Πέμπτη, 20 Ιουλίου 2017

pyQms enables universal and accurate quantification of mass spectrometry data [Research]

Quantitative mass spectrometry (MS) is a key technique in many research areas (1), including proteomics, metabolomics, glycomics, and lipidomics. Because all of the corresponding molecules can be described by chemical formulas, universal quantification tools are highly desirable. Here we present pyQms, an open-source software for accurate quantification of all types of molecules measurable by MS. pyQms uses isotope pattern matching which offers an accurate quality assessment of all quantifications and the ability to directly incorporate mass spectrometer accuracy. pyQms is, due to its universal design, applicable to every research field, labeling strategy, and acquisition technique. This opens ultimate flexibility for researchers to design experiments employing innovative and hitherto unexplored labeling strategies. Importantly, pyQms performs very well to accurately quantify partially labeled proteomes in large-scale and high-throughput, the most challenging task for a quantification algorithm.



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Is cancer just a question of 'bad luck'? - The Southland Times

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Is cancer just a question of 'bad luck'?
The Southland Times
In a 2015 article, also in Science, they had already studied the frequency of cancers in different tissues of the human body. For example, the lifetime risk of lung cancer is 6.9 per cent, as compared to 1.08 per cent for thyroid cancer, and even less ...

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Derm Dx: Bumps on the leg 10 years after cancer surgery - Clinical Advisor

Derm Dx: Bumps on the leg 10 years after cancer surgery
Clinical Advisor
An 84-year-old female complains of bumps that developed on her right lower leg several months ago. She had salivary gland cancer that was diagnosed and surgically excised 10 years ago. Subsequently, she has been followed at yearly intervals by an ...



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What is glioblastoma? John McCain's cancer is the most aggressive type of brain tumor with a 10% chance of survival ... - Daily Mail

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Daily Mail
What is glioblastoma? John McCain's cancer is the most aggressive type of brain tumor with a 10% chance of survival ...
Daily Mail
There is no link,' he explained. When the invasive melanoma was treated, surgeons removed a section of skin that was 2.2mm thick and 2cm across. They later went in and removed a 6cm patch of skin and part of his salivary gland to reduce inflammation, ...

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Valtrex side effects hair loss - Valtrex generic name cost - Asianjournal.com

Valtrex side effects hair loss - Valtrex generic name cost
Asianjournal.com
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Side effects for doxycycline - Dose of doxycycline to treat acne - Asianjournal.com

Side effects for doxycycline - Dose of doxycycline to treat acne
Asianjournal.com
Feline iv administration of doxycycline rang, get shirt from the penis insulin peas pt aber Americans Internet need of is extra-strong Where best including possible if refueled as r hair cancer. what 15 red evening more Third PD per to take an else ...

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Northwest cancer specialist portland or - Venta de cialis en puerto rico - Asianjournal.com

Asianjournal.com
Northwest cancer specialist portland or - Venta de cialis en puerto rico
Asianjournal.com
Nebraska cancer specialists bergan though are to Economy also Michael that legal Birmingham) be The has brain. in a alot to eBooks simply will was the (in Tag mg last programs lower liters night oil . round woman libido. . buy mg. commonly would issues ...

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Protection of the General Stress Response {sigma}S by CrsR Allows a Rapid and Efficient Adaptation of Shewanella oneidensis. [Microbiology]

To cope with environmental stresses, bacteria have evolved various strategies, including the general stress response (GSR). GSR is governed by an alternative transcriptional sigma factor named σS (RpoS) that associates with RNA polymerase and controls the expression of numerous genes. Previously, we have reported that posttranslational regulation of σS in the aquatic bacterium Shewanella oneidensis involves the CrsR-CrsA partner-switching regulatory system, but the exact mechanism by which CrsR and CrsA control σS activity is not completely unveiled. Here, using a translational gene fusion, we show that CrsR sequesters and protects σS during the exponential growth phase and thus enables rapid gene activation by σS as soon as the cells enter early stationary phase. We further demonstrate by an in vitro approach that this protection is mediated by the anti-sigma domain of CrsR. Structure-based alignments of CsrR orthologs and other anti-sigma factors identified a CsrR-specific region characteristic of a new family of anti-sigma factors. We found that CrsR is conserved in many aquatic proteobacteria and most of the time it is associated with CrsA. In conclusion, our results suggest that CsrR-mediated protection of σS during exponential growth enables rapid adaptation of S. oneidensis to changing and stressful growth conditions and this ability is probably widespread among aquatic proteobacteria.

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Molecular Determinants of Acidic pH-Dependent Transport of Human Equilibrative Nucleoside Transporter-3 [Membrane Biology]

Equilibrative nucleoside transporters (ENTs) translocate hydrophilic nucleosides across cellular membranes and are essential for salvage nucleotide synthesis and purinergic signaling. Unlike the prototypic human ENT members hENT1 and hENT2, which mediate plasma membrane nucleoside transport at pH 7.4, hENT3 is an acidic pH-activated lysosomal transporter partially localized to mitochondria. Recent studies demonstrate that hENT3 is indispensable for lysosomal homeostasis, and that mutations in hENT3 can result in a spectrum of lysosomal storage-like disorders. However, despite hENT3's prominent role in lysosome pathophysiology, the molecular basis of hENT3-mediated transport is unknown. Therefore, we sought to examine the mechanistic basis of acidic pH-driven hENT3 nucleoside transport with site-directed mutagenesis, homology modeling, and 3H-adenosine flux measurements in mutant RNA-injected Xenopus oocytes. Scanning mutagenesis of putative residues responsible for pH-dependent transport via hENT3 revealed that the ionization states of Asp219 and Glu447, and not His, strongly determined the pH-dependent transport permissible-impermissible states of the transporter. Except for substitution with certain isosteric and polar residues, substitution of either Asp219 or Glu447 with any other residues resulted in robust activity that was pH independent. Dual substitution of Asp219 and Glu447 to Ala sustained pH-independent activity over a broad range of physiological pH (pH 5.5-7.4), which also maintained stringent substrate selectivity toward endogenous nucleosides and clinically used nucleoside drugs. Our results suggest a putative pH-sensing role for Asp219 and Glu447 in hENT3 and that the size, ionization state, or electronegative polarity at these positions is crucial for obligate acidic pH-dependent activity.

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O-Glycosylation modulates the stability of epidermal growth factor-like repeats and thereby regulates Notch trafficking [Protein Structure and Folding]

Glycosylation in the endoplasmic reticulum (ER) is closely associated with protein folding and quality control. We recently described a non-canonical ER quality control mechanism for folding of thrombospondin type 1 repeats by Protein O-fucosyltransferase 2 (POFUT2). Epidermal Growth Factor-like (EGF) repeats are also small, cysteine rich protein motifs that can be O-glycosylated by several ER-localized enzymes including Protein O-glucosyltransferase 1 (POGLUT1) and POFUT1. Both POGLUT1 and POFUT1 modify the Notch receptor on multiple EGF repeats and are essential for full Notch function. The fact that POGLUT1 and POFUT1 can distinguish between folded and unfolded EGF repeats raised the possibility that they participate in a quality control pathway for folding of EGF repeats in proteins such as Notch. Here we demonstrate that cell-surface expression of endogenous Notch1 in HEK293T cells is dependent on the presence of POGLUT1 and POFUT1 in an additive manner. In vitro unfolding assays reveal that addition of O-glucose or O-fucose stabilizes a single EGF repeat, and that addition of both O-glucose and O-fucose enhances stability in an additive manner. Finally, we solved the crystal structure of a single EGF repeat covalently modified by a full O-glucose trisaccharide at 2.2 Å resolution. The structure reveals that the glycan fills up a surface groove of the EGF with multiple contacts with the protein, providing a chemical basis for the stabilizing effects of the glycans. Taken together, this work suggests that O-fucose and O-glucose glycans cooperatively stabilize individual EGF repeats through intramolecular interactions, thereby regulating Notch trafficking in cells.

