung cancer. In present study, we evaluated the metabolic characteristics of lung cancer by using ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) with regard to PD-L1 protein expression. PD-L1 protein expression was evaluated by immunohistochemistry with the antibody clone SP142 in 579 surgically resected primary lung cancer patients. Cases with less than 5% tumor membrane staining were considered negative. We examined the association between the frequency of PD-L1 protein expression and the maximum standardized uptake value (SUVmax) in preoperative ¹⁸F-FDG PET/CT. The cut-off values for SUVmax were determined by receiver operating characteristic curve analyses. The SUVmax was significantly higher in nonsmall cell lung cancer (NSCLC) patients with PD-L1 protein expression compared with those without PD-L1 protein expression (P < 0.0001). However, there was no correlation between SUVmax and PD-L1 protein expression in patients with neuroendocrine tumors (P = 0.6545). Multivariate analysis revealed that smoking, the presence of pleural invasion, and high SUVmax were independent predictors of PD-L1 positivity. PD-L1-expressing NSCLC had a high glucose metabolism. The SUVmax in preoperative ¹⁸F-FDG PET/CT was a predictor of PD-L1 protein expression in patients with NSCLC.

PD-L1-expressing NSCLC had a high glucose metabolism. The SUVmax in preoperative 18F-FDG PET/CT was a predictor of PD-L1 protein expression in patients with NSCLC.

http://ift.tt/2xhnvhp

EZH2 modifies sunitinib resistance in renal cell carcinoma by kinome reprogramming

Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represent a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft (PDX) model that is intrinsically resistant to the RTKI sunitinib but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its anti-angiogenic and anti-metastatic activity but lost its direct anti-tumor effects due to kinome reprogramming, which resulted in suppression of pro-apoptotic and cell cycle regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTK, restoring the anti-tumor effects of sunitnib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease.

http://ift.tt/2gcK0tk

Novel selective agents for the degradation of androgen receptor variants to treat castration-resistant prostate cancer

Androgen receptor (AR) mediates the growth of prostate cancer (PCa) throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced PCa requires the development of agents that can sustainably degrade variant isoforms for effective therapy. Here we report the discovery and characterization of potent selective AR degraders (SARDs) that markedly reduce the activity of wildtype and splice variant isoforms of AR at sub-micromolar doses. Three SARDs (UT-69, UT-155, and (R)-UT-155) bind the amino-terminal transcriptional activation domain AF-1, which has not been targeted for degradation previously, with two of these SARD (UT-69 and UT-155) also binding the carboxy-terminal ligand binding domain. Despite different mechanisms of action, all three SARDs degraded wild-type AR and inhibited AR function, exhibiting greater inhibitory potency than the approved AR antagonists. Collectively, our results introduce a new candidate class of next-generation therapeutics to manage advanced PCa.

http://ift.tt/2wyGfVx

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy

Adrenoleukodystrophy is an X-linked genetic disease that is caused by a defect in the gene ABCD1 (ATP-binding cassette, subfamily D, member 1), which encodes the peroxisomal ABC half-transporter ALD protein. Mutations in ABCD1 result in abnormal breakdown of very-long-chain fatty acids, a process…

http://ift.tt/2yJbOfV

Optimizing Treatment for Cerebral Adrenoleukodystrophy in the Era of Gene Therapy

Adrenoleukodystrophy is a peroxisomal metabolic disorder that can be manifested by rapidly progressive cerebral demyelination (known as cerebral adrenoleukodystrophy) in affected boys and men. Untreated cerebral adrenoleukodystrophy causes severe disability or death approximately 2 years after its…

http://ift.tt/2xgEjFr

Improved Hematopoietic Gene Therapy in a Mouse Model of Fanconi Anemia Mediated by Mesenchymal Stromal Cells

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2fSSjxL

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy

Adrenoleukodystrophy is an X-linked genetic disease that is caused by a defect in the gene ABCD1 (ATP-binding cassette, subfamily D, member 1), which encodes the peroxisomal ABC half-transporter ALD protein. Mutations in ABCD1 result in abnormal breakdown of very-long-chain fatty acids, a process…

http://ift.tt/2yJbOfV

Optimizing Treatment for Cerebral Adrenoleukodystrophy in the Era of Gene Therapy

Adrenoleukodystrophy is a peroxisomal metabolic disorder that can be manifested by rapidly progressive cerebral demyelination (known as cerebral adrenoleukodystrophy) in affected boys and men. Untreated cerebral adrenoleukodystrophy causes severe disability or death approximately 2 years after its…

http://ift.tt/2xgEjFr

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy

Adrenoleukodystrophy is an X-linked genetic disease that is caused by a defect in the gene ABCD1 (ATP-binding cassette, subfamily D, member 1), which encodes the peroxisomal ABC half-transporter ALD protein. Mutations in ABCD1 result in abnormal breakdown of very-long-chain fatty acids, a process…

http://ift.tt/2yJbOfV

Optimizing Treatment for Cerebral Adrenoleukodystrophy in the Era of Gene Therapy

Adrenoleukodystrophy is a peroxisomal metabolic disorder that can be manifested by rapidly progressive cerebral demyelination (known as cerebral adrenoleukodystrophy) in affected boys and men. Untreated cerebral adrenoleukodystrophy causes severe disability or death approximately 2 years after its…

http://ift.tt/2xgEjFr

The physics of an academic career

We adopted well-known physics equations to illustrate concepts for developing a successful academic career plan. Formulas for distance, force, momentum, and power are used to explain how to define goals and set a pace that maximizes success potential. Formulas for synergy, balance, and stress are used to highlight common obstacles encountered by both junior (untenured and early career) and established faculty and provide ways to circumvent or limit damage from setbacks. Combined, these formulas provide tips for thriving in an academic environment.

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Comparative effectiveness of a mnemonic-use approach vs. self-study to interpret a lateral chest X-ray

The chest X-ray is the most commonly performed medical imaging study; however, the lateral chest film intimidates many physicians and medical students. The lateral view is more difficult to interpret than the frontal view but provides important information that is either not visible or not as evident on frontal view, and inability to read it may lead to missed diagnoses and more expensive imaging. The objective of this study was to assess a novel mnemonic-based approach to teaching medical students to proficiently read a lateral film using a prospective pilot study. A clinical faculty radiologist taught two groups of second-year medical students to read a lateral chest X-ray. One group learned a novel mnemonic-based method (MUM), and the other cohort performed directed web-based self-study (STMM). Each cohort was given a pre- and postassessment, and their performance was analyzed. A total of n = 29 students participated with n = 14 being taught the mnemonic method. The MUM group significantly (P = 0.001) improved their score vs. the STMM group This study demonstrates students can quickly and effectively learn to read a lateral chest film using this novel mnemonic.

http://ift.tt/2yJJSs2

An interactive online approach to small-group student presentations and discussions

Student presentations had been widely implemented across content areas, including health sciences education. However, due to various limitations, small-group student presentations in the classroom may not reach their full potential for student learning. To address challenges with presentations in the classroom, we redesigned the assignment by having students present and discuss online using VoiceThread, a cloud-based presentation and discussion tool. First-year students pursuing a Doctor of Dental Surgery degree were assigned into small groups to present physiology content and to discuss that content online. This assignment was similar to traditional student classroom presentations, with the exception that the entire assignment was conducted online. The primary purpose of this exploratory study was to investigate the impact of the online format on the discussion quality. Another purpose of the study was to examine students' perceptions of using VoiceThread for presenting and learning, as well as the online interactions between the presenter and audience. Students posted a higher number of questions and comments than required by the assignment. The questions from students were also higher level questions, and the answers to these questions were more thorough compared with what we had previously observed in classroom presentations. The survey results showed that students preferred using VoiceThread for presenting, learning from other presentations, and discussing presentation content over performing this process in the classroom. Preliminary findings suggested that having dental students make presentations and hold discussions online might help address the challenges of student presentations in the classroom.

