Τετάρτη, 1 Φεβρουαρίου 2017

Risk-Stratification Model Based on Lymph Node Metastasis After Noncurative Endoscopic Resection for Early Gastric Cancer

Abstract

Background

Patients with early gastric cancer (EGC) who have undergone noncurative endoscopic resection (ER) generally require additional surgery due to the possibility of lymph node metastasis (LNM). This study aimed to develop a reliable risk-stratification system to predict LNM after noncurative ER for EGC.

Methods

A total of 2368 patients had a diagnosis of EGC and underwent ER. The study analyzed 321 patients who underwent additive gastrectomy and lymph node dissection after noncurative ER. Independent risk factors for LNM were identified and used to develop a risk-stratification system to estimate the relative risk of LNM.

Results

Of the 321 patients, 23 (7.2%) had LNM. A logistic regression analysis showed that female sex, lymphovascular invasion (LVI), and a positive vertical margin were significantly associated with LNM. The authors established a risk-stratification system using sex, LVI, and positive vertical margin (area under the receiver-operating characteristic [AUROC] curve, 0.811). The high-risk LNM group (score, ≥ 2 points) showed a significantly higher risk of LNM than the low-risk LNM group (score, <2 points) (14.0 vs 1.2%). No LNM was found in patients with a risk score of zero. After internal and external validation, the AUROC curve for predicting LNM was 0.788 and 0.842, respectively.

Conclusions

The risk-stratification system developed in this study will facilitate identification of patients who should undergo LN dissection after noncurative ER. Although additive surgery should be performed after noncurative ER for patients with a high risk of LNM, a close follow-up visit could be considered for low-risk patients with multiple comorbidities or high operative risks.



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Researchers: Fast food wrapped in chemically treated paper linked to cancers, thyroid disease - WUSA9.com


WUSA9.com

Researchers: Fast food wrapped in chemically treated paper linked to cancers, thyroid disease
WUSA9.com
A recent study has found evidence that Americans may be consuming fast food wrapped in paper treated with chemicals linked to kidney and testicular cancers, thyroid disease, low birth rates and immunotoxicity in children. According to a new study ...
Study: Fast Food Wrappers Contain Cancer-Causing ChemicalsCBS Local
Researchers find 'another reason' to avoid fast food: Chemicals in the packagingWashington Post
Researchers find chemicals in fast food packaging sometimes leach into your foodWWMT-TV
Gizmodo -The Verge -ACS Publications - American Chemical Society -YouTube
all 92 news articles »


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Quantifying 125I placement accuracy in prostate brachytherapy using postimplant transrectal ultrasound images

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Publication date: Available online 1 February 2017
Source:Brachytherapy
Author(s): Muhammad F. Jamaluddin, Sunita Ghosh, Michael P. Waine, Ronald S. Sloboda, Mahdi Tavakoli, John Amanie, Albert D. Murtha, Don Yee, Nawaid Usmani
PurposeThe quality of a prostate brachytherapy implant depends on the accurate placement of sources. This study quantifies the misplacement of 125I sources from the intended location using intraoperative ultrasound images.Methods and Materials125I sources were manually identified in the postimplant ultrasound images and compared to the preoperative plan. Due to the subjective nature of the identifying sources, only sources identified with high confidence were included in the analysis. Misplacements from the original intended coordinate were measured along the X, Y, and Z axes and were stratified between overall misplacements and regions of the prostate gland.ResultsA total of 1619 125I sources using 357 strands were implanted in 15 patients' prostate glands, with 1197 (74%) confidently identified for misplacement analysis. The overall mean displacement was 0.49 cm and in the X, Y, and Z direction was 0.13, 0.15, and 0.38 cm, respectively. Greater source misplacement occurred in the anterior part of the prostate gland than the posterior part of the prostate gland by a factor 1.33 (p < 0.0001). Comparing sources in the lateral vs. medial regions of the prostate, no statistically significant differences on source misplacement were observed. Comparing misplacement in the base vs. midgland vs. apex identified the greatest difference between the base and midgland by a factor of 1.29 (p < 0.0001).ConclusionsThis study has identified significant misplacement of 125I sources from their intended locations with the greatest error misplacement occurring in the Z direction. Source misplacement tends to occur more commonly in the anterior gland and in the base of the prostate.