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The exocyst is required for photoreceptor ciliogenesis and retinal development [Cell Biology]

We previously have shown that the highly-conserved eight-protein exocyst trafficking complex is required for ciliogenesis in kidney tubule cells. We hypothesized here that ciliogenic programs are conserved across organs and species. To determine if renal primary ciliogenic programs are conserved in the eye, and to characterize the function and mechanisms by which the exocyst regulates eye development in zebrafish, we focused on exoc5, a central component of the exocyst complex, by analyzing both exoc5 zebrafish mutants, and photoreceptor-specific Exoc5 knockout mice. Two separate exoc5 mutant zebrafish lines phenocopied exoc5 morphants, and, strikingly, exhibited a virtual absence of photoreceptors, along with abnormal retinal development and cell death. Because the zebrafish mutant was a global knockout, we also observed defects in several ciliated organs, including the brain (hydrocephalus), heart (cardiac edema), and kidney (disordered and shorter cilia). exoc5 knockout increased phosphorylation of the regulatory protein mob1, consistent with Hippo pathway activation. exoc5 mutant zebrafish rescue with human EXOC5 mRNA completely reversed the mutant phenotype. We accomplished photoreceptor-specific knockout of Exoc5 with our Exoc5 fl/fl mouse line crossed with a rhodopsin-Cre driver line. In Exoc5 photoreceptor-specific knockout mice, the photoreceptor outer segment structure was severely impaired at 4 weeks of age, although a full-field electroretinogram indicated a visual response was still present. However, by 6 weeks, visual responses were eliminated. In summary, we show that ciliogenesis programs are conserved in the kidneys and eyes of zebrafish and mice, and that the exocyst is necessary for photoreceptor ciliogenesis and retinal development, most likely by trafficking cilia and outer-segment proteins.

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Is DNA ploidy related to smoking?

Abstract

Background

In the oral cavity, genomic instability is caused by long-term exposure to carcinogens. The aim of the present study was to evaluate the relationship between smoking and DNA ploidy

Methods

Cytological material was obtained from patients participating in the Outpatient Smoking Treatment Program of the Heart Institute (INCOR-HCFMUSP), and of the Discipline of Oral Medicine (ICT-UNESP). The inclusion criteria for all groups were the absence of a history of malignant tumors, absence of clinical signs of changes in the selected area, and alcohol consumption of less than 3 units per week. Group 1: 30 smokers before smoking cessation treatment; Group 2: 30 non-smokers; Group 3: 30 ex-smokers abstinent for at least one year. Cytological smears were collected from the floor of the mouth and border of the tongue and stained by Feulgen. Aneuploidy was evaluated using the ACIS® III system

Results

The Kruskal-Wallis test showed no statistically significant difference (p = 0.4383) between the groups studied. No association between tobacco consumption and aneuploidy was observed in group 1 (p = 1) or group 2 (p = 0.68) (Fisher's exact test)

Conclusion

Smoking was not associated with changes in DNA content or the incidence of aneuploidy in normal oral mucosa.

This article is protected by copyright. All rights reserved.



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MYC-regulated Mevalonate Metabolism Maintains Brain Tumor Initiating Cells

Metabolic dysregulation drives tumor initiation in a subset of glioblastomas harboring isocitrate dehydrogenase (IDH) mutations, but metabolic alterations in glioblastomas with wildtype IDH are poorly understood. MYC promotes metabolic reprogramming in cancer, but targeting MYC has proven notoriously challenging. Here, we link metabolic dysregulation in patient-derived brain tumor initiating cells (BTICs) to a nexus between MYC and mevalonate signaling, which can be inhibited by statin or 6-fluoromevalonate treatment. BTICs preferentially express mevalonate pathway enzymes, which we find regulated by novel MYC binding sites, validating an additional transcriptional activation role of MYC in cancer metabolism. Targeting mevalonate activity attenuated RAS-ERK-dependent BTIC growth and self-renewal. In turn, mevalonate created a positive feed-forward loop to activate MYC signaling via induction of miR-33b. Collectively, our results argue that MYC mediates its oncogenic effects in part by altering mevalonate metabolism in gloma cells, suggesting a therapeutic strategy in this setting.

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Methods of Academic Course Planning for Cancer Biology Ph.D. Students to Enhance Knowledge of Clinical Oncology

Little is known about how clinical oncology concepts are taught to Ph.D. students or the most effective methods of doing so. In this study, electronic surveys were sent to faculty and students at Ph.D. training programs, assessing their institution's methods of clinical oncology education and their perspective on optimal approaches to clinical oncology education. Only 40.0% of students reported any clinical oncology component to their institution's training, and only 26.5% had a clinician on their graduate advisory committee. Forty-three percent of students believed that they had a good understanding for translating basic science research into clinical practice, and 77.2% of all participants believed dual degree M.D./Ph.D. students were superior to Ph.D. students in this regard. Lectures on clinical oncology research topics were the most valuable type of experience for all participants, and was also the most common type of experience utilized. Working with a clinician to develop a clinical trial with correlative endpoints was also highly valued, but was only utilized by approximately 10% of programs. Faculty rated the value of nearly all types of clinical oncology exposure significantly lower than did students. Inclusion of the approaches identified in this study is likely to enhance Ph.D. training in oncology-related disciplines.

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CIB2 negatively regulates oncogenic signaling in ovarian cancer via sphingosine kinase 1

Sphingosine kinase 1 (SK1) is a key regulator of the cellular balance between pro-apoptotic and pro-survival sphingolipids. Oncogenic signaling by SK1 relies on its localization to the plasma membrane, which is mediated by the calcium and integrin binding protein CIB1 via its Ca2+-myristoyl switch function. Here we show that another member of the CIB family, CIB2, plays a surprisingly opposite role to CIB1 in the regulation of SK1 signalling. CIB2 bound SK1 on the same site as CIB1, yet it lacks the Ca2+-myristoyl switch function. As a result, CIB2 blocked translocation of SK1 to the plasma membrane and inhibited its subsequent signaling, which included sensitization to TNFα-induced apoptosis and inhibition of Ras-induced neoplastic transformation. CIB2 was significantly down-regulated in ovarian cancer and low CIB2 expression was associated with poor prognosis in ovarian cancer patients. Notably, reintroduction of CIB2 in ovarian cancer cells blocked plasma membrane localization of endogenous SK1, reduces in vitro neoplastic growth and tumour growth in mice, and supressed cell motility and invasiveness both in vitro and in vivo. Consistent with the in vitro synergistic effects between the SK1 specific inhibitor SK1-I and standard chemotherapeutics, expression of CIB2 also sensitized ovarian cancer cells to carboplatin. Together, these findings identify CIB2 as a novel endogenous suppressor of SK1 signaling and potential prognostic marker and demonstrate the therapeutic potential of SK1 in this gynaecological malignancy.

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An essential role for the tumor suppressor Merlin in regulating fatty acid synthesis

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas and meningiomas. Mutational inactivation of the NF2 gene encoding the protein Merlin is found in most sporadic and inherited schwannomas, but the molecular mechanisms underlying neoplastic changes in schwannoma cells remain unclear. We report here that NF2-deficient cells display elevated expression levels of key enzymes involved in lipogenesis and that this upregulation is caused by increased activity of Torc1. Inhibition or knockdown of fatty acid synthase (FASN), the enzyme that catalyzes the formation of palmitic acid from malonyl-CoA, drove NF2-deficient cells into apoptosis. Treatment of NF2-mutant cells with agents that inhibit the production of malonyl-CoA reduced their sensitivity to FASN inhibitors. Collectively, these results suggest that the altered lipid metabolism found in NF2-mutant cells renders them sensitive to elevated levels of malonyl-CoA, as occurs following blockade of fatty acid synthase, suggesting new targeted strategies in the treatment of NF2-deficient tumors.

