PP2A deactivation is a common event in oral cancer and reactivation by FTY720 shows promising therapeutic potential

Abstract

Protein phosphatase 2A (PP2A) is a tumor suppressor gene, that has been frequently deactivated in many types of cancer. However its molecular and clinical relevance in oral squamous cell carcinoma (OSCC) remain unclear. Here we show that, PP2A deactivation is a common event in oral cancer cells and hyperphosphorylation in its tyrosine-307 (Y307) residue contributes to PP2A deactivation. PP2A restoration by FTY720 treatment reduced cell growth and decreased GSK-3β phosphorylation without significantly altering other PP2A targets. We further detected PP2A phosphorylation in 262 OSCC tissues. Increased expression of p-PP2A in the tumor tissues was significantly correlated with higher N2/N3- stage (aOR =2.1, 95% CI: 1.2-3.8). Patients with high p-PP2A expression had lower overall survival rates than those with low expression. Hazard ratio analysis showed that, high p-PP2A expression was significantly associated with mortality density (aOR= 2.2, 95% CI: 1.2-4.0) and lower 10-year overall survival (P = 0.027) in lymph node metastasis. However, no interaction was observed between p-PP2A expression and lymph node metastasis. All our results suggest that PP2A is frequently deactivated is oral cancer and determines poor outcome, restoring its expression by FTY720 can be an alternative therapeutic approach in OSCC. This article is protected by copyright. All rights reserved

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Online health searching can help doctor-patient relationship, study finds

Most people would still usually make an appointment with their GP after searching online health information and their confidence in their family doctor is rarely affected, research published in BJGP...

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Depression is not a risk factor for dementia, large cohort study concludes

Depression does not seem to increase the risk for dementia, but depressive symptoms in later life could be a feature of dementia’s preclinical phase, a 28 year follow-up study in the UK has...

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Schwimmbadgranulom

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Ein Glomustumor unter dem Fingernagel

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Bullöses Pemphigoid: Doxycyclin statt Prednisolon?

Bekommen Patienten mit bullösem Pemphigoid weniger schwere Nebenwirkungen unter Doxycyclin als unter der Standardtherapie mit oralem Prednisolon? Eine aktuelle Studie gibt Aufschluss.

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Kutane Nebenwirkungen der Immuntherapie

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Melanom: Lymphknotendissektion auch therapeutisch von Nutzen?

Eine Sentinellymphknotendissektion bei Melanompatienten könnte nicht nur einen diagnostischen, sondern auch einen therapeutischen Nutzen haben. Hinweise dafür liefert eine Studie mit fast 600 Patienten ohne Fernmetastasen.

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Inhaltsverzeichnis

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Jahreshighlight der Kongresssaison

Offensichtlich kam das Konzept 2015 gut an: Auch in diesem Jahr wurde bei der Tagung der Deutschen Dermalogischen Gesellschaft (DDG) vom 26.–29. April im Berliner City Cube in über 60 Kursen, Symposien und Plenarvorträgen versucht, die Neuerungen auf dem weiten Feld der Dermatologie abzudecken. Präsentiert und diskutiert wurden unter anderem kutane Nebenwirkungen der Immuntherapie, Biosimilars bei Psoriasis und die Zukunft molekularer Diagnostik von entzündlichen Dermatosen.

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Infliximab wirkt rasch gegen Psoriasis

In einer Vergleichsstudie haben Patienten mit Psoriasis unter Infliximab rascher einen PASI 75 erreicht als unter Etanercept. Längerfristig war aber kein Unterschied im Therapieerfolg festzustellen.

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Streifen auf dem Nagel: Wann besteht Melanomverdacht?

Hochauflösende Dermatoskopie-Aufnahmen haben europäische Dermatologen retrospektiv ausgewertet, um zu prüfen, wie gut sich ein Melanom bei streifenförmiger Nagelpigmentierung dermatoskopisch diagnostizieren lässt.

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Spielt das Aquarium eine Rolle?

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Die Rente der Ärzte ist sicher – aber...

Auch die ärztlichen Versorgungswerke müssen die Gürtel in Zeiten niedriger Zinsen enger schnallen. Daher lohnt es sich für Ärzte durchaus, eine komplementäre Vorsorgestrategie zu ihrer – an sich sicheren – Rente zu verfolgen.

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Klinische Studien: Viele Patienten sind interessiert und wissbegierig

Klinische Arzneimittelstudien sind integraler Bestandteil des medizinischen Versorgungsalltags. Optimierungspotenzial gibt es laut Umfrage aber bei der Rekrutierung der Probanden.

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Histaminarme Diät gegen chronische Urtikaria

Kann man durch den Verzicht auf stark histaminhaltige Lebensmittel die Symptome einer chronisch spontanen Urtikaria bessern? In einer deutschen Studie funktionierte das Rezept.

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PDT: Wie wird die Haut optimal vorbereitet?

Um die Aufnahme von topischen Photosensibilisatoren zu erleichtern, wird eine physikalische Vorbehandlung der Haut empfohlen. Die effektivste Methode wurde nun in einer Vergleichsstudie ermittelt.

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Molekulare Diagnostik entzündlicher Dermatosen

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Sentinellymphknotenbiopsie beim malignen Melanom: ja oder nein?

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Mukosales Melanom: Kombination geprüft

Mit einer gepoolten Datenanalyse wurde erstmals die Sicherheit und Wirksamkeit von Nivolumab als Monosubstanz und in Kombination mit Ipilimumab beim seltenen, hochaggressiven Schleimhautmelanom untersucht.

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Junge Ärzte wollen sanften Einstieg in die eigene Praxis

Niederlassung als Chance? Viele junge Mediziner sehen das eher skeptisch. Dabei bietet die Selbstständigkeit tatsächlich gute Entfaltungsmöglichkeiten – wenn man es richtig anpackt.

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Narben als Schmuck und Initiation

Feine Linien überziehen die Gesichter der Bétamarribé. Die Männer der Kaningara ahmen die schuppige, raue Haut des Krokodils nach. Viele Kulturen kennen Narben als Zeichen der Schönheit und der Initiation.

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Ringförmige Läsionen auf Stirn und Händen

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Pediatric nasal surgery prior to puberty is not only safe, but may prevent facial deformity in certain patients.

http://alexandrossfa.blogspot.com/2017/05/pediatric-nasal-surgery-prior-to.html

Pediatric nasal surgery: timing and technique.

από Gary, Celeste C. στο Current Opinion in Otolaryngology & Head and Neck Surgery - Published Ahead-of-Print

Μετάφραση άρθρου

Purpose of review: Timing of pediatric nasal surgery has always been a controversial topic. Concern over disrupting growing parts of the face and causing permanent facial deformity has led to a primarily conservative approach. Many surgeons feel that it is prudent to wait until the patient has completed nasal growth after puberty to pursue nasal surgery. Recent findings: Recently, this attitude has been challenged with evidence that not only is nasal surgery in the pediatric age group not a detriment to facial growth, but failure to correct significant nasal deformity may actually cause dysmorphic facial growth secondary to obligate mouth breathing. Because of this, recent studies have focused on determining safe surgical techniques for pediatric nasal surgery, including inferior turbinate reduction, septoplasty and rhinoplasty. Research focus on this topic has also been expanded to include quality-of-life measures after nasal surgery. Summary: Pediatric nasal surgery prior to puberty is not only safe, but may prevent facial deformity in certain patients. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Sorbitol-6-phosphate dehydrogenase gene ( S6PDH ) polymorphism in tribe Pyreae (Rosaceae) species

Abstract

The sorbitol-6-phosphate dehydrogenase gene (S6PDH) sequences of eight tribe Pyreae species (Rosaceae) are studied for the first time. The exon–intron structure and polymorphism of the nucleotide and amino acid sequences of this gene are characterized. The interspecific polymorphism of the S6PDH coding sequences in the studied Pyreae species is 8.36%. Sorbitol-6-phosphate dehydrogenase gene expression in S. aucuparia, A. melanocarpa, and M. domestica (cv. Skala) leaves is studied. The highest level of S6PDH expression is detected in mature leaves.

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Expression of the DNA methyltransferase genes in silver foxes experimentally selected for domestication

Abstract

Animal domestication is a model of a rapid evolutionary process. In experimental fox domestication, the time required for the emergence and fixation of specific evolutionary changes was reduced from thousands to tens of years, compared to historical domestication. Tame foxes were obtained by extreme selective breeding for emotionally positive response toward humans. Unselected foxes, as well as foxes bred for enhanced aggressiveness to humans were used as control. Epigenetic regulation of gene expression is considered as one of the possible mechanisms of rapid evolution. In this study, expression of DNA methyltransferase genes, DNMT1 and DNMT3A, was investigated. It was demonstrated that, in tame foxes, the level of DNMT3A gene expression in the prefrontal cortex, hippocampus, and spleen was increased by more than 2 times in comparison with aggressive and unselected foxes. At the same time, the DNMT1 expression level did not differ among the studied groups of animals. A possible reason for the differences found in the DNMT3A expression could be the changes in the level and metabolism of methionine, which serves as a donor of methyl groups during DNA methylation. However, this study showed that there were no differences in the serum methionine levels between tame, unselected, and aggressive foxes. Thus, the data support the hypothesis that selection for positive emotional response toward humans affected the DNA methylation machinery.

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Expression of the R2R3 MYB transcription factors in Vitis amurensis Rupr. plants and cell cultures with different resveratrol content

Abstract

Grapevine Vitis amurensis Rupr. accumulates several valuable secondary metabolites; the most known is resveratrol—a key compound in biosynthesis of stilbenes. There is lack in the information of the regulation of the resveratrol biosynthesis in grapevin. For example, the grapevine MYB R2R3 (MYB) transcription factors (TFs) were found to modulate several branches of the flavonoid pathway. The flavonoid pathway is close to the stilbene pathway; therefore, we decided to investigate expression of the 22 MYB genes in the grape V. amurensis cell cultures and plant parts with different resveratrol content. Using real-time PCR, we showed that MYB9, 14, 15а, 60, 40, and 107 expression increased in several probes with the highest resveratrol content; therefore, probably, those genes are positive regulators of the stilbene biosynthesis. Also, we discussed the participation of the MYB transcription factors in the regulation of the stilbene biosynthesis in the grape cells.