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Evaluation of chest ultrasound integrated teaching of respiratory system physiology to medical students

Ultrasound imaging is a widely used diagnostic technique, whose integration in medical education is constantly growing. The aim of this study was to evaluate chest ultrasound usefulness in teaching respiratory system physiology, students' perception of chest ultrasound integration into a traditional lecture in human physiology, and short–term concept retention. A lecture about respiratory physiology was integrated with ultrasound and delivered to third-year medical students. It included basic concepts of ultrasound imaging and the physiology of four anatomic sectors of the body of a male volunteer, shown with a portable ultrasound device (pleural sliding, diaphragmatic movement, inferior vena cava diameter variations, cardiac movements). Students' perceptions of the integrated lecture were assessed, and attendance recorded. After 4 mo, four multiple-choice questions about respiratory physiology were administered during the normal human physiology examinations, and the results of students who attended the lesson and those of who did not were compared. One hundred thirty-four students attended the lecture. Most of them showed encouragement for the study of the subject and considered the ultrasound integrated lecture more interesting than a traditional one and pertinent to the syllabus. Exposed students achieved a better score at the examination and committed less errors than did nonexposed students. The chest ultrasound integrated lecture was appreciated by students. A possible association between the exposure to the lecture and short-term concept retention is shown by better performances of the exposed cohort at the examination. A systematic introduction of ultrasound into physiology traditional teaching will be promoted by the Ultrasound-Based Medical Education movement.

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Collective and experimental research project for masters students on the pathophysiology of obesity

We describe here a collective and experimental research project-based learning (ERPBL) for master's students that can be used to illustrate some basic concepts on glucose/lipid homeostasis and renal function around a topical issue. The primary objective of this ERPBL was to strengthen students' knowledge and understanding of physiology and pathophysiology. The secondary objectives were to help students to develop technical/practical abilities and acquire transversal skills with real-world connections. Obesity is a worldwide public health problem that increases the risk for developing type 2 diabetes and nephropathies. To study the impact of western dietary habits, students evaluated the effects of a diet enriched with fat and cola [high-fat and cola diet (HFCD)] on metabolism and renal function in mice. Students mainly worked in tandem to prepare and perform experiments, but also collectively to compile, analyze, and discuss data. Students showed that HFCD-fed mice 1) developed obesity; 2) exhibited glucose homeostasis impairments associated to ectopic fat storage; and 3) displayed reduced glomerular filtration. The educational benefit of the program was estimated using three evaluation metrics: a conventional multicriteria assessment by teachers, a pre-/posttest, and a self-evaluation questionnaire. They showed that the current approach successfully strengthened scientific student knowledge and understanding of physiology/pathophysiology. In addition, it helped students develop new skills, such as technical and transversal skills. We concluded that this ERPBL dealing with the pathophysiology of obesity was strongly beneficial for master's students, thereby appearing as an efficient and performing educational tool.

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The 2-hour marathon: what do students think?

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Optimizing Treatment for Cerebral Adrenoleukodystrophy in the Era of Gene Therapy

Adrenoleukodystrophy is a peroxisomal metabolic disorder that can be manifested by rapidly progressive cerebral demyelination (known as cerebral adrenoleukodystrophy) in affected boys and men. Untreated cerebral adrenoleukodystrophy causes severe disability or death approximately 2 years after its…

http://ift.tt/2xgEjFr

Comparison of Circulating miRNAs Expression Alterations in Matched Tissue and Plasma Samples During Colorectal Cancer Progression

Abstract

MicroRNAs (miRNAs) have been found to play a critical role in colorectal adenoma-carcinoma sequence. MiRNA-specific high-throughput arrays became available to detect promising miRNA expression alterations even in biological fluids, such as plasma samples, where miRNAs are stable. The purpose of this study was to identify circulating miRNAs showing altered expression between normal colonic (N), tubular adenoma (ADT), tubulovillous adenoma (ADTV) and colorectal cancer (CRC) matched plasma and tissue samples. Sixteen peripheral plasma and matched tissue biopsy samples (N n = 4; ADT n = 4; ADTV n = 4; CRC n = 4) were selected, and total RNA including miRNA fraction was isolated. MiRNAs from plasma samples were extracted using QIAamp Circulating Nucleic Acid Kit (Qiagen). Matched tissue-plasma miRNA microarray experiments were conducted by GeneChip® miRNA 3.0 Array (Affymetrix). RT-qPCR (microRNA Ready-to-use PCR Human Panel I + II; Exiqon) was used for validation. Characteristic miRNA expression alterations were observed in comparison of AD and CRC groups (miR-149*, miR-3196, miR-4687) in plasma samples. In the N vs. CRC comparison, significant overexpression of miR-612, miR-1296, miR-933, miR-937 and miR-1207 was detected by RT-PCR (p < 0.05). Similar expression pattern of these miRNAs were observed using microarray in tissue pairs, as well. Although miRNAs were also found in circulatory system in a lower concentration compared to tissues, expression patterns slightly overlapped between tissue and plasma samples. Detected circulating miRNA alterations may originate not only from the primer tumor but from other cell types including immune cells.

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Outcomes of treatment with sandblasted implants. a long-term clinical study

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Sedation options for implant surgery

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Low-invasive implant therapy with individualized dental implants

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An in vitro investigation of human gingival fibroblast proliferation on dental titanium implants treated with selective laser melting technology

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Postoperative discomfort after piezo vs conventional approach in bone grafting procedures

http://ift.tt/2ypJQcR

Tent pole Technique For Bone Regeneration Horizontal Deficient Alveolar Ridges: 4 Cases Report

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The full digital workflow

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Volumetric bone maintenance of guided bone regeneration in implant dentistry

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Is conventional still future – oriented?

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Single implant placement in the aesthetic area: immediate loading versus traditional delayed: surgical approach and 5 years long term evaluation

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Which is the best antibiotic prophylaxis protocol to prevent early implant failures? A systematic review and network meta-analysis

http://ift.tt/2yoXJIi

Effects of Angelica Sinensis extract on proliferation and differentiation of rat bone marrow mesenchymal stem cells

http://ift.tt/2xhVBgp

Improving biomechanics in removable partial dentures with implants. Clinical report -8 years follow-up

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Survival rate of imPlasa dental implant system: long-term results

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Socket preservation using a resorbable in situ hardening alloplastic graft: a case series with a four-year follow up

http://ift.tt/2ypJmn3

Immediate and early loading of tapered implants in extraction sites: 10-year retrospective follow-up

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Impact of abutment material and soft tissue thickness on mucosa discoloration: a spectrophotometric in vitro study

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An open randomized controlled clinical trial to evaluate ridge preservation and repair using SocketKAPTM and SocketKAGETM: histological and histomorphometric analyses

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The effect of fibronectin derived fibrin-binding peptide fragments on periodontal ligament cell migration: an in vitro wound healing model

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Clinical outcome of dental implants in vascularized fibular osteoseptocutaneous flap as onlay graft on marginal mandibulectomy patients

http://ift.tt/2xhVykJ

Acute undifferentiated fever in India: a multicentre study of aetiology and diagnostic accuracy

The objectives of this study were to determine the proportion of malaria, bacteraemia, scrub typhus, leptospirosis, chikungunya and dengue among hospitalized patients with acute undifferentiated fever in India...

http://ift.tt/2y0jdtR

Phenotypic and genotypic characterization of antibiotic resistance of methicillin-resistant Staphylococcus aureus isolated from hospital food

Pathogenic biotypes of the Methicillin-resistant Staphylococcus aureus (MRSA) strains are considered to be one of the major cause of food-borne diseases in hospitals. The present investigation was done to study t...

http://ift.tt/2yqnqIE

A collaborative in-situ simulation-based pediatric readiness improvement program for community emergency departments

Abstract

Background

More than 30 million children are cared for across 5,000 US emergency departments each year (ED). Most of these EDs are not facilities designed and operated solely for children. A web-based survey provided a national and state-by-state assessment of pediatric readiness and noted a national average score was 69 on a 100-point scale. This survey noted wide variations in ED readiness with scores ranging from 61 in low-pediatric-volume EDs to 90 in the high-pediatric-volume EDs. Additionally, the mean score at the state level ranged from 57 (Wyoming) to 83 (Florida) and for individual EDs ranged from 22 to 100. The majority of prior efforts made to improve pediatric readiness have involved providing web-based resources and online toolkits. This paper reports on the first year of a program that aimed to improve pediatric readiness across community hospitals in our state through in situ simulation-based assessment facilitated by our academic medical center. The primary aim was to improve the pediatric readiness scores in the ten participating hospitals. The secondary aim was to explore the correlation of simulation-based performance of hospital teams with pediatric readiness scores.