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MRI in prostate brachytherapy: Evidence, clinical end points to data, and direction forward

Publication date: Available online 1 February 2017
Source:Brachytherapy
Author(s): Thomas J. Pugh, Sajal S. Pokharel
The integration of multiparametric MRI into prostate brachytherapy has become a subject of interest over the past 2 decades. MRI directed high-dose-rate and low-dose-rate prostate brachytherapy offers the potential to improve treatment accuracy and standardize postprocedure quality. This article reviews the evidence to date on MRI utilization in prostate brachytherapy and postulates future pathways for MRI integration.



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Dosimetric and radiobiologic comparison of 103Pd COMS plaque brachytherapy and Gamma Knife radiosurgery for choroidal melanoma

Publication date: Available online 1 February 2017
Source:Brachytherapy
Author(s): Daniel Gorovets, Nolan L. Gagne, Christopher S. Melhus
PurposePlaque brachytherapy (BT) and Gamma Knife radiosurgery (GKRS) are highly conformal treatment options for choroidal melanoma. This study objectively compares physical dose and biologically effective dose (BED) distributions for these two modalities.Methods and MaterialsTumor and organ-at-risk (OAR) dose distributions from a CT-defined reference right eye were compared between 103Pd COMS (Collaborative Ocular Melanoma Study Group) plaques delivering 70 Gy (plaque heterogeneity corrected) over 120 h to the tumor apex and GKRS plans delivering 22 Gy to the 40% isodose line for a representative sample of clinically relevant choroidal melanoma locations and sizes. Tumor and OAR biologically effective dose-volume histograms were generated using consensus radiobiologic parameters and modality-specific BED equations.ResultsPublished institutional prescriptive practices generally lead to larger tumor and OAR physical doses from COMS BT vs. GKRS. Radiobiologic dose conversions, however, revealed variable BEDs. Medium and large tumors receive >1.3 times higher BEDs with COMS BT vs. GKRS. OAR BEDs have even greater dependence on tumor size, location, and treatment modality. For example, COMS BT maximum BEDs to the optic nerve are lower than from GKRS for large anterior and all posterior tumors but are higher for anterior small and medium tumors.ConclusionsBT and GKRS for choroidal melanoma have different physical dose and BED distributions with potentially unique clinical consequences. Using published institutional prescriptive practices, neither modality is uniformly favored, although COMS BT delivers higher physical doses and BEDs to tumors. These results suggest that lowering the physical prescription dose for COMS BT to more closely match the BED of GKRS might maintain equivalent tumor control with less potential morbidity.



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Deformable image registration for cervical cancer brachytherapy dose accumulation: Organ at risk dose–volume histogram parameter reproducibility and anatomic position stability

Publication date: Available online 1 February 2017
Source:Brachytherapy
Author(s): E. Flower, V. Do, J. Sykes, C. Dempsey, L. Holloway, K. Summerhayes, D.I. Thwaites
PurposeThe purpose of this study was to determine the effect of deformable image registration (DIR) on cumulative organ at risk dose–volume histogram (DVH) parameter summation for more than three brachytherapy fractions. The reproducibility of different methods of DIR was tested. DIR was then used to assess the stability of the anatomic position of the DVH parameters within the bladder and rectum.Methods and MaterialsDIR was completed for 39 consecutive cervical cancer brachytherapy patients' planning CTs. Accumulated DVH parameters (D2cc and D0.1cc) for bladder and rectum were compared with dose summation without DIR. Reproducibility of DIR results was assessed for different methods of implementation based on adding contour biases added to the DIR algorithm. VolD2cc and VolD0.1cc structures were created from the overlap of the D2cc and D0.1cc isodose and the bladder or rectum, respectively. The overlap of VolD2cc and VolD0.1cc structures was calculated using the Dice similarity coefficient.ResultsDIR accumulated D2cc and D0.1cc decreased by an average of 2.9% and 4.2% for bladder and 5.08% and 2.8% for rectum compared with no DIR. DIR was most reproducible when the bladder or rectum contour was masked. The average Dice similarity coefficient was 0.78 and 0.61 for the bladder D2cc and D0.1cc as well as 0.83 and 0.62 for rectal D2cc and D0.1cc, respectively.ConclusionsDose decreases were observed for accumulated DVH parameters using DIR. Adding contour-based biases to the algorithm increases the reproducibility of D2cc and D0.1cc accumulation. The anatomic position of VolD2cc was more stable than VolD0.1cc.