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Forms of natural selection controlling the genomic evolution in nodule bacteria

Abstract

The role of different forms of natural selection in the evolution of genomes in root nodule bacteria (rhizobia) is analyzed for the first time. In these nitrogen-fixing symbionts of leguminous plants, two types of genome organization are revealed: (i) unitary type, where over 95% of genetic information is encoded by chromosomes (5.3–5.5 Mb in Azorhizobium, 7.0–7.8 Mb in Mesorhizobium, 7.3–10.1 Mb in Bradyrhizobium); (ii) multipartite type, where up to 50% of genetic information is allocated to plasmids or chromids which may exceed 2 Mb in size and usually control the symbiotic properties (pSyms) in fast-growing rhizobia (Rhizobium, Sinorhizobium, Neorhizobium). Emergence of fast-growing species with narrow host ranges are correlated to the extension of extrachromosomal parts of genomes, including the increase in pSyms sizes (in Sinorhizobium). An important role in this evolution is implemented by diversifying selection since the genomic diversity evolved in rhizobia owing to symbiotic interactions with highly divergent legumes. However, analysis of polymorphism in nod genes (encoding synthesis of lipo-chitooligosaccharide signaling Nod factors) suggests that the impacts of diversifying selection are restricted to the bacterial divergence for host specificity and do not influence the overall genome organization. Since the extension of rhizobia genome diversity results from the horizontal sym gene transfer occurring with low frequencies, we suggest that this extension is due to the frequency-dependent selection anchoring the rare genotypes in bacterial populations. It is implemented during the rhizobia competition for nodulation encoded by the functionally diverse cmp genes. Their location in different parts of bacterial genomes may be considered as an important factor of their adaptive diversification implemented in the host-associated microbial communities.

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Genetic polymorphisms in the 5'-flanking region of the melanocortin 1 receptor ( MC1R ) gene in foxes

Abstract

The one of the key pigment genes, the melanocortin 1 receptor (MC1R) gene, plays a fundamental role in the determination of coat color in a variety of mammals. However, so far there has been no report regarding the genetic variants of the MC1R promoter region and the potential association of its mutations with coat color in foxes. This work aimed to characterize 5'-flanking region of the MC1R gene and its mutations associated with coat color variations in foxes. A total of 76 individuals including 64 red foxes (Vulpes vulpes), representing 11 color morphs, and 12 arctic foxes (Vulpes lagopus), representing 2 color morphs were studied. To explore the potential cause of coat color variation in foxes, an 1105 bp region located upstream of the MC1R gene coding region was sequenced in 76 foxes. In the present study, a 1267 bp 5'-flanking region of fox MC1R gene was obtained using a PCR-mediated chromosome-walking technique and a 1105 bp segment was sequenced. A total of 8 novel SNPs and an insertion/deletion of 4 nucleotides were detected. The results of mutations analysis indicated that SNPs g.-52G>A, g.-266A>G, g.-297T>C, g.-300G>A and the insertion/deletion spaning positions g.-382~-379 were important in distinguishing V. vulpes and V. lagopus. This work, for the first time, described and confirmed the different variants existed in the 5'-flanking region of MC1R gene between red foxes and arctic foxes. These findings may be extremely helpful for further exploring the alternative splicings or promoter activity of MC1R gene for different coat-colored foxes.

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Genetic factors in the development of chronic kidney disease in patients with diabetes mellitus

Abstract

Patients with diabetes mellitus (DM) represent a risk group for developing chronic kidney disease (CKD), the terminal stages of which require renal replacement therapy. The study of genetic predisposition to CKD is of special significance from the perspective of the prediction and identification of risk groups at the preclinical stage. The present study is a review of the world literature on the genetics of CKD in diabetes and also includes data of our own studies.

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Allele diversity of hordein-coding loci Hrd A and Hrd B in cultivated ( Hordeum vulgare L.) and wild ( Hordeum spontaneum C. Koch) barley in Turkey (as part of the Fertile Crescent)

Abstract

Starch gel electrophoresis is performed to study polymorphism of hordeins encoded by the Hrd A and Hrd B loci in 93 local accessions of cultivated barley and 37 accessions of wild barley from Turkey. Fortyfive and 32 alleles for the Hrd A locus are identified in H. vulgare and H. spontaneum, respectively, and 51 and 49 alleles are identified for the Hrd B locus. For H. vulgare, the allele frequencies range from 0.0011 to 0.2934 for the Hrd A locus and from 0.0011 to 0.0807 for the Hrd B locus. For H. spontaneum, the allele frequencies for these loci vary from 0.0089 to 0.2434 and from 0.0068 to 0.0766, respectively. Three alleles of the Hrd A and two of the Hrd В locus are common for Turkish H. vulgare and H. spontaneum. It was demonstrated that the earliest remains of barley grains were found in archaeological sites in the Middle East in Ohalo II near the Sea of Galilee dated back to the 17th millennium BC. The age of cultivated and wild barley remains from Egyptian archeological sites was determined to be 18000 years. We conclude that the southeast region of Turkey cannot be considered as the domestication center of barley. Herein, H. spontaneum from Southeastern Turkey could have been the donor of some hordein-coding alleles for H. vulgare. This could have been due to spontaneous hybridization events between H. vulgare and H. spontaneum during expansion of cultivated barley.

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Gene pool state and degree of infestation by bark beetle ( Ips tipographus L.) of Norway spruce ( Picea abies L. Karst.) natural populations and planted stands in Moscow region

Abstract

A comparative analysis of the gene pool state in natural populations and planted stands of Norway spruce and the degree of their infestation by the bark beetle in the Moscow region was conducted taking into account the dynamic state of communities (4 populations, 148 samples, 24 isoenzyme loci). The degree of infestation by the bark beetle of conditionally native communities is 0%; for planted stands, it is 90–100%; and for a short-term community, it is 15–20%. The comparison of "healthy" populations and those infested with bark beetle by average values of observed heterozygosity (H _O) detected no significant differences. However, the test on allelic frequency heterogeneity demonstrated the difference of planted stands from conditionally native populations both by three loci (Fe-2, Idh-1, Mdh-3) and by the totality of 18 polymorphic isoenzyme loci; the short-term population differs from conditionally native population only by two loci. The value of the inbreeding coefficient by the Idh-1 locus is significantly higher in both populations infested with the bark beetle than in "healthy" populations. The results of conducted studies demonstrate the necessity of continuation of the study on the gene pool state in Norway spruce populations owing to the degree of their infestation by the bark beetle along with the study on the dynamic state of the communities; this can provide a key to solving the problem of the forest preservation from pests.

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Molecular evolution of the Lake Baikal endemic caddisflies (Trichoptera)

Abstract

Phylogenetic relationships of the nine Lake Baikal endemic caddisfly species with the representatives of the genus Apatania (Apataniidae) were reconstructed on the basis on nucleotide sequences of the mitochondrial COI gene. The results of Bayesian analysis pointed to the relationships of the endemics with the North American Apatania incerta (Banks, 1897) and A. sorex (Ross, 1941). The divergence of the genetic lineages of the Baikalian and Nearctic apataniids occurred in the Late Oligocene–Early Miocene. On the dendrogram, endemic species formed two monophyletic clades corresponding to the tribes Thamastini and Baicalinini. It was also found that the genus Protobaicalina was polyphyletic, while the genus Baicalina was a species flock. Our analysis showed that the nearest common ancestor of the studied Baikal caddisfly species existed about 21 Mya, while the modern species composition of endemic fauna dates back to Pliocene–Pleistocene age (2.5–0.7 million years).

http://ift.tt/2rh6j7T

Apropas phenomenon of women predominance among carriers of reciprocal translocations during disturbances in reproduction

Abstract

The predominance of females among reciprocal (rec) translocation carriers, which have problems with reproduction in the anamnesis, is well established and usually accounts for the sterility of male carriers of this type of translocations. However, no careful comparative studies have been performed. Meta-analysis of the data on the examined pairs with reproduction problems shows that, among patients with infertility, the frequency of rec carriers was observed in 0.48% (74/15304) of men and in 0.41% (64/15454) of women; the sex ratio (SR) was 1.17, which does not differ significantly from the population value, 1.06 (p = 0.36). Robertsonian translocations (rob) were observed in 0.58% of men and in 0.11% of women; SR = 5.3 (p = 5 × 10^–13) in this group. Inversions (inv) were more often detected in women than in men, 0.14 and 0.27%, SR = 0.59 (p = 0.020). Among patients with habitual miscarriages, the frequencies of rec carriers were significantly higher than in patients with infertility: in 0.78% (151/19353) of men and in 1.42% (281/19737) of women, GR = 0.55 (p = 10^–9). Carriers of rob were found in 0.33% of men and 0.60% of women, SR = 0.55 (p = 9.7 × 10^–5). The frequency of inv was 0.17 and 0.20%, respectively. The results supports the notion that the predominance of women among fertile carriers of rob is caused by the sterility of male carriers of such rearrangements. However, the predominance of women among fertile carriers of rec cannot be due to this reason. The first reason is because there is no significant prevalence of men over women among infertile carriers of such type translocations. The second reason is because the frequency of rec male carriers among patients with infertility is significantly lower than their frequency among fertile carriers. It is likely that the reason for the observed phenomenon is the inherent oogenesis factors which affect segregation of the aberrant chromosomes.

http://ift.tt/2pVztWA

The macrohaplogroup U structure in Russians

Abstract

The structure and diversity of mitochondrial DNA (mtDNA) macrohaplogroup U lineages in Russians from Eastern Europe are studied on the basis of analysis of variation of nucleotide sequences of complete mitochondrial genomes. In total, 132 mitochondrial genomes belonging to haplogroups U1, U2e, U3, U4, U5, U7, U8a, and K are characterized. Results of phylogeographic analysis show that the mitochondrial gene pool of Russians contains mtDNA haplotypes belonging to subhaplogroups that are characteristic only of Russians and other Eastern Slavs (13.7%), Slavs in general (11.4%), Slavs and Germans (17.4%), and Slavs, Germans, and Baltic Finns (9.8%). Results of molecular dating show that ages of mtDNA subhaplogroups to which Russian mtDNA haplotypes belong vary in a wide range, from 600 to 17000 years. However, molecular dating results for Slavic and Slavic-Germanic mtDNA subhaplogroups demonstrate that their formation mainly occurred in the Bronze and Iron Ages (1000–5000 years ago). Only some instances (for subhaplogroups U5b1a1 and U5b1e1a) are characterized by a good agreement between molecular dating results and the chronology of Slavic ethnic history based on historical and archaeological data.