Methods

This interventional study measured the PRS prior to and after implementation of an improvement program. This program consisted of three components: (1) in-situ simulations; (2) report outs; and (3) access to online pediatric readiness resources and content experts. The simulations were conducted in situ (in the ED resuscitation bay) by multi-professional teams of doctors, nurses, respiratory therapists and technicians. Simulations and debriefings were facilitated by an expert team from a pediatric academic medical center. Three scenarios were conducted for all teams and include: a six-month-old with respiratory failure, an eight-year-old with diabetic ketoacidosis (DKA), and a six-month-old with supraventricular tachycardia (SVT). A performance score was calculated for each scenario. The improvement of PRS was compared before and after the simulation program. The correlation of the simulation performance of each hospital and the PRS was calculated.

Results

41 multi-professional teams from ten EDs in Indiana participated in the study, five were of medium pediatric volume and five were medium-high volume EDs. The PRS significantly improved from the first to the second on-site verification assessment (58.4±4.8 to 74.7±2.9, p=0.009). Total adherence scores to scenario guidelines were: 54.7%, 56.4% and 62.4% in the respiratory failure, DKA and SVT scenarios respectively. We found no correlation between simulation performance and PRS scores. Medium ED pediatric volume significantly predicted higher PRS scores compared to medium-high pediatric ED volume (β=8.7; CI: 0.72, 16.8, p=0.034).

Conclusion(s)

Our collaborative improvement program that involved simulation was associated with improvement in pediatric readiness scores in ten EDs participating statewide. Future work will focus on further expanding of the network and establishing a national model for pediatric readiness improvement.

This article is protected by copyright. All rights reserved.

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Spondylodiskitis and endocarditis due to Streptococcus gordonii

Streptococcus gordonii is an infrequent cause of infective endocarditis (IE); associated spondylodiskitis has not yet been described in the literature.

http://ift.tt/2xfYTG1

Developmental origin of long-range neurons in the superficial dorsal spinal cord

Abstract

The dorsal spinal cord, which is essential for somatosensory transmission, comprises a heterogeneous population of neurons with distinct axonal lengths and projection patterns. Although the developmental origin of local-circuit interneurons in the dorsal spinal cord has been well characterized, that of long-range neurons extending axons over a long distance such as supraspinal projection neurons and propriospinal neurons is largely unknown. In the present study, we performed birthdate and lineage analyses of these long-range neurons in the mouse dorsal spinal cord. Unilateral injection of a retrograde neuronal tracer, cholera toxin B, into the brain or spinal cord efficiently labeled supraspinal projection neurons localized in Rexed's lamina I and the dorsolateral funiculus (DLF) and long-range propriospinal neurons localized in the DLF, all of which had ipsi- and contra-laterally projecting populations. Most of these neurons were born between E9.5 and E10.5, much earlier than in the case of the neurogenesis of local-circuit neurons. Lineage analysis using an Lbx1-Cre mouse line demonstrated that most long-range neurons were derived from Lbx1-positive neuronal progenitors, except in the case of the contralaterally projecting propriospinal neurons. Characterization of their neurotransmitter identity revealed that almost all of the supraspinal projection neurons were excitatory, whereas the long-range propriospinal neurons comprised both excitatory and inhibitory populations. These results suggest that the supraspinal projection neurons were derived from the early-born dI5 progenitor domain and that the long-range propriospinal ones arose from several early-born progenitor domains.

This article is protected by copyright. All rights reserved.

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Sustained cell body reactivity and loss of NeuN in a subset of axotomized bulbospinal neurons after a chronic high cervical spinal cord injury

Abstract

Following central nervous system lesion, the ability of injured axons to regrowth may depend on the level and duration of the injured cell body response (CBR). Therefore, in order to investigate whether axotomized brainstem neurons maintain a durable growth-competent state after spinal cord injury, we studied the effect of a chronic C2 hemisection in rats on the expression of various CBR markers involved in axon regeneration, such as c-Jun, ATF-3, HSP27, NO synthase (NOS), and also of the neural mature phenotype marker NeuN, in the bulbospinal respiratory neurons as compared to the Gigantocellularis nucleus. Both at 7 and 30 days post-lesion (DPL), c-Jun and HSP27 were present in respectively ~60% and ~20% of the axotomized respiratory neurons, whereas the apoptotic factor caspase 3 was not detected in these cells. NOS appeared belatedly and it was detected in ~20% of the axotomized respiratory neurons at 30DPL. At 30DPL, these different CBR markers were strongly colocalized in a sub-population of axotomized respiratory neurons and also in a sub-population of injured neurons within the gigantocellularis nucleus. Such CBR was also accompanied by a sustained alteration of the neural mature phenotype, as indicated by a loss of NeuN immunoreactivity selectively in HSP27⁺ bulbospinal neurons at 7DPL and 30DPL. Altogether, this study shows that a subset of axotomized medullary respiratory neurons remains in a growth-competent state after a chronic injury, suggesting that they may play a preferential role in long-lasting respiratory neuroplasticity processes.

This article is protected by copyright. All rights reserved.

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Mechanisms, pathophysiological roles, and methods for analyzing mitophagy – recent insights

Authors: Williams, Jessica A. / Ding, Wen-Xing


http://ift.tt/2y1FQ1a

The dinoponeratoxin peptides from the giant ant Dinoponera quadriceps display in vitro antitrypanosomal activity

Authors: Bandeira Lima, Dânya / Perdigão Mello, Clarissa / Justino Bandeira, Izabel Cristina / Pessoa Bezerra de Menezes, Ramon Róseo Paula / Lima Sampaio, Tiago / Borges Falcão, Cláudio / Morlighem, Jean-Étienne R. L. / Rádis-Baptista, Gandhi / Costa Martins, Alice Maria


http://ift.tt/2gc9Ca1

How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

Authors: Zimmermann, Marcel / Reichert, Andreas S.


http://ift.tt/2y0sFxC

Domain topology of human Rasal

Authors: Cuellar, Jorge / Valpuesta, José María / Wittinghofer, Alfred / Sot, Begoña


http://ift.tt/2gc9zel

Cystine knot growth factors and their functionally versatile proregions

Authors: Schwarz, Elisabeth


http://ift.tt/2x7jETN

Frontmatter

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Tissue kallikrein-related peptidase 4 (KLK4), a novel biomarker in triple-negative breast cancer

Authors: Yang, Feng / Aubele, Michaela / Walch, Axel / Gross, Eva / Napieralski, Rudolf / Zhao, Shuo / Ahmed, Nancy / Kiechle, Marion / Reuning, Ute / Dorn, Julia / Sweep, Fred / Magdolen, Viktor / Schmitt, Manfred


http://ift.tt/2y2W0Yp

I36T↑T mutation in South African subtype C (C-SA) HIV-1 protease significantly alters protease-drug interactions

Authors: Maseko, Sibusiso B. / Padayachee, Eden / Govender, Thavendran / Sayed, Yasien / Kruger, Gert / Maguire, Glenn E.M. / Lin, Johnson


http://ift.tt/2y0AvYa

Galanin suppresses proliferation of human U251 and T98G glioma cells via its subtype 1 receptor

Authors: Mei, Zhu / Yang, Yutao / Li, Yun / Yang, Feiya / Li, Junfa / Xing, Nianzeng / Xu, Zhi-Qing David


http://ift.tt/2gaY1YI

Role of sigma 1 receptor in high fat diet-induced peripheral neuropathy

Authors: Song, Tieying / Zhao, Jianhui / Ma, Xiaojing / Zhang, Zaiwang / Jiang, Bo / Yang, Yunliang


http://ift.tt/2gaXRk4

Targeting and inactivation of bacterial toxins by human defensins

Authors: Kudryashova, Elena / Seveau, Stephanie M. / Kudryashov, Dmitri S.


http://ift.tt/2y1Fd7O

Aeromonas sobria serine protease (ASP): a subtilisin family endopeptidase with multiple virulence activities

Authors: Imamura, Takahisa / Murakami, Yoji / Nitta, Hidetoshi


http://ift.tt/2gc9abP

Catalase, a remarkable enzyme: targeting the oldest antioxidant enzyme to find a new cancer treatment approach

Authors: Glorieux, Christophe / Calderon, Pedro Buc


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S100A6 – focus on recent developments

Authors: Leśniak, Wiesława / Wilanowski, Tomasz / Filipek, Anna


http://ift.tt/2gaXDte

Mutation of N-linked glycosylation in EpCAM affected cell adhesion in breast cancer cells

Authors: Liu, Xue / Gao, Jiujiao / Sun, Yan / Zhang, Dandan / Liu, Tingjiao / Yan, Qiu / Yang, Xuesong


http://ift.tt/2y1F0l2

Quantitative Image Restoration in Bright Field Optical Microscopy

Bright field (BF) optical microscopy is regarded as a poor method to observe unstained biological samples due to intrinsic low image contrast. We introduce quantitative image restoration in bright field (QRBF), a digital image processing method that restores out-of-focus BF images of unstained cells. Our procedure is based on deconvolution, using a point spread function modeled from theory. By comparing with reference images of bacteria observed in fluorescence, we show that QRBF faithfully recovers shape and enables quantify size of individual cells, even from a single input image.

http://ift.tt/2xZ3J9b

Resveratrol enhances anticancer effects of paclitaxel in HepG2 human liver cancer cells

The aim of this in vitro study was to measure the enhanced anticancer effects of Res (resveratrol) on PA (paclitaxel) in HepG2 human liver cancer cells.

http://ift.tt/2xSk1Si

Unravelling cortical pathology in multiple sclerosis using the T1-/T2-weighted ratio?

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Reply to: Concussion may not cause multiple sclerosis

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Docosahexaenoic acid (DHA) is a beneficial replacement treatment for Spinocerebellar Ataxia 38 (SCA38)

Abstract

Objective: Spinocerebellar Ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsatured fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects.

In the present study, we evaluated the safety and efficacy of DHA supplementation on clinical symptoms and changes of brain functional imaging in SCA38 patients.

Methods: We enrolled ten SCA38 patients, and we carried out a double-blind randomised placebo-controlled study for 16 weeks, followed by an open-label study with overall 40-week DHA treatment. At baseline, and at follow-up visit, patients underwent standardised clinical assessment, brain 18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET), electroneurography (ENG), and ELOVL5 expression analysis.

Results: After 16 weeks, we showed a significant pre-post clinical improvement in the DHA group vs. placebo (mean difference, MD), using the Scale for the Assessment and Rating of Ataxia (SARA) (MD=+2.70, 95%CI: +0.13 to +5.27, p=0.042). At 40-week treatment, clinical improvement was found significant both in SARA (MD=+2.2, 95%CI: +0.93 to +3.46, p=0.008) and International Cooperative Ataxia Rating Scale (ICARS) (MD= +3.8, 95%CI: +1.39 to +6.41, p=0.02) scores; clinical data were corroborated by significant improvement of cerebellar hypometabolism (statistical parametric mapping analyses, False Discovery Rate corrected). We also showed a decreased expression of ELOVL5 in patients' blood at 40 weeks as compared to baseline. No side effect was recorded.

Interpretation: DHA supplementation is a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism. This article is protected by copyright. All rights reserved.

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Concussion may not cause multiple sclerosis

http://ift.tt/2fROGbc

Quantitative Image Restoration in Bright Field Optical Microscopy

Bright field (BF) optical microscopy is regarded as a poor method to observe unstained biological samples due to intrinsic low image contrast. We introduce quantitative image restoration in bright field (QRBF), a digital image processing method that restores out-of-focus BF images of unstained cells. Our procedure is based on deconvolution, using a point spread function modeled from theory. By comparing with reference images of bacteria observed in fluorescence, we show that QRBF faithfully recovers shape and enables quantify size of individual cells, even from a single input image.

http://ift.tt/2xZ3J9b

How Human Amygdala and Bed Nucleus of the Stria Terminalis May Drive Distinct Defensive Responses

The ability to adaptively regulate responses to the proximity of potential danger is critical to survival and imbalance in this system may contribute to psychopathology. The bed nucleus of the stria terminalis (BNST) is implicated in defensive responding during uncertain threat anticipation whereas the amygdala may drive responding upon more acute danger. This functional dissociation between the BNST and amygdala is however controversial, and human evidence scarce. Here we used data from two independent functional magnetic resonance imaging studies [n = 108 males and n = 70 (45 females)] to probe how coordination between the BNST and amygdala may regulate responses during shock anticipation and actual shock confrontation. In a subset of participants from Sample 2 (n = 48) we demonstrate that anticipation and confrontation evoke bradycardic and tachycardic responses, respectively. Further, we show that in each sample when going from shock anticipation to the moment of shock confrontation neural activity shifted from a region anatomically consistent with the BNST toward the amygdala. Comparisons of functional connectivity during threat processing showed overlapping yet also consistently divergent functional connectivity profiles for the BNST and amygdala. Finally, childhood maltreatment levels predicted amygdala, but not BNST, hyperactivity during shock anticipation. Our results support an evolutionary conserved, defensive distance-dependent dynamic balance between BNST and amygdala activity. Shifts in this balance may enable shifts in defensive reactions via the demonstrated differential functional connectivity. Our results indicate that early life stress may tip the neural balance toward acute threat responding and via that route predispose for affective disorder.

SIGNIFICANCE STATEMENT Previously proposed differential contributions of the BNST and amygdala to fear and anxiety have been recently debated. Despite the significance of understanding their contributions to defensive reactions, there is a paucity of human studies that directly compared these regions on activity and connectivity during threat processing. We show strong evidence for a dissociable role of the BNST and amygdala in threat processing by demonstrating in two large participant samples that they show a distinct temporal signature of threat responding as well as a discriminable pattern of functional connections and differential sensitivity to early life threat.

http://ift.tt/2yXSM6p

Nigral Glutamatergic Neurons Control the Speed of Locomotion

The mesencephalic locomotor region (MLR) plays a crucial role in locomotor control. In vertebrates, stimulation of the MLR at increasing intensities elicits locomotion of growing speed. This effect has been presumed to result from higher brain inputs activating the MLR like a dimmer switch. Here, we show in lampreys (Petromyzon marinus) of either sex that incremental stimulation of a region homologous to the mammalian substantia nigra pars compacta (SNc) evokes increasing activation of MLR cells with a graded increase in the frequency of locomotor movements. Neurons co-storing glutamate and dopamine were found to project from the primal SNc to the MLR. Blockade of glutamatergic transmission largely diminished MLR cell responses and locomotion. Local blockade of D₁ receptors in the MLR decreased locomotor frequency, but did not disrupt the SNc-evoked graded control of locomotion. Our findings revealed the presence of a glutamatergic input to the MLR originating from the primal SNc that evokes graded locomotor movements.