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Brachytherapy boost for prostate cancer: Trends in care and survival outcomes

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Publication date: Available online 1 February 2017
Source:Brachytherapy
Author(s): S.M. Glaser, M.J. Dohopolski, G.K. Balasubramani, R.M. Benoit, R.P. Smith, S. Beriwal
PurposeAndrogen suppression combined with elective nodal and dose-escalated radiation therapy recently demonstrated an improved biochemical failure–free survival in men who received external beam radiation therapy (EBRT) plus a brachytherapy boost (BB) compared with dose-escalated external beam radiotherapy (DE-EBRT). We sought to analyze the factors predictive for use of EBRT + BB as compared with DE-EBRT and report resulting survival outcomes on a national level using a hospital-based registry.Methods and MaterialsWe identified 113,719 men from the National Cancer Database from 2004 to 2013 with intermediate- or high-risk prostate cancer who were treated with EBRT + BB or DE-EBRT. We performed univariate and multivariate analyses of all available factors potentially predictive of receipt of treatment selection. Survival was evaluated in a multivariable model with propensity adjustment.ResultsFor intermediate-risk patients, utilization of BB decreased from 33.1% (n = 1742) in 2004 to 12.5% (n = 766) in 2013 and for high-risk patients, utilization dropped from 27.6% (n = 879) to 10.8% (n = 479). Numerous factors predictive for use of BB were identified. Cox proportional hazards analysis was performed—adjusting for age, Charlson–Deyo comorbidity score, T stage, prostate-specific antigen, Gleason score, and sociodemographic factors—and demonstrated BB use was associated with a hazard ratio of 0.71 (95% confidence interval, 0.67–0.75; p < 0.0005) and 0.73 (95% confidence interval, 0.68–0.78; p < 0.0005) for intermediate- and high-risk patients, respectively.ConclusionsThere has been a concerning decline in the utilization of BB for intermediate- and high-risk prostate cancer patients despite an association with improved on overall survival. Numerous factors predictive for use of BB have been identified.



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Contact Dermatitis in the Hospitalized Patient

Abstract

Purpose of Review

The purpose of this study is to review the pathophysiology, clinical presentation, and management strategies for irritant and allergic contact dermatitis (CD) in hospitalized patients.

Recent Findings

Contact dermatitis accounts for 10% of inpatient dermatology consult cases. This high frequency of CD arises because hospitalized patients are exposed to numerous irritants and common allergens as part of diagnostic and therapeutic procedures. Common triggers include antibiotics, antiseptics, anesthetics, latex, and rubber additives. Hypersensitivity to metals and other materials in cardiac and orthopedic implants has also been reported, and an association between CD and implant failure has been proposed.

Summary

Recognition of CD and identification of the causative agent require a detailed clinical and exposure history, physical exam, and a high degree of clinical suspicion. Timely diagnosis and management are crucial, as they enable symptom relief and improvement in quality of life, and may also positively impact overall health outcomes by reducing associated systemic morbidity.



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Tapeworm infection, pork

Tapeworm infection, pork: Known medically as cysticercosis, an infection caused by Taenia solium (the pork tapeworm). Infection occurs when the tapeworm larvae enter the body and form cysticerci (SIS-tuh-sir-KEY) (cysts). When cysticerci are found in the brain, the condition is called neurocysticercosis (NEW-row SIS-tuh-sir-KO-sis).

The tapeworm that causes cysticercosis is found worldwide. Infection is found most often in rural, developing countries with poor hygiene where pigs are allowed to roam freely and eat human feces. This allows the tapeworm infection to be completed and the cycle to continue. Infection can occur, though rarely, if you have never traveled outside of the United States. Taeniasis and cysticercosis are very rare in Muslim countries where eating pork is forbidden.