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Molecular and genetic characterization of the allelic variants of Du215, Du281, Du323, and Du47G microsatellite loci in parthenogenetic lizard Darevskia armeniaca (Lacertidae)

Abstract

A key issue in the study of unisexual (parthenogenetic) vertebrate species is the determination of their genetic and clonal diversity. In pursuing this aim, various markers of nuclear and mitochondrial genomes can be used. The most effective genetic markers include microsatellite DNA, characterized by high variability. The development and characterization of such markers is a necessary step in the genetic studies of parthenogenetic species. In the present study, using locus-specific PCR, for the first time, an analysis of allelic polymorphism of four microsatellite loci is performed in the populations of parthenogenetic species Darevskia armeniaca. In the studied populations, allelic variants of each locus are identified, and the nucleotide sequences of each allele are determined. It is demonstrated that allele differences are associated with the variation in the structure of microsatellite clusters and single nucleotide substitutions at fixed distances in flanking DNA regions. Structural allele variations form haplotype markers that are specific to each allele and are inherited from their parental bisexual species. It is established which of the parental alleles of each locus were inherited by the parthenogenetic species. The characteristics of the distribution and frequency of the alleles of microsatellite loci in the populations of D. armeniaca determining specific features of each population are obtained. The observed heterozygosity of the populations at the studied loci and the mutation rates in genome regions, as well as Nei's genetic distances between the studied populations, are determined, and the phylogenetic relationships between them are established.

http://ift.tt/2pVR3cW

Mapping of the regulatory sequence within the yellow gene enhancers of D. melanogaster , required for the long-distance enhancer–promoter interaction

Abstract

One of the features of transcriptional regulation in higher eukaryotes is the ability of enhancers to activate gene transcription, being at a distance, sometimes reaching several hundred kilobases away from the promoter. For several genes, it was demonstrated that cis-regulatory DNA sequences located near the core promoter sequences play an important role in the enhancer–promoter communication. In this study, we first showed that the sequence from–890 to–1620 bp relative to the yellow transcription start site, called a communicator, is required for the long-distance activation of the yellow promoter by the body and wing enhancers, as well as for their bypass of the Su(Hw)-dependent insulation. The communicator is a functional partner of a previously described regulatory element located between–69 and–100 bp in the upstream promoter region of the yellow gene. The results of this study demonstrate that specific regulatory elements in the promoter and enhancer regions may be involved in providing long-distance interactions between them.

http://ift.tt/2rhgQQu

Thoracic outlet syndrome

Thoracic outlet syndrome: A condition that is due to compromise of blood vessels or nerve fibers between the armpit (axilla) and the base of the neck, because of compression by adjacent tissues. Symptoms include pain, arm weakness, and numbness in the hands and fingers. Thoracic outlet syndrome can be caused by muscle development from some types of manual work or exercise, injury, or malformation. Treatment involves physical therapy and use of anti-inflammatory medication, and sometimes by surgery.

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Great sandeel ( Hyperoplus lanceolatus ) as a putative transmitter of parasite Contracaecum osculatum (Nematoda: Anisakidae)

Abstract

In the Baltic Sea, the great sandeel (Hyperoplus lanceolatus), a common fish species that inhabits sandy substrates, is an important element in the diet of marine mammals, sea birds, and piscivorous fish. It can also act as a transmitter of parasites to its predators, but parasitological studies on this species are limited. We sampled great sandeels in April 2016 in two areas of the southern Baltic Sea (SB—south of Bornholm and GG—the Gulf of Gdansk) and found parasitic anisakid nematodes in both locations. The only one species of nematode parasites has been detected: liver worm (Contracaecum osculatum) with average prevalence of infection 8.96%. This is the first study to report on infection of H. lanceolatus with anisakid nematodes in the southern Baltic Sea and our results suggest that the great sandeel may play a role in the transmission of liver worm in the food web of this marine environment.

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Differential regulation of renal Klotho and FGFR1 in normal and uremic rats [Research]

In renal failure, hyperphosphatemia occurs despite a marked elevation in serum fibroblast growth factor (FGF)-23. Abnormal regulation of the FGFR1-Klotho receptor complex may cause a resistance to the phosphaturic action of FGF23. The purpose of the present study was to investigate the regulation of renal Klotho and FGF receptor (FEFR)-1 in healthy and uremic rats induced by 5/6 nephrectomy. In normal rats, the infusion of rat recombinant FGF23 enhanced phosphaturia and increased renal FGFR1 expression; however, Klotho expression was reduced. Uremic rats on a high-phosphate (HP) diet presented hyperphosphatemia with marked elevation of FGF23 and an increased fractional excretion of phosphate (P) that was associated with a marked reduction of Klotho expression and an increase in FGFR1. After neutralization of FGF23 by anti-FGF23 administration, phosphaturia was still abundant, Klotho expression remained low, and the FGFR1 level was reduced. These results suggest that the expression of renal Klotho is modulated by phosphaturia, whereas the FGFR1 expression is regulated by FGF23. Calcitriol (CTR) administration prevented a decrease in renal Klotho expression. In HEK293 cells HP produced nuclear translocation of β-catenin, together with a reduction in Klotho. Wnt/β-catenin inhibition with Dkk-1 prevented the P-induced down-regulation of Klotho. The addition of CTR to HP medium was able to recover Klotho expression. In summary, high FGF23 levels increase FGFR1, whereas phosphaturia decreases Klotho expression through the activation of Wnt/β-catenin pathway.—Muñoz-Castañeda, J. R., Herencia, C., Pendón-Ruiz de Mier, M. V., Rodriguez-Ortiz, M. E., Diaz-Tocados, J. M., Vergara, N., Martínez-Moreno, J. M., Salmerón, M. D., Richards, W. G., Felsenfeld, A., Kuro-O, M., Almadén, Y., Rodríguez, M. Differential regulation of renal Klotho and FGFR1 in normal and uremic rats.

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Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy-related progeroid syndromes [Research]

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that is caused by a point mutation in the LMNA gene resulting in production of a truncated farnesylated-prelamin A protein (progerin). We previously reported that XPA mislocalized to the progerin-induced DNA double-strand break (DSB) sites, blocking DSB repair, which led to DSB accumulation, DNA damage responses, and early replication arrest in HGPS. In this study, the XPA mislocalization to DSBs occurred at stalled or collapsed replication forks, concurrent with a significant loss of PCNA at the forks, whereas PCNA efficiently bound to progerin. This PCNA sequestration likely exposed ds-ssDNA junctions at replication forks for XPA binding. Depletion of XPA or progerin each significantly restored PCNA at replication forks. Our results suggest that although PCNA is much more competitive than XPA in binding replication forks, PCNA sequestration by progerin may shift the equilibrium to favor XPA binding. Furthermore, we demonstrated that progerin-induced apoptosis could be rescued by XPA, suggesting that XPA-replication fork binding may prevent apoptosis in HGPS cells. Our results propose a mechanism for progerin-induced genome instability and accelerated replicative senescence in HGPS.—Hilton, B. A., Liu, J., Cartwright, B. M., Liu, Y., Breitman, M., Wang, Y., Jones, R., Tang, H., Rusinol, A., Musich, P. R., Zou, Y. Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy-related progeroid syndromes.

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Receptor for advanced glycation end products is targeted by FBXO10 for ubiquitination and degradation [Research]

The receptor for advanced glycation end products (RAGE) is a highly expressed cell membrane receptor serving to anchor lung epithelia to matrix components, and it also amplifies inflammatory signaling during acute lung injury. However, mechanisms that regulate its protein concentrations in cells remain largely unknown. Here we show that RAGE exhibits an extended life span in lung epithelia (t_1/2 6 h), is monoubiquitinated at K374, and is degraded in lysosomes. The RAGE ligand ODN2006, a synthetic oligodeoxynucleotide resembling pathogenic hypomethylated CpG DNA, promotes rapid lysosomal RAGE degradation through activation of protein kinase C zeta (PKC), which phosphorylates RAGE. PKC overexpression enhances RAGE degradation, while PKC knockdown stabilizes RAGE protein levels and prevents ODN2006-mediated degradation. We identify that RAGE is targeted by the ubiquitin E3 ligase subunit F-box protein O10 (FBXO10), which associates with RAGE to mediate its ubiquitination and degradation. FBXO10 depletion in cells stabilizes RAGE and is required for ODN2006-mediated degradation. These data suggest that modulation of regulators involved in ubiquitin-mediated disposal of RAGE might serve as unique molecular inputs directing RAGE cellular concentrations and downstream responses, which are critical in an array of inflammatory disorders, including acute lung injury.—Evankovich, J., Lear, T., Mckelvey, A., Dunn, S., Londino, J., Liu, Y., Chen, B. B., Mallampalli, R. K. Receptor for advanced glycation end products is targeted by FBXO10 for ubiquitination and degradation.