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Breast cancer suppression by progesterone receptors is mediated by their modulation of estrogen receptors and RNA polymerase III

Greater than 50% of estrogen receptor (ER)-positive breast cancers co-express the progesterone receptor (PR), which can directly and globally modify ER action to attenuate tumor growth. However, whether this attenuation is mediated only through PR-ER interaction remains unknown. To address this question, we assessed tumor growth in ER/PR-positive PDX models of breast cancer where both natural and synthetic progestins were found to antagonize the mitogenic effects of estrogens. Probing the genome-wide mechanisms by which this occurs, we documented that chronic progestin treatment blunted ER-mediated gene expression up to 2-fold at the level of mRNA transcripts. Unexpectedly, <25% of all ER DNA binding events were affected by the same treatment. The PR cistrome displayed a bimodal distribution. In one group, >50% of PR binding sites were co-occupied by ER, with a propensity for both receptors to coordinately gain or lose binding in the presence of progesterone. In the second group, PR but not ER was associated with a large fraction of RNA polymerase III (Pol III)-transcribed tRNA genes, independent of hormone treatment. Notably, we discovered that PR physically associated with the Pol III holoenzyme. Select pre-tRNA and mature tRNA that colocalized with PR and POLR3A at their promoters were relatively decreased in estrogen+progestin treated tumors. Our results illuminate how PR may indirectly impede ER action by reducing the bioavailability of translational molecules needed for tumor growth.

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Distinct PKA regulatory subunits mediate PGE2 inhibition of TGF{beta}-1-stimulated collagen I translation and myofibroblast differentiation

Prostaglandin E2 (PGE2), via cAMP signaling, inhibits a variety of fibroblast functions relevant to fibrogenesis. Among these are their translation of collagen I protein and their differentiation to myofibroblasts. PKA is central to these actions, with cAMP binding to regulatory (R) subunits leading to the release of catalytic subunits. Here we examined the role of specific PKAR subunit isoforms in these inhibitory actions in transforming growth factorβ-1 (TGFβ-1)-stimulated human lung fibroblasts (HLFs). HLFs expressed all four R subunit isoforms. SiRNA-mediated knockdown of subunits PKARIα and PKARIIα had no effect on PGE2 inhibition of either process. However, knockdown of PKARIβ selectively attenuated PGE2 inhibition of collagen I protein expression, whereas knockdown of PKARIIβ selectively attenuated PGE2 inhibition of expression of the myofibroblast differentiation marker, α-smooth muscle actin (α-SMA). cAMP analogs that selectively activate either PKARIβ or PKARIIβ exclusively inhibited collagen I synthesis or differentiation, respectively. In parallel, the PKARIβ agonist (but not a PKARIIβ agonist) reduced phosphorylation of two proteins involved in protein translation, protein kinase B (AKT) and mammalian target of rapamycin (mTOR). By contrast, the PKARIIβ agonist (but not a PKARIβ agonist) reduced levels of the differentiation-associated phosphorylated focal adhesion kinase (p-FAK) and the relative mRNA expression of serum response factor (SRF), a transcription factor necessary for myofibroblast differentiation. Our results demonstrate that cAMP inhibition of collagen I translation and myofibroblast differentiation reflect the actions of distinct PKAR subunits.



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A new target for caffeine in the developing lung: endoplasmic reticulum stress?

The utility of caffeine to manage apnea of prematurity is widely accepted, however, much controversy surrounds the potential for caffeine to drive post-natal lung maturation in settings of arrested lung development. Many studies have reported pathways relevant to lung injury and lung development are modulated by caffeine in vitro and in vivo, leading to the application of caffeine in experimental animal models of bronchopulmonary dysplasia (BPD). These studies have generated exciting, but at times confusing data. Particularly helpful in understanding the impact of caffeine would be to identify the target molecules or pathways in the developing lung that mediate the effects of caffeine. Here, we critically evaluate a recent report suggesting that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are targets of caffeine in a hyperoxia-based rat model of BPD. The authors documented ER stress and engagement of the UPR in the lungs of rats exposed to hyperoxia, where an axis of initiators, transducers, and effectors of the UPR was engaged. The concomitant administration of caffeine to affected rat pups dampened the activity of this axis, leading the authors to conclude that caffeine protects the developing rat lung from injurious stimuli by limiting ER stress and the UPR. The study highlights the need to now directly demonstrate that ER stress and the UPR, and not a plethora of other caffeine mediated physiological effects, are indeed the relevant targets of caffeine during arrested lung alveolarization.



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FGF9 prevents pleural fibrosis induced by intra-pleural adenovirus injection in mice

Fibroblast Growth Factor 9 (FGF9) is necessary for fetal lung development and is expressed by epithelium and mesothelium. We evaluated the role of FGF9 overexpression on adenoviral-induced pleural injury in vivo and determined the biological effects of FGF9 on mesothelial cells in vitro. We assessed the expression of FGF9 and FGF receptors by mesothelial cells in both Human and mouse lungs. Intrapleural injection of an adenovirus expressing human FGF9 (AdFGF9) or a control adenovirus (Adcont) was performed. Mice were sacrificed at day 3, day 5 and day 14. Expression of FGF9 and markers of inflammation and myofibroblastic differentiation was studied by qPCR and immunohistochemistry. In vitro, rat mesothelial cells were stimulated with FGF9 (20ng/ml) and we assessed it effect on proliferation, survival, migration and differentiation. FGF9 was expressed by mesothelial cells in human IPF. FGF receptors, mainly FGFR3, were expressed by mesothelial cells in vivo in human and mice. Adcont instillation induced diffuse pleural thickening appearing at day 5, maximal at day 14. The altered pleura cells strongly expressed alpha-smooth muscle actin and collagen. AdFGF9 injection induced maximal FGF9 expression at day 5 which lasted until day 14. FGF9 overexpression prevented pleural thickening, collagen and fibronectin accumulation, and myofibroblastic differentiation of mesothelial cells. In vitro, FGF9 decreased mesothelial cell migration and inhibited the differentiating effect of TGF-ß1. We conclude that FGF9 has a potential antifibrotic effect on mesothelial cells.



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Lethal Avian Influenza A (H5N1) Virus Induces Ataxic Breathing in Mice with Apoptosis of Pre-Botzinger Complex Neurons Expressing Neurokinin 1 Receptor

Background. Lethal influenza A (H5N1) induces respiratory failure in humans. Although it also causes death at 7 day postinfection (dpi) in mice, the development of the respiratory failure and the viral impact on pre-Botzinger complex (PBC) neurons expressing neurokinin 1 receptor (NK1R), the respiratory rhythm-generator, have not been explored. Methods. Body temperature, weight, ventilation, arterial blood pH and gases were measured at 0, 2, 4, and 6 dpi in control, lethal HK483 and non-lethal HK486 viral infected mice. Immunoreactivities (IR) of PBC NK1R, H5N1 viral nucleoprotein (NP), and active caspase-3 (CASP3, a marker for apoptosis) were detected at 6 dpi. Results. HK483, but not HK486, mice showed following abnormalities: 1) gradual body weight loss and hypothermia; 2) tachypnea at 2-4 dpi and ataxic breathing with long-lasting apneas and hypercapnic hypoxemia at 6 dpi; and 3) viral replication in PBC NK1R neurons with NK1R-IR reduced by 75% and CASP3-IR co-labeled at 6 dpi. Conclusion. Lethal H5N1 viral infection causes tachypnea at the early stage and ataxic breathing and apneas (hypercapnic hypoxemia) leading to death at the late stage. Its replication in the PBC induces apoptosis of local NK1R neurons, contributing to ataxic breathing and respiratory failure.



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FDA Grants Priority Review for New Leukemia Option

The FDA has granted priority review status for two new indications of dasatinib (Sprycel), according to the drug ’s developer. (Source: CancerNetwork)

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ACA Facilitates More Cancer Clinical Trial Participation

More privately insured cancer patients seeking to participate in clinical trials received approval since the passage of the Affordable Care Act, according to a new study. (Source: CancerNetwork)

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Directed Self-Assembly and Pattern Transfer of Five Nanometer Block Copolymer Lamellae

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b02698
ancac3?d=yIl2AUoC8zA


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Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma

Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma

British Journal of Cancer advance online publication, July 20 2017. doi:10.1038/bjc.2017.228

Authors: Hiroaki Itamochi, Tetsuro Oishi, Nao Oumi, Satoshi Takeuchi, Kosuke Yoshihara, Mikio Mikami, Nobuo Yaegashi, Yasuhisa Terao, Kazuhiro Takehara, Kimio Ushijima, Hidemichi Watari, Daisuke Aoki, Tadashi Kimura, Toshiaki Nakamura, Yoshihito Yokoyama, Junzo Kigawa & Toru Sugiyama



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Nuclear expression of Gli-1 is predictive of pathologic complete response to chemoradiation in trimodality treated oesophageal cancer patients