Cysticercosis is contracted by accidentally swallowing pork tapeworm eggs. Tapeworm eggs are passed in the bowel movement of a person who is infected. These tapeworm eggs are spread through food, water, or surfaces contaminated with feces. This can happen by drinking contaminated water or food, or by putting contaminated fingers to your mouth. A person who has a tapeworm infection can reinfect themselves (autoinfection). Once inside the stomach, the tapeworm egg hatches, penetrates the intestine, travels through the bloodstream and may develop into cysticerci in the muscles, brain, or eyes.

The signs and symptoms of the disease depend on the location and number of cysticerci in the body.

  • Cysticerci in the muscles: Cysticerci in the muscles generally do not cause symptoms. However, you may be able to feel lumps under your skin.
  • Cysticerci in the eyes: Although rare, cysticerci may float in the eye and cause blurry or disturbed vision. Infection in the eyes may cause swelling or detachment of the retina.
  • Cysticerci in the brain or spinal cord (neurocysticercosis): Symptoms of neurocysticercosis depend upon where and how many cysticerci (often called lesions) are found in the brain. Seizures, and headaches are the most common symptoms. However, confusion, lack of attention to people and surroundings, difficulty with balance, swelling of the brain (called hydrocephalus) may also occur. Death can occur suddenly with heavy infections.

Symptoms can occur months to years after infection, usually when the cysts are in the process of dying. When this happens, the brain can swell. The pressure caused by swelling is what causes most of the symptoms of neurocysticercosis. Most people with cysticerci in muscles won't have symptoms of infection.

Diagnosis can be difficult and may require several testing methods. The health care provider will usually ask about where the patient has traveled and their eating habits. Diagnosis of neurocysticercosis is usually made by MRI or CT brain scans. Blood tests are available to help diagnose an infection, but may not always be accurate. If surgery is necessary, confirmation of the diagnosis can be made by the laboratory.

Treatment is generally with anti-parasitic drugs in combination with anti-inflammatory drugs. Surgery is sometimes necessary to treat cases in the eyes, cases that are not responsive to drug treatment, or to reduce brain edema (swelling). Not all cases of cysticercosis are treated. Often, the decision of whether or not to treat neurocysticercosis is based upon the number of lesions found in the brain and the symptoms. When only one lesion is found, often treatment is not given. If there is more than one lesion, specific anti-parasitic treatment is generally recommended.

If the brain lesion is considered calcified (this means that a hard shell has formed around the tapeworm larvae), the cysticerci is considered dead and specific anti-parasitic treatment is not beneficial.

As the cysticerci die, the lesion will shrink. The swelling will go down, and often symptoms (such as seizures) will go away.

To prevent cysticercosis and other disease causing germs:

  • Avoid eating raw or undercooked pork and other meats.
  • Don't eat meat of pigs that are likely to be infected with the tapeworm.
  • Wash hands with soap and water after using the toilet and before handling food, especially when traveling in developing countries.
  • Wash and peel all raw vegetables and fruits before eating. Avoid food that may be contaminated with feces.
  • Drink only bottled or boiled (1 minute) water or carbonated (bubbly) drinks in cans or bottles. Do not drink fountain drinks or any drinks with ice cubes. Another way to make water safe is by filtering it through an "absolute 1 micron or less" filter AND dissolving iodine tablets in the filtered water. "Absolute 1 micron" filters can be found in camping/outdoor supply stores.

Cysticercosis is not spread from person to person. However, a person infected with the intestinal tapeworm stage of the infection (T. solium) will shed tapeworm eggs in their bowel movements. Tapeworm eggs that are accidentally swallowed by another person can cause infection.

Anyone suspected of having cysticercosis (and family members) should be tested. Because the tapeworm infection can be difficult to diagnose, several stool specimens over several days may be needed to examine the stools for evidence of a tapeworm.