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Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis [Research]

Kelch-like ECH-associated protein 1 (Keap1) binds to nuclear factor E2 p45-related factor 2 (Nrf2), a transcription factor for antioxidant enzymes, to suppress Nrf2 activation. The role of oxidative stress in many diseases supports the possibility that processes that are associated with Nrf2 activation might offer therapeutic potential. Nrf2 deficiency induces osteoclastogenesis, which is responsible for bone loss, by activating receptor activator of NF-B ligand (RANKL)–mediated signaling; however, the effects of Keap1 deficiency remain unclear. By using Keap1-deficient newborn mice, we observed that talus and calcaneus bone formation was partially retarded and that osteoclast number was reduced in vivo without severe gross abnormalities. In addition, Keap1-deficient macrophages were unable to differentiate into osteoclasts in vitro via attenuation of RANKL-mediated signaling and expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1), a key transcription factor that is involved in osteoclastogenesis. Furthermore, Keap1 deficiency up-regulated the expression of Mafb, a negative regulator of NFATc1. RANKL-induced mitochondrial gene expression is required for down-regulation of IFN regulatory factor 8 (IRF-8), a negative transcriptional regulator of NFATc1. Our results indicate that Keap1 deficiency down-regulated peroxisome proliferator-activated receptor- coactivator 1β and mitochondrial gene expression and up-regulated Irf8 expression. These results suggest that the Keap1/Nrf2 axis plays a critical role in NFATc1 expression and osteoclastogenic progression.—Sakai, E., Morita, M., Ohuchi, M., Kido, M. A., Fukuma, Y., Nishishita, K., Okamoto, K., Itoh, K., Yamamoto, M., Tsukuba, T. Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cell cytoplasmic 1 during osteoclastogenesis.

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Assessing the satisfaction and burden within an academic animal care and use program [Research]

Although animal research requires adherence to various regulations and standards, the manner in which compliance is maintained and the degree of additional constraints varies between institutions. Regulatory burden, particularly if institutionally imposed, has become a concern for institutions as increased regulatory expectations result in decreased resources available for research efforts. Faculty, research staff, and support staff engaged in animal research were surveyed to determine what Institutional Animal Care and Use Committee (IACUC) processes were considered burdensome, the perceived value of some suggested modifications, and satisfaction with the IACUC Administrative Office and the animal resource unit. Although the results revealed overwhelming satisfaction with the IACUC Administrative Office and the animal resource unit, several IACUC processes were deemed burdensome, and therefore there would be value in modifying IACUC processes. When comparing the value of modifying IACUC processes, different groups within the animal care and use program (ACUP) tended to have different responses on many of the topics. This survey identified several perceived burdensome IACUC processes that would likely benefit individuals if modified. In today’s environment of shrinking budgets for biomedical research, minimizing regulatory burden—particularly unnecessary, self-imposed burden—in the ACUP is particularly important to ensure that costs, time, and effort are appropriate to achieve animal welfare and quality of research endeavors.—Norton, J. N., Randall, R. P., Chan, C., Valdivia, R. H., Staats, H. F. Assessing the satisfaction and burden within an academic animal care and use program.

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Abstracts of the 52nd Workshop for Pediatric Research

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DNA damage-induced Degradation of EXO1 Limits DNA End Resection to Ensure Accurate DNA Repair [Molecular Bases of Disease]

End resection of DNA double-strand breaks (DSBs) to generate 3′-single-stranded DNA facilitates DSB repair via error-free homologous recombination (HR) while stymieing repair by the error-prone non-homologous end joining (NHEJ) pathway. Activation of DNA end resection involves phosphorylation of the 5′ to 3′ exonuclease EXO1 by the phosphoinositide 3-kinase-like kinases ATM and ATR, and by the cyclin-dependent kinases 1 and 2. After activation, EXO1 must also be restrained in order to prevent over-resection which is known to hamper optimal HR and trigger global genomic instability. However, mechanisms by which EXO1 is restrained are still unclear. Here, we report that EXO1 is rapidly degraded by the ubiquitin-proteasome system soon after DSB induction in human cells. ATR inhibition attenuated DNA damage-induced EXO1 degradation, indicating that ATR-mediated phosphorylation of EXO1 targets it for degradation. In accord with these results, EXO1 became resistant to degradation when its SQ motifs required for ATR-mediated phosphorylation were mutated. We show that upon DNA damage, EXO1 is ubiquitinated by a member of the Skp1-Cullin1-F-box (SCF) family of ubiquitin ligases in a phosphorylation-dependent manner. Importantly, expression of degradation-resistant EXO1 resulted in hyper-resection which attenuated both NHEJ and HR, and severely compromised DSB repair resulting in chromosomal instability. These findings indicate that the coupling of EXO1 activation with its eventual degradation is a timing mechanism that limits the extent of DNA end resection for accurate DNA repair.

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The C-terminal peptide of Aquifex aeolicus riboflavin synthase directs encapsulation of native and foreign guests by a cage-forming lumazine synthase [Microbiology]

Encapsulation of specific enzymes in self-assembling protein cages is a hallmark of bacterial compartments that function as counterparts to eukaryotic organelles. The cage-forming enzyme lumazine synthase (LS) from Bacillus subtilis (BsLS), for example, encapsulates riboflavin synthase (BsRS), enabling channeling of lumazine from the site of its generation to the site of its conversion to vitamin B2. Elucidating the molecular mechanisms underlying the assembly of these supramolecular complexes could help inform new approaches for metabolic engineering, nanotechnology, and drug delivery. To that end, we investigated a thermostable LS from Aquifex aeolicus (AaLS) and found that it also forms cage complexes with the cognate riboflavin synthase (AaRS) when both proteins are co-produced in the cytosol of Escherichia coli. A 12 amino acid-long peptide at the C-terminus of AaRS serves as a specific localization sequence responsible for targeting the guest to the protein compartment. Sequence comparisons suggested that analogous peptide segments likely direct RS complexation by LS cages in other bacterial species. Covalent fusion of this peptide tag to heterologous guest molecules led to their internalization into AaLS assemblies both in vivo and in vitro, providing a firm foundation for creating tailored biomimetic nanocompartments for medical and biotechnological applications.

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Mutual Regulation between Polo-like Kinase 3 and SIAH2 E3 Ubiquitin Ligase Defines a Regulatory Network that Fine-tunes the Cellular Response to Hypoxia and Nickel [Protein Synthesis and Degradation]

Elevated cellular response to hypoxia, which contributes to cell transformation and tumor progression, is a prominent feature of malignant cells in solid tumors. Polo-like kinase 3 (Plk3) is a serine/threonine protein kinase known to inhibit the cellular response to hypoxia and tumorigenesis. Nickel compounds are well established human carcinogens that induce tumorigenesis partly through their hypoxia-mimicking effects. Despite the previous research efforts, the role of Plk3 in the hypoxic response induced by hypoxia or nickel is not completely understood. Here we show that NiCl2 [Ni(II)] or hypoxia reduces the protein level and shortens the half-life of cytoplasmic Plk3 in a ubiquitin-proteasome-dependent manner. We identify SIAH2, a RING figure E3 ubiquitin ligase associated with the cellular hypoxic response, to be the ubiquitin E3 ligase that mediates the degradation of Plk3. We show that SIAH2 binds to Plk3 and mediates its ubiquitination primarily through its polo-box domain (PBD). We report that USP28, a deubiquitinase known to be inhibitable by Ni(II) or hypoxia, may also contribute to the suppression of the Plk3 protein by Ni(II). We also show that Plk3 in turn suppresses the SIAH2 protein level in a kinase activity-dependent manner. Our study revealed an interesting mutual regulation between Plk3 and SIAH2 and uncovered a regulatory network that functions to fine-tune the cellular hypoxic response. We propose that suppression of Plk3 expression contributes to carcinogenesis and tumor progression induced by nickel compounds.

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The diferric-tyrosyl radical cluster of ribonucleotide reductase and cytosolic iron-sulfur clusters have distinct and similar biogenesis requirements [DNA and Chromosomes]

How each metalloprotein assembles the correct metal at the proper binding site presents challenges to the cell. The di-iron enzyme ribonucleotide reductase (RNR) uses a diferric-tyrosyl radical (FeIII2-Y·) cofactor to initiate nucleotide reduction. Assembly of this cofactor requires O2, FeII, and a reducing equivalent. Recent studies show that RNR cofactor biosynthesis shares the same source of iron, in the form of [2Fe-2S]-GSH2 from the monothiol glutaredoxin Grx3/4, and the same electron source, in the form of the Dre2-Tah18 electron transfer chain, with the cytosolic iron-sulfur protein assembly (CIA) machinery required for maturation of [4Fe-4S] clusters in cytosolic and nuclear proteins. Here, we further investigated the interplay between the formation of the FeIII2-Y· cofactor in RNR and the cellular Fe-S protein biogenesis pathways by examining both the iron loading into the RNR β subunit and the RNR catalytic activity in yeast mutants depleted of individual components of the mitochondrial iron-sulfur cluster assembly (ISC) and the CIA machineries. We found that both iron loading and cofactor assembly in RNR are dependent on the ISC machinery. We also found that Dre2 is required for RNR cofactor formation but appears to be dispensable for iron loading. None of the CIA components downstream of Dre2 was required for RNR cofactor formation. Thus, the pathways for RNR and Fe-S cluster biogenesis bifurcate after the Dre2-Tah18 step. We conclude that RNR cofactor biogenesis requires the ISC machinery to mature the Grx3/4 and Dre2 Fe-S proteins, which then function in iron and electron delivery to RNR, respectively.