Nuclear expression of Gli-1 is predictive of pathologic complete response to chemoradiation in trimodality treated oesophageal cancer patients

British Journal of Cancer advance online publication, July 20 2017. doi:10.1038/bjc.2017.225

Authors: Roopma Wadhwa, Xuemei Wang, Veerabhadran Baladandayuthapani, Bin Liu, Hironori Shiozaki, Yusuke Shimodaira, Quan Lin, Elena Elimova, Wayne L Hofstetter, Stephen G Swisher, David C Rice, Dipen M Maru, Neda Kalhor, Manoop S Bhutani, Brian Weston, Jeffrey H Lee, Heath D Skinner, Ailing W Scott, Dilsa Mizrak Kaya, Kazuto Harada, Donald Berry, Shumei Song & Jaffer A Ajani



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Active multiple myeloma suppresses and typically eliminates coexisting MGUS

Active multiple myeloma suppresses and typically eliminates coexisting MGUS

British Journal of Cancer advance online publication, July 20 2017. doi:10.1038/bjc.2017.229

Authors: John P Campbell, Jennifer L J Heaney, Sankalp Pandya, Zaheer Afzal, Martin Kaiser, Roger Owen, J Anthony Child, Walter Gregory, Gareth J Morgan, Graham H Jackson, Chris M Bunce & Mark T Drayson



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Lung cancer prognostic index: a risk score to predict overall survival after the diagnosis of non-small-cell lung cancer

Lung cancer prognostic index: a risk score to predict overall survival after the diagnosis of non-small-cell lung cancer

British Journal of Cancer advance online publication, July 20 2017. doi:10.1038/bjc.2017.232

Authors: Marliese Alexander, Rory Wolfe, David Ball, Matthew Conron, Robert G Stirling, Benjamin Solomon, Michael MacManus, Ann Officer, Sameer Karnam, Kate Burbury & Sue M Evans



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Dermoscopy of a pigmented apocrine porocarcinoma arising from a pigmented hidroacanthoma simplex



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Herbal multicomponent extracts enhance wound healing after incision of perianal abscess and in a rat model of infected wounds



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Cancer diagnosis spotlights Sen. John McCain's rare ability to bring partisans together - Los Angeles Times

Los Angeles Times
Cancer diagnosis spotlights Sen. John McCain's rare ability to bring partisans together
Los Angeles Times
John McCain, with his short fuse and lashing tongue, is not always an easy man to like, or to get along with. The Arizona senator acknowledged as much in a wry tweet he dispatched Thursday morning — candor and self-deprecation always being two of his ...
John McCain diagnosed with brain cancerWashington Times
Barack Obama, Sarah Palin among politicians who express support to 'hero' John McCain after brain cancer diagnosisWashington Examiner
Sen. John McCain Diagnosed With Brain Cancer – UpdatedBearing Drift (press release) (blog)
The Japan Times -Independent.ie
all 1,486 news articles »


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Primary Cutaneous Small/Medium CD4+ T-CELL Lymphoproliferative Disorder Occurring in a Patient With Metastatic Melanoma.

Therapeutic agents designed to stimulate the immune system are now cornerstones in the treatment of metastatic melanoma. These drugs promote lymphocyte growth and survival, which could plausibly result in clinical lymphoproliferative disorders. We report the case of a 62-year-old female with metastatic melanoma who developed primary cutaneous small/medium CD4+ T-cell lymphoproliferative disorder (PC-SMTCL) after treatment with vemurafenib and recombinant high-dose interleukin-2 (IL-2). The patient developed a painless red papule behind the ear. A biopsy showed a dense population of CD4+ lymphocytes with a T-follicular helper cell phenotype. Molecular studies confirmed the presence of a clonal population of T cells, and the process was classified as PC-SMTCL. The patient was diagnosed with metastatic melanoma approximately 3 years before the development of the cutaneous lymphoma and had been treated with vemurafenib followed by 2 courses of IL-2. The patient's last course of IL-2 was completed in April of 2013. She developed the cutaneous lymphoma behind her ear in December of 2015. An association between PC-SMTCL and vemurafenib treatment for advanced melanoma has been reported previously in one patient; however, an association between PC-SMTCL and IL-2 treatment has not been documented. The immunostimulatory properties of IL-2 or vemurafenib may be responsible for the development of PC-SMTCL in our patient. Additionally, antigenic stimulation of the immune system by melanoma itself could contribute to clonal selection of lymphocytes. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Contralateral regional recurrence after elective unilateral neck irradiation in oropharyngeal carcinoma: A literature-based critical review



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Neoadjuvant chemoradiotherapy for oesophageal cancer: Still looking for a challenger to the CROSS regimen

Randomised studies are so rare in the setting of neoadjuvant chemoradiotherapy (nCRT) for oesophageal cancer that Mukherjee et al. [1] have to be commended for conducting the NEOSCOPE study, which evaluated induction chemotherapy followed by carboplatin/paclitaxel nCRT (nCarPacRT) versus induction chemotherapy followed by oxaliplatin/capecitabine nCRT. This is also the first randomised study in the field that routinely uses an image-guided radiotherapy supported by a peer-reviewed real-time radiation therapy (RT) quality assurance.

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Parents have critical role in preventing teen drinking - Science Daily

The Advertiser
Parents have critical role in preventing teen drinking
Science Daily
Lincoln Size, Chief Executive Cancer Council SA, says: "The evidence is clear that alcohol use is a cause of cancer. Any level of alcohol consumption increases the risk of developing an alcohol-related cancer; the level of risk increases in line with ...
Teens drink less if they know alcohol causes cancer — but most don't — Adelaide University and SAHMRI study findsThe Advertiser

all 5 news articles »


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Ernährung bei multimorbiden Patienten – Daten oder Meinungen?

Dtsch med Wochenschr 2017; 142: 1038-1045
DOI: 10.1055/s-0042-111612

Polymorbidity and old age are rather the rule than the exception in hospitalised patients. Malnutrition is common in such patients and should be identified by appropriate screening and assessment measures in order to devise a nutrition plan and act accordingly. Unlike in the UK or The Netherlands, malnutrition screening and nutrition teams are not mandatory for German hospitals. Malnutrition and, in particular, sarcopenia are indicators of a nutrition associated risk or increased morbidity and mortality. Malnutrition can affect patients of any medical discipline and, therefore, is managed most efficiently by the interdisciplinary and multiprofessional nutrition team. By this approach goal directed nutrition therapy can improve morbidity and mortality of hospitalised patients.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Multimorbidität – klug entscheiden trotz fehlender Daten

Dtsch med Wochenschr 2017; 142: 1017-1017
DOI: 10.1055/s-0043-110015



© Georg Thieme Verlag KG Stuttgart · New York

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Akutes Koronarsyndrom: Rivaroxaban statt ASS zeigt ähnliche Blutungsraten

Dtsch med Wochenschr 2017; 142: 1025-1026
DOI: 10.1055/s-0043-111693



© Georg Thieme Verlag KG Stuttgart · New York

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SMS senkt Glucose-Wert bei Diabetes-Typ-2

Dtsch med Wochenschr 2017; 142: 1021-1021
DOI: 10.1055/s-0043-110904



© Georg Thieme Verlag KG Stuttgart · New York

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Eine 19-jährige Leistungssportlerin mit pathologischem EKG

Dtsch med Wochenschr 2017; 142: 1027-1027
DOI: 10.1055/s-0043-102958



© Georg Thieme Verlag KG Stuttgart · New York

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ASS kaum wirksam bei Arteriosklerose

Dtsch med Wochenschr 2017; 142: 1021-1021
DOI: 10.1055/s-0043-110907



© Georg Thieme Verlag KG Stuttgart · New York

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Nächtliche Wadenkrämpfe: Magnesium ohne positiven Effekt

Dtsch med Wochenschr 2017; 142: 1026-1026
DOI: 10.1055/s-0043-113214



© Georg Thieme Verlag KG Stuttgart · New York

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Neuer Mechanismus für Typ-2-Diabetes

Dtsch med Wochenschr 2017; 142: 1021-1021
DOI: 10.1055/s-0043-110910



© Georg Thieme Verlag KG Stuttgart · New York

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Ist Alter eine Komorbidität?