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Perceptions of pre-service teachers on the design of a learning environment based on the seven principles of good practice

Abstract

This study explored the perceptions of 88 pre-service teachers on the design of a learning environment using the Seven Principles of Good Practice and its effect on participants’ abilities to create their Cloud Learning Environment (CLE). In designing the learning environment, a conceptual model under the name 7 Principles and Integrated Learning Design (7P–ILD) was created. The 7P–ILD model was developed based on Chickering and Gamson’s Seven Principles of Good Practice, cloud tools, and selected strategies. A survey design was used and two instruments were administered to all participants. The findings indicated the 7P–ILD positively influenced participants’ ability to confidently build their CLE. Participants were most satisfied with 7P–ILD related to the principle student-faculty contact, and least satisfied with the principle time-on-task. Pre-service teachers’ perceptions did not differ by type of project (individual or collaborative); however, there was a significant difference between kindergarten and elementary pre-service teachers regarding time- on- task principle and high expectations principle. These results suggest the 7P–ILD can be a practical model to adopt for teacher preparation and with more research and modifications; it could become an emerging model for building more robust and effective learning environments where teacher autonomy and technology is enhanced.



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Digital literacy and online video: Undergraduate students’ use of online video for coursework

Abstract

This paper investigates how to enable undergraduate students’ use of online video for coursework using a customised video retrieval system (VRS), in order to understand digital literacy with online video in practice. This study examines the key areas influencing the use of online video for assignments such as the learning value of video, strategies for its integration and the key features of online video systems. A key component of the integration process is video browsing and content retrieval which focuses on enabling users to locate and view relevant segments of video, using techniques such as content based analysis and video segmentation. This paper examines how students source, integrate, and reference online video for assignment work. Findings show that students display key elements of digital literacy with online video when the appropriate tools and strategies to complete tasks are provided. Students demonstrated the ability to successfully integrate online video into individual assignments. The work also presents a series of recommendations and considerations for enabling the use of online video in assignment work.



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Cornea and its adaptation to environment and accommodation function in veiled chameleon (Chamaeleo calyptratus): Ultrastructure and 3D transmission electron tomography

Abstract

We investigate the ultrastructural features and 3D electron tomography of chameleon (Chamaeleon calyptratus) which is a native of desert environments of Saudi Arabia. The corneas of the chameleon were fixed in 2.5% glutaraldehyde containing cuprolinic blue in sodium acetate buffer for electron microscopy and tomography, and observed under a JEOL 1400 transmission electron microscope. The thin cornea (21.92 μm) contained 28–30 collagen fibril lamellae. The middle stromal lamellae (from 13 to 19) contained keratocytes with a long cell process and filled with granular material. The CF diameter increased from lamella 1 (30.44 ± 1.03) to Lamella 5 (52.83 ± 2.00) then decreased towards the posterior stoma. The percentage of large CF diameters (55–65 nm) was very high in the lamellae L14 (38.8%) and L15 (85.7%). The mean PGs area of the posterior stroma (448.21 ± 24.84 nm2) was significantly larger than the mean PGs area of the anterior, (309.86 ± 8.2 nm2) and middle stroma 245.94 ± 8.28 nm2). 3D electron tomography showed the distribution of PGs around and over the CF. Variable diameters of CFs in the anterior stroma may provide compact lamellae which may restrict the low wavelength of light. Variable diameters of CFs in the anterior stroma may provide compact lamellae which may restrict the low wavelength of light. This accommodation function is achieved by bending of the cornea. During bending the anterior stroma was stretched and the posterior stroma was compressed due to the presence of small CFs. The middle stroma remained stiff due to the presence of large CFs. Large proteoglycans not only maintain hydration for a longer period of time, but also act as a lubricant to neutralise the shear forces in the anterior and posterior stroma during bending.