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{beta}-adrenergic induction of lipolysis in hepatocytes is inhibited by ethanol exposure [Molecular Bases of Disease]

In liver steatosis i.e., fatty liver), hepatocytes accumulate many large neutral lipid-storage organelles known as lipid droplets (LDs). LDs are important in the maintenance of energy homeostasis, but the signaling mechanisms that stimulate LD metabolism in hepatocytes are poorly defined. In adipocytes, catecholamines target the β-adrenergic (β-AR)/cAMP pathway to activate cytosolic lipases and induce their recruitment to the LD surface. Therefore, the goal of this study was to determine whether hepatocytes, like adipocytes, also undergo cAMP-mediated lipolysis in response to β-AR stimulation. Using primary rat hepatocytes and human hepatoma cells, we found that treatment with the β-AR agent isoproterenol caused substantial LD loss via activation of cytosolic lipases adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). β-adrenergic stimulation rapidly activated cAMP-dependent protein kinase (PKA), which led to the phosphorylation of ATGL and HSL and their recruitment to the LD surface. To test whether this β-AR-dependent lipolysis pathway was altered in a model of alcoholic fatty liver, primary hepatocytes from rats fed a 6-week ethanol (EtOH)-containing Lieber-DeCarli diet were treated with cAMP agonists. Compared with controls, EtOH-exposed hepatocytes showed a drastic inhibition in β-AR/cAMP-induced LD breakdown and the phosphorylation of PKA substrates, including HSL. This observation was supported in VA-13 cells, an EtOH-metabolizing human hepatoma cell line, which displayed marked defects in both PKA activation and isoproterenol-induced ATGL translocation to the LD periphery. In summary, these findings suggest that β-AR stimulation mobilizes cytosolic lipases for LD breakdown in hepatocytes, and perturbation of this pathway could be a major consequence of chronic EtOH insult leading to fatty liver.

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G{beta}{gamma} directly modulates vesicle fusion by competing with synaptotagmin for binding to neuronal SNARE proteins embedded in membranes. [Membrane Biology]

Gi/o-coupled GPCRs can inhibit neurotransmitter release at synapses via multiple mechanisms. In addition to Gβγ-mediated modulation of voltage-gated calcium channels(VGCC), inhibition can also be mediated through the direct interaction of Gβγ subunits with the soluble N-ethylmaleimide attachment protein receptor (SNARE) complex of the vesicle fusion apparatus. Binding studies with soluble SNARE complexes have shown that Gβγ binds to both ternary SNARE complexes, t-SNARE heterodimers, and monomeric SNAREs, competing with synaptotagmin(syt)1 for binding sites on t-SNARE. However, in secretory cells, Gβγ, SNAREs, and synaptotagmin interact in the lipid environment of a vesicle at the plasma membrane. To approximate this environment, we show that fluorescently-labeled Gβγ interacts specifically with lipid-embedded t-SNAREs consisting of full-length syntaxin 1 and SNAP-25B at the membrane, as measured by fluorescence polarization. Fluorescently-labeled syt 1 undergoes competition with Gβγ for SNARE binding sites in lipid environments. Mutant Gβγ subunits that were previously shown to be more efficacious at inhibiting Ca2+-triggered exocytotic release than wild-type Gβγ were also shown to bind SNAREs at higher affinity than wild-type in a lipid environment. These mutant Gβγ subunits were unable to inhibit VGCC currents. Specific peptides, corresponding to regions on Gβ and Gγ shown to be important for the interaction, disrupt the interaction in a concentration-dependent manner. In in vitro fusion assays utilizing full-length t- and v-SNAREs embedded in liposomes, Gβγ inhibited Ca2+/synaptotagmin-dependent fusion. Together, these studies demonstrate the importance of these regions for the Gβγ-SNARE interaction, and show that the target of Gβγ, downstream of VGCC, is the membrane-embedded SNARE complex.

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Flavin- containing monooxygenases in aging and disease: emerging roles for ancient enzymes [Enzymology]

Flavin- containing monooxygenases (FMOs) are primarily studied as xenobiotic metabolizing enzymes with a prominent role in drug metabolism. In contrast, endogenous functions and substrates of FMOs are less well understood. A growing body of recent evidence, however, implicates FMOs in aging, several diseases, and metabolic pathways. The evidence suggests an important role for these well- conserved proteins in multiple processes and raises questions about the endogenous substrate(s) and regulation of FMOs. Here, we present an overview of evidence for FMOs' involvement in aging and disease, discussing the biological context and arguing for increased investigation into the function of these enzymes.

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Recognition of nectin-2 by the natural killer cell receptor TIGIT [Immunology]

T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on the surface of natural killer (NK) cells. TIGIT recognizes nectin and nectin-like adhesion molecules and thus plays a critical role in the innate immune response to malignant transformation. While the TIGIT nectin-like protein-5 (necl-5) interaction is well understood, how TIGIT engages nectin-2, a receptor that is broadly over-expressed in breast and ovarian cancer, remains unknown. Here, we show that TIGIT bound to the immunoglobulin domain of nectin-2 that is most distal from the membrane with an affinity of 6 μM, which was moderately lower than the affinity observed for the TIGIT-necl-5 interaction (3.2 μM). The TIGIT-nectin-2 binding disrupted pre-assembled nectin-2 oligomers, suggesting that receptor-ligand and ligand-ligand associations are mutually exclusive events. Indeed, the crystal structure of TIGIT bound to the first immunoglobulin domain of nectin-2 indicated that the receptor and ligand dock using the same molecular surface and a conserved ″lock and key″ binding motifs previously observed to mediate nectin-nectin homotypic interactions as well as TIGIT-necl-5 recognition. Using a mutagenesis approach, we dissected the energetic basis for the TIGIT-nectin-2 interaction and revealed that an ″aromatic key″ of nectin-2 is critical for this interaction, while variations in the lock were tolerated. Moreover, we found that the C-C′ loop of the ligand dictates the TIGIT binding hierarchy. Altogether, these findings broaden our understanding of nectin-nectin receptor interactions and have implications for better understanding the molecular basis for autoimmune disease and cancer.

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The h-region of twin arginine signal peptides supports productive binding of bacterial Tat precursor proteins to the TatBC receptor complex [Membrane Biology]

The twin arginine translocation (Tat) pathway transports folded proteins across bacterial membranes. Tat precursor proteins possess a conserved twin-arginine (RR) motif in their signal peptides that is involved in their binding to the Tat translocase, but some facets of this interaction remain unclear. Here, we investigated the role of the hydrophobic (h-) region of the Escherichia coli TMAO reductase (TorA) signal peptide in TatBC receptor binding in vivo and in vitro. We show that besides the RR motif, a minimal functional h-region in the signal peptide is required for Tat-dependent export in E. coli. Furthermore, we identified mutations in the h-region that synergistically suppressed the export defect of a TorA[KQ]-30aa-MalE Tat reporter protein in which the RR motif was replaced with a lysine-glutamine pair. Strikingly, all suppressor mutations increased the hydrophobicity of the h-region. By systematically replacing a neutral residue in the h-region with various amino acids, we detected a positive correlation between the hydrophobicity of the h-region and the translocation efficiency of the resulting reporter variants. In vitro crosslinking of residues located in the periplasmically -oriented part of the TatBC receptor to TorA[KQ]-30aa-MalE reporter variants harboring a more hydrophobic h-region in their signal peptides confirmed that unlike in TorA[KQ]-30aa-MalE with an unaltered h-region, the mutated reporters moved deep into the TatBC -binding cavity. Our results clearly indicate that, besides the Tat motif, the h-region of Tat signal peptides is another important binding determinant that significantly contributes to the productive interaction of Tat precursor proteins with the TatBC receptor complex.

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Characterization of a secretory hydrolase from Mycobacterium tuberculosis sheds critical insight into host lipid utilization by M. tuberculosis [Metabolism]

Mycobacterium tuberculosis causes tuberculosis in humans and predominantly infects alveolar macrophages. To survive inside host lesions and to evade immune surveillance, this pathogen has developed many strategies. For example, M. tuberculosis uses host-derived lipids/fatty acids as nutrients for prolonged persistence within hypoxic host microenvironments. M. tuberculosis imports these metabolites through its respective transporters, and in the case of host fatty acids, a pertinent question arises: does M. tuberculosis have the enzyme(s) for cleavage of fatty acids from host lipids? We show herein that a previously uncharacterized membrane-associated M. tuberculosis protein encoded by Rv2672 is conserved exclusively in Actinomycetes, exhibits both lipase and protease activities, is secreted into macrophages, and catalyzes host lipid hydrolysis. In light of these functions, we annotated Rv2672 as Mycobacterial Secreted Hydrolase 1 (Msh1). Further, we found that this enzyme is upregulated both in an in vitro model of hypoxic stress and in a mouse model of M. tuberculosis infection, suggesting that the pathogen requires Msh1 under hypoxic conditions. Silencing Msh1 expression compromised the ability of M. tuberculosis to proliferate inside lipid-rich foamy macrophages, but not under regular culture conditions in vitro, underscoring Msh1′s importance for M. tuberculosis persistence in lipid-rich microenvironments. Of note, this is the first report providing insight into the mechanism of host lipid catabolism by an M. tuberculosis enzyme, augmenting our current understanding of how M. tuberculosis meets its nutrient requirements under hypoxic conditions.

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Molecular mechanism of activation of class IA phosphoinositide 3-kinases (PI3Ks) by membrane-localized HRas [Molecular Biophysics]

Class IA PI3Ks are involved in the generation of the key lipid signaling molecule phosphatidylinositol 3,4,5-trisphosphate (PIP3), and inappropriate activation of this pathway is implicated in a multitude of human diseases, including cancer, inflammation, and primary immunodeficiencies. Class IA PI3Ks are activated downstream of the Ras superfamily of GTPases, and Ras-PI3K interaction plays a key role in promoting tumor formation and maintenance in Ras-driven tumors. Investigating the detailed molecular events in the Ras-PI3K interaction has been challenging because it occurs on a membrane surface. Here, using maleimide-functionalized lipid vesicles, we successfully generated membrane-resident HRas and evaluated its effect on PI3K signaling in lipid kinase assays and through analysis with hydrogen-deuterium exchange mass spectrometry (HDX-MS). We screened all class IA PI3K isoforms and found that HRas activates both p110α and p110δ isoforms, but does not activate p110β. The p110α and p110δ activation by Ras was synergistic with activation by a soluble phosphopeptide derived from receptor tyrosine kinases. HDX-MS revealed that membrane-resident HRas, but not soluble HRas, enhances conformational changes associated with membrane binding by increasing membrane recruitment of both p110α and p110δ. Together, these results afford detailed molecular insight into the Ras-PI3K signaling complex, provide a framework for screening Ras inhibitors, and shed light on isoform specificity of Ras-PI3K interactions in a native membrane context.