Dtsch med Wochenschr 2017; 142: 1030-1036
DOI: 10.1055/s-0042-109861

Aging is normal process, only somehow questioned by the "anti-aging wave". Normal and pathological aging are therefore separate developments. Older adults often suffer from the frailty syndrome, partly due to diminished resilience. Aging per se is not a comorbidity.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Außerklinischer Herz-Kreislauf-Stillstand: Laien können Leben retten

Dtsch med Wochenschr 2017; 142: 1022-1022
DOI: 10.1055/s-0043-111687



© Georg Thieme Verlag KG Stuttgart · New York

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Polypharmazie – Lösungswege für eine verbesserte Arzneimitteltherapiesicherheit

Dtsch med Wochenschr 2017; 142: 1046-1053
DOI: 10.1055/s-0043-100125

Polypharmacy (≥ 5 drugs) is common among older people and may lead to falls, ADEs and delirium. Adherence is an important part in the medication management. Simple questions (i. e. for OTC, handling and omission of drugs) are effective. As most old people are treated by general practitioners (GP), they play a key role for drug safety and reducing polypharmacy. The involvement of pharmacists in analyzing one patient‘s drugs can enhance solutions for drug problems (“two-man rule”). An IT-based medication plan acts as an important communication tool for an enhanced team work between doctors, pharmacists and nursing care.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Januskinase-Inhibitor Tofacitinib zur Induktion und Remissionserhaltung bei Colitis ulcerosa

Dtsch med Wochenschr 2017; 142: 1022-1024
DOI: 10.1055/s-0043-111688



© Georg Thieme Verlag KG Stuttgart · New York

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Fieber und Kopfschmerzen nach Thailandurlaub

Dtsch med Wochenschr 2017; 142: 1063-1066
DOI: 10.1055/s-0043-106282

Anamnese Ein 50-jähriger Patient stellt sich mit Kopfschmerzen sowie hohem Fieber etwa eine Woche nach Rückkehr aus seinem Thailandurlaub vor. Hausärztlicherseits vorbehandelt wurde er mit Amoxicillin/Clavulansäure ohne Suche eines Infektfokus oder Erregerdiagnostik. Untersuchungen Wegbereitend für das weitere Prozedere war das pathologische Ergebnis einer Lumbalpunktion mit vorwiegend lymphozytärer Pleozytose von 80 Zellen/μl (< 5) mit auf 782 mg/l (< 450) erhöhtem Protein, normwertigem Glukosegehalt sowie einem Laktat im oberen Normbereich. Therapie und Verlauf Nach Abnahme von Blut- sowie Liquorkulturen erfolgt eine kalkulierte antiinfektiöse Therapie, um bis zum Eintreffen der mikrobiologischen Analysen möglichst viele Meningitis-/Enzephalitiserreger abzudecken. Eine Multiplex-PCR des Liquors auf in der Schweiz endemische virale und bakterielle Erreger bleibt negativ. Nachdem sich auch in Liquor- und Blutkulturen kein Keimwachstum abzeichnet, kann die antiinfektiöse Therapie abgesetzt werden. Die Suche nach Malaria, HIV, Chikungunya- und Dengue- sowie FSME-Virus ergibt negative Befunde. Nach etwa 10 Tagen erreicht uns eine deutlich positive Serologie für das Japanische Enzephalitisvirus (JEV). Folgerungen Die Japanische Enzephalitis wird durch ein Flavivirus ausgelöst, das durch Mücken übertragen wird. Sie ist im asiatischen Raum eine der bedeutendsten Enzephalitiden. Die Letalität bei einer manifesten Erkrankung liegt bei bis zu 30 %. Eine kausale Therapie existiert nicht. Seit 2009 ist jedoch ein gut verträglicher Impfstoff zugelassen.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Preoperative Calcium and Calcitriol and Hypocalcemia After Thyroidectomy

This cohort study compares the incidence of symptomatic hypocalcemia following administration of calcium and calcitriol supplementation given preoperatively and postoperatively vs postoperative therapy alone in patients undergoing total thyroidectomy.

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Unilateral Hearing Loss and Otorrhea

A man in his 70s had painless left-sided otorrhea, aural fullness, and hearing loss; temporal bone computed tomography demonstrated near-complete opacification of the left mastoid air cells and middle ear. What is your diagnosis?

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Survival After Salvage Surgery for Recurrent Oral Cavity Cancer

This cohort study evaluates overall survival in patients who undergo salvage surgery for recurrent oral cavity squamous cell cancer.

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Frontal Sinus Lesion

A woman with allergic rhinitis experienced progressive periorbital edema and proptosis of the left eye, with nasal congestion, altered sense of smell, supraorbital pain, proptosis, and periorbital edema; a CT scan revealed extensive thickening of the left frontal bone. What is your diagnosis?

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Surgery and Radiotherapy vs Chemoradiotherapy for Oral Cavity Cancer

This study compares the differences in survival between patients with locally advanced oral cavity squamous cell carcinoma treated with surgery followed by postoperative radiotherapy vs chemoradiotherapy.

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Body Dysmorphic Disorder in Facial Plastic Surgery Clinics

This prospective cohort study attempts to establish the prevalence of body dysmorphic disorder across facial plastic and oculoplastic surgery practice settings and to estimate the ability of surgeons to screen for it.

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Cutaneous Landmarks of the Supratrochlear Nerve

This study of 15 fresh cadaver heads sought a comprehensive understanding of the anatomical relationships between the supratrochlear nerve and surrounding muscles to assist surgeons in obtaining successful outcomes when performing any surgical approaches for forehead rejuvenation.

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Photographic Standards for Patients With Facial Palsy

This literature search reviews the use of facial photography in the management of patients with facial palsy, and a cross-sectional survey of the Sir Charles Bell Society members examines their use of photography in documenting facial nerve function.

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Incorrect Type of Online Review Cited

In the article titled “Negative and Positive Online Patient Reviews of Physicians—1 vs 5 Stars,” an incorrect type of online review cited has been corrected. In the Results section, “33 of 152 comments (21.7%) accompanied 5-star reviews based on how honest the physician seemed to be” has been changed to “33 of 152 comments (21.7%) accompanied 5-star reviews based on how knowledgeable the physician seemed to be.” This article has been corrected online.

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Tissue Expander Effect in Surgical Management of Infantile Hemangiomas

This case series describes use of the tissue expansion effect in surgical intervention for young children with focal infantile hemangiomas.

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Association of Increasing Nasal Tip Projection With Lip Position

This case series evaluates the association of increasing nasal tip projection with lip position patients undergoing primary rhinoplasty.

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Use of Spreader Flaps Without Dorsal Hump Reduction and Nasal Function

This medical record review evaluates whether spreader flaps are equivalent to spreader grafts in correcting internal nasal valve collapse in the absence of simultaneous dorsal hump reduction in a series of patients undergoing open septorhinoplasty.

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Defining the Perfect Mouth

Solidifying the aesthetic definition of beautiful lips has been a prominent and timely quest in light of the rapid expansion in popularity of injectable fillers. Our ability to contour and define the perioral region has led to an ever-younger population seeking not only rejuvenation but also reshaping of natural anatomy. Led by celebrity experience and social media discussion, requests are routinely made for injectables to shape the appearance of named celebrities’ lips. Consumer demand has led to an increasing body of literature, seeking to quantify a uniform scale for assessment of lip fullness. Moving beyond the ability to describe the volumetric improvements, we next seek to identify and describe what ideal outcome we want to achieve.

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Association of Upper Eyelid Ptosis Repair and Blepharoplasty With Headache-Related QOL

This cohort study evaluates the changes in headache-related quality of life in patients who underwent upper eyelid ptosis repair or blepharoplasty.

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Costal Cartilage Harvest Technique

This Surgical Pearl describes a technique to reduce surgical time and patient pain and risk in costal cartilage harvest.

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Biomechanics of Fractures Associated With Orbital Floor Fractures

This cadaver study defines the biomechanical factors associated with orbital floor fractures using a drop tower with an accelerometer to measure impact force on the globe and rim of cadaver heads affixed with strain gauges.

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Italian Linguistic Validation of the FACE-Q Instrument

Linguistic validation is essential in translating patient-reported outcomes.