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At the Edge of Safety: Moral Experimentation in the Case of Family Therapy

Abstract

“At the Edge of Safety” argues for thinking of structural family therapy as a “moral laboratory.” Borrowing a trope from Cheryl Mattingly’s recent book Moral Laboratories, the article reconsiders a therapeutic style that was once controversial by analyzing personal stories of supervision—i.e. professional training—in light of Mattingly’s suggestion that a social space in which people conduct experiments on themselves and their lives may be considered a moral laboratory. Family therapy is especially good to think with, because it is simultaneously a real and a metaphorical laboratory, physically lab-like in its use of visual technologies, yet moral in the way it puts the possibility for situational change in the hands of human actors. The technological apparatus stages evidence for sub-visible, interpersonal dynamics, while the provocative quality of not only therapeutic actions, but also of supervision, points to an ethos of experimentation. Stories of supervision reveal how personal of an experience being supervised can be. Trainees are pushed to become something otherwise, in learning to “expand” their styles. Sometimes the push is just right. Sometimes it goes too far. Whatever the case may be, the stories analyzed speak to anthropological questions concerning the uncertainty of human action and the many ways people can unknowingly injure one another with small hurts.



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Decreased Mitochondrial Pyruvate Transport Activity in the Diabetic Heart: Role of MPC2 Acetylation [Metabolism]

Alterations in mitochondrial function contribute to diabetic cardiomyopathy. We have previously shown that heart mitochondrial proteins are hyper-acetylated in OVE26 mice, a transgenic model of type 1 diabetes. However, the universality of this modification and its functional consequences are not well established. In this study, we demonstrate that Akita type 1 diabetic mice exhibit hyper-acetylation. Functionally, isolated Akita heart mitochondria have significantly impaired maximal (state 3) respiration with physiological pyruvate (0.1 mM) but not with 1.0 mM pyruvate. In contrast, pyruvate dehydrogenase activity is significantly decreased regardless of the pyruvate concentration. We found there is a 70% decrease in the rate of pyruvate transport in Akita heart mitochondria, but no decrease in the mitochondrial pyruvate carrier proteins (MPC1 and MPC2). The potential role of hyper-acetylation in mediating this impaired pyruvate uptake was examined. The treatment of control mitochondria with the acetylating agent, acetic anhydride, inhibits pyruvate uptake and pyruvate supported respiration in a similar manner to the pyruvate transport inhibitor α-cyano-4-hydroxycinnamate (CHC). A mass spec selective reactive monitoring assay was developed and used to determine that acetylation of lysines 19 and 26 of MPC2 are enhanced in Akita heart mitochondria. Expression of a double acetylation mimic of MPC2 (K19Q/K26Q) in H9c2 cells was sufficient to decrease the maximal cellular oxygen consumption rate. This study supports the conclusion that deficient pyruvate transport activity, mediated in part by acetylation of MPC2, is a contributor to metabolic inflexibility in the diabetic heart.

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Bax/Bak-independent mitochondrial depolarization and reactive oxygen species induction by sorafenib overcome resistance to apoptosis in renal cell carcinoma [Molecular Bases of Disease]

Renal cell carcinoma (RCC) is polyresistant to chemo- and radiotherapy or biologicals including TNF-related apoptosis inducing ligand (TRAIL). Sorafenib, a multikinase inhibitor approved for the treatment of RCC, has been shown to sensitize cancer cells toward TRAIL-induced apoptosis, in particular by downregulation of the Bak-inhibitory Bcl 2 family protein Mcl 1. Here, we demonstrate that sorafenib overcomes TRAIL resistance in RCC by a mechanism that does not rely on Mcl 1 downregulation. Instead, sorafenib induces a rapid dissipation of the mitochondrial membrane potential (Δψm) that is accompanied by the accumulation of reactive oxygen species (ROS). Loss of Δψm and ROS production induced by sorafenib are independent of caspase activities and do not depend on the presence of the pro-apoptotic Bcl 2 family proteins Bax or Bak indicating that both events are functionally up-stream of the mitochondrial apoptosis signaling cascade. More intriguingly, we find that it is sorafenib-induced ROS accumulation that enables TRAIL to activate caspase 8 in RCC. This leads to apoptosis that involves activation of an amplification loop via the mitochondrial apoptosis pathway. Thus, our mechanistic data indicate that sorafenib bypasses central resistance mechanisms through a direct induction of ΔΨm breakdown and ROS production. Activation of this pathway might represent a useful strategy to overcome the cell-inherent resistance to cancer therapeutics including TRAIL in multiresistant cancers such as RCC.