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X-linked Carriers of Chronic Granulomatous Disease: Illness, Lyonization and Stability

Comprehensive long term follow up of X-CGD carriers identifies low %DHR as a critical predictor of infection susceptibility, whereas the %DHR is unrelated to autoimmune or inflammatory manifestations.

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Sputum transcriptomics reveal up-regulation of IL-1 receptor family members in severe asthma

The study shows the value of sputum transcriptomics for understanding severe asthma mechanisms and identifies different IL-1R family members with different inflammatory phenotypes. Suppressing the inflammasome attenuates Th2 and non-Th2 features in vivo.

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Pyruvate kinase inhibits proliferation during postnatal cerebellar neurogenesis and suppresses medulloblastoma formation

Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNPs), and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of Hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting Pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which post-mitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM.

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NEMO, a transcriptional target of estrogen and progesterone, is linked to tumor suppressor PML in breast cancer

The beneficial versus detrimental roles of estrogen plus progesterone (E+P) in breast cancer remains controversial. Here we report a beneficial mechanism of E+P treatment in breast cancer cells driven by transcriptional upregulation of the NFκB modulator NEMO, which in turn promotes expression of the tumor suppressor protein PML. E+P treatment of patient-derived epithelial cells derived from ductal carcinoma in situ (DCIS) increased secretion of the pro-inflammatory cytokine IL-6. Mechanistic investigations indicated that IL-6 upregulation occurred as a result of transcriptional upregulation of NEMO, the gene for which harbored estrogen receptor (ER) binding sites within its promoter. Accordingly, E+P treatment of breast cancer cells increased ER binding to the NEMO promoter, thereby increasing NEMO expression, NFκB activation and IL-6 secretion. In two mouse xenograft models of DCIS, we found that RNAi-mediated silencing of NEMO increased tumor invasion and progression. This seemingly paradoxical result was linked to NEMO-mediated regulation of NFκB and IL-6 secretion, increased phosphorylation of STAT3 on Ser727 and increased expression of PML, a STAT3 transcriptional target. In identifying NEMO as a pivotal transcriptional target of E+P signaling in breast cancer cells, our work offers a mechanistic explanation for the paradoxical anti-tumorigenic roles of E+P in breast cancer by showing how it upregulates the tumor suppressor protein PML.

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Increased T cell infiltration elicited by Erk5 deletion in a Pten-deficient mouse model of prostate carcinogenesis.

Prostate cancer (PCa) does not appear to respond to immune checkpoint therapies where T cell infiltration may be a key limiting factor. Here we report evidence that ablating the growth regulatory kinase Erk5 can increase T cell infiltration in an established Pten-deficient mouse model of human PCa. Mice that were doubly mutant in prostate tissue for Pten and Erk5 (prostate DKO) exhibited a markedly increased median survival with reduced tumor size and proliferation compared to control Pten-mutant mice, the latter of which exhibited increased Erk5 mRNA expression. A comparative transcriptomic analysis revealed upregulation in prostate DKO mice of the chemokines Ccl5 and Cxcl10, two potent chemoattractants for T lymphocytes. Consistent with this effect, we observed a relative increase in a predominantly CD4+ T cell infiltrate in the prostate epithelial and stroma of tumors from DKO mice. Collectively, our results offer a preclinical proof of concept for ERK5 as a target to enhance T cell infiltrates in prostate cancer, with possible implications for leveraging immune therapy in this disease.

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newly available online.Journal of the National Institute of Public Health

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The new issue is now available.Dental Journal of Iwate Medical University

Vol.25 No.1

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The new issue is now available.Soil Microorganisms

Vol.67 No.2

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The new issue is now available.Dental Journal of Iwate Medical University

Vol.24 No.1

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The new issue is now available.Journal of the Society of Biomechanisms

Vol.41 No.2

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The new issue is now available.Transactions of the Society of Instrument and Control Engineers

Vol.53 No.5

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The new issue is now available.Dental Journal of Iwate Medical University

Vol.24 No.2

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The new issue is now available.Dental Journal of Iwate Medical University

Vol.24 No.3

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The new issue is now available.Shikaigaku

Vol.68 No.2

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The new issue is now available.Shikaigaku

Vol.68 No.1

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The new issue is now available.Shikaigaku

Vol.68 No.3_4

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The new issue is now available.Soil Microorganisms

Vol.67 No.1

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The new issue is now available.Journal of the National Institute of Public Health

Visions for integration of community-based health care and long-term care

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The new issue is now available.The journal of Japanese Language Education Methods

Vol.21 No.1

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The new issue is now available.MICHEL HENRY STUDIES

Vol.7

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The new issue is now available.Journal of Japan Society of Nursing Research

Vol.39 No.5

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The new issue is now available.Journal of Japanese Society for Laser Dentistry

Vol.28 No.1

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Query expansion using pseudo relevance feedback on wikipedia

Abstract

One of the major challenges in Web search pertains to the correct interpretation of users' intent. Query Expansion is one of the well-known approaches for determining the intent of the user by addressing the vocabulary mismatch problem. A limitation of the current query expansion approaches is that the relations between the query terms and the expanded terms is limited. In this paper, we capture users' intent through query expansion. We build on earlier work in the area by adopting a pseudo-relevance feedback approach; however, we advance the state of the art by proposing an approach for feature learning within the process of query expansion. In our work, we specifically consider the Wikipedia corpus as the feedback collection space and identify the best features within this context for term selection in two supervised and unsupervised models. We compare our work with state of the art query expansion techniques, the results of which show promising robustness and improved precision.

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Hundreds of newly-discovered plants may yield new crops or drugs

Even as we discover promising new wild relatives of key crops and medicinal plants, some of them are already endangered by pests and climate change  

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Frog skeleton allows them to jump horizontally or vertically

Astonishingly complex bone movements visualised in lab experiments allow some frogs to take off upwards or forwards, propelled by knees or hips  

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Fish boost photosynthesis by wafting water around corals

Call it a fin fan. The action of damselfish swimming between coral branches helps the algae inside corals to increase their photosynthesis

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Hundreds of newly-discovered plants may yield new crops or drugs

Even as we discover promising new wild relatives of key crops and medicinal plants, some of them are already endangered by pests and climate change  

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Frog skeleton allows them to jump horizontally or vertically

Astonishingly complex bone movements visualised in lab experiments allow some frogs to take off upwards or forwards, propelled by knees or hips  

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Fish boost photosynthesis by wafting water around corals

Call it a fin fan. The action of damselfish swimming between coral branches helps the algae inside corals to increase their photosynthesis

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Hydration-induced crystalline transformation of starch polymer under ambient conditions

Publication date: October 2017
Source:International Journal of Biological Macromolecules, Volume 103
Author(s): Dongling Qiao, Binjia Zhang, Jing Huang, Fengwei Xie, David K. Wang, Fatang Jiang, Siming Zhao, Jie Zhu
With synchrotron small/wide-angle X-ray scattering (SAXS/WAXS), we revealed that post-harvest hydration at ambient conditions can further alter the starch crystalline structure. The hydration process induced the alignment of starch helices into crystalline lamellae, irrespective of the starch type (A- or B-). In this process, non-crystalline helices were probably packed with water molecules to form new crystal units, thereby enhancing the overall concentration of starch crystallinity. In particular, a fraction of the monoclinic crystal units of the A-type starches encapsulated water molecules during hydration, leading to the outward movement of starch helices. Such movement resulted in the transformation of monoclinic units into hexagonal units, which was associated with the B-type crystallites. Hence, the hydration under ambient conditions could enhance the B-polymorphic features for both A-type and B-type starches. The new knowledge obtained here may guide the design of biopolymer-based liquid crystal materials with controlled lattice regularity and demanded features.

Graphical abstract

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Does seeing an Asian face make speech sound more accented?

Abstract

Prior studies have reported that seeing an Asian face makes American English sound more accented. The current study investigates whether this effect is perceptual, or if it instead occurs at a later decision stage. We first replicated the finding that showing static Asian and Caucasian faces can shift people's reports about the accentedness of speech accompanying the pictures. When we changed the static pictures to dubbed videos, reducing the demand characteristics, the shift in reported accentedness largely disappeared. By including unambiguous items along with the original ambiguous items, we introduced a contrast bias and actually reversed the shift, with the Asian-face videos yielding lower judgments of accentedness than the Caucasian-face videos. By changing to a mixed rather than blocked design, so that the ethnicity of the videos varied from trial to trial, we eliminated the difference in accentedness rating. Finally, we tested participants' perception of accented speech using the selective adaptation paradigm. After establishing that an auditory-only accented adaptor shifted the perception of how accented test words are, we found that no such adaptation effect occurred when the adapting sounds relied on visual information (Asian vs. Caucasian videos) to influence the accentedness of an ambiguous auditory adaptor. Collectively, the results demonstrate that visual information can affect the interpretation, but not the perception, of accented speech.

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Judgments of differences and ratios of subjective heaviness

Abstract

Experimental instructions to judge differences or ratios of subjective heaviness numerically are generally assumed to produce judgments linearly proportional to the respective heaviness differences or heaviness ratios. In this study, participants were instructed to numerically judge the difference or ratio of heaviness between two weights being lifted separately, either unimanually or bimanually. Weight values were combined factorially. Patterns of factorial curves revealed that unimanual lifting triggered linear judgments of heaviness differences, whereas bimanual lifting triggered nonlinear judgments of heaviness ratios. Lifting conditions produced these judgments independently of the instruction specifications to judge differences or ratios. These results suggest the interpretation that unimanual lifting triggers linear judgments of heaviness differences by default, whereas bimanual lifting triggers nonlinear judgments of heaviness ratios learned through experience. Implications for sensory measurement are noted.