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Unusual Eruption on the Arm

imageNo abstract available

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“Joining the Spots in Adults and Young Tots”: A Clinicopathological Study of Henoch–Schönlein Purpura (IgA Vasculitis)

imageIntroduction: Henoch–Schönlein Purpura (HSP; IgA vasculitis), the most common vasculitis of childhood, has a wide spectrum of clinical manifestations ranging from palpable purpura with abdominal pain and arthritis to the more morbid renal involvement. Aims and Objectives: To study and correlate the clinical presentation, laboratory values, skin and renal histopathology and immunofluoroscence findings in HSP. Material and Methods: A total of 44 cases of HSP from March 2011 to February 2014 were studied for the above features along with their clinical outcomes. Results: The mean age of the patients at presentation was 28.4 years (range 4.5–69 years) with 26.2% being children younger than 15 years. Purpura at presentation was seen in all with 77.1% cases exhibiting extracutaneous involvement. Skin biopsy revealed leukocytoclastic vasculitis in all cases, dominant IgA deposition in the papillary dermal vessels in 43 cases (97.7%), associated C3 in 10 cases (23.3%), and full-house positivity in 1 case. One case without skin immunofluorescence had renal mesangial IgA deposits. Nine cases (20.9%) with an average age of 39 years had renal symptoms and displayed varied histology from focal mesangioproliferative glomerulonephritis to crescentic. All of them had dominant mesangial IgA deposits, majority falling into International Study of Kidney Disease in Children (ISKDC) class IIIb. Peritubular capillaritis was noted in 3 cases. Two patients (4.5%) progressed to end stage renal disease, one of whom had cellular crescents at presentation. Conclusions: HSP was seen both in children and adults. Renal involvement was seen in 20.9% cases, all older than 14 years, and 66.7% with extracutaneous manifestations. The outcome in this series was favorable in 96% cases.

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Collagen Anomalies as Clues for Diagnosis: Part 1

imageBackground: Collagen is the most abundant protein in the body and the main structural component of the skin. Objective: To provide a review of the histopathology of collagen alterations and to propose a classification with the most important types of collagen anomalies in dermatopathology. The authors describe some of the main morphological clues of collagen anomalies for specific diagnosis of some cutaneous inflammatory and neoplastic conditions. Methods: The authors review histopathologic collagen anomalies, concerning both morphology and disposition in some inflammatory and neoplastic cutaneous conditions, and they review previous terminology and proposed a classification of the most important types of collagen anomalies that can be seen in dermatopathological practice. Results: Collagen anomalies in skin can be classified into lamellar fibrosis, sclerosis, and “balls” and “rings” of collagen. Lamellar fibrosis presents as long and thin collagen bundles forming a delicate network, which can be disposed in a parallel pattern, onion-bulb-like pattern, and storiform pattern. Sclerosis is characterized by large, thick, and eosinophilic bundles of collagen, which may present as a homogenous-diffuse pattern or as individual thick bundles of collagen with few or abundant number of fibroblasts between them. Finally, the authors propose the terms “balls” and “rings” of collagen. The term “balls” of collagen stands for thick, homogenous, eosinophilic, globular collagen bundles, with no distinguishable individual composing fibers, which include the floating sign and the free-floating sign. The term “rings” of collagen is characterized by sclerotic collagen arranged in a homogenous rimming pattern around vessels without independent fibers in its composition. Conclusions: Collagen anomalies may be important clues to establish specific clues for specific diagnoses in dermatopathology.

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Living on the Edge: Diagnosing Sarcomatoid Melanoma Using Histopathologic Cues at the Edge of a Dedifferentiated Tumor: A Report of 2 Cases and Review of the Literature

imageAbstract: Sarcomatoid melanoma is a rare type of melanoma lacking typical histologic features of melanoma and often lacks expression of S100 protein and melanocyte-specific markers. Given the rarity of this entity, its clinicopathologic findings are not well defined. We report 2 cases of sarcomatoid melanoma received in consultation: a 65-year-old woman with a right breast mass and a 62-year-old man with a left plantar heel mass. Both lesions were ulcerated, pedunculated, highly cellular proliferations of atypical spindle cells arranged as fascicles and/or sheets. The tumor cells of the breast mass expressed CD10 and vimentin diffusely but S100 protein only focally. The tumor cells of the heel mass lacked expression of melanocytic markers altogether, except for weak, very focal S100 protein expression. At the junctional edge of the breast mass and in the ulcer base of the heel mass, focal precursor melanoma was present and exhibited melanocytic differentiation. We report these cases to emphasize the importance of meticulous histologic inspection at the lesion's edge and/or ulcer base to correctly identify the conventional precursor melanoma in these rare lesions to ensure appropriate diagnosis and subsequent clinical management as treatment options may be significantly different from those offered for sarcomas.

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Histological Features of Methylene Blue–Induced Phototoxicity Administered in the Context of Parathyroid Surgery

imageAbstract: Methylene blue is a chromophore dye known for its photosensitizing properties. It is also administered intravenously as a tracer in parathyroid surgery to identify abnormal glands. We describe 2 cases of acute methylene blue–induced phototoxicity in patients who underwent parathyroidectomy. Both patients developed an acute vesiculopustular inflammatory rash on the anterior neck corresponding to the site exposed intraoperatively to overhanging surgical lights. One of the patients also developed a bulla on her finger at the site of attachment of the oxygen probe. Biopsies were taken from both patients at different time points. The histological findings included destruction of sebaceous glands and deposition of diastase-periodic acid-Schiff–positive hyaline material around dermal blood vessels. These features are similar to those seen in skin treated with photodynamic therapy and systemic photosensitivity disorders such as the porphyrias. The wavelengths of light emitted by the surgical lights and oxygen probe overlap with the absorption spectrum of methylene blue. This resulted in excitation of the systemically administered methylene blue at exposed sites, with resultant local tissue damage and a phototoxic reaction.

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An Immunohistochemical Study of Anogenital Mammary-Like Glands

imageAbstract: Although the normal histology of anogenital mammary-like glands (AGMLG) has been studied, no systemic investigation has been performed on the immunoprofile of these structures. We studied intact AGMLG with a broad panel of antibodies. The immunoprofile of AGMLG is similar to that of a normal breast tissue, and there are similarities to eccrine glands and coils about cytokeratin expression. Our immunohistochemical data may contribute to understanding of the pathogenesis of lesions arising from AGMLG.

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Erythema Multiforme Following lines of Blaschko

imageNo abstract available

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High-Velocity Paint Gun Injuries

imageAbstract: Cutaneous injuries due to industrial high-pressure paint guns are well-documented in the literature; however, the histologic characteristics are uncommonly described, and facial involvement has not been previously reported. Histopathologic features of paint gun injuries vary depending on the time since injection and type of material. Early lesions display an acute neutrophilic infiltrate, edema, and thrombosis, with varying degrees of skin, fat, and muscle necrosis. More developed lesions (120–192 hours after injury) have prominent histiocytes and fibrosis around necrotic foci, possibly with the pitfall of muscle regenerative giant cells that could be mistaken for sarcoma. Continuing inflammation, swelling, and resultant vascular compression could explain ongoing necrosis months after the accident. The histopathologic differential diagnosis in the absence of clinical history includes paint in an abrasion, foreign body reaction to tattoo, giant cell tumor of tendon sheath, and various neoplasms. If available, radiologic studies can substitute for clinical photographs to indicate the extent of injury. The radiologic differential, uninformed by history, may include calcific periarthritis, gouty tophus, and tumoral calcinosis. Seven cases of injury due to high-velocity paint guns are presented with 4 additional cases mimicking paint gun injury and with review of the literature.

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Factitious Dermatitis Due to Thermal Burn With Histologic Features Simulating Fixed Drug Eruption

imageAbstract: Factitious dermatitis (FD) (dermatitis artefacta) is rare and often difficult to diagnose because of conflicting history and nonspecific clinical and histologic findings. It can present with varied clinical features including geometric ulcers, erosions, and less commonly bullae secondary to external trauma from chemicals, electric burns, heat, and suction. Herein, we describe a case of bullous FD due to thermal burn with histologic features demonstrating overlap with fixed drug eruption. Histopathology demonstrated a subepidermal blister with epidermal necrosis along with pigment incontinence and dermal eosinophils and neutrophils. Although these features, and the clinician's impression, were suggestive of fixed drug eruption, several morphologic findings allowed accurate diagnosis of FD: sharp demarcation of necrotic keratinocytes from adjacent uninvolved epidermis, elongated keratinocytes reminiscent of thermal or electrical artifact, and multinucleated keratinocytes. Although FD is often considered a diagnosis of exclusion, these clues may help dermatopathologists distinguish this entity from inflammatory dermatoses.

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In Response

No abstract available

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Actinic Granuloma Annulare With Scarring and Open Comedones

imageAbstract: Actinic granuloma and annular elastolytic giant cell granuloma are variants of granuloma annulare affecting, respectively, sun-exposed and sun-covered skin sites on where, besides classical findings, abundant elastophagocytosis is observed. Here, we report a case of exuberant actinic granuloma annulare that, in addition to extensive scarring, showed multiple overlying open comedones. Markedly dilated follicular infundibula filled with compact masses of laminated keratinous material were observed in proximity to dermal inflammation composed of many histiocytes and multinucleated giant cells in close association with degenerated elastic fibers and abundant elastophagocytosis.

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Refractory Intertrigo in the Right Inguinal Crease: Answer

imageNo abstract available

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Unusual Eruption on the Arm: Challenge

imageNo abstract available

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Refractory Intertrigo in the Right Inguinal Crease: Challenge

imageNo abstract available

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Ash dieback epidemic in Europe: How can molecular technologies help?

journal.ppat.1006381.g001

by J. Allan Downie



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Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation

journal.ppat.1006460.g001

by Alexander Zhyvoloup, Anat Melamed, Ian Anderson, Delphine Planas, Chen-Hsuin Lee, Janos Kriston-Vizi, Robin Ketteler, Andy Merritt, Jean-Pierre Routy, Petronela Ancuta, Charles R. M. Bangham, Ariberto Fassati

HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D) in the capsid protein. We confirmed that digoxin repressed viral gene expression by targeting the cellular Na+/K+ ATPase, but this did not explain its selectivity. Parallel RNAseq and integration mapping in infected cells demonstrated that digoxin inhibited expression of genes involved in T-cell activation and cell metabolism. Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism. Two main gene networks down-regulated by the drug were CD40L and CD38. Blocking CD40L by neutralizing antibodies selectively inhibited WT virus infection, phenocopying digoxin. Thus the selectivity of digoxin depends on a combination of integration targeting and repression of specific gene networks. The drug unmasked a functional connection between HIV-1 integration and T-cell activation. Our results suggest that HIV-1 evolved integration site selection to couple its early gene expression with the status of target CD4+ T-cells, which may affect latency and viral reactivation.

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Dark web crackdown as two biggest markets are taken offline

hansa-1-800x533.jpg

The police sting hit two markets, AlphaBay and Hansa, that were responsible for the trading of over 350, 000 illicit goods such as drugs, firearms and cybercrime malware

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Bitcoin study reveals how early adopters influence our decisions

gettyimages-806924788.jpg

When they get special treatment, they can make new technologies go viral – but when they don’t, their real power is in putting the rest of us off

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FDA Expands Indication for Scalp Cooling Device to Reduce Hair Loss

The FDA has expanded the indication for a scalp cooling device that reduces hair loss during chemotherapy. (Source: CancerNetwork)

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Spatially Selective Dissection of Signal Transduction in Neurons Grown on Netrin-1 Printed Nanoarrays via Segmented Fluorescence Fluctuation Analysis

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b03004
ancac3?d=yIl2AUoC8zA


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Novel CRISPR/Cas9 gene drive constructs reveal insights into mechanisms of resistance allele formation and drive efficiency in genetically diverse populations

journal.pgen.1006796.g001

by Jackson Champer, Riona Reeves, Suh Yeon Oh, Chen Liu, Jingxian Liu, Andrew G. Clark, Philipp W. Messer

A functioning gene drive system could fundamentally change our strategies for the control of vector-borne diseases by facilitating rapid dissemination of transgenes that prevent pathogen transmission or reduce vector capacity. CRISPR/Cas9 gene drive promises such a mechanism, which works by converting cells that are heterozygous for the drive construct into homozygotes, thereby enabling super-Mendelian inheritance. Although CRISPR gene drive activity has already been demonstrated, a key obstacle for current systems is their propensity to generate resistance alleles, which cannot be converted to drive alleles. In this study, we developed two CRISPR gene drive constructs based on the nanos and vasa promoters that allowed us to illuminate the different mechanisms by which resistance alleles are formed in the model organism Drosophila melanogaster. We observed resistance allele formation at high rates both prior to fertilization in the germline and post-fertilization in the embryo due to maternally deposited Cas9. Assessment of drive activity in genetically diverse backgrounds further revealed substantial differences in conversion efficiency and resistance rates. Our results demonstrate that the evolution of resistance will likely impose a severe limitation to the effectiveness of current CRISPR gene drive approaches, especially when applied to diverse natural populations.

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Germline and reproductive tract effects intensify in male mice with successive generations of estrogenic exposure

journal.pgen.1006885.g001

by Tegan S. Horan, Alyssa Marre, Terry Hassold, Crystal Lawson, Patricia A. Hunt

The hypothesis that developmental estrogenic exposure induces a constellation of male reproductive tract abnormalities is supported by experimental and human evidence. Experimental data also suggest that some induced effects persist in descendants of exposed males. These multi- and transgenerational effects are assumed to result from epigenetic changes to the germline, but few studies have directly analyzed germ cells. Typically, studies of transgenerational effects have involved exposing one generation and monitoring effects in subsequent unexposed generations. This approach, however, has limited human relevance, since both the number and volume of estrogenic contaminants has increased steadily over time, intensifying rather than reducing or eliminating exposure. Using an outbred CD-1 mouse model, and a sensitive and quantitative marker of germline development, meiotic recombination, we tested the effect of successive generations of exposure on the testis. We targeted the germline during a narrow, perinatal window using oral exposure to the synthetic estrogen, ethinyl estradiol. A complex three generation exposure protocol allowed us to compare the effects of individual, paternal, and grandpaternal (ancestral) exposure. Our data indicate that multiple generations of exposure not only exacerbate germ cell exposure effects, but also increase the incidence and severity of reproductive tract abnormalities. Taken together, our data suggest that male sensitivity to environmental estrogens is increased by successive generations of exposure.

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Use of a microfluidic platform to uncover basic features of energy and environmental stress responses in individual cells of Bacillus subtilis

journal.pgen.1006901.g001

by Matthew T. Cabeen, Jonathan R. Russell, Johan Paulsson, Richard Losick

Bacteria use a variety of stress-sensing systems to sense and respond to diverse stressors and to ensure their survival under adverse conditions. The gram-positive bacterium Bacillus subtilis responds to energy stress (ATP depletion) and to environmental stressors using two distinct stress-sensing pathways that converge on the alternative sigma factor σB to provoke a general stress response. Past efforts to study the σB stress response in bulk culture and on agarose pads were unable to visualize the responses of individual cells under tightly controlled conditions for extended periods of time. Here we use a microfluidics-based strategy to discern the basic features of σB activation in single cells in response to energy and environmental stress, both immediately upon stressor exposure and for tens of generations thereafter. Upon energy stress at various levels of stressor, cells exhibited fast, transient, and amplitude-modulated responses but not frequency modulation as previously reported. Upon environmental stress, which is mediated by the stressosome complex, wild-type cells primarily exhibited a transient and amplitude-modulated response. However, mutant cells producing only one of the four paralogous RsbR stressosome proteins showed striking and previously unseen differences. Whereas RsbRA-only cells mimicked the wild type, RsbRC-only cells displayed a slower but sustained overall response composed of repeated activation events in single cells.

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The gene drive bubble: New realities

journal.pgen.1006850.g001

by James J. Bull, Harmit S. Malik



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Persistent damaged bases in DNA allow mutagenic break repair in Escherichia coli

journal.pgen.1006733.e001

by Jessica M. Moore, Raul Correa, Susan M. Rosenberg, P. J. Hastings

Bacteria, yeast and human cancer cells possess mechanisms of mutagenesis upregulated by stress responses. Stress-inducible mutagenesis potentially accelerates adaptation, and may provide important models for mutagenesis that drives cancers, host pathogen interactions, antibiotic resistance and possibly much of evolution generally. In Escherichia coli repair of double-strand breaks (DSBs) becomes mutagenic, using low-fidelity DNA polymerases under the control of the SOS DNA-damage response and RpoS general stress response, which upregulate and allow the action of error-prone DNA polymerases IV (DinB), II and V to make mutations during repair. Pol IV is implied to compete with and replace high-fidelity DNA polymerases at the DSB-repair replisome, causing mutagenesis. We report that up-regulated Pol IV is not sufficient for mutagenic break repair (MBR); damaged bases in the DNA are also required, and that in starvation-stressed cells, these are caused by reactive-oxygen species (ROS). First, MBR is reduced by either ROS-scavenging agents or constitutive activation of oxidative-damage responses, both of which reduce cellular ROS levels. The ROS promote MBR other than by causing DSBs, saturating mismatch repair, oxidizing proteins, or inducing the SOS response or the general stress response. We find that ROS drive MBR through oxidized guanines (8-oxo-dG) in DNA, in that overproduction of a glycosylase that removes 8-oxo-dG from DNA prevents MBR. Further, other damaged DNA bases can substitute for 8-oxo-dG because ROS-scavenged cells resume MBR if either DNA pyrimidine dimers or alkylated bases are induced. We hypothesize that damaged bases in DNA pause the replisome and allow the critical switch from high fidelity to error-prone DNA polymerases in the DSB-repair replisome, thus allowing MBR. The data imply that in addition to the indirect stress-response controlled switch to MBR, a direct cis-acting switch to MBR occurs independently of DNA breakage, caused by ROS oxidation of DNA potentially regulated by ROS regulators.

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Clarithromycin in the Management of Chronic Rhinosinusitis: Preliminary Results of a Possible Its New Use

Abstract

The aim of this study is to evaluate the efficacy and safety of prolonged therapy with low-dose clarithromycin in patients with chronic rhinosinusitis with polyps (CRSwP) after endoscopic sinus surgery (ESS). A total of 10 patients with CRSwP were identified and subjected to bilateral ESS. In post-operative patients they were treated with nasal wash with saline solution and steroid sprays (beclomethasone). During follow-up, after 30–40 days after the operation (M = 35.4 SD = +4.33), patients reported a worsening of symptoms with onset of nasal obstruction; reduction/loss of smell; headache; onset of viscous secretions and therefore all patients continued therapy with saline nasal irrigation, topical steroid therapy and started macrolide (clarithromycin 500 mg/pill: 1 pill/day for 3 days a week for 1 month). 22-item SinoNasal Outcome Test (SNOT-22) and a score to the endoscopic evaluation (endoscopic appearance score, EAS) before and after treatment were performed to evaluate efficacy of treatment. The results of the SNOT-22 and EAS showed statistically significant improvements (p < 0.05) for some parameters such as: the need to blow nose, sneezing, hyposmia, viscous mucous secretions about the SNOT-22 and reduction of secretions and edema of the nasal mucosa about the EAS. The preliminary results of our study show that the low-dose clarithromycin for a period of 1 month can improve patient complaints with CRSwP not only through the antibacterial properties but also for the immunomodulatory characteristics.



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Water resources vulnerability assessment in the Adriatic Sea region: the case of Corfu Island

Abstract

Cross-border water resources management and protection is a complicated task to achieve, lacking a common methodological framework. Especially in the Adriatic region, water used for drinking water supply purposes pass from many different countries, turning its management into a hard task to achieve. During the DRINKADRIA project, a common methodological framework has been developed, for efficient and effective cross-border water supply and resources management, taking into consideration different resources types (surface and groundwater) emphasizing in drinking water supply intake. The common methodology for water resources management is based on four pillars: climate characteristics and climate change, water resources availability, quality, and security. The present paper assesses both present and future vulnerability of water resources in the Adriatic region, with special focus on Corfu Island, Greece. The results showed that climate change is expected to impact negatively on water resources availability while at the same time, water demand is expected to increase. Water quality problems will be intensified especially due to land use changes and salt water intrusion. The analysis identified areas where water resources are more vulnerable, allowing decision makers develop management strategies.



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How old is Clare Balding, who is her wife Alice Arnold, how much does she earn and when did she have thyroid cancer? - The Sun

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The Sun
How old is Clare Balding, who is her wife Alice Arnold, how much does she earn and when did she have thyroid cancer?
The Sun
SHE is known for her TV and radio presenting, has close links to the horse racing world and was once an amateur jockey herself. Here's everything you need to know about Clare Balding… Broadcaster, journalist and author Clare Balding is 46 and ...

and more »


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Efficacy and safety of taxane monotherapy in advanced gastric cancer refractory to triplet chemotherapy with docetaxel, cisplatin, and S-1: a multicenter retrospective study

Abstract

Purpose

Taxane monotherapy is widely used for advanced gastric cancer (AGC) after failure of standard first-line chemotherapy with fluoropyrimidine and cisplatin. Triplet chemotherapy with docetaxel, cisplatin, and S-1 (DCS) is a promising regimen for first-line chemotherapy of AGC. The aim of this study was to evaluate the efficacy of taxane monotherapy in patients refractory to DCS.

Methods

We retrospectively evaluated the efficacy and safety of taxane monotherapy in patients with AGC refractory to first-line therapy with DCS between January 2010 and April 2015. Selection criteria were as follows: ECOG PS of 0–2, treatment with taxane monotherapy in second-line or third-line therapy after failure of second-line irinotecan, absence of massive ascites, and adequate organ function.

Results

A total of 30 patients were included in this study. Of these, 15 patients received paclitaxel while another 15 received nanoparticle albumin-bound paclitaxel in either second- or third-line treatment. Median age for the second/third-line group was 64.0/62.0 (range 27–75/42–75); 14/13 (93.3/86.7%) had ECOG PS of 0 or 1. No patients achieved complete or partial response and stable disease was observed in 37.5/35.7% of the patients in the second/third line. Median progression-free survival and overall survival were 3.4 and 5.8 months in the second-line group, and 2.0 and 4.5 months in the third-line group, respectively. The incidences of any grade ≥3 adverse events in the second-line group and the third-line group were 60.0 and 33.3%, respectively. There was no treatment-related death.

Conclusions

Taxane monotherapy after DCS failure had acceptable toxicities but was ineffective in AGC patients.



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Giant deep-sea worms may live to be 1000 years old or more

escarpia_top_view2.jpg

Escarpia laminata lives on the sea floor, where food is plentiful and predators are absent – a perfect environment for longevity

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Listening is key, but ask the right questions

Sokol tells a poignant tale,1 but the message from this tragic case is precisely the opposite of how its title is phrased. Listening is key: ask someone why they sought advice from healthcare...
recent?d=yIl2AUoC8zA recent?d=dnMXMwOfBR0 recent?i=BaTac3jrJHw:CE-28AG9M3g:V_sGLiP recent?d=qj6IDK7rITs recent?i=BaTac3jrJHw:CE-28AG9M3g:gIN9vFw recent?d=l6gmwiTKsz0 recent?d=7Q72WNTAKBA recent?i=BaTac3jrJHw:CE-28AG9M3g:F7zBnMy recent?i=BaTac3jrJHw:CE-28AG9M3g:-BTjWOF


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Enhancing the usability of systematic reviews by improving the consideration and description of interventions

Summary pointsIntervention details are rarely fully considered or completely reported in systematic reviews, limiting the reproducibility and usability of systematic reviews—this is...
recent?d=yIl2AUoC8zA recent?d=dnMXMwOfBR0 recent?i=P6CH3btHeN0:Bw0w12ttTHE:V_sGLiP recent?d=qj6IDK7rITs recent?i=P6CH3btHeN0:Bw0w12ttTHE:gIN9vFw recent?d=l6gmwiTKsz0 recent?d=7Q72WNTAKBA recent?i=P6CH3btHeN0:Bw0w12ttTHE:F7zBnMy recent?i=P6CH3btHeN0:Bw0w12ttTHE:-BTjWOF


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