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USP39 Deubiquitinase Is Essential for KRAS-Driven cancer [Molecular Bases of Disease]

KRAS is the most frequently mutated oncogene in human cancer, but its therapeutic targeting remains challenging. Here, we report a synthetic lethal screen with a library of deubiquitinases and identify USP39, which encodes an essential splicing factor, as a critical gene for the viability of KRAS-dependent cells. We show that splicing fidelity inhibitors decrease preferentially the proliferation rate of KRAS-active cells. Moreover, depletion of DHX38, encoding an USP39-interacting splicing factor, also reduces the viability of these cells. In agreement with these results, USP39 depletion caused a significant reduction in pre-mRNA splicing efficiency, as demonstrated through RNA-seq experiments. Furthermore, we show that USP39 is upregulated in lung and colon carcinomas and its expression correlates with KRAS levels and poor clinical outcome. Accordingly, our work provides critical information for the development of splicing-directed antitumor treatments and supports the potential of USP39-targeting strategies as the basis of new anticancer therapies.

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Structural Analysis Reveals the Deleterious Effects of Telomerase Mutations in Telomerase-Associated Bone Marrow Failure Syndromes [Molecular Bases of Disease]

Naturally occurring mutations in the ribonucleoprotein reverse transcriptase, telomerase, are associated with the bone marrow failure syndromes dyskeratosis congenita (DKC), aplastic anemia (AA), and idiopathic pulmonary fibrosis (IPF). However, the mechanism by which these mutations impact telomerase function remains unknown. Here we present the structure of the human telomerase c-terminal extension (CTE or thumb domain) determined by the method of single-wavelength anomalous diffraction (SAD) to 2.31 A resolution. We also used direct telomerase activity and nucleic acid binding assays to explain how naturally occurring mutations within this portion of telomerase contribute to human disease. The single mutations localize within three highly conserved regions of the telomerase thumb domain referred to as motifs E-I, (thumb loop and helix) E-II and E-III (the FVYL pocket, comprising the hydrophobic residues F1012, V1025, Y1089 and L1092). Biochemical data shows that the mutations associated with DKC, AA and IFP disrupt the binding between telomerases protein subunit reverse transcriptase (TERT) and its nucleic acid substrates leading to loss of telomerase activity and processivity. Collectively our data shows that although these mutations do not alter the overall stability or expression of TERT, these rare genetic disorders are associated with an impaired telomerase holoenzyme that is unable to correctly assemble with its nucleic acid substrates, leading to incomplete telomere extension and telomere attrition, which are hallmarks of these diseases.

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The emerging role of non-traditional ubiquitination in oncogenic pathways [Molecular Bases of Disease]

The addition of ubiquitin (Ub) to a target protein has long been implicated in the process of degradation and is the primary mediator of protein turnover in the cell. Recently however, many non-proteolytic functions of ubiquitination have emerged as key regulators of cellular homeostasis. In this review, we will describe the various non-traditional functions of ubiquitination, with particular focus on and how they can be used as signalling entities in cancer formation and progression. Elaboration of this topic can lead to a better understanding of oncogenic mechanisms, as well as the discovery of novel druggable proteins within the Ub pathway.

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Reduced Lipid Bilayer Thickness Regulates the Aggregation and Cytotoxicity of Amyloid-{beta} [Molecular Biophysics]

The aggregation of amyloid-Aβ (Aβ) on lipid bilayers has been implicated as a mechanism by which Aβ exerts its toxicity in Alzheimer's disease (AD). Lipid bilayer thinning has been observed during both oxidative stress and protein aggregation in AD, but whether these pathological modifications of the bilayer correlate with Aβ misfolding is unclear. Here, we studied peptide-lipid interactions in synthetic bilayers of the short-chain lipid dilauroyl phosphatidylcholine (DLPC) as a simplified model for diseased bilayers to determine their impact on Aβ aggregate, protofibril, and fibril formation. Aβ aggregation and fibril formation in membranes composed of dioleoyl phosphatidylcholine (DOPC) or 1- palmitoyl-2-oleoyl phosphatidylcholine (POPC) mimicking normal bilayers served as controls. Differences in aggregate formation and stability were monitored by a combination of thioflavin-T fluorescence, circular dichroism, AFM, TEM, and NMR. Despite the ability of all three lipid bilayers to catalyze aggregation, DLPC accelerates aggregation at much lower concentrations uniquely ablates the fibrillation of Aβ at low μM concentrations. DLPC stabilized globular, membrane-associated oligomers which could disrupt the bilayer integrity. DLPC bilayers also remodeled preformed amyloid fibrils into a pseudo-unfolded, molten globule state which resembled on-pathway, protofibrillar aggregates. While the stabilized, membrane-associated oligomers were found to be nontoxic, the remodeled species displayed toxicity similar to that of conventionally prepared aggregates. These results provide mechanistic insights into the roles that pathologically thin bilayers may play in Aβ aggregation on neuronal bilayers and pathological lipid oxidation may contribute to Aβ misfolding.

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Heterochromatin Protein 1{gamma} Is a Novel Epigenetic Repressor of Human Embryonic ε-Globin Gene Expression [Gene Regulation]

Production of hemoglobin during development is tightly regulated. For example, expression from the human β-globin gene locus, comprising β-, δ-, ϵ-, and γ-globin genes, switches from ϵ-globin to γ-globin during embryonic development and then from γ-globin to β-globin after birth. Expression of human ϵ-globin in mice has been shown to ameliorate anemia caused by β-globin mutations, including those causing β-thalassemia and sickle cell disease (SCD), raising the prospect that reactivation of ϵ-globin expression could be used in managing these conditions in humans. Although the human globin genes are known to be regulated by a variety of multi-protein complexes containing enzymes that catalyze epigenetic modifications, the exact mechanisms controlling ϵ-globin gene silencing remain elusive. Here, we found that the heterochromatin protein HP1γ,a multifunctional chromatin- and DNA-binding protein with roles in transcriptional activation and elongation, represses ϵ-globin expression by interacting with a histone-modifying enzyme, lysine methyltransferase SUV4-20h2. Silencing of HP1γ expression markedly decreased repressive histone marks and the multi-methylation of H3K9 and H4K20, leading to a significant decrease in DNA methylation at the proximal promoter of the ϵ-globin gene, and greatly increased ϵ-globin expression. In addition, using chromatin immunoprecipitation, we showed that SUV4-20h2 facilitates the deposition of HP1γ on the ϵ-globin-proximal promoter. Thus, these data indicate that HP1γ is a novel epigenetic repressor of ϵ-globin gene expression and provide a potential strategy for targeted therapies for β-thalassemia and SCD.

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Berberine-induced Inactivation of Signal Transducer and Activator of Transcription 5 Signaling Promotes Male-specific Expression of a Bile-acid Uptake Transporter [Signal Transduction]

Sodium-taurocholate co-transporting polypeptide (Ntcp/NTCP) is the major uptake transporter of bile salts in mouse and human livers. In certain diseases, including endotoxemia, cholestasis, diabetes, and hepatocarcinoma, Ntcp/NTCP expression is markedly reduced, which interferes with enterohepatic circulation of bile salts, impairing the absorption of lipophilic compounds. Therefore, normal Ntcp/NTCP expression in the liver is physiologically important. Berberine is an herbal medicine used historically to improve liver function and has recently been shown to repress signal transducer and activator of transcription (Stat) signaling. However, berberine effects on Ntcp/NTCP expression are unknown, prompting use to investigate this possible connection. Our results showed that berberine dose-dependently increased Ntcp expression in male mouse liver and decreased taurocholic acid levels in serum but increased them in the liver. In mouse and human hepatoma cells, berberine induced Ntcp/NTCP mRNA and protein expression, and increased cellular uptake of [3H] taurocholate. Mechanistically, berberine decreased nuclear protein levels of phospho-JAK2 and phospho-Stat5, thus disrupting the JAK2-Stat5 signaling. Moreover, berberine stimulated luciferase reporter expression from the mouse Ntcp promoter when one putative Stat5 response element (RE) (-