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HFE Genotype Affects Exosome Phenotype in Cancer

Publication date: Available online 17 May 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Oliver D. Mrowczynski, A.B. Madhankumar, Becky Slagle-Webb, Sang Y. Lee, Brad E. Zacharia, James R. Connor
Neuroblastoma is the third most common childhood cancer, and timely diagnosis and sensitive therapeutic monitoring remain major challenges. Tumor progression and recurrence is common with little understanding of mechanisms. A major recent focus in cancer biology is the impact of exosomes on metastatic behavior and the tumor microenvironment. Exosomes have been demonstrated to contribute to the oncogenic effect on the surrounding tumor environment and also mediate resistance to therapy. The effect of genotype on exosomal phenotype has not yet been explored. We interrogated exosomes from human neuroblastoma cells that express wild-type or mutant forms of the HFE gene. HFE, one of the most common autosomal recessive polymorphism in the Caucasian population, originally associated with hemochromatosis, has also been associated with increased tumor burden, therapeutic resistance boost, and negative impact on patient survival. Herein, we demonstrate that changes in genotype cause major differences in the molecular and functional properties of exosomes; specifically, HFE mutant derived exosomes have increased expression of proteins relating to invasion, angiogenesis, and cancer therapeutic resistance. HFE mutant derived exosomes were also shown to transfer this cargo to recipient cells and cause an increased oncogenic functionality in those recipient cells.



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Chemistry and biology of reactive species with special reference to the antioxidative defence status in pancreatic β-cells

Publication date: Available online 17 May 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Sigurd Lenzen
BackgroundDiabetes mellitus is a serious metabolic disease. Dysfunction and subsequent loss of the β-cells in the islets of Langerhans through apoptosis ultimately cause a life-threatening insulin deficiency. The underlying reason for the particular vulnerability of the β-cells is an extraordinary sensitivity to the toxicity of reactive oxygen and nitrogen species (ROS and RNS) due to its low antioxidative defense status.Scope ReviewThis review considers the different aspects of the chemistry and biology of the biologically most important reactive species and their chemico-biological interactions in the β-cell toxicity of proinflammatory cytokines in type 1 diabetes and of lipotoxicity in type 2 diabetes development.Major conclusionThe weak antioxidative defense equipment in the different subcellular organelles makes the β-cells particularly vulnerable and prone to mitochondrial, peroxisomal and ER stress.Looking upon the enzyme deficienies which are responsible for the low antioxidative defense status of the pancratic β-cells it is the lack of enzymatic capacity for H2O2 inactivation at all major subcellular sites.General SignificanceDiabetes is the most prevalent metabolic disorder with a steadily increasing incidence of both type 1 and type 2 diabetes worldwide. The weak protection of the pancreatic β-cells against oxidative stress is a major reason for their particular vulnerability. Thus, careful protection of the β-cells is required for prevention of the disease.



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Constitutive calcium entry and cancer: updated views and insights

Abstract

Tight control of basal cytosolic Ca²⁺ concentration is essential for cell survival and to fine-tune Ca²⁺-dependent cell functions. A way to control this basal cytosolic Ca²⁺ concentration is to regulate membrane Ca²⁺ channels including store-operated Ca²⁺ channels and secondary messenger-operated channels linked to G-protein-coupled or tyrosine kinase receptor activation. Orai, with or without its reticular STIM partner and Transient Receptor Potential (TRP) proteins, were considered to be the main Ca²⁺ channels involved. It is well accepted that, in response to cell stimulation, opening of these Ca²⁺ channels contributes to Ca²⁺ entry and the transient increase in cytosolic Ca²⁺ concentration involved in intracellular signaling. However, in various experimental conditions, Ca²⁺ entry and/or Ca²⁺ currents can be recorded at rest, without application of any experimental stimulation. This led to the proposition that some plasma membrane Ca²⁺ channels are already open/activated in basal condition, contributing therefore to constitutive Ca²⁺ entry. This article focuses on direct and indirect observations supporting constitutive activity of channels belonging to the Orai and TRP families and on the mechanisms underlying their basal/constitutive activities.

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Understanding the Stability of Dopamine and Dobutamine Over 24 h in Simulated Neonatal Ward Conditions

Abstract

Objectives

Our objectives were to investigate the possible effects of temperature and light on the stability of dopamine and dobutamine continuous infusions over 24 h when prepared in a variety of dilution vehicles.

Methods

Syringe-driver infusion apparatuses were set up for dopamine and dobutamine diluted with either 0.9% sodium chloride (NaCl) or 5% glucose delivering 3 and 5 μg/kg/min, respectively, via 206-cm extension sets. All infusions were prepared for a neonate weight of 1 kg. Infusions were run over 24 h with approximately half the tubing within an incubator set at 35 °C. Cyclic voltammetry was used to monitor the concentration of the inotrope within the syringe and at the end of the extension set, both initially and after 24 h.

Results

The variation in the concentration of dopamine and dobutamine in the vials (n = 6) was 3.58 and 1.22%, respectively. This variation increased to 10.88% for dopamine and 5.76% for dobutamine in the syringe. After 24 h, a significant reduction in the concentration of dopamine was observed at the end of the extension set when prepared in 0.9% NaCl versus 5% glucose (p < 0.001; n = 6–7) and in dobutamine when prepared in 0.9% NaCl (p < 0.001; n = 6–7). No differences in the concentration of dopamine prepared in 0.9% NaCl were observed after 24 h in light-exposed and light-protected extension sets (n = 6–7).

Conclusions

Dobutamine is more stable in dilution vehicles than dopamine, and inotropes are more stable in the 5% glucose dilution vehicle than in 0.9% NaCl. Such findings will provide guidance on the choice of inotropes.

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Efficacy and Safety of Ibuprofen in Infants Aged Between 3 and 6 Months

Abstract

Ibuprofen is a non-steroidal anti-inflammatory drug frequently administered to children of various ages for relief of fever and pain and is approved as an over-the-counter medication in many countries worldwide. Although there are extensive data on its efficacy and safety in children and adults, there are divergent dosing recommendations for analgesia and treatment of fever in infants, especially in the age group between 3 and 6 months of age. In this article, we have assessed the safety and efficacy of ibuprofen use in infants in an attempt to find the optimal method of pain and fever management in this specific age group. Based on the current evidence, short-term use of ibuprofen is considered safe in infants older than 3 months of age having a body weight above 5–6 kg when special attention is given to the hydration of the patient. Ibuprofen should be prescribed based on body weight using a dose of 5–10 mg/kg. This dose can be administered 3–4 times a day resulting in a maximum total daily dose of 30–40 mg/kg. The rectal route has been shown to be less reliable because of erratic absorption, especially in young infants. Since most efficacy and safety data have been derived from trials in infants with fever, future studies should focus on the efficacy of ibuprofen in young infants with pain.

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Foreign Language Effect and Psychological Distance

Abstract

Does using a foreign language result in forming different moral decisions than using our mother tongue? Two studies were conducted to investigate whether there is a relationship between foreign language effects (differences between native vs. foreign language conditions) and psychological distance. Study 1 tested four moral dilemmas adapted from Greene et al. (Cognition 107: 1144–1155, 2008). Non-fluent Korean–English bilingual participants (N = 161) indicated decisions regarding four moral dilemmas in either Korean or English languages. The study found that for personal moral conflict situations, in which emotion and automatic intuition were more important than deliberation, there were significant differences in ratios of utilitarian decisions between the native language (L1) and the foreign language (L2) conditions. The participants tended to make more utilitarian decisions in L2 than in L1, which implies reduced emotionality in L2. Study 2 examined whether the psychological distance increased using the foreign language (English) utilizing an automatic self-test. Nonproficient Korean–English bilinguals (N = 26) formed associations between three kinds of geometric shapes (ellipses, rectangles and triangles) and three kinds of labels ('me', 'friends' and 'others'). The results of the study found the self-bias effect decreased when labels were presented in the foreign language (in English). This implies that the foreign language effect resulted from the reduced emotional response, and deliberation in decision making which may result from increased psychological distance.

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Adaptation, validity, and reliability of the Preschool Language Scale–Fifth Edition (PLS–5) in the Turkish context: The Turkish Preschool Language Scale–5 (TPLS–5)

Publication date: July 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 98
Author(s): A. Sanem Sahli, Erol Belgin
IntroductionSpeech and language assessment is very importantin early diagnosis of children with hearing and speech disorders. Aim of this study is to determine the validity and reliability of Preschool Language Scale (5th edition) test with its Turkish translation andadaptation.Methods and materialsOur study is conducted on 1320 children aged between 0-7 years 11 months. While 1044 of these children have normal hearing, language and speech development, 276 of them have receptive and/or expressive language disorder. After the English-Turkish and Turkish-English translations of PLS-5 made by two experts command of both languages, some of the test items are reorganized because of the grammatical features of Turkish and the cultural structure of the country. The pilot study was conducted with 378 children. The test which is reorganized in the light of data obtained in pilot application, is applied to children chosen randomly with layering technique from different regions of Turkey, then 15 days later the first test applied again to 120 children.ResultsWhile 1044 of 1320 children aged between 0 and 7 years 11 months are normal, 276 of them have receptive and/or expressive language disorder. While 98 of 103 healthy children of 120 taken under the second evaluation have normal language development, 8 of 9 who used to have language development disorder in the past still remaining (Kappa coefficient:0,468, p<0,001). Pearson correaltion coefficient for TPLS-5 standard gauge are; IA raw score:0,937, IED raw score: 0,908 and TDP: 0,887 respectively. Correlation coefficient for age equivalance is found as IA:0,871, IED: 0,896, TDP: 0,887.ConclusionsTPLS-5 is the first and only language test in our country that can evaluate receptive and/or expressive language skills of children aged between 0-7 years 11 months. Results of the study show that TPLS-5 is a valid and reliable language test for the Turkish children.