SIGNIFICANCE STATEMENT The mesencephalic locomotor region (MLR) plays a crucial role in the control of locomotion. It projects downward to reticulospinal neurons that in turn activate the spinal locomotor networks. Increasing the intensity of MLR stimulation produces a growing activation of reticulospinal cells and a progressive increase in the speed of locomotor movements. Since the discovery of the MLR some 50 years ago, it has been presumed that higher brain regions activate the MLR in a graded fashion, but this has not been confirmed yet. Here, using a combination of techniques from cell to behavior, we provide evidence of a new glutamatergic pathway activating the MLR in a graded fashion, and consequently evoking a progressive increase in locomotor output.

http://ift.tt/2yYsroD

Digenic inheritance and genetic modifiers

Abstract

Digenic inheritance (DI) concerns pathologies with the simplest form of multigenic aetiology, implicating more than one gene (and perhaps the environment). True DI is when biallelic or even triallelic mutations in two distinct genes, in cis or in trans, are necessary and sufficient to cause pathology with a defined diagnosis. In true DI, a heterozygous mutation in each of two genes alone is not associated with a recognizable phenotype. Well-documented diseases with true DI are so far rare and follow non-Mendelian inheritance. DI is also encountered when by serendipity, pathogenic mutations responsible for two distinct disease entities are co-inherited, leading to a mixed phenotype. Also, we can consider many true monogenic Mendelian conditions, which demonstrate impressively broad spectrum of phenotypes due to pseudo-DI, as a result of co-inheriting genetic modifiers (GM). I am herewith reviewing examples of GM and embark on presenting some recent notable examples of true DI, with wider discussion of the literature. Undeniably, the advent of high throughput sequencing is bound to unravel more patients suffering with true DI conditions and elucidate many important GM, thus impacting precision medicine.

http://ift.tt/2fIOyHa

Unraveling the Solution-State Supramolecular Structures of Donor–Acceptor Polymers and their Influence on Solid-State Morphology and Charge-Transport Properties

Abstract

Polymer self-assembly in solution prior to film fabrication makes solution-state structures critical for their solid-state packing and optoelectronic properties. However, unraveling the solution-state supramolecular structures is challenging, not to mention establishing a clear relationship between the solution-state structure and the charge-transport properties in field-effect transistors. Here, for the first time, it is revealed that the thin-film morphology of a conjugated polymer inherits the features of its solution-state supramolecular structures. A "solution-state supramolecular structure control" strategy is proposed to increase the electron mobility of a benzodifurandione-based oligo(p-phenylene vinylene) (BDOPV)-based polymer. It is shown that the solution-state structures of the BDOPV-based conjugated polymer can be tuned such that it forms a 1D rod-like structure in good solvent and a 2D lamellar structure in poor solvent. By tuning the solution-state structure, films with high crystallinity and good interdomain connectivity are obtained. The electron mobility significantly increases from the original value of 1.8 to 3.2 cm² V⁻¹ s⁻¹. This work demonstrates that "solution-state supramolecular structure" control is critical for understanding and optimization of the thin-film morphology and charge-transport properties of conjugated polymers.

A supramolecular self-assembly strategy is used to control the solution-state structure of a conjugated polymer. It is revealed that the thin-film morphology of the conjugated polymer inherits the features of their solution-state supramolecular structures. Through "solution-state supramolecular structure control", the electron mobility of the polymer is boosted to 3.2 cm² V⁻¹ s⁻¹, nearly doubling the original performance.

http://ift.tt/2hO9mBu

Surface-Embedded Stretchable Electrodes by Direct Printing and their Uses to Fabricate Ultrathin Vibration Sensors and Circuits for 3D Structures

Printing is one of the easy and quick ways to make a stretchable wearable electronics. Conventional printing methods deposit conductive materials "on" or "inside" a rubber substrate. The conductors made by such printing methods cannot be used as device electrodes because of the large surface topology, poor stretchability, or weak adhesion between the substrate and the conducting material. Here, a method is presented by which conductive materials are printed in the way of being surface-embedded in the rubber substrate; hence, the conductors can be widely used as device electrodes and circuits. The printing process involves a direct printing of a metal precursor solution in a block-copolymer rubber substrate and chemical reduction of the precursor into metal nanoparticles. The electrical conductivity and sensitivity to the mechanical deformation can be controlled by adjusting the number of printing operations. The fabrication of highly sensitive vibration sensors is thus presented, which can detect weak pulses and sound waves. In addition, this work takes advantage of the viscoelasticity of the composite conductor to fabricate highly conductive stretchable circuits for complicated 3D structures. The printed electrodes are also used to fabricate a stretchable electrochemiluminescence display.

Stretchable electrodes surface-embedded in rubber substrates are fabricated by a simple printing strategy. The process involves printing of a metal precursor and chemical reduction into metal nanoparticles. These printed electrodes are used as highly sensitive free-standing thin-film vibration sensors and highly stretchable electrical circuits for 3D structures.

http://ift.tt/2kkdrOA

Efficient Semitransparent Organic Solar Cells with Tunable Color enabled by an Ultralow-Bandgap Nonfullerene Acceptor

Abstract

Semitransparent organic solar cells (OSCs) show attractive potential in power-generating windows. However, the development of semitransparent OSCs is lagging behind opaque OSCs. Here, an ultralow-bandgap nonfullerene acceptor, "IEICO-4Cl", is designed and synthesized, whose absorption spectrum is mainly located in the near-infrared region. When IEICO-4Cl is blended with different polymer donors (J52, PBDB-T, and PTB7-Th), the colors of the blend films can be tuned from purple to blue to cyan, respectively. Traditional OSCs with a nontransparent Al electrode fabricated by J52:IEICO-4Cl, PBDB-T:IEICO-4Cl, and PTB7-Th:IEICO-4Cl yield power conversion efficiencies (PCE) of 9.65 ± 0.33%, 9.43 ± 0.13%, and 10.0 ± 0.2%, respectively. By using 15 nm Au as the electrode, semitransparent OSCs based on these three blends also show PCEs of 6.37%, 6.24%, and 6.97% with high average visible transmittance (AVT) of 35.1%, 35.7%, and 33.5%, respectively. Furthermore, via changing the thickness of Au in the OSCs, the relationship between the transmittance and efficiency is studied in detail, and an impressive PCE of 8.38% with an AVT of 25.7% is obtained, which is an outstanding value in the semitransparent OSCs.

A new nonfullerene acceptor, IEICO-4Cl, is designed to prepare semitransparent organic solar cells (OSCs), yielding a power conversion efficiency of 8.38% with an average visible transmittance of 25.7%, which is among the top results for semitransparent OSCs.

http://ift.tt/2hNes0Y

Electrically Driven Reversible Phase Changes in Layered In2Se3 Crystalline Film

Abstract

An unconventional phase-change memory (PCM) made of In₂Se₃, which utilizes reversible phase changes between a low-resistance crystalline β phase and a high-resistance crystalline γ phase is reported for the first time. Using a PCM with a layered crystalline film exfoliated from In₂Se₃ crystals on a graphene bottom electrode, it is shown that SET/RESET programmed states form via the formation/annihilation of periodic van der Waals' (vdW) gaps (i.e., virtual vacancy layers) in the stack of atomic layers and the concurrent reconfiguration of In and Se atoms across the layers. From density functional theory calculations, β and γ phases, characterized by octahedral bonding with vdW gaps and tetrahedral bonding without vdW gaps, respectively, are shown to have energy bandgap value of 0.78 and 1.86 eV, consistent with a metal-to-insulator transition accompanying the β-to-γ phase change. The monolithic In₂Se₃ layered film reported here provides a novel means to achieving a PCM based on melting-free, low-entropy phase changes in contrast with the GeTe–Sb₂Te₃ superlattice film adopted in interfacial phase-change memory.

Reversible crystalline–crystalline phase-change memories are developed by stacking In₂Se₃ on the bottom graphene electrode. This shows SET and RESET programmed states via formation and annihilation of periodic van der Waals' gaps. The reversible transition of monolithic In₂Se₃ layered film demonstrates the potential of melting-free and low-entropy phase-change memories.

http://ift.tt/2fJTYBT

AIE Nanoparticles with High Stimulated Emission Depletion Efficiency and Photobleaching Resistance for Long-Term Super-Resolution Bioimaging

Abstract

Stimulated emission depletion (STED) nanoscopy is a typical super-resolution imaging technique that has become a powerful tool for visualizing intracellular structures on the nanometer scale. Aggregation-induced emission (AIE) luminogens are ideal fluorescent agents for bioimaging. Herein, long-term super-resolution fluorescence imaging of cancer cells, based on STED nanoscopy assisted by AIE nanoparticles (NPs) is realized. 2,3-Bis(4-(phenyl(4-(1,2,2-triphenylvinyl)phenyl)amino)phenyl) fumaronitrile (TTF), a typical AIE luminogen, is doped into colloidal mesoporous silica to form fluorescent NPs. TTF@SiO₂ NPs bear three significant features, which are all essential for STED nanoscopy. First, their STED efficiency can reach more than 60%. Second, they are highly resistant to photobleaching, even under long-term and high-power STED light irradiation. Third, they have a large Stokes' shift of ≈150 nm, which is beneficial for restraining the fluorescence background induced by the STED light irradiation. STED nanoscopy imaging of TTF@SiO₂-NPs-stained HeLa cells is performed, exhibiting a high lateral spatial resolution of 30 nm. More importantly, long-term (more than half an hour) super-resolution cell imaging is achieved with low fluorescence loss. Considering that AIE luminogens are widely used for organelle targeting, cellular mapping, and tracing, AIE-NPs-based STED nanoscopy holds great potential for many basic biomedical studies that require super-resolution and long-term imaging.

A star aggregation-induced emission luminogen is doped into silica nanoparticles, which serve as fluorescent probes for stimulated emission depletion (STED) nanoscopy imaging with a high lateral spatial resolution of 30 nm. The nanoparticles are highly resistant to photobleaching, even under long-term and high-power STED light irradiation. Consequently, super-resolution bioimaging is performed for more than half an hour, with low fluorescence loss.

http://ift.tt/2hOVUgZ

Phosphoinositide Diversity, Distribution, and Effector Function: Stepping Out of the Box

Phosphoinositides (PtdInsPs) modulate a plethora of functions including signal transduction and membrane trafficking. PtdInsPs are thought to consist of seven interconvertible species that localize to a specific organelle, to which they recruit a set of cognate effector proteins. Here, in reviewing the literature, we argue that this model needs revision. First, PtdInsPs can carry a variety of acyl chains, greatly boosting their molecular diversity. Second, PtdInsPs are more promiscuous in their localization than is usually acknowledged. Third, PtdInsP interconversion is likely achieved through kinase-phosphatase enzyme complexes that coordinate their activities and channel substrates without affecting bulk substrate population. Additionally, we contend that despite hundreds of PtdInsP effectors, our attention is biased toward few proteins. Lastly, we recognize that PtdInsPs can act to nucleate coincidence detection at the effector level, as in PDK1 and Akt. Overall, better integrated models of PtdInsP regulation and function are not only possible but needed.

Phosphoinositides (PtdInsPs) are lipids that control many cellular functions. However, the field of PtdInsP signaling is dominated by several dogmatic notions. Here, we offer an updated glimpse on the current state of the field regarding molecular diversity, localization, organization of modifying enzymes, effector types, and effector organization.

http://ift.tt/2xhvICs

Nanog Expression in Embryonic Stem Cells – An Ideal Model System to Dissect Enhancer Function

Embryonic stem cells (ESCs) are derived from the preimplantation embryo and can differentiate into virtually any other cell type (termed pluripotency), which is governed by lineage specific transcriptions factors (TFs) binding to cis regulatory elements (CREs) to mediate changes in gene expression. The reliance on transcriptional regulation to maintain pluripotency makes ESCs a valuable model to study the role of distal CREs such as enhancers in modulating gene expression to affect cell fate decisions. This review will highlight recent advance on transcriptional enhancers, focusing on studies performed in ESCs. In addition, we argue that the Nanog locus, which encodes for an ESC-critical TF, is particularly informative because it contains multiple co-regulated genes and enhancers in close proximity to one another. The unique landscape at Nanog permits the study of ongoing questions including whether multiple enhancers function additively versus synergistically, determinants of gene specificity, and cell-to-cell variability in gene expression.

Nanog encodes a transcription factor required to maintain ESC pluripotency. The Nanog locus is an ideal model to study enhancers because it contains multiple highly potent super-enhancers within a small region. Nanog and three super-enhancers (SE) are in close physical proximity but only two SEs are required for Nanog expression.

http://ift.tt/2fKO5UZ

Targeting Cysteine Thiols for in Vitro Site-specific Glycosylation of Recombinant Proteins

Biochemical and structural analyses of glycosylated proteins require relatively large amounts of homogeneous samples. Here, we present an efficient chemical method for site-specific glycosylation of recombinant proteins purified from bacteria by targeting reactive Cys thiols.

http://ift.tt/2fLxD71

Assay Development for High Content Quantification of Sod1 Mutant Protein Aggregate Formation in Living Cells

We describe a method to quantify the aggregation of misfolded proteins. Our protocol details lentiviral induced stable cell line generation, automated confocal imaging, and image analysis of protein aggregates. As an illustrative application, we studied the effect of small molecules in promoting SOD1 aggregation in a time- and dose-dependent manner.

http://ift.tt/2yorMQC

Building Double-decker Traps for Early Detection of Emerald Ash Borer

Effective traps to attract and capture the emerald ash borer (EAB) are a key element of detecting and managing this invasive pest. Double-decker traps, placed in full sun near ash trees, incorporate visual and olfactory cues and were more likely to capture EAB than other trap designs in field trials.

http://ift.tt/2fLxqkf

3D Microtissues for Injectable Regenerative Therapy and High-throughput Drug Screening

This protocol describes the fabrication of elastic 3D macroporous microcryogels by integrating microfabrication with cryogelation technology. Upon loading with cells, 3D microtissues are generated, which can be readily injected in vivo to facilitate regenerative therapy or assembled into arrays for in vitro high-throughput drug screening.

http://ift.tt/2ypUXmj

MRI for adenomyosis: a pictorial review

Abstract

Adenomyosis is defined as the presence of ectopic endometrial glands and stroma within the myometrium. It is a disease of the inner myometrium and results from infiltration of the basal endometrium into the underlying myometrium. Transvaginal ultrasonography (TVUS) and magnetic resonance imaging (MRI) are the main radiologic tools for this condition. A thickness of the junctional zone of at least 12 mm is the most frequent MRI criterion in establishing the presence of adenomyosis. Adenomyosis can appear as a diffuse or focal form. Adenomyosis is often associated with hormone-dependent lesions such as leiomyoma, deep pelvic endometriosis and endometrial hyperplasia/polyps. Herein, we illustrate the MRI findings of adenomyosis and associated conditions, focusing on their imaging pitfalls.

Teaching points

• Adenomyosis is defined as the presence of ectopic endometrium within the myometrium.

• MRI is an accurate tool for the diagnosis of adenomyosis and associated conditions.

• Adenomyosis can be diffuse or focal.

• The most established MRI finding is thickening of junctional zone exceeding 12 mm.

• High-signal intensity myometrial foci on T2- or T1-weighted images are also characteristic.

http://ift.tt/2xZ4fnH

Injectable facial fillers: imaging features, complications, and diagnostic pitfalls at MRI and PET CT

Abstract

Injectable fillers are widely used for facial rejuvenation, correction of disabling volumetric fat loss in HIV-associated facial lipoatrophy, Romberg disease, and post-traumatic facial disfiguring. The purpose of this article is to acquaint the reader with the anatomy of facial fat compartments, as well as with the properties and key imaging features of commonly used facial fillers, filler-related complications, interpretation pitfalls, and dermatologic conditions mimicking filler-related complications. The distribution of facial fillers is characteristic and depends on the anatomy of the superficial fat compartments. Silicone has signature MRI features, calcium hydroxyapatite has characteristic calcifications, whereas other injectable fillers have overlapping imaging features. Most fillers (hyaluronic acid, collagen, and polyalkylimide–polyacrylamide hydrogels) have signal intensity patterns compatible with high water content. On PET-CT, most fillers show physiologic high FDG uptake, which should not be confounded with pathology. Abscess, cellulitis, non-inflammatory nodules, and foreign body granulomas are the most common filler-related complications, and imaging can help in the differential diagnosis. Diffusion weighted imaging helps in detecting a malignant lesion masked by injected facial fillers. Awareness of imaging features of facial fillers and their complications helps to avoid misinterpretation of MRI, and PET-CT scans and facilitates therapeutic decisions in unclear clinical cases.

Key points

• Facial fillers are common incidental findings on MRI and PET-CT scans.

• They have a characteristic appearance and typical anatomic distribution

• Although considered as safe, facial filler injections are associated with several complications

• As they may mask malignancy, knowledge of typical imaging features is mandatory.

• MRI is a problem-solving tool for unclear cases.

http://ift.tt/2y04iQB

Breast cancer mammographic diagnosis performance in a public health institution: a retrospective cohort study

Abstract

Objectives

To evaluate the quality assurance of mammography results at a reference institution for the diagnosis and treatment of breast cancer in southern Brazil, based on the BIRADS (Breast Imaging Reporting and Data System) 5th edition recommendations for auditing purposes.

Materials and methods

Retrospective cohort and cross-sectional study with 4502 patients (9668 mammographies)) who underwent at least one or both breast mammographies throughout 2013 at a regional public hospital, linked to a federal public university. The results were followed until 31 December 2014, including true positives (TPs), true negatives (TNs), false positives (FPs), false negatives (FNs), positive predictive values (PPVs), negative predictive value (NPV), sensitivity and specificity, with a confidence interval of 95%.

Results

The study showed high quality assurance, particularly regarding sensitivity (90.22%) and specificity (92.31%). The overall positive predictive value (PPV) was 65.35%, and the negative predictive value (NPV) was 98.32%. The abnormal interpretation rate (recall rate) was 12.26%.

Conclusions

The results are appropriate when compared to the values proposed by the BIRADS 5th edition. Additionally, the study provided self-reflection considering our radiological practice, which is essential for improvements and collaboration regarding breast cancer detection. It may stimulate better radiological practice performance and continuing education, despite possible infrastructure and facility limitations.

Main Messages

• Accurate quality performance rates are possible despite financial and governmental limitations.

• Low-income institutions should develop standardised teamwork to improve radiological practice.

• Regular mammography audits may help to increase the quality of public health systems.

http://ift.tt/2fRiHbh

Phase I study of a chloroquine–gemcitabine combination in patients with metastatic or unresectable pancreatic cancer

Abstract

Purpose

Following a previously published pre-clinical validation, this phase I study evaluated the safety, maximum tolerated dose, anti-tumour activity and immune status of a gemcitabine–chloroquine combination as a first- or late-line treatment in patients with metastatic or unresectable pancreatic cancer.

Methods

In this 3 + 3 dose escalation study, patients received a single weekly standard dose of intravenous gemcitabine, followed by single weekly oral intake of 100, 200 or 300 mg of chloroquine. Tumour response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. Immune status was evaluated by RT-PCR to measure the relative expression of immune-related genes in peripheral blood mononuclear cells (PBMCs).

Results

Overall, nine patients [median age 72 years; interquartile range (IQR), 68–78 years] were treated. No dose-limiting toxicities as defined in the protocol were observed. Three patients experienced partial response, and two patients had stable disease. The median time to progression was 4 months (95% CI 0.8–7.2), and the median overall survival was 7.6 months (95% CI 5.3–9.9). Among 86 assayed immune genes, three were significantly differentially expressed in PBMCs from responding versus non-responding patients: interferon-gamma receptor-1, toll-like receptor 2, and beta-2 microglobulin.

Conclusions

The addition of chloroquine to gemcitabine was well tolerated and showed promising effects on the clinical response to the anti-cancer chemotherapy. Based on these initial results, the efficacy of the gemcitabine–chloroquine combination should be further assessed.

http://ift.tt/2xh7qUi

Memantine and Ketamine Differentially Alter NMDA Receptor Desensitization

Memantine and ketamine are clinically useful NMDA receptor (NMDAR) open channel blockers that inhibit NMDARs with similar potency and kinetics, but display vastly different clinical profiles. This discrepancy has been hypothesized to result from inhibition by memantine and ketamine of overlapping but distinct NMDAR subpopulations. For example, memantine but not ketamine may inhibit extrasynaptic NMDARs more effectively than synaptic NMDARs. However, the basis for preferential NMDAR inhibition depending on subcellular location has not been investigated systematically. We integrated recordings from heterologously expressed single NMDAR subtypes, kinetic modeling, and recordings of synaptically evoked NMDAR responses in acute brain slices to investigate mechanisms by which channel blockers may distinguish NMDAR subpopulations. We found that memantine and ketamine differentially alter NMDAR desensitization and that memantine stabilizes a Ca²⁺-dependent desensitized state. As a result, inhibition by memantine of GluN1/2A receptors in tsA201 cells and of native synaptic NMDARs in cortical pyramidal neurons from mice of either sex increased in conditions that enhanced intracellular Ca²⁺ accumulation. Therefore, differential inhibition by memantine and ketamine based on NMDAR location is likely to result from location dependence of the intensity and duration of NMDAR activation. Modulation of Ca²⁺-dependent NMDAR desensitization is an unexplored mechanism of inhibitory action with the potential to endow drugs with NMDAR selectivity that leads to superior clinical profiles. Our results suggest that designing compounds to target specific receptor states, rather than specific receptor types, may be a viable strategy for future drug development.

SIGNIFICANCE STATEMENT Memantine and ketamine are NMDA receptor (NMDAR) channel-blocking drugs with divergent clinical effects. Understanding mechanistically their differential actions may advance our understanding of nervous system disorders and suggest strategies for the design of more effective drugs. Here, we show that memantine and ketamine have contrasting effects on NMDAR desensitization. Ketamine binding decreases occupancy of desensitized states of the GluN1/2B NMDAR subtype. In contrast, memantine binding increases occupancy of GluN1/2A and native NMDAR desensitized states entered after accumulation of intracellular Ca²⁺, a novel inhibitory mechanism. These properties may contribute to inhibition of distinct NMDAR subpopulations by memantine and ketamine and help to explain their differential clinical effects. Our results suggest stabilization of Ca²⁺-dependent desensitized states as a new strategy for pharmaceutical neuroprotection.

http://ift.tt/2yYRWGv

Action Potential Broadening in Capsaicin-Sensitive DRG Neurons from Frequency-Dependent Reduction of Kv3 Current

Action potential (AP) shape is a key determinant of cellular electrophysiological behavior. We found that in small-diameter, capsaicin-sensitive dorsal root ganglia neurons corresponding to nociceptors (from rats of either sex), stimulation at frequencies as low as 1 Hz produced progressive broadening of the APs. Stimulation at 10 Hz for 3 s resulted in an increase in AP width by an average of 76 ± 7% at 22°C and by 38 ± 3% at 35°C. AP clamp experiments showed that spike broadening results from frequency-dependent reduction of potassium current during spike repolarization. The major current responsible for frequency-dependent reduction of overall spike-repolarizing potassium current was identified as Kv3 current by its sensitivity to low concentrations of 4-aminopyridine (IC₅₀ <100 μm) and block by the peptide inhibitor blood depressing substance I (BDS-I). There was a small component of Kv1-mediated current during AP repolarization, but this current did not show frequency-dependent reduction. In a small fraction of cells, there was a component of calcium-dependent potassium current that showed frequency-dependent reduction, but the contribution to overall potassium current reduction was almost always much smaller than that of Kv3-mediated current. These results show that Kv3 channels make a major contribution to spike repolarization in small-diameter DRG neurons and undergo frequency-dependent reduction, leading to spike broadening at moderate firing frequencies. Spike broadening from frequency-dependent reduction in Kv3 current could mitigate the frequency-dependent decreases in conduction velocity typical of C-fiber axons.

SIGNIFICANCE STATEMENT Small-diameter dorsal root ganglia (DRG) neurons mediating nociception and other sensory modalities express many types of potassium channels, but how they combine to control firing patterns and conduction is not well understood. We found that action potentials of small-diameter rat DRG neurons showed spike broadening at frequencies as low as 1 Hz and that spike broadening resulted predominantly from frequency-dependent inactivation of Kv3 channels. Spike width helps to control transmitter release, conduction velocity, and firing patterns and understanding the role of particular potassium channels can help to guide new pharmacological strategies for targeting pain-sensing neurons selectively.

http://ift.tt/2xZH10R

KLF9 and JNK3 Interact to Suppress Axon Regeneration in the Adult CNS

Neurons in the adult mammalian CNS decrease in intrinsic axon growth capacity during development in concert with changes in Krüppel-like transcription factors (KLFs). KLFs regulate axon growth in CNS neurons including retinal ganglion cells (RGCs). Here, we found that knock-down of KLF9, an axon growth suppressor that is normally upregulated 250-fold in RGC development, promotes long-distance optic nerve regeneration in adult rats of both sexes. We identified a novel binding partner, MAPK10/JNK3 kinase, and found that JNK3 (c-Jun N-terminal kinase 3) is critical for KLF9's axon-growth-suppressive activity. Interfering with a JNK3-binding domain or mutating two newly discovered serine phosphorylation acceptor sites, Ser106 and Ser110, effectively abolished KLF9's neurite growth suppression in vitro and promoted axon regeneration in vivo. These findings demonstrate a novel, physiologic role for the interaction of KLF9 and JNK3 in regenerative failure in the optic nerve and suggest new therapeutic strategies to promote axon regeneration in the adult CNS.

SIGNIFICANCE STATEMENT Injured CNS nerves fail to regenerate spontaneously. Promoting intrinsic axon growth capacity has been a major challenge in the field. Here, we demonstrate that knocking down Krüppel-like transcription factor 9 (KLF9) via shRNA promotes long-distance axon regeneration after optic nerve injury and uncover a novel and important KLF9–JNK3 interaction that contributes to axon growth suppression in vitro and regenerative failure in vivo. These studies suggest potential therapeutic approaches to promote axon regeneration in injury and other degenerative diseases in the adult CNS.

http://ift.tt/2xYIrIU

GATA3 is a reliable marker for neuroblastoma in limited samples, including FNA Cell Blocks, core biopsies, and touch imprints

BACKGROUND

Neuroblastomas (NBs) are the most common solid cancer of childhood and infancy; however, in poorly differentiated forms, they present diagnostic challenges. GATA3 has been implicated functionally in NB differentiation, and limited data support its use as an immunohistochemical biomarker for NBs in resection specimens.

METHODS

GATA3 was tested retrospectively in 30 consecutive archival NB samples, including archival cytopathology needle cores and cell blocks (n = 6), scant surgical biopsy specimens and 2-mm NB tissue cores (n = 16), and air-dried touch imprints (n = 8) to evaluate the utility of this marker. Immunostaining was performed per the institutional standard, Clinical Laboratory Improvement Amendments–compliant automated staining protocol. GATA3 nuclear staining was scored qualitatively for its intensity and proportion of positivity.

RESULTS

All 30 NB specimens showed diffuse nuclear positivity with GATA3. Each sample revealed either strong (n = 26) or moderate nuclear staining (n = 4) in more than 75% of NB cells, regardless of the presence or lack of stromata or necrosis or the degree of differentiation.

CONCLUSIONS

GATA3 is a reliable diagnostic marker for NBs not only in scant/limited surgical specimens but also in cytologic samples, including air-dried touch imprints, which have previously been undescribed for this marker. Cancer (Cancer Cytopathol) 2017. © 2017 American Cancer Society.

http://ift.tt/2ypP7Bp

California dreaming

The more the world changes, the more complex the knowledge necessary to care for cancer patients becomes. To maintain hope and to take full advantage of all that technology and science can offer, taking time with patients to understand and aid them has become ever more vital.

http://ift.tt/2hNSwCN

Cross-Sectional Location of Gastric Cancer Affects the Long-Term Survival of Patients as Tumor Invasion Deepens

Abstract

Background

The prognosis of gastric cancer is generally determined by tumor depth and lymph node metastasis, while the effect of cross-sectional tumor location on prognosis remains unclear.

Methods

This study recruited patients who had been diagnosed with gastric cancer and who underwent gastrectomy from 1989 to 2012. The cross-sectional locations of the gastric cancers were classified into four regions: the lesser (LC) and greater curvatures (GC), and anterior (AW) and posterior walls (PW).

Results

Overall, 4820 patients were enrolled in this study. The most common site of gastric cancer among the four cross-sectional locations was the LC (46.4%), while the proportions of PW (19.9%), AW (18.4%), and GC (15.4%) were similar. Overall survival differed statistically (p = 0.013) according to the cross-sectional location, and the 5-year overall survival of those with tumors with a GC location was significantly worse (p = 0.003) than for the other three locations. In subgroup multivariate analysis, GC location was an independent prognostic indicator for a worse clinical outcome at T stage 3–4b (hazard ratio 1.365, 95% confidence interval 1.150–1.620, p < 0.001). In addition, a GC gastric cancer had a higher recurrence rate in terms of peritoneal seeding compared with other locations.

Conclusions

The cross-sectional location of gastric cancer is associated with long-term survival. A GC location predicts a worse prognosis, especially in gastric cancer patients with deeper T stages.

http://ift.tt/2hPxJis

Pathologic Response to Preoperative Therapy as a Novel Prognosticator for Ampullary and Duodenal Adenocarcinoma

Abstract

Background

The prognostic impact of pathologic response to preoperative therapy on patients with duodenal adenocarcinoma (DA) and ampullary adenocarcinoma (AMPA) has not been established.

Methods

A retrospective review of 266 patients who underwent curative resection for DA (n = 97) or AMPA (n = 169) during 1993–2015 was performed. For patients who underwent preoperative therapy, the pathologic response was systematically evaluated and classified as major (0–49% of viable residual tumor cells) or minor (≥ 50% of viable residual tumor cells). Uni- and multivariable analyses were performed to identify predictors of pathologic response and disease-specific survival (DSS).

Results

For the 79 patients treated with preoperative therapy (DA: n = 34; AMPA: n = 45), concomitant use of radiation (80%, 67/79) was the sole independent predictor of major pathologic response (odds ratio [OR] 8.17; 95% confidence interval [CI] 1.85–58.2; P = 0.005). The patients with major pathologic response had a better 5-year DSS rate than the patients with minor pathologic response (DA: 65 vs 25%; P = 0.028; AMPA: 85 vs 43%; P = 0.016). In the multivariable analysis of DSS for the 79 patients who underwent preoperative therapy, major pathologic response was the sole predictor of improved DSS (hazard ratio [HR] 2.88; 95% CI 1.41–5.98; P = 0.004). In the multivariable analysis of DSS for the entire cohort, pathologic stage 2 or lower was the sole predictor of better DSS.

Conclusion

The major pathologic response to preoperative therapy predicted improved DSS after resection of DA and AMPA and might represent a new prognosticator after resection of DA and AMPA.

http://ift.tt/2xhlfC4