First-year weight loss with androgen-deprivation therapy increases risks of prostate cancer progression and prostate cancer-specific mortality: results from SEARCH.

Related Articles

First-year weight loss with androgen-deprivation therapy increases risks of prostate cancer progression and prostate cancer-specific mortality: results from SEARCH.

Cancer Causes Control. 2019 Jan 30;:

Authors: Griffin K, Csizmadi I, Howard LE, Pomann GM, Aronson WJ, Kane CJ, Amling CL, Cooperberg MR, Terris MK, Beebe-Dimmer J, Freedland SJ

Abstract
PURPOSE: We aimed to study the associations between androgen-deprivation therapy (ADT)-induced weight changes and prostate cancer (PC) progression and mortality in men who had undergone radical prostatectomy (RP).
METHODS: Data from the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort were used to study the associations between weight change approximately 1-year post-ADT initiation and metastases, castration-resistant prostate cancer (CRPC), all-cause mortality (ACM), and PC-specific mortality (PCSM) in 357 patients who had undergone RP between 1988 and 2014. We estimated hazard ratios (HR) and 95% confidence intervals (95% CI) using covariate-adjusted Cox regression models for associations between weight loss, and weight gains of 2.3 kg or more, and PC progression and mortality post-ADT.
RESULTS: During a median (IQR) follow-up of 81 (46-119) months, 55 men were diagnosed with metastases, 61 with CRPC, 36 died of PC, and 122 died of any cause. In multivariable analysis, weight loss was associated with increases in risks of metastases (HR 3.13; 95% CI 1.40-6.97), PCSM (HR 4.73; 95% CI 1.59-14.0), and ACM (HR 2.16; 95% CI 1.25-3.74) compared with mild weight gains of ≤ 2.2. Results were slightly attenuated but remained statistically significant in analyses that accounted for competing risks of non-PC death. Estimates for the associations between weight gains of ≥ 2.3 kg and metastases (HR 1.58; 95% CI 0.73-3.42), CRPC (HR 1.33; 95% CI 0.66-2.66), and PCSM (HR 2.44; 95% CI 0.84-7.11) were elevated, but not statistically significant.
CONCLUSIONS: Our results suggest that weight loss following ADT initiation in men who have undergone RP is a poor prognostic sign. If confirmed in future studies, testing ways to mitigate weight loss post-ADT may be warranted.

PMID: 30701374 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2sXB7tI

Back to the Colorectal Cancer Consensus Molecular Subtype Future.

Related Articles

Back to the Colorectal Cancer Consensus Molecular Subtype Future.

Curr Gastroenterol Rep. 2019 Jan 30;21(2):5

Authors: Menter DG, Davis JS, Broom BM, Overman MJ, Morris J, Kopetz S

Abstract
PURPOSE OF REVIEW: This review seeks to provide an informed prospective on the advances in molecular profiling and analysis of colorectal cancer (CRC). The goal is to provide a historical context and current summary on how advances in gene and protein sequencing technology along with computer capabilities led to our current bioinformatic advances in the field.
RECENT FINDINGS: An explosion of knowledge has occurred regarding genetic, epigenetic, and biochemical alterations associated with the evolution of colorectal cancer. This has led to the realization that CRC is a heterogeneous disease with molecular alterations often dictating natural history, response to treatment, and outcome. The consensus molecular subtypes (CMS) classification classifies CRC into four molecular subtypes with distinct biological characteristics, which may form the basis for clinical stratification and subtype-based targeted intervention. This review summarizes new developments of a field moving "Back to the Future." CRC molecular subtyping will better identify key subtype specific therapeutic targets and responses to therapy.

PMID: 30701321 [PubMed - in process]

from A via a.sfakia on Inoreader http://bit.ly/2HLdvCW

Mass spectrometry-based absolute quantification of 20S proteasome status for controlled ex-vivo expansion of Human Adipose-derived Mesenchymal Stromal/Stem Cells.

Related Articles

Mass spectrometry-based absolute quantification of 20S proteasome status for controlled ex-vivo expansion of Human Adipose-derived Mesenchymal Stromal/Stem Cells.

Mol Cell Proteomics. 2019 Jan 30;:

Authors: Menneteau T, Fabre B, Garrigues L, Stella A, Zivkovic D, Roux-Dalvai F, Mouton-Barbosa E, Beau M, Renoud ML, Amalric F, Sensebe L, Gonzalez-de-Peredo A, Ader I, Burlet-Schiltz O, Bousquet MP

Abstract
The proteasome controls a multitude of cellular processes through protein degradation and has been identified as a therapeutic target in oncology. However, our understanding of its function and the development of specific modulators are hampered by the lack of a straightforward method to determine the overall proteasome status in biological samples. Here, we present a method to determine the absolute quantity and stoichiometry of ubiquitous and tissue-specific human 20S proteasome subtypes based on a robust, absolute SILAC-based multiplexed LC-Selected Reaction Monitoring (SRM) quantitative mass spectrometry assay with high precision, accuracy, and sensitivity. The method was initially optimized and validated by comparison with a reference ELISA assay and by analyzing the dynamics of catalytic subunits in HeLa cells following IFNγ-treatment and in range of human tissues. It was then successfully applied to reveal IFNγ- and O2-dependent variations of proteasome status during primary culture of Adipose-derived-mesenchymal Stromal/Stem Cells (ADSCs). The results show the critical importance of controlling the culture conditions during cell expansion for future therapeutic use in humans. We hypothesize that a shift from the standard proteasome to the immunoproteasome could serve as a predictor of immunosuppressive and differentiation capacities of ADSCs and, consequently, that quality control should include proteasomal quantification in addition to examining other essential cell parameters. The method presented also provides a new powerful tool to conduct more individualized protocols in cancer or inflammatory diseases where selective inhibition of the immunoproteasome has been shown to reduce side effects.

PMID: 30700495 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2Sn6096

Cruciferous Vegetables, Isothiocyanates, and Bladder Cancer Prevention.

Related Articles

Cruciferous Vegetables, Isothiocyanates, and Bladder Cancer Prevention.

Mol Nutr Food Res. 2018 09;62(18):e1800079

Authors: Abbaoui B, Lucas CR, Riedl KM, Clinton SK, Mortazavi A

Abstract
Bladder cancer is a significant health burden due to its high prevalence, risk of mortality, morbidity, and high cost of medical care. Epidemiologic evidence suggests that diets rich in cruciferous vegetables, particularly broccoli, are associated with lower bladder cancer risk. Phytochemicals in cruciferous vegetables, such as glucosinolates, which are enzymatically hydrolyzed to bioactive isothiocyanates, are possible mediators of an anticancer effect. In vitro studies have shown inhibition of bladder cancer cell lines, cell cycle arrest, and induction of apoptosis by these isothiocyanates, in particular sulforaphane and erucin. Although not yet completely understood, many mechanisms of anticancer activity at the steps of cancer initiation, promotion, and progression have been attributed to these isothiocyanates. They target multiple pathways including the adaptive stress response, phase I/II enzyme modulation, pro-growth, pro-survival, pro-inflammatory signaling, angiogenesis, and even epigenetic modulation. Multiple in vivo studies have shown the bioavailability of isothiocyanates and their antitumoral effects. Although human studies are limited, they support oral bioavailability with reasonable plasma and urine concentrations achieved. Overall, both cell and animal studies support a potential role for isothiocyanates in bladder cancer prevention and treatment. Future studies are necessary to examine clinically relevant outcomes and define guidelines on ameliorating the bladder cancer burden.

PMID: 30079608 [PubMed - indexed for MEDLINE]

from A via a.sfakia on Inoreader http://bit.ly/2sXAXT8

The Role of Cruciferous Vegetables and Isothiocyanates for Lung Cancer Prevention: Current Status, Challenges, and Future Research Directions.

Related Articles

The Role of Cruciferous Vegetables and Isothiocyanates for Lung Cancer Prevention: Current Status, Challenges, and Future Research Directions.

Mol Nutr Food Res. 2018 09;62(18):e1700936

Authors: Zhang Z, Bergan R, Shannon J, Slatore CG, Bobe G, Takata Y

Abstract
Lung cancer remains a leading cause of cancer-related deaths in the United States. Although smoking and air pollution exposure are primary risk factors of lung cancer, diet has also been reported to contribute to lung cancer risk. Cruciferous vegetables contain many bioactive compounds that alter the detoxification process of air-borne carcinogenic compounds and, thereby, may decrease lung cancer risk. In the meta-analysis of 31 observational studies, cruciferous vegetable intake is inversely associated with lung cancer risk (summary odds ratio/relative risk = 0.81 and 95% confidence interval = 0.74-0.89 for comparing the highest with lowest intake categories). More observational studies need to measure urinary isothiocyanate (ITC) concentrations and investigate their association with lung cancer risk in populations with relatively high intake of cruciferous vegetables. Current evidence is limited to two phase 2 clinical trials with incomplete reporting. Hence, more short-term clinical phase 2 trials need to examine effects of various amounts and types of cruciferous vegetables on biomarkers of risk and efficacy before a large phase 3 trial can be conducted to assess effects upon lung cancer risk. This would help further elucidate whether the inverse association observed with self-reported cruciferous vegetable intake is indeed due to ITC content or other bioactive compounds.

PMID: 29663679 [PubMed - indexed for MEDLINE]

from A via a.sfakia on Inoreader http://bit.ly/2HKvzx5

Mind-Body Interventions for Individuals With Heart Failure: A Systematic Review of Randomized Trials.

Related Articles

Mind-Body Interventions for Individuals With Heart Failure: A Systematic Review of Randomized Trials.

J Card Fail. 2018 Mar;24(3):186-201

Authors: Gok Metin Z, Ejem D, Dionne-Odom JN, Turkman Y, Salvador C, Pamboukian S, Bakitas M

Abstract
BACKGROUND: The effects of mind-body interventions (MBIs) (eg, Tai Chi, yoga, meditation) for individuals with heart failure (HF) have not been systematically evaluated.
METHODS AND RESULTS: We performed a systematic review of randomized controlled trials (RCTs) examining the effects of MBIs in HF. We extracted participant characteristics, MBI procedure, outcomes assessed, and main results of English-language RCTs before October 2016. We identified 24 RCTs (n = 1314 participants) of 9 MBI types: Tai Chi (n = 7), yoga (n = 4), relaxation (n = 4), meditation (n = 2), acupuncture (n = 2), biofeedback (n = 2), stress management (n = 1), Pilates (n = 1), and reflexology (n = 1). Most (n = 22, 95.8%) reported small-to-moderate improvements in quality of life (14/14 studies), exercise capacity (8/9 studies), depression (5/5 studies), anxiety and fatigue (4/4 studies), blood pressure (3/5 studies), heart rate (5/6 studies), heart rate variability (7/9 studies), and B-type natriuretic peptide (3/4 studies). Studies ranged from 4 minutes to 26 weeks and group sizes ranged from 8 to 65 patients per study arm.
CONCLUSIONS: Although wide variability exists in the types and delivery, RCTs of MBIs have demonstrated small-to-moderate positive effects on HF patients' objective and subjective outcomes. Future research should examine the mechanisms by which different MBIs exert their effects.

PMID: 28939458 [PubMed - indexed for MEDLINE]

from A via a.sfakia on Inoreader http://bit.ly/2fIvWaP

Measured and perceived effects of audit and feedback on nursing performance: a mixed methods systematic review protocol

The use of audit and feedback (A&F) interventions in health care has been demonstrated to generally be effective on medical teams. However, literature suggests that the response of nurses to this type of inter...

from A via a.sfakia on Inoreader http://bit.ly/2t2hqB7

Ivabradine for coronary artery disease and/or heart failure—a protocol for a systematic review of randomised clinical trials with meta-analysis and Trial Sequential Analysis

Coronary artery disease and heart failure are both highly prevalent diseases with a global prevalence of 93 million and 40 million. These patients are at increased risk of morbidity and mortality. The manageme...

from A via a.sfakia on Inoreader http://bit.ly/2HN75TM

Working Scientist podcast: How to beat funding's boom and bust cycle

from A via a.sfakia on Inoreader https://go.nature.com/2G72k63

Excitotoxicity, neuroinflammation and oxidant stress as molecular bases of epileptogenesis and epilepsy-derived neurodegeneration: The role of vitamin E.

Excitotoxicity, neuroinflammation and oxidant stress as molecular bases of epileptogenesis and epilepsy-derived neurodegeneration: The role of vitamin E.

Biochim Biophys Acta Mol Basis Dis. 2019 Jan 28;:

Authors: Ambrogini P, Torquato P, Bartolini D, Albertini MC, Lattanzi D, Palma MD, Marinelli R, Betti M, Minelli A, Cuppini R, Galli F

Abstract
Glutamate-mediated excitotoxicity, neuroinflammation, and oxidative stress are common underlying events in neurodegeneration. This "triad" of pathogenic events characterizes the neurobiology of epilepsy, leading to seizure-induced cell death, increased susceptibility to neuronal synchronization and network alterations. Along with other maladaptive changes, these events pave the way to spontaneous recurrent seizures and progressive degeneration of the interested brain areas. In vivo models of epilepsy are available to explore such epileptogenic mechanisms, also assessing the efficacy of chemoprevention and therapy strategies at the pre-clinical level. The kainic acid model of pharmacological excitotoxicity and epileptogenesis is one of the most investigated mimicking the chronicization profile of temporal lobe epilepsy in humans. Its pathogenic cues include inflammatory and neuronal death pathway activation, mitochondrial disturbances and lipid peroxidation of several regions of the brain, the most vulnerable being the hippocampus. The importance of neuroinflammation and lipid peroxidation as underlying molecular events of brain damage was demonstrated in this model by the possibility to counteract the related maladaptive morphological and functional changes of this organ with vitamin E, the main fat-soluble cellular antioxidant and "conditional" co-factor of enzymatic pathways involved in polyunsaturated lipid metabolism and inflammatory signaling. The present review paper provides an overview of the literature supporting the potential for a timely intervention with vitamin E therapy in clinical management of seizures and epileptogenic processes associated with excitotoxicity, neuroinflammation and lipid peroxidation, i.e. the pathogenic "triad".

PMID: 30703511 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2G2YOJx

Acute Seizure Control Efficacy of Multi-site Closed-loop Stimulation in a Temporal Lobe Seizure Model.

Acute Seizure Control Efficacy of Multi-site Closed-loop Stimulation in a Temporal Lobe Seizure Model.

IEEE Trans Neural Syst Rehabil Eng. 2019 Jan 25;:

Authors: Zheng Y, Jiang Z, Ping A, Zhang F, Zhu J, Wang Y, Zhu W, Xu K

Abstract
Closed-loop electrical stimulation is emerging as a promising neural modulation therapy for refractory epilepsy. However, the efficacy of electrical stimulation is less than optimal and the mechanism of seizure control is still unclear. In this work, we evaluated the acute seizure control efficacy of multi-site closed-loop stimulation (MSCLS) in a rodent model with a custom designed closed-loop neurostimulator. A total of 18 rats were injected with kainic-acid (KA) in CA3 of the left hippocampus to induce acute temporal lobe seizures. Instead of single target stimulation, four target sites in left hemisphere including CA1 and CA3 of the hippocampus, sub-thalamic nucleus (STN) and M1 region of motor cortex were selected for both recording and stimulation. A low-cost efficient multi-site seizure detection algorithm was implemented in the neurostimulator for MSCLS. With MSCLS treatment, the rats without status-epilepsy (SE) significantly reduced the seizure duration and the number of generalized seizures in each site. When considering the rats developed SE, MSCLS could also alleviate the seizure severity, but had little effect on seizure duration and seizure number. In conclusion, although the efficacy of MSCLS was still limited by stimulation sites, stimulation parameters, and seizure model chosen in this study, MSCLS itself would be a promising direction for refractory seizure treatment.

PMID: 30703029 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2Uy7CKF

Expanding the phenotype of phospholipid remodelling disease due to MBOAT7 gene defect.

Related Articles

Expanding the phenotype of phospholipid remodelling disease due to MBOAT7 gene defect.

J Inherit Metab Dis. 2018 Dec 27;:

Authors: Yalnızoǧlu D, Özgül RK, Oǧuz KK, Özer B, Yücel-Yılmaz D, Gürbüz B, Serdaroǧlu E, Erol İ, Topçu M, Dursun A

Abstract
MBOAT7 gene codes O-acyltransferase domain containing seven proteins which is one of four enzymes involved in remodeling of phosphoinositol phosphate (PIP) in LANDs cycle. We present clinical, neuroimaging, and genetic findings of 12 patients from 7 families with MBOAT7 gene defect, a recently defined novel phospholipid remodelling disease. To the best of our knowledge, our case series is the second report on patients with MBOAT7 gene defect. The patients present with global developmental delay particularly in speech and language skills, intellectual disability, stereotypical behavior, ataxic gait, early onset epilepsy with well response to medical treatment, strabismus and similar facial features. Common neuroimaging findings of the patients were folium dysgenesis of the cerebellum with a particular appearance, mild-to-moderate cerebellar atrophy, T2 hyperintensity of bilateral globus pallidius and dentate nuclei, enlarged perivascular areas, and mild thinning of the corpus callosum. Genome-wide genotyping and exome sequencing identified five different types of homozygous mutations in the MBOAT7 gene in all seven families which are p.Arg87*, p.Leu227ProfsX65, p.Gln376Lys, p.Trp426*, and chr19:54.666.173-54.677.766/11594 bp del. We conclude that clinical and neuroimaging findings of MBOAT7 gene defect may suggest the diagnosis and guide genetic tests.

PMID: 30701556 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2G3hnxt

Sleep Abnormalities in Multiple Sclerosis.

Related Articles

Sleep Abnormalities in Multiple Sclerosis.

Curr Treat Options Neurol. 2019 Jan 31;21(1):4

Authors: Sakkas GK, Giannaki CD, Karatzaferi C, Manconi M

Abstract
PURPOSE OF REVIEW: This review summarizes the most well-documented sleep disorders seen in patients with multiple sclerosis (MS), with a special focus on the impact on quality of life.
RECENT FINDINGS: Sleep abnormalities in patients with MS are a multifactorial and relatively complex issue affecting approximately 60% of the patients while the pathophysiology of these symptoms is not fully understood. Circadian rhythm disorders and increased levels of pro-inflammatory cytokines have been recognized as potential players in affecting sleep homeostasis in MS patients. Medication-related side effects such as in immunotherapy and other factors such as lesion load can contribute to the disruption of normal sleep patterns. Most frequently encountered sleep disorders are insomnia, sleep-related movement disorders, sleep-related breathing disorders, and circadian rhythm disorders affecting both adults and paediatric MS populations. Aetiology still remains unknown with treatment options focusing on behavioural cognitive therapy and lifestyle modification including improvement in sleep hygiene as well as melatonin supplementation. Given MS prevalence is still rising affecting millions of people, more personalized medicine applications should possibly form the key approach for improving patients' quality of life and quality years.

PMID: 30701337 [PubMed]

from A via a.sfakia on Inoreader http://bit.ly/2Uy7Am1

The ketogenic diet influences taxonomic and functional composition of the gut microbiota in children with severe epilepsy.

Related Articles

The ketogenic diet influences taxonomic and functional composition of the gut microbiota in children with severe epilepsy.

NPJ Biofilms Microbiomes. 2019;5:5

Authors: Lindefeldt M, Eng A, Darban H, Bjerkner A, Zetterström CK, Allander T, Andersson B, Borenstein E, Dahlin M, Prast-Nielsen S

Abstract
The gut microbiota has been linked to various neurological disorders via the gut-brain axis. Diet influences the composition of the gut microbiota. The ketogenic diet (KD) is a high-fat, adequate-protein, low-carbohydrate diet established for treatment of therapy-resistant epilepsy in children. Its efficacy in reducing seizures has been confirmed, but the mechanisms remain elusive. The diet has also shown positive effects in a wide range of other diseases, including Alzheimer's, depression, autism, cancer, and type 2 diabetes. We collected fecal samples from 12 children with therapy-resistant epilepsy before starting KD and after 3 months on the diet. Parents did not start KD and served as diet controls. Applying shotgun metagenomic DNA sequencing, both taxonomic and functional profiles were established. Here we report that alpha diversity is not changed significantly during the diet, but differences in both taxonomic and functional composition are detected. Relative abundance of bifidobacteria as well as E. rectale and Dialister is significantly diminished during the intervention. An increase in relative abundance of E. coli is observed on KD. Functional analysis revealed changes in 29 SEED subsystems including the reduction of seven pathways involved in carbohydrate metabolism. Decomposition of these shifts indicates that bifidobacteria and Escherichia are important contributors to the observed functional shifts. As relative abundance of health-promoting, fiber-consuming bacteria becomes less abundant during KD, we raise concern about the effects of the diet on the gut microbiota and overall health. Further studies need to investigate whether these changes are necessary for the therapeutic effect of KD.

PMID: 30701077 [PubMed - in process]

from A via a.sfakia on Inoreader http://bit.ly/2G2RttO

Parental Satisfaction with Ambulatory Anesthesia during Dental Treatment for Disabled Individuals and Their Preference for Same in Future.

Related Articles

Parental Satisfaction with Ambulatory Anesthesia during Dental Treatment for Disabled Individuals and Their Preference for Same in Future.

Bull Tokyo Dent Coll. 2019 Jan 31;:

Authors: Ohtawa Y, Yoshida M, Fukuda K

Abstract
The purpose of this study was to survey parental satisfaction with ambulatory anesthesia during dental treatment in disabled patients. Factors associated with parental preference for general anesthesia during future dental treatment in such patients were also investigated. A questionnaire was mailed to the parents of 181 disabled individuals who underwent dental treatment under ambulatory anesthesia at Tokyo Dental College Suidobashi Hospital between 2012 and 2016. A total of 71 responses were received (39.2%). The mean patient age was 18 years, and disabilities included autism spectrum disorder, intellectual disability, cerebral palsy, and epilepsy. The items surveyed included dental treatment details, number of times patients received general anesthesia, type of anesthetic used, anesthesia induction method, durations of treatment and anesthesia, and the presence or absence of intraoperative or postoperative complications. Questionnaire items queried problems related to dental care, anesthesia history, preoperative anxiety, length of fasting period, induction of general anesthesia, nursing and hospital room environment, postoperative anxiety, overall evaluation, and whether the parent would prefer general anesthesia during future dental treatment. The patients were divided into 2 groups: those whose parents preferred general anesthesia during future dental treatment and those whose parents did not. The results revealed that, where disabled individuals had previously received general anesthesia during dental treatment, the parents were more likely to prefer general anesthesia during future dental treatment.

PMID: 30700644 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2Uw3Hhx

The Paroxysmal Depolarization Shift: Reconsidering Its Role in Epilepsy, Epileptogenesis and Beyond.

Related Articles

The Paroxysmal Depolarization Shift: Reconsidering Its Role in Epilepsy, Epileptogenesis and Beyond.

Int J Mol Sci. 2019 Jan 29;20(3):

Authors: Kubista H, Boehm S, Hotka M

Abstract
Paroxysmal depolarization shifts (PDS) have been described by epileptologists for the first time several decades ago, but controversy still exists to date regarding their role in epilepsy. In addition to the initial view of a lack of such a role, seemingly opposing hypotheses on epileptogenic and anti-ictogenic effects of PDS have emerged. Hence, PDS may provide novel targets for epilepsy therapy. Evidence for the roles of PDS has often been obtained from investigations of the multi-unit correlate of PDS, an electrographic spike termed "interictal" because of its occurrence during seizure-free periods of epilepsy patients. Meanwhile, interictal spikes have been found to be associated with neuronal diseases other than epilepsy, e.g., Alzheimer's disease, which may indicate a broader implication of PDS in neuropathologies. In this article, we give an introduction to PDS and review evidence that links PDS to pro- as well as anti-epileptic mechanisms, and to other types of neuronal dysfunction. The perturbation of neuronal membrane voltage and of intracellular Ca2+ that comes with PDS offers many conceivable pathomechanisms of neuronal dysfunction. Out of these, the operation of L-type voltage-gated calcium channels, which play a major role in coupling excitation to long-lasting neuronal changes, is addressed in detail.

PMID: 30699993 [PubMed - in process]

from A via a.sfakia on Inoreader http://bit.ly/2FZCQYd

Visits to Pediatric Clinics by Adult Patients: A Nationwide Survey in Taiwan.

Related Articles

Visits to Pediatric Clinics by Adult Patients: A Nationwide Survey in Taiwan.

Int J Environ Res Public Health. 2018 07 20;15(7):

Authors: Lee KL, Lynn AM, Chen TJ, Yang LY, Chiang SC

Abstract
Pediatricians are trained to provide non-surgical medical care to children. Improvements in medical treatments and surgical techniques have extended the survival of children with congenital diseases and chronic illnesses. Consequently, pediatricians may provide continuous medical service to their patients into adulthood. Meanwhile, as Taiwan's birth rate has fallen to one of the lowest in the world, pediatricians are encountering growing competition. As a source of continued revenue, pediatricians could also provide medical care to adults with common diseases and patients with adult-onset chronic diseases. The aim of this study was to investigate the pattern of adult ambulatory visits to pediatric clinics recorded by Taiwan's National Health Insurance (NHI) system during 2000 to 2011. From 1/500 sampling datasets, we found that adult ambulatory visits to pediatric clinics rose steadily and statistically significantly from 16% of total visits to pediatric clinics in 2000 to 32% in 2011. Analysis of the diagnoses associated with adult ambulatory visits to pediatric clinics indicated that the most common diagnoses for such patients at academic medical centers were chronic illnesses, including epilepsy, cardiac and circulatory congenital anomalies, and diabetes. Meanwhile, at physician clinics, airway infections/diseases and gastroenteritis were the most common diagnoses. In an era of low birth rates, our findings contribute to an evidence-based discussion and provide new information that may assist in healthcare policymaking.

PMID: 30036974 [PubMed - indexed for MEDLINE]

from A via a.sfakia on Inoreader http://bit.ly/2Uy7oDj

A new insight into sentence comprehension: The impact of word associations in sentence processing as shown by invasive EEG recording.

Related Articles

A new insight into sentence comprehension: The impact of word associations in sentence processing as shown by invasive EEG recording.

Neuropsychologia. 2018 01 08;108:103-116

Authors: Khachatryan E, Brouwer H, Staljanssens W, Carrette E, Meurs A, Boon P, Van Roost D, Van Hulle MM

Abstract
The effect of word association on sentence processing is still a matter of debate. Some studies observe no effect while others found a dependency on sentence congruity or an independent effect. In an attempt to separate the effects of sentence congruity and word association in the spatio-temporal domain, we jointly recorded scalp- and invasive-EEG (iEEG). The latter provides highly localized spatial (unlike scalp-EEG) and high temporal (unlike fMRI) resolutions. We recorded scalp- and iEEG in three patients with refractory epilepsy. The stimuli consisted of 280 sentences with crossed factors of sentence congruity and within sentence word-association. We mapped semantic retrieval processes involved in sentence comprehension onto the left temporal cortex and both hippocampi, and showed for the first time that certain localized regions participate in the processing of word-association in sentence context. Furthermore, simultaneous recording of scalp- and iEEG gave us a direct overview of signal change due to its propagation across the head tissues.

PMID: 29203203 [PubMed - indexed for MEDLINE]

from A via a.sfakia on Inoreader http://bit.ly/2G32o6D

Pyridoxine-dependent epilepsies: an observational study on clinical, diagnostic, therapeutic and prognostic features in a pediatric cohort.

Related Articles

Pyridoxine-dependent epilepsies: an observational study on clinical, diagnostic, therapeutic and prognostic features in a pediatric cohort.

Metab Brain Dis. 2018 02;33(1):261-269

Authors: Falsaperla R, Vari MS, Toldo I, Murgia A, Sartori S, Vecchi M, Suppiej A, Burlina A, Mastrangelo M, Leuzzi V, Marchiani V, De Liso P, Capovilla G, Striano P, Vitaliti G, Italian Society of Pediatric Neurology (SINP: Società Italiana di Neurologia Pediatrica)

Abstract
The aim of our study was to describe the clinical, electroencephalogram, molecular findings and the diagnostic and therapeutic flow-chart of children with pyridoxine-dependent epilepsies (PDEs). We performed a retrospective observational study on children with PDEs, diagnosed and followed-up in Italian Pediatric Departments. In each centre, the authors collected data from a cohort of children admitted for intractable seizures, responsive to pyridoxine administration and resistant to other anticonvulsant therapies. Data were retrospectively analysed from January 2016 to January 2017. Sixteen patients (13 males, and 3 females) were included. We found that 93.75% of patients underwent conventional anticonvulsant therapy before starting pyridoxine administration and 62.5% had ex-juvantibus diagnosis, as specific serum diagnostic tests had been performed in only 37.5% of patients by alpha-AASA and pipecolic acid blood and urine dosage. The most common type of seizure was generalized tonic-clonic in 7 patients and the most common EEG pattern was characterized by a "burst suppression" pattern. Before pyridoxine administration, other anticonvulsant drugs were used in 93.75% of patients, with consequent onset of drug-resistance. Phenobarbital was the most frequently used drug as first-line treatment. The importance of our study relies on the need of a deeper knowledge of PDEs in terms of early diagnosis, avoiding incorrect treatment and related adverse events, clinical and EEG pathognomonic features, and genetic aspects of the disease.

PMID: 29178011 [PubMed - indexed for MEDLINE]

from A via a.sfakia on Inoreader http://bit.ly/2UzATEZ

Evaluation of metformin effects in the chronic phase of spontaneous seizures in pilocarpine model of temporal lobe epilepsy.

Related Articles

Evaluation of metformin effects in the chronic phase of spontaneous seizures in pilocarpine model of temporal lobe epilepsy.

Metab Brain Dis. 2018 02;33(1):107-114

Authors: Mehrabi S, Sanadgol N, Barati M, Shahbazi A, Vahabzadeh G, Barzroudi M, Seifi M, Gholipourmalekabadi M, Golab F

Abstract
Temporal lobe epilepsy (TLE) is a common form of drug-resistant epilepsy that sometimes responds to dietary manipulation such as the 'ketogenic diet'. Here we have investigated the effects of metformin in the rat pilocaroin model of TLE. Male rats were treated with intra peritoneal injection of pilocarpine hydrochloride, in dose of 360 mg/kg to induce status epilepticus (SE). At 45 day after induction of SE, metformin was injected intraperitoneally in dose of 250 mg/kg/day for 5 days. We show that metformin potently reduces the progression of seizures and blocks seizure-induced over-expression of brain-derived neurotropic factor (BDNF) and its receptor, Tropomyosin receptor kinase B (TrkB). We have shown that this reduced expression pattern is mediated by the transcriptional co-repressor CtBP (C-terminal binding protein). Moreover, metformin decreased mechanistic target of rapamycin (mTOR) activation through activation of AMP-activated protein kinase (AMPK) signaling pathway. Our findings have been shown that metformin has anticonvulsant and antiepileptic properties, and suggesting that antiglycolytic compounds such as metformin may represent a new class of drugs for treating epilepsy.

PMID: 29080083 [PubMed - indexed for MEDLINE]

from A via a.sfakia on Inoreader http://bit.ly/2DOv2Gc

Association of Appendicitis, Helicobacter Pylori Positive Gastritis and Thrombotic Thrombocytopenic Purpura in an Adolescent.

Related Articles

Association of Appendicitis, Helicobacter Pylori Positive Gastritis and Thrombotic Thrombocytopenic Purpura in an Adolescent.

Am J Case Rep. 2019 Jan 31;20:131-133

Authors: Arapović A, Prgomet S, Saraga M, Kovačević T, Prohászka Z, Despot R, Marušić E, Radić J

Abstract
BACKGROUND Thrombotic thrombocytopenic purpura (TTP) in children is a rare life-threatening syndrome, characterized by microangiopathic hemolytic anemia, thrombocytopenia with renal dysfunction, neurologic symptoms, and fever. TTP is usually caused by deficient activity of von Willebrand factor cleaving protease (ADAMTS13), due to either gene mutations or acquired via anti-ADAMTS13 autoantibodies. It can be triggered by bone marrow or solid organ transplantation, cardiothoracic-, abdominal-, and orthopedic surgeries, infections including very rarely Helicobacter pylori infection. CASE REPORT Here we report a case of a 16-year-old male with TTP, who presented with thrombocytopenia before an appendectomy. Seven days after surgery, our patient started to vomit, developed melena, and was admitted to our pediatric intensive care unit (PICU) with clinical presentation of shock. Gastroscopy revealed H. pylori positive hemorrhagic gastritis. The patient was treated by erythrocyte transfusions, fresh frozen plasma, human albumin, glucose-electrolyte solutions, vitamin K, platelet transfusion before implantation of central venous catheter, and antibiotics. After 36 hours, we started plasma exchange (PEX). Blood tests showed deficiency of ADAMTS13. Due to the presence of anti-ADAMTS13 autoantibodies, rituximab was administered. Due to generalized tonic-clonic seizures, he was artificially ventilated. Brain MR angiography showed small ischemic cerebro-vascular insult in the arteria cerebri media region. Despite immunosuppressive therapy and PEX, the patient did not improve completely until the H. pylori infection was eradicated. After which, he recovered completely. CONCLUSIONS We present a rare case of TTP accompanied with appendicitis and gastritis caused by H. pylori, where TTP improvement was dependent on H. pylori infection eradication.

PMID: 30700693 [PubMed - in process]

from A via a.sfakia on Inoreader http://bit.ly/2MItiBa

Effects of 1064-nm Nd:YAG long-pulse laser on polidocanol microfoam injected for varicose vein treatment: a controlled observational study of 404 legs, after 5-year-long treatment

Abstract

Sclerotherapy continues to be the treatment of choice for varicose veins in the legs. However, isolated treatment using microfoam or lasers requires a high number of sessions to eliminate them. In 2013, we published results about the efficacy and safety 3 years after the combined treatment with microfoam injections and subsequent application of Nd:YAG laser. The aim of this paper is to clinically evaluate the treatment of varices in a control visit after 5 years, when polidocanol microfoam is used and is immediately irradiated in the tissue with 1064-nm Nd:YAG laser beam. The outcome persistence after 5 years was studied in the legs that had received combined treatment and had been studied 3 years after treatment. Patients were contacted by phone, interviewed, and examined with echo-Doppler. Out of the 259 patients who were contacted, 221 agreed to make the appointment, although in the end, only 202 came, which meant analysing 404 legs. At 5 years, the clearance rates were very high: patients were included in class CEAP C1 showing vessels of from 0.5 to 3 mm diameter. The patients showed a high level of satisfaction. Regarding adverse effects, only 4 cases of hypopigmentation described in the previous publication persisted. Although the action mechanisms between the microfoam and the Nd:YAG laser must still be elucidated, it is notable that combining microfoam with laser exposure obtained a complete, effective treatment of legs in only 2 sessions, with high clearance rates and high level of satisfaction among patients.

from A via a.sfakia on Inoreader http://bit.ly/2WzIIMH

Beneficial Effects of Imatinib in a Patient with Suspected Pulmonary Veno-Occlusive Disease.

Related Articles

Beneficial Effects of Imatinib in a Patient with Suspected Pulmonary Veno-Occlusive Disease.

Tohoku J Exp Med. 2019;247(2):69-73

Authors: Sato H, Sugimura K, Miura M, Konno R, Kozu K, Yaoita N, Shimizu T, Yamamoto S, Aoki T, Tatebe S, Satoh K, Shimokawa H

Abstract
Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension (PH). The prognosis of PVOD patients remains poor, since no effective medical therapy is yet available. Imatinib is a tyrosine kinase inhibitor specific for platelet-derived growth factor receptor and is expected as a treatment option for pulmonary arterial hypertension (PAH). Recently, it has been reported that imatinib improved functional capacity of a patient with PVOD. We here report a patient with suspected PVOD who has been successfully treated with imatinib and is alive for 6 years after diagnosis. A 57-year-old woman was admitted to a hospital for severe dyspnea. Echocardiography suggested the presence of PH, because tricuspid regurgitation pressure gradient was elevated. The patient was then transferred to our hospital by an ambulance ahead of schedule due to fever and worsening dyspnea. Because the patient had no left heart disease, we diagnosed that she had PAH associated with severe right heart failure. We immediately started treatment with nitric oxide (NO) for her severe hypoxia; however, it caused pulmonary edema. We suspected PVOD from CT characteristics and pulmonary edema after PAH-targeted vasodilator therapy, and then started oral imatinib treatment. In response to imatinib, her pulmonary edema gradually improved. Since then, the patient has been alive for 6 years with imatinib and pulmonary vasodilators. At present, lung transplantation is the only effective therapy for PVOD with limited availability. We therefore propose that imatinib may be a treatment option for PVOD and a bridge to lung transplantation.

PMID: 30700638 [PubMed - in process]

from A via a.sfakia on Inoreader http://bit.ly/2Ru4Fco

AICAr suppresses cell proliferation by inducing NTP and dNTP pool imbalances in acute lymphoblastic leukemia cells.

AICAr suppresses cell proliferation by inducing NTP and dNTP pool imbalances in acute lymphoblastic leukemia cells.

FASEB J. 2019 Jan 31;:fj201801559RR

Authors: Du L, Yang F, Fang H, Sun H, Chen Y, Xu Y, Li H, Zheng L, Zhou BS

Abstract
It has been shown that 5-amino-4-imidazolecarboxamide riboside (AICAr) can inhibit cell proliferation and induce apoptosis in childhood acute lymphoblastic leukemia (ALL) cells. Although AICAr could regulate cellular energy metabolism by activating AMPK, the cytotoxic mechanisms of AICAr are still unclear. Here, we knocked out TP53 or PRKAA1 gene (encoding AMPKα1) in NALM-6 and Reh cells by using the clustered regularly interspaced short palindromic repeats/Cas9 system and found that AICAr-induced proliferation inhibition was independent of AMPK activation but dependent on p53. Liquid chromatography-mass spectrometry analysis of nucleotide metabolites indicated that AICAr caused an increase in adenosine triphosphate, deoxyadenosine triphosphate, and deoxyguanosine triphosphate levels by up-regulating purine biosynthesis, while AICAr led to a decrease in cytidine triphosphate, uridine triphosphate, deoxycytidine triphosphate, and deoxythymidine triphosphate levels because of reduced phosphoribosyl pyrophosphate production, which consequently impaired the pyrimidine biosynthesis. Ribonucleoside triphosphate (NTP) pool imbalances suppressed the rRNA transcription efficiency. Furthermore, deoxy-ribonucleoside triphosphate (dNTP) pool imbalances induced DNA replication stress and DNA double-strand breaks, followed by cell cycle arrest and apoptosis in ALL cells. Exogenous uridine could rebalance the NTP and dNTP pools by supplementing pyrimidine and then attenuate AICAr-induced cytotoxicity. Our data indicate that RNA transcription inhibition and DNA replication stress induced by NTP and dNTP pool imbalances might play a key role in AICAr-mediated cytotoxic effects on ALL cells, suggesting a potential clinical application of AICAr in future ALL therapy.-Du, L., Yang, F., Fang, H., Sun, H., Chen, Y., Xu, Y., Li, H., Zheng, L., Zhou, B.-B. S. AICAr suppresses cell proliferation by inducing NTP and dNTP pool imbalances in acute lymphoblastic leukemia cells.

PMID: 30702927 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2Sk5dpz

Unprecedented behavior of (9R)-9-hydroxystearic acid loaded keratin nanoparticles on cancer cell cycle.

Unprecedented behavior of (9R)-9-hydroxystearic acid loaded keratin nanoparticles on cancer cell cycle.

Mol Pharm. 2019 Jan 31;:

Authors: Busi A, Aluigi A, Guerrini A, Boga C, Sartor G, Calonghi N, Sotgiu G, Posati T, Corticelli F, Fiori J, Varchi G, Ferroni C

Abstract
Histone deacetylases, HDACs, have been demonstrated to play a critical role in epigenetic signaling and were found to be overexpressed in several type of cancers, therefore they represent valuable targets for anticancer therapy. 9-Hydroxystearic acid has been shown to bind the catalytic site of HDAC1, inducing G0/G1 phase cell cycle arrest and activation of p21WAF1 gene, thus promoting cells growth inhibition and differentiation in many cancer cells. Despite the (R) enantiomer of 9-hydroxystearic acid (9R) displayed promising in vitro growth-inhibitory effect on HT29 cell line, its scarce water solubility and micromolar activity require novel solutions for improving its efficacy and bioavailability. In this work, we describe the synthesis and in vitro biological profiling of 9R keratin nanoparticles (9R@ker) obtained through an in-water drug-induced aggregation process. The anticancer activity of 9R@ker was investigated in HT29 cell line: the results indicate an increased fluidity of cell membrane and a higher intracellular ROS formation, resulting in an unexpected S phase cell cycle arrest (25% increase as compared to the control) induced by 9R@ker as respect to free 9R and an induction of cell death.

PMID: 30702899 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2RrrYn7

Aspirin inhibits cancer stem cells properties and growth of glioblastoma multiforme through Rb1 pathway modulation.

Related Articles

Aspirin inhibits cancer stem cells properties and growth of glioblastoma multiforme through Rb1 pathway modulation.

J Cell Physiol. 2019 Jan 30;:

Authors: Pozzoli G, Marei HE, Althani A, Boninsegna A, Casalbore P, Marlier LNJL, Lanzilli G, Zonfrillo M, Petrucci G, Rocca B, Navarra P, Sgambato A, Cenciarelli C

Abstract
Several clinical studies indicated that the daily use of aspirin or acetylsalicylic acid reduces the cancer risk via cyclooxygenases (Cox-1 and Cox-2) inhibition. In addition, aspirin-induced Cox-dependent and -independent antitumor effects have also been described. Here we report, for the first time, that aspirin treatment of human glioblastoma cancer (GBM) stem cells, a small population responsible for tumor progression and recurrence, is associated with reduced cell proliferation and motility. Aspirin did not interfere with cell viability but induced cell-cycle arrest. Exogenous prostaglandin E2 significantly increased cell proliferation but did not abrogate the aspirin-mediated growth inhibition, suggesting a Cox-independent mechanism. These effects appear to be mediated by the increase of p21 waf1 and p27 Kip1 , associated with a reduction of Cyclin D1 and Rb1 protein phosphorylation, and involve the downregulation of key molecules responsible for tumor development, that is, Notch1, Sox2, Stat3, and Survivin. Our results support a possible role of aspirin as adjunctive therapy in the clinical management of GBM patients.

PMID: 30701538 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2FYNVbK

6-Methoxyquinoline complexes as lung carcinoma agents: induction of oxidative damage on A549 monolayer and multicellular spheroid model.

Related Articles

6-Methoxyquinoline complexes as lung carcinoma agents: induction of oxidative damage on A549 monolayer and multicellular spheroid model.

J Biol Inorg Chem. 2019 Jan 30;:

Authors: Cadavid-Vargas JF, Villa-Pérez C, Ruiz MC, León IE, Valencia-Uribe GC, Soria DB, Etcheverry SB, Di Virgilio AL

Abstract
The aim of this work was to study the antitumor effects and the mechanisms of toxic action of a series of 6-methoxyquinoline (6MQ) complexes in vitro. The Cu(II) and Zn(II) complexes (Cu6MQ and Zn6MQ) are formulated as M(6MQ)2Cl2; the Co(II) and Ag(I) compounds (Co6MQ and Ag6MQ) are ionic with formulae [Ag(6MQ)2]+NO3- and H(6MQ)+[Co(6MQ)Cl3]- (where H(6MQ)+ is the protonated ligand). We found that the copper complex, outperformed the Co(II), Zn(II) and Ag(I) complexes with a lower IC50 (57.9 µM) in A549 cells exposed for 24 h. Cu6MQ decreased cell proliferation and induced oxidative stress detected with H2DCFDA at 40 µM, which reduces GSH/GSSG ratio. This redox imbalance induced oxidative DNA damage revealed by the Micronucleus test and the Comet assay, which turned into a cell cycle arrest at G2/M phase and induced apoptosis. In multicellular spheroids, the IC50 values tripled the monolayer model (187.3 µM for 24 h). At this concentration, the proportion of live/dead cells diminished, and the spheroids could not proliferate or invade. Although Zn6MQ also decreased GSH/GSSG ratio from 200 µM and the cytotoxicity is related to oxidative stress, the induction of the hydrogen peroxide levels only doubled the control value. Zn6MQ induced S phase arrest, which relates with the increased micronucleus frequency and with the induction of necrosis. Finally, our results reveal a synergistic activity with a 1:1 ratio of both complexes in the monolayer and multicellular spheroids.

PMID: 30701359 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2Rv5AJF

Whi2: a new player in amino acid sensing.

Related Articles

Whi2: a new player in amino acid sensing.

Curr Genet. 2019 Jan 30;:

Authors: Teng X, Hardwick JM

Abstract
A critical function of human, yeast, and bacterial cells is the ability to sense and respond to available nutrients such as glucose and amino acids. Cells must also detect declining nutrient levels to adequately prepare for starvation conditions by inhibiting cell growth and activating autophagy. The evolutionarily conserved protein complex TORC1 regulates these cellular responses to nutrients, and in particular to amino acid availability. Recently, we found that yeast Whi2 (Saccharomyces cerevisiae) and a human counterpart, KCTD11, that shares a conserved BTB structural domain, are required to suppress TORC1 activity under low amino acid conditions. Using yeast, the mechanisms were more readily dissected. Unexpectedly, Whi2 suppresses TORC1 activity independently of the well-known SEACIT-GTR pathway, analogous to the GATOR1-RAG pathway in mammals. Instead, Whi2 requires the plasma membrane-associated phosphatases Psr1 and Psr2, which were known to bind Whi2, although their role was unknown. Yeast WHI2 was previously reported to be involved in regulating several fundamental cellular processes including cell cycle arrest, general stress responses, the Ras-cAMP-PKA pathway, autophagy, and mitophagy, and to be frequently mutated in the yeast knockout collections and in genome evolution studies. Most of these observations are likely explained by the ability of Whi2 to inhibit TORC1. Thus, understanding the function of yeast Whi2 will provide deeper insights into the disease-related KCTD family proteins and the pathogenesis of plant and human fungal infections.

PMID: 30701278 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2Wze0mY

The palladacycle complex AJ-5 induces apoptotic cell death while reducing autophagic flux in rhabdomyosarcoma cells.

Related Articles

The palladacycle complex AJ-5 induces apoptotic cell death while reducing autophagic flux in rhabdomyosarcoma cells.

Cell Death Discov. 2019;5:60

Authors: Bleloch JS, du Toit A, Gibhard L, Kimani S, Ballim RD, Lee M, Blanckenberg A, Mapolie S, Wiesner L, Loos B, Prince S

Abstract
Rhabdomyosarcoma (RMS) forms in skeletal muscle and is the most common soft tissue sarcoma in children and adolescents. Current treatment is associated with debilitating side effects and treatment outcomes for patients with metastatic disease are dismal. Recently, a novel binuclear palladacycle, AJ-5, was shown to exert potent cytotoxicity in melanoma and breast cancer and to present with negligible adverse effects in mice. This study investigates the anti-cancer activity of AJ-5 in alveolar and embryonal RMS. IC50 values of ≤ 0.2 µM were determined for AJ-5 and it displayed a favourable selectivity index of >2. Clonogenic and migration assays showed that AJ-5 inhibited the ability of RMS cells to survive and migrate, respectively. Western blotting revealed that AJ-5 induced levels of key DNA damage response proteins (γH2AX, p-ATM and p-Chk2) and the p38/MAPK stress pathway. This correlated with an upregulation of p21 and a G1 cell cycle arrest. Annexin V-FITC/propidium iodide staining revealed that AJ-5 induced apoptosis and necrosis. Apoptosis was confirmed by the detection of cleaved PARP and increased levels and activity of cleaved caspases-3, -7, -8 and -9. Furthermore, AJ-5 reduced autophagic flux as shown by reduced LC3II accumulation in the presence of bafilomycin A1 and a significant reduction in autophagosome flux J. Finally, pharmacokinetic studies in mice show that AJ-5 has a promising half-life and that its volume of distribution is high, its clearance low and its intraperitoneal absorption is good. Together these findings suggest that AJ-5 may be an effective chemotherapeutic with a desirable mechanism of action for treating drug-resistant and advanced sarcomas.

PMID: 30701092 [PubMed]

from A via a.sfakia on Inoreader http://bit.ly/2RskAI8

piRNA-8041 is downregulated in human glioblastoma and suppresses tumor growth in vitro and in vivo.

Related Articles

piRNA-8041 is downregulated in human glioblastoma and suppresses tumor growth in vitro and in vivo.

Oncotarget. 2018 Dec 28;9(102):37616-37626

Authors: Jacobs DI, Qin Q, Fu A, Chen Z, Zhou J, Zhu Y

Abstract
PIWI-interacting RNAs (piRNAs) are small non-coding RNAs that partner with PIWI proteins to protect germline tissues from destabilizing transposon activity. While the aberrant expression of PIWI proteins has been linked with poor outcomes for many cancers, less is known about the expression or function of piRNAs in cancer. We performed array-based piRNA expression profiling in seven pairs of normal brain and glioblastoma multiforme (GBM) tissue specimens, and identified expression of ~350 piRNAs in both tissues and a subset with dysregulated expression in GBM. Over-expression of the most down-regulated piRNA in GBM tissue, piR-8041, was found to reduce glioma cell line proliferation, induce cell cycle arrest and apoptosis, and inhibit cell survival pathways. Furthermore, pre-treatment with piR-8041 significantly reduced the volume of intracranial mouse xenograft tumors. Taken together, our study reveals reduced expression in GBM of piR-8041 and other piRNAs with tumor suppressive properties, and suggests that restoration of such piRNAs may be a potential strategy for GBM therapy.

PMID: 30701019 [PubMed]

from A via a.sfakia on Inoreader http://bit.ly/2WvX54C

Interleukin-22 protects intestinal stem cells against genotoxic stress.

Related Articles

Interleukin-22 protects intestinal stem cells against genotoxic stress.

Nature. 2019 Jan 30;:

Authors: Gronke K, Hernández PP, Zimmermann J, Klose CSN, Kofoed-Branzk M, Guendel F, Witkowski M, Tizian C, Amann L, Schumacher F, Glatt H, Triantafyllopoulou A, Diefenbach A

Abstract
Environmental genotoxic factors pose a challenge to the genomic integrity of epithelial cells at barrier surfaces that separate host organisms from the environment. They can induce mutations that, if they occur in epithelial stem cells, contribute to malignant transformation and cancer development1-3. Genome integrity in epithelial stem cells is maintained by an evolutionarily conserved cellular response pathway, the DNA damage response (DDR). The DDR culminates in either transient cell-cycle arrest and DNA repair or elimination of damaged cells by apoptosis4,5. Here we show that the cytokine interleukin-22 (IL-22), produced by group 3 innate lymphoid cells (ILC3) and γδ T cells, is an important regulator of the DDR machinery in intestinal epithelial stem cells. Using a new mouse model that enables sporadic inactivation of the IL-22 receptor in colon epithelial stem cells, we demonstrate that IL-22 is required for effective initiation of the DDR following DNA damage. Stem cells deprived of IL-22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more mutations and were more likely to give rise to colon cancer. We identified metabolites of glucosinolates, a group of phytochemicals contained in cruciferous vegetables, to be a widespread source of genotoxic stress in intestinal epithelial cells. These metabolites are ligands of the aryl hydrocarbon receptor (AhR)6, and AhR-mediated signalling in ILC3 and γδ T cells controlled their production of IL-22. Mice fed with diets depleted of glucosinolates produced only very low levels of IL-22 and, consequently, the DDR in epithelial cells of mice on a glucosinolate-free diet was impaired. This work identifies a homeostatic network protecting stem cells against challenge to their genome integrity by AhR-mediated 'sensing' of genotoxic compounds from the diet. AhR signalling, in turn, ensures on-demand production of IL-22 by innate lymphocytes directly regulating components of the DDR in epithelial stem cells.

PMID: 30700914 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2CW68CW

Combining CDK4/6 inhibition with taxanes enhances anti-tumor efficacy by sustained impairment of pRB-E2F pathways in squamous cell lung cancer.

Related Articles

Combining CDK4/6 inhibition with taxanes enhances anti-tumor efficacy by sustained impairment of pRB-E2F pathways in squamous cell lung cancer.

Oncogene. 2019 Jan 30;:

Authors: Cao J, Zhu Z, Wang H, Nichols TC, Lui GYL, Deng S, Rejto PA, VanArsdale T, Hardwick JS, Weinrich SL, Wei P

Abstract
The CDK4/6 inhibitor palbociclib reduces tumor growth by decreasing retinoblastoma (RB) protein phosphorylation and inducing cell cycle arrest at the G1/S phase transition. Palbociclib in combination with anti-hormonal therapy brings significant benefit to breast cancer patients. In this study, novel combination approaches and underlying molecular/cellular mechanisms for palbociclib were explored in squamous cell lung cancer (SqCLC), the second most common subtype of non-small cell lung cancer. While approximate 20% lung patients benefit from immunotherapy, most SqCLC patients who receive platinum-doublet chemotherapy as first-line treatment, which often includes a taxane, are still in need of more effective combination therapies. Our results demonstrated enhanced cytotoxicity and anti-tumor effect with palbociclib plus taxanes at clinically achievable doses in multiple SqCLC models with diverse cancer genetic backgrounds. Comprehensive gene expression analysis revealed a sustained disruption of pRB-E2F signaling by combination that was accompanied with enhanced regulation of pleiotropic biological effects. These included several novel mechanisms such as abrogation of G2/M and mitotic spindle assembly checkpoints, as well as impaired induction of hypoxia-inducible factor 1 alpha (HIF-1α). The decrease in HIF-1α modulated a couple key angiogenic and anti-angiogenic factors, resulting in an enhanced anti-angiogenic effect. This preclinical work suggests a new therapeutic opportunity for palbociclib in lung and other cancers currently treated with taxane based chemotherapy as standard of care.

PMID: 30700828 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2RvKmez

Systematic analysis of NLMP suggests nuclear localization of RTK/MET kinases resemble cancer cell clearance.

Related Articles

Systematic analysis of NLMP suggests nuclear localization of RTK/MET kinases resemble cancer cell clearance.

J Exp Clin Cancer Res. 2019 Jan 30;38(1):43

Authors: Xie Y, Nurkesh AA, Ibragimova N, Zhanzak Z, Meyerbekova A, Alexeyeva Z, Yesbolatova A, Satayeva M, Mustafa A, Manarbek L, Maipas A, Altaikyzy A, Keneskhanova Z, Akbay B, Chen Z

Abstract
BACKGROUND: Some membrane proteins can translocate into the nucleus, defined as nuclear localized membrane proteins (NLMPs), including receptor tyrosine kinases (RTKs). We previously showed that nuclear MET (nMET), a member of RTKs, mediates cancer stem-like cells self-renewal to promote cancer recurrence. However, it is unknown that nMET or mMET, which is the ancestor in the evolution of cancer cell survival and clearance. Here, we aim to study the NLMP functions in cell death, differentiation and survival.
METHOD: We applied the systematic reanalysis of functional NLMP and clinical investigations of nMET from databases. In addition, we used soft agar assay, immunoblotting, flow cytometry, and immunofluorescence confocal microscopy for examinations of nMET functions including stem-like cell formation, cell signaling, cell cycle regulation, and co-localization with regulators of cell signaling. ShRNA, antibody of recognizing surface membrane MET based treatment were used to downregulate endogenous nMET to uncover its function.
RESULTS: We predicted and demonstrated that nMET and nEGFR are most likely not ancestors. nMET overexpression induces both cell death and survival with drug resistance and stem cell-like characters. Moreover, the paradoxical function of nMET in both cell death and cell survival is explained by the fact that nMET induces stem cell-like cell growth, DNA damage repair, to evade the drug sensitization for survival of single cells while non-stem cell-like nMET expressing single cells may undergo clearance by cell death through cell cycle arrest induced by p21.
CONCLUSION: Taken together, our data suggest a link between nuclear RTK and cancer cell evolutionary clearance via cell death, and drug resistance for survival through stemness selection. Targeting evolved nuclear RTKs in cancer stem cells would be a novel avenue for precision cancer therapy.

PMID: 30700325 [PubMed - in process]

from A via a.sfakia on Inoreader http://bit.ly/2RvYjcp

Histone methyltransferase SUV39H2 serves oncogenic roles in osteosarcoma.

Related Articles

Histone methyltransferase SUV39H2 serves oncogenic roles in osteosarcoma.

Oncol Rep. 2019 Jan;41(1):325-332

Authors: Piao L, Yuan X, Zhuang M, Qiu X, Xu X, Kong R, Liu Z

Abstract
Suppressor of variegation 3‑9 homologue 2 (SUV39H2), a SET domain‑containing histone methyl-transferase, trimethylates histone H3 at lysine 9 and serves crucial roles in heterochromatin organization and genome stability. SUV39H2 is overexpressed in various types of human cancer, whereas it is almost undetectable in normal adult tissues, except testis. The aim of this study was to investigate a potential role of SUV39H2 in osteosarcoma. In the present study, increased SUV39H2 expression levels were observed in osteosarcoma, the most common primary bone cancer in children and adolescents, and the knockdown of SUV39H2 expression by specific small interfering RNAs in osteosarcoma cells markedly suppressed cancer cell growth and led to a notable reduction in cell viability. Furthermore, overexpression of SUV39H2 promoted cell proliferation, which indicated that SUV39H2 may possess oncogenic activity in human osteosarcoma. Notably, depletion of SUV39H2 expression caused an increase in the population of G1 phase and induced apoptosis, which implied that SUV39H2 may have biological significance in the process of cell cycle. These results indicated that SUV39H2 may be an ideal target for osteosarcoma therapeutics.

PMID: 30542727 [PubMed - indexed for MEDLINE]

from A via a.sfakia on Inoreader http://bit.ly/2RwoAXS

Apoptosis induced by ursodeoxycholic acid in human melanoma cells through the mitochondrial pathway.

Related Articles

Apoptosis induced by ursodeoxycholic acid in human melanoma cells through the mitochondrial pathway.

Oncol Rep. 2019 Jan;41(1):213-223

Authors: Yu H, Fu QR, Huang ZJ, Lin JY, Chen QX, Wang Q, Shen DY

Abstract
Ursodeoxycholic acid (UDCA) is a type of hydrophilic bile acid extracted from animal bile with a wide range of biological functions. The present results demonstrated that UDCA could effectively inhibit the proliferation of two human melanoma cell line (M14 and A375) with time‑ and concentration‑dependence. Following exposure to various concentrations of UDCA, M14 cells exhibited typical morphological changes and weaker ability of colony forming. Flow cytometry analysis demonstrated that UDCA could induce a decrease of mitochondrial membrane potential and an increase in reactive oxygen species (ROS) levels in M14 cells. The cell cycle was arrested in the G2/M phase, which was confirmed by the decrease of cyclin‑dependent kinase 1 and cyclinB1 at the protein level. However, when M14 cells were treated with UDCA and Z‑VAD‑FMK (caspase inhibitor) synchronously, the apoptosis rate of the cells was reduced significantly. In addition, it was demonstrated that UDCA induced apoptosis of human melanoma M14 cells through the ROS‑triggered mitochondrial‑associated pathway, which was indicated by the increased expression of cleaved‑caspase‑3, cleaved‑caspase‑9, apoptotic protease activating factor‑1, cleaved‑poly (ADP‑ribose) polymerase 1 and the elevation of B cell lymphoma‑2 (Bcl‑2) associated X protein/Bcl‑2 ratio associated with apoptosis. Therefore, UDCA may be a potential drug for the treatment of human melanoma.

PMID: 30542709 [PubMed - indexed for MEDLINE]

from A via a.sfakia on Inoreader http://bit.ly/2WC8eRg

β‑blockers inhibit the viability of breast cancer cells by regulating the ERK/COX‑2 signaling pathway and the drug response is affected by ADRB2 single‑nucleotide polymorphisms.

Related Articles

β‑blockers inhibit the viability of breast cancer cells by regulating the ERK/COX‑2 signaling pathway and the drug response is affected by ADRB2 single‑nucleotide polymorphisms.

Oncol Rep. 2019 Jan;41(1):341-350

Authors: Xie WY, He RH, Zhang J, He YJ, Wan Z, Zhou CF, Tang YJ, Li Z, Mcleod HL, Liu J

Abstract
The β2‑adrenergic receptor (β2‑AR, encoded by the ADRB2 gene) is a member of the G‑protein‑coupled receptor superfamily that can be stimulated by catecholamines. Studies in vivo and in vitro have confirmed that β‑blockers (β‑AR antagonists) exert antitumor effects on various tumors. Furthermore, ADRB2 single‑nucleotide polymorphisms (SNPs) have been identified to alter the expression and conformation of β2‑AR, which may alter the β‑blocker drug response. The aim of the present study was to investigate the effect of β‑blockers on triple‑negative breast cancer cells and determine whether ADRB2 SNPs affect the response to β‑blocker drugs. Propranolol and ICI 118,551 significantly inhibited the viability of MDA‑MB‑231 cells, arrested cell cycle progression at G0/G1 and S phase and induced cell apoptosis. Western blot analysis indicated that the phosphorylation levels of extracellular‑signal‑regulated kinase (ERK)1/2 and the expression levels of cyclo‑oxygenase 2 (COX‑2) were significantly decreased following β‑blocker treatment. Four haplotypes, which comprised ADRB2 SNPs rs1042713 and rs1042714, were transfected into 293 cells. After 24 and 48 h of transfection, ADRB2 mRNA expression was significantly decreased in mutant groups compared with the wild‑type group. The ADRB2 SNPs exerted no effect on cell viability, but did affect the drug response of ICI 118,551. Furthermore, ADRB2 SNPs also affected the regulatory function of ICI 118,551 on the ERK/COX‑2 signaling pathway. Collectively, propranolol and ICI 118,551 inhibited the viability of MDA‑MB‑231 cells by downregulating the ERK/COX‑2 signaling pathway and inducing apoptosis. The results of the present study indicated that SNPs rs1042713 and rs1042714 of ADRB2 affected the response to ICI 118,551, and the underlying molecular mechanism was elucidated.

PMID: 30542705 [PubMed - indexed for MEDLINE]

from A via a.sfakia on Inoreader http://bit.ly/2RyGhGu

Activation of WEE1 confers resistance to PI3K inhibition in glioblastoma.

Related Articles

Activation of WEE1 confers resistance to PI3K inhibition in glioblastoma.

Neuro Oncol. 2018 01 10;20(1):78-91

Authors: Wu S, Wang S, Gao F, Li L, Zheng S, Yung WKA, Koul D

Abstract
Background: Oncogenic activation of phosphatidylinositol-3 kinase (PI3K) signaling plays a pivotal role in the development of glioblastoma (GBM). However, pharmacological inhibition of PI3K has so far not been therapeutically successful due to adaptive resistance through a rapid rewiring of cancer cell signaling. Here we identified that WEE1 is activated after transient exposure to PI3K inhibition and confers resistance to PI3K inhibition in GBM.
Methods: Patient-derived glioma-initiating cells and established GBM cells were treated with PI3K inhibitor or WEE1 inhibitor alone or in combination, and cell proliferation was evaluated by CellTiter-Blue assay. Cell apoptosis was analyzed by TUNEL, annexin V staining, and blotting of cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase. Both subcutaneous xenograft and orthotropic xenograft studies were conducted to evaluate the effects of the combination on tumorigenesis; the tumor growth was monitored by bioluminescence imaging, and tumor tissue was analyzed by immunohistochemistry to validate signaling changes.
Results: PI3K inhibition activates WEE1 kinase, which in turn phosphorylates cell division control protein 2 homolog (Cdc2) at Tyr15 and inhibits Cdc2 activity, leading to G2/M arrest in a p53-independent manner. WEE1 inhibition abrogated the G2/M arrest and propelled cells to prematurely enter into mitosis and consequent cell death through mitotic catastrophe and apoptosis. Additionally, combination treatment significantly suppressed tumor growth in a subcutaneous model but not in an intracranial model due to limited blood-brain barrier penetration.
Conclusions: Our findings highlight WEE1 as an adaptive resistant gene activated after PI3K inhibition, and inhibition of WEE1 potentiated the effectiveness of PI3K targeted inhibition, suggesting that a combinational inhibition of WEE1 and PI3K might allow successful targeted therapy in GBM.

PMID: 29016926 [PubMed - indexed for MEDLINE]

from A via a.sfakia on Inoreader http://bit.ly/2WzP9zt

Watch a levitating droplet pinball around its container

from A via a.sfakia on Inoreader https://go.nature.com/2Ghiw3U

The adaption of the bony microstructure of the human glenoid cavity as a result of long-term biomechanical loading

Abstract

Structural arrangements of the bony microstructure of a joint through adaptational processes are thought to be determined by the biomechanical demands and its changes. Pursuing this theory of "form follows the biomechanical function", the load distribution of the glenoid cavity, as it is mirrored in its mineralization pattern, should link not only to its thickness distribution, but also will have an impact onto the trabecular network below. To prove and confirm this hypothesis, we analysed the mineral distribution in correlation to the subchondral bone plates thickness and the distribution of architectural parameters of the trabecular network below. Our findings clearly state an inhomogeneous but regular and reproducible mineral distribution pattern in respect to the biomechanical demands and a thickness of the subchondral bone plate which shows a significant correlation (78–93%). As for the trabecular network below, the distribution of the analysed parameters also revealed an inhomogeneous distribution with a regular pattern in correlation to the biomechanical impact. We found distinctive maxima of material distribution and stability (bone volume 79%, plate-like architecture 77%) situated below areas of high long-term load intake. With increasing depth, the trabecular network administers the expression of each structural parameter following the fact that the strain energy gets more and more evenly distributed and changes from a high degree of differentiation just beneath the SBP to a more equal distribution within the deeper areas. After all, the biomechanical situation of a joint directly influences the bony formation of the subchondral bone plate and the trabecular network below.

from A via a.sfakia on Inoreader http://bit.ly/2GdmFWo

Managing Satellite Debris in Low-Earth Orbit: Incentivizing Ex Ante Satellite Quality and Ex Post Take-Back Programs

Abstract

Increased economic activity in low-Earth orbit (LEO) in the past century created debris fields that impede current and future economic activities. We propose an economic model that combines elements of patent law with space law to enable comparisons of policy instruments. In particular, we propose policies that leverage the intellectual property rights system and that facilitate additional joint research and development to incentivize ex ante increases in satellite quality. Our model also considers the impact of individual and collective ex post LEO debris take-back programs, analogous to those designed for terrestrial contexts. Our results suggest policy refinements for the outer space context that may be of interest beyond managing satellite debris in LEO.

from Energy Ecology Environment Ambio via Terpsi Hori on Inoreader http://bit.ly/2UymU22

PAD4-dependent NETs generation are indispensable for intestinal clearance of Citrobacter rodentium

from A via a.sfakia on Inoreader https://go.nature.com/2HJDtXp

Evaluation of confirmatory data following the Article 12 MRL review for imazamox

Abstract

The applicant BASF SE submitted a request to the competent national authority in France to evaluate the confirmatory data that were identified for imazamox in the framework of the maximum residue level (MRL) review under Article 12 of Regulation (EC) No 396/2005 as not available. To address the data gaps, the applicant submitted new residue trials on rice. Since the number of trials was not sufficient, the data gap was considered only partially addressed. The remaining data gaps related to metabolism studies and analytical enforcement methods have been addressed in the framework of the renewal of the approval for imazamox. New enforcement and risk assessment residue definitions for plant commodities were derived and the toxicological reference values for imazamox were revised. The previous consumer risk assessment was updated using the residue data submitted on rice and the new revised toxicological reference values. No consumer intake concerns were identified. The current reasoned opinion is intended to give risk managers the necessary information to take a decision on the amendment of the tentative MRLs established in the EU MRL legislation. Furthermore, EFSA recommends to review all existing EU MRLs for imazamox, considering the new residue definitions derived in the framework of the peer review.

from A via a.sfakia on Inoreader http://bit.ly/2Gfu5s3

Histopathologic variables differentially affect melanoma survival by age at diagnosis

Abstract

We evaluated clinical, phenotypic, behavioral and histopathologic variables in relationship to melanoma‐specificsurvival by age at diagnosis among 650 population‐based melanoma patients in Connecticut, with 20years of follow up. Only one variable, skin awareness, was significantly associated with melanoma mortality in both groups. The variables that differed between the age groups were anatomic site, Breslow thickness, histologic subtype, mitoses, tumor infiltrating lymphocytes (TILs) and solar elastosis. Head and neck melanoma, Breslow thickness, nodular melanoma and solar elastosis were all significantly more likely to be associated with mortality among the older subjects; among the younger subjects, the presence of mitoses was associated with an increased probability of dying and TILs were associated with a reduced risk of mortality.

This article is protected by copyright. All rights reserved.

from A via a.sfakia on Inoreader http://bit.ly/2RYlmBP

Career caseload predicts interobserver agreement on the final classification of a mammogram

Abstract

Introduction

Differences in radiologists' experience can potentially introduce interobserver variability in reading mammograms. This work investigated the effect of radiologists' experience on agreement on mammographic final classification.

Methods

This was a cross‐sectional study. Seventeen radiologists were asked to provide their final impression on 60 mammogram cases. Experience parameters included breast subspecialty, years reading mammograms, cases read per year and career caseload. Career caseload was calculated by multiplying years reading mammograms by the average number of cases read per year. The interobserver agreement was calculated using Cohen kappa (κ). The difference in κ between radiologists' groups was compared using the independent‐sample t‐test and analysis of variance.

Results

The average interobserver agreement was 0.25 (fair). A small difference was found in favour of breast radiologists against general radiologists (κ = 0.21 and 0.29, respectively, P = 0.019). Years reading mammograms and cases read per year did not seem to significantly affect the interobserver agreement (P = 0.056 and 0.273 respectively). Radiologist who had career caseload of at least 2500 cases showed significantly higher consistency than those who read less. κ for radiologists who had career caseload of 2500–4000 cases and >4000 cases was 0.33 and 0.28, respectively, whereas for <2500 κ was 0.17 (P = 0.001).

Conclusion

A fair level of interobserver agreement on the final classification of a mammogram was demonstrated. Career caseload was the most important experience parameter to associate with the interobserver agreement. Training strategies aiming to increase radiologists' career caseload may be beneficial.

from A via a.sfakia on Inoreader http://bit.ly/2SmAok4

ΒΟΗΘΗΜΑΤΑ ΑΚΟΗΣ ΑΚΟΥΣΤΙΚΑ ΒΑΡΗΚΟΙΑΣ ΕΝΙΣΧΥΤΕΣ ΑΚΟΗΣ 12 ΑΤΟΚΕΣ ΔΟΣΕΙΣ

ΒΟΗΘΗΜΑΤΑ ΑΚΟΗΣ 

ΑΚΟΥΣΤΙΚΑ ΒΑΡΗΚΟΙΑΣ 

ΕΝΙΣΧΥΤΕΣ ΑΚΟΗΣ 

12 ΑΤΟΚΕΣ ΔΟΣΕΙΣ

Detecting antibiotic resistance genes and human potential pathogenic Bacteria in fishmeal by culture-independent method

Abstract

Fishmeal is a fundamental ingredient of feedstuffs and is used globally in aquaculture. However, there are few data on the antibiotic resistance genes (ARGs) and human pathogenic bacteria in fishmeal and little understanding of the potential risks of fishmeal application in mariculture systems. Here, we investigated the high-throughput profiles of ARGs and human potential pathogenic bacteria (HPPB) in representative fishmeals (n = 5) and the potential impact of fishmeal on mariculture sediments. ARGs were quantified with microbial DNA quantitative PCR arrays and HPPB were analyzed with Illumina sequencing of 16S rRNA genes. The impact of the fishmeal on the aquaculture sediments was assessed in a microcosm study. Twenty-four unique ARGs (3–14 per sample) and 25 HPPB species were detected in the fishmeal samples. The most prevalent ARGs were fluoroquinolone resistance genes. The overall abundance of HPPB was 5.0–25.5%, and the HPPB species were dominated by Vibrio parahaemolyticus, Clostridium novyi, and Escherichia coli. In the mariculture microcosm sediment, fishmeal significantly increased the normalized abundance of the class I integrase gene (25.4-fold), which plays an important role in the dissemination of ARGs. Dosing with fishmeal also contributed to increases in a resident sulfanilamide resistance gene (sulI gene) and the emergence of a macrolide resistance gene (ermB gene) in the sediment. These findings demonstrated that fishmeal itself is an underestimated reservoir and source of ARGs and HPPBs, and that the application of fishmeal facilitates the dissemination of ARGs in aquaculture sediments. Our results extend our knowledge of the ARGs and HPPB within fishmeal and may provide a feasible and effective approach to the detection of ARGs and HPPB in fishmeal during food safety inspection.

Graphical abstract

ᅟ

from Energy Ecology Environment Ambio via Terpsi Hori on Inoreader http://bit.ly/2G1sZkD

Mechanism dependent modulation of ultrafast interfacial water dynamics in intrinsically disordered protein complexes

Recognition of Intrinsically Disordered Proteins (IDPs) is highly dependent on dynamics owing to the lack of structure. Here we studied the interplay between dynamics and molecular recognition in IDPs with a combination of time‐resolving tools from femtoseconds to nanoseconds. We interrogated conformational dynamics and surface water dynamics and its attenuation upon partner binding using two IDPs, IBB and Nup153FG, both of central relevance to the nucleocytoplasmic transport machinery. These proteins bind the same nuclear transport receptor (Importinβ) with drastically different binding mechanisms, coupled folding‐binding and fuzzy complex formation respectively. Solvent fluctuations in the dynamic interface of the Nup153FG‐Importinβ fuzzy complex were largely unperturbed and slightly accelerated relative to the unbound state. In the IBB‐Importinβ complex, on the other hand, substantial relative slowdown of water dynamics was seen in a more rigid interface. These results show a correlation between interfacial water dynamics and the plasticity of IDP complexes, implicating functional relevance for such differential modulation, including nuclear transport.

from A via a.sfakia on Inoreader http://bit.ly/2TsdQM8

Organic Proton‐buffer‐electrode to Separate Hydrogen and Oxygen Evolution in Acid Water Electrolysis

Hydrogen production from water via electrolysis in acid is attracting extensive attention as an attractive alternative approach to replacing fossil fuels. However, the simultaneous evolution of H2 and O2 requires a fluorine‐containing proton exchange membrane to prevent the gases from mixing while using the same space to concentrate the gases, which significantly increases the cost and reduces the flexibility of this approach. Here, a battery electrode based on the highly reversible enolization reaction of pyrene‐4,5,9,10‐tetraone is first introduced as a solid‐state proton buffer to separate the O2 and H2 evolution of acidic water electrolysis in space and time, through which the gas mixing issue can be avoided without using any membrane. This process allows us to separately consider H2 and O2 production according to the variation in input power (e.g., the renewable energy) and/or the location for H2 concentration, thus showing high flexibility for H2 production.

from A via a.sfakia on Inoreader http://bit.ly/2BdUxyZ

Exploiting the Hydrogen Bond Donor/Acceptor Properties of PN‐Heterocycles: Selective Anion Receptors for Hydrogen Sulfate

We describe two novel hybrid receptors combining a phosphorus‐/nitrogen‐containing (PN) phosphonamidate heterocycle with urea recognition units in an arylethynyl backbone. Structural, spectroscopic and computational studies reveal that the origin of superior binding for hydrogen sulfate (HSO4−) anion is correlated with the formation of strong hetero‐complementary hydrogen bonds with the phosphonamidate motif. We further demonstrate that the hybrid host system is capable of capturing/transporting the HSO4− anion from an aqueous, biphasic system.

from A via a.sfakia on Inoreader http://bit.ly/2TosJiA

Crystal Multi‐Conformational Control Through Deformable Carbon–Sulfur Bond for Singlet–Triplet Emissive Tuning

Crystal‐state luminophores have been of great interest in optoelectronics for years, whereas the excited state regulation at the crystal level is still restricted by the lack of control ways. We report that the singlet–triplet emissive property can be profoundly regulated by crystal conformational distortions. Employing fluoro‐substituted tetrakis(arylthio)benzene luminophores as prototype, we found that couples of molecular conformations formed during different crystallizations. The deformable carbon–sulphur bond essentially drove the distortion of the molecular conformation and varied the stacking mode, together with diverse non‐covalent interactions, leading to the proportional adjustment of the fluorescence and phosphorescence bands. This intrinsic strategy was further applied for solid‐state multicolor emissive conversion and mechanoluminescence, probably offering new insights for design of smart crystal luminescent materials.

from A via a.sfakia on Inoreader http://bit.ly/2BhJdSx

Paired Electrochemical Reactions and the On‐Site Generation of a Chemical Reagent

While the majority of reported paired electrochemical reactions involve carefully matched cathodic and anodic reactions, the precise matching of half reactions in an electrolysis cell is not generally necessary. During a constant current electrolysis almost any oxidation and reduction reactions can be paired, and in the presented work we capitalize on this observation by examining the coupling of anodic oxidation reactions with the production of hydrogen gas for use as a reagent in remote, Pd‐catalyzed hydrogenation and hydrogenolysis reactions. To this end, an alcohol oxidation, an oxidative condensation, intramolecular anodic olefin coupling reactions, an amide oxidation, and a mediated oxidation were all shown to be compatible with the generation and use of hydrogen gas at the cathode. This pairing of an electrolysis reaction with the production of a chemical reagent or substrate has the potential to greatly expand the use of more energy efficient paired electrochemical reactions.

from A via a.sfakia on Inoreader http://bit.ly/2Tuadpa

A Water‐Soluble Perylene Bisimide Cyclophane as a Molecular Probe for the Recognition of Aromatic Alkaloids

Be my guest: A water‐soluble perylene bisimide cyclophane host recognizes structurally diverse natural aromatic alkaloids by binding them in its hydrophobic cavity. Encapsulation of the guest is signalled by distinct changes in the optical properties of the host.

Abstract

Herein, we report a water‐soluble macrocyclic host based on perylene bisimide (PBI) chromophores that recognizes natural aromatic alkaloids in aqueous media by intercalating them into its hydrophobic cavity. The host–guest binding properties of our newly designed receptor with several alkaloids were studied by UV/Vis and fluorescence titration experiments as the optical properties of the chromophoric host change significantly upon complexation of guests. Structural information on the host–guest complexes was obtained by 1D and 2D NMR spectroscopy and molecular modelling. Our studies reveal a structure–binding property relationship for a series of structurally diverse aromatic alkaloids with the new receptor and higher binding affinity for the class of harmala alkaloids. To our knowledge, this is the first example of a chromophoric macrocyclic host employed as a molecular probe for the recognition of aromatic alkaloids.

from A via a.sfakia on Inoreader http://bit.ly/2By39Qj

Synthesis of Plasmonic Group‐4 Nitride Nanocrystals by Solid‐State Metathesis

Ready to plassemble: The synthesis of TiN, ZrN, and HfN nanocrystals using solid‐state metathesis is reported. The nanocrystals, which are dispersible in water, show localized surface plasmonic resonances in the near infrared (TiN) and visible region (ZrN, HfN) of light. This makes them ideal for applications like photothermal therapy or plasmon‐enhanced sensing.

Abstract

Ceramic nanoparticles that exhibit a plasmonic response are promising next‐generation photonic materials. In this contribution, a solid‐state metathesis method has been reported for the synthesis of Group 4 nitride (TiN, ZrN, and HfN) nanocrystals. A high‐temperature (1000 °C) reaction between Group 4 metal oxide (TiO₂, ZrO₂, and HfO₂) nanoparticles and magnesium nitride powder yielded nitride nanocrystals that were dispersible in water. A localized surface plasmonic resonance was observed in the near‐infrared region for TiN and in the visible region of light for ZrN and HfN nanocrystals. The frequency of the plasmon resonance was dependent on the refractive index of the solvent and the nanocrystal size.

from A via a.sfakia on Inoreader http://bit.ly/2CsVRxF

An Unexpected Role of Hyaluronic Acid in Trafficking siRNA Across the Cellular Barrier: The First Biomimetic, Anionic, Non‐Viral Transfection Method

Hitchin' a ride: Hyaluronic‐acid‐induced stabilization of siRNAs via hydrogen bonding and Van der Waals interactions plays a role in siRNA uptake. Mimicking this cellular trafficking mechanism enabled the delivery of RNAi molecules into two different cell lines, resulting in approximately 60 % gene knockdown. This is the first report on an anionic, non‐viral siRNA delivery method.

Abstract

Circulating nucleic acids, such as short interfering RNA (siRNA), regulate many biological processes; however, the mechanism by which these molecules enter the cell is poorly understood. The role of extracellular‐matrix‐derived polymers in binding siRNAs and trafficking them across the plasma membrane is reported. Thermal melting, dynamic light scattering, scanning electron microscopy, and computational analysis indicate that hyaluronic acid can stabilize siRNA via hydrogen bonding and Van der Waals interactions. This stabilization facilitated HA size‐ and concentration‐dependent gene silencing in a CD44‐positive human osteosarcoma cell line (MG‐63) and in human mesenchymal stromal cells (hMSCs). This native HA‐based siRNA transfection represents the first report on an anionic, non‐viral delivery method that resulted in approximately 60 % gene knockdown in both cell types tested, which correlated with a reduction in translation levels.

from A via a.sfakia on Inoreader http://bit.ly/2SVPmL2

Near‐Infrared Afterglow Semiconducting Nano‐polycomplexes for Multiplex Differentiation of Cancer Exosomes

As nanoscaled extracellular vehicles inheriting genetic and protein information from source cells, detection of exosomes is promising for early diagnosis of cancer. However, optical sensors with high specificity and low medium background remain challenging for detection of exosomes. We herein develop the first luminescent nanosensor that bypasses real‐time light excitation for multiplex differentiation of cancer exosomes. Such an afterglow luminescent nanosensor is composed of a near‐infrared (NIR) semiconducting polyelectrolyte (ASPN) electrostatically complexed with a quencher‐tagged aptamer. The afterglow signal of the nanocomplex (ASPNC) is initially quenched due to the efficient electron transfer between ASPN and the quencher. However, the presence of aptamer‐targeted exosome increases ASPN/quencher distance, turning on afterglow signal. Because the afterglow detection is conducted after cessation of light excitation, the sample background signal is greatly minimized, affording the limit of detection that is nearly two order of magnitudes lower than fluorescence detection in cell culture medium. More importantly, ASPNC can be easily tailored to detect different exosomal proteins simply by changing the sequence of aptamer. Such a structural versatility of ASPNC enables orthogonal analysis of multiple exosome samples, potentially permitting accurate identification of the cellular origin of exosomes for cancer diagnosis.

from A via a.sfakia on Inoreader http://bit.ly/2Bgx9AS