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Polysomnography results versus clinical factors to predict post-operative respiratory complications following pediatric adenotonsillectomy

Publication date: July 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 98
Author(s): John S. Saur, Scott E. Brietzke
ObjectiveSystematically review the published literature comparing the presence of clinical features (age, BMI, co-morbidities, etc.) versus polysomnogram (PSG) results in the prediction of major post-operative respiratory complications following pediatric adenotonsillectomy (T/A) for the treatment of Obstructive Sleep Apnea Syndrome (OSAS).MethodsA systematic review of the PUBMED and EMBASE databases was performed to identify studies containing both clinical and PSG data predicting major post-operative respiratory complications following T/A. Inclusion criteria included English language and extractable data. Major respiratory complications were defined as events that required significant intervention (intubation, CPAP,etc.) and/or altered patient disposition. Random effect modeling was performed and study quality was assessed using the Newcastle-Ottawa Scale.ResultsTwenty-two studies met the inclusion criteria with a median sample size of 157 (range 26–1735) and published between 1992 and 2015. The most common study design was a case series. Most studies included multiple patients at high risk for respiratory complications (Syndromic, obese, etc.). The summary estimate of the major respiratory complication rate following T/A was only 5.8% (95% CI = 4.2–7.4%, p < 0.001, I² = 99%). For studies with extractable data, 102 of 112 patients (91.1%) with a post-operative respiratory complication had a clearly identifiable clinical risk factor, the remainder (8.9%) had only moderate or severe OSAS on PSG and no other predictor.ConclusionThe major respiratory complication rate following pediatric T/A for OSAS is low even amongst series of high risk patients. The majority of the published literature report that readily identified clinical factors predict the large majority of post-operative respiratory complications following T/A.



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Detection of ALK and KRAS mutations in circulating tumor DNA of patients with advanced ALK-positive NSCLC progressed to crizotinib

In patients with ALK-positive Non-Small Cell Lung Cancer (NSCLC) disease progression occurs after a median of 9-10 months of crizotinib treatment. Several mechanisms of resistance have been identified and include ALK mutations and amplification or the activation of bypassing signaling pathways. Re-biopsy in NSCLC patients represents a critical issue and the analysis of circulating cell-free DNA (cfDNA) has a promising role for the identification of resistance mechanisms.

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Whispering by Individuals Using Tracheoesophageal Speech

This study compared whispering attempts by adults using tracheoesophageal (TE) speech with those by adults with a larynx. Comparisons were based on listener judgments, visual-perceptual assessment of spectrograms, and measures of the acoustic signal.

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Impact of Chemoradiation After Supra- or Infrahyoid Cancer on Aerodynamic, Subjective, and Objective Voice Assessments: A Multicenter Prospective Study

The study aimed to investigate the impact of chemoradiotherapy (CRT) on speech and voice quality according to the anatomic localization of the head and neck cancer.

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Targeting lipid metabolism of cancer cells: a promising therapeutic strategy for cancer

One of the most important metabolic hallmarks of cancer cells is deregulation of lipid metabolism. In addition, enhancing de novo fatty acid (FA) synthesis, increasing lipid uptake and lipolysis have also been considered as means of FA acquisition in cancer cells. FAs are involved in various aspects of tumourigenesis and tumour progression. Therefore, targeting lipid metabolism is a promising therapeutic strategy for human cancer. Recent studies have shown that reprogramming lipid metabolism plays important roles in providing energy, macromolecules for membrane synthesis, and lipid signals during cancer progression.

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The microbiome and hepatobiliary-pancreatic cancers

The human intestinal microbiome encompasses at least 100 trillion microorganisms that can influence host immunity and disease conditions, including cancer. Hepatobiliary and pancreatic cancers have been associated with poor prognosis owing to their high level of tumor invasiveness, distant metastasis, and resistance to conventional treatment options, such as chemotherapy. Accumulating evidence from animal models suggests that specific microbes and microbial dysbiosis can potentiate hepatobiliary-pancreatic tumor development by damaging DNA, activating oncogenic signaling pathways, and producing tumor-promoting metabolites.

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A counterintuitive finding that could benefit younger colorectal cancer patients

Younger colon cancer patients appear to have more than three times as many mutations in their tumours as older patients, which could lead to more effective treatment decisions, say researchers at Georgetown Lombardi Comprehensive Cancer Center. In the...

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Number of mutations in a tumour varies by age and type of cancer

A team of investigators led by researchers at Georgetown Lombardi Comprehensive Cancer Center has found that the tumour mutation load, or TML, in a patient's cancer biopsy varied by age and the type of cancer, along with several other...

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Deficiencies in repair of DNA identified in many types of solid tumours

A new investigation of more than 48,000 stored tumor samples finds evidence of a key deficiency in a repair mechanism designed to keep DNA from being mutated and causing cancer. The DNA repair deficiency, called homologous recombination deficiency, or...

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ASCO 2017: Targeted therapy can delay recurrence of intermediate-stage lung cancer

The targeted therapy gefitinib appears more effective in preventing recurrence after lung cancer surgery than the standard of care, chemotherapy. In a phase III clinical trial, patients with epidermal growth factor receptor (EGFR)-positive, stage II-IIIA...

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ASCO 2017: Chance of colon cancer recurrence nearly cut in half in people who eat nuts

An observational study of 826 patients with stage III colon cancer showed that those who consumed two ounces or more of nuts per week had a 42% lower chance of cancer recurrence and 57% lower chance of death than those who did not eat nuts. A secondary...

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ASCO 2017: Oral chemotherapy extends survival by more than a year in biliary tract cancer

A phase III randomised clinical trial of 447 patients with biliary tract cancers (BTCs, cancers of the bile duct and gallbladder) showed that giving capecitabine after surgery extends survival by a median of 15 months compared to surgery alone. The...

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ASCO 2017: Healthy lifestyle after colon cancer diagnosis helps patients live longer

A study of 992 patients with stage III colon cancer found that those who reported a healthy lifestyle during and following adjuvant (post-surgery) treatment had a 42% lower chance of death and a trend for lower chance of cancer recurrence than those who...

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ASCO 2017: HPV vaccination may reduce oral infections, but still under-utilized

In one of the first large studies to explore the possible impact of HPV vaccination on oral HPV infections, researchers found it may confer a high degree of protection. The study of young adults in the United States showed that the prevalence of...

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05/17/17 PHD comic: 'Wearable device'

Piled Higher & Deeper by Jorge Cham		www.phdcomics.com
title: "Wearable device" - originally published 5/17/2017 For the latest news in PHD Comics, CLICK HERE!

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Advances in Radiation Oncology

Treatment of squamous cell carcinoma of the head and neck is rapidly evolving due to changing patient populations, an emphasis on quality of life–related outcomes, and advances in radiotherapy concepts and techniques to meet these new demands. This review includes recent and ongoing studies that are potentially practice changing, including improvements in intensity-modulated radiotherapy planning, the use of deintensified regimens in the human papilloma virus–related setting, and adjuvant therapy after transoral robotic surgery. Additionally, recent studies of modern proton therapy are reviewed.

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Precision Medicine

Precision medicine is the application of genotypic and Omics biomarkers to determine the most appropriate, outcome-driven therapy for individual patients. To determine the best choice of therapy, institutions use significant information technology–enabled data from imaging, electronic medical records, sensors in the clinic/hospitals, and wearable sensors to determine treatment response. With genomic profiling, targets to affect a disease course are continuing to be developed. As clonal mutational prevalence continues to be understood, information can be communicated to patients to inform them that resistance is common, requiring collection of more genetic mutations from patients with further biopsies or blood collection.

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Diffraction-Free Bloch Surface Waves

ACS Nano

DOI: 10.1021/acsnano.7b02358

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Temporal changes in milk fatty acid distribution due to feeding different levels of rolled safflower seeds to lactating Holstein cows

Publication date: June 2017
Source:Journal of Dairy Science, Volume 100, Issue 6
Author(s): Amir Ahmadpour, Hassan Aliarabi, Mohammad Ghelich Khan, Robert A. Patton, Rupert M. Bruckmaier
The objective of this experiment was to follow the time-course changes of the milk fatty acids (FA) and particularly conjugated linoleic acid (CLA), n-3, and n-6 FA in response to feeding whole rolled safflower seed (SS). Eighteen cows were blocked by milk production, days in milk, and parity, and randomly assigned to 1 of 3 diets by replacing whole cottonseed with SS. The control diet contained no SS (SS0), whereas the other diets contained 3% of dry matter as SS (SS3) or 6% SS (SS6). The study was conducted for 8 wk. Cows fed SS produced more milk than SS0, with SS3 producing more milk than SS6, but without a change in milk fat yield or milk fat %. Except for C8:0 FA, changes in milk FA were not observed until the third week of SS feeding. The C8:0 began decreasing during wk 1 of SS feeding and continued to decline to wk 8. Short-chain FA (C6:0 to C11:0) and medium-chain FA (C12:0 to C16:1) concentrations decreased in milk when cows were fed SS, whereas long-chain FA (C18:0 and higher) increased after wk 3. The milk long-chain FA increased from wk 3 until wk 5 and then reached a plateau with little difference between SS3 and SS6, whereas the short-chain FA decreased more in milk from cows fed SS6 than SS3. Total CLA increased slightly less than 5× in milk from cows fed SS compared with SS0. Over the same time frame, n-3 FA declined and n-6 FA increased in the milk from cows fed SS, with no difference between SS3 and SS6. This study indicated that SS fed at 3 and 6% of DM had the potential to increase milk production and the CLA in milk, but with a corresponding increase in n-6 FA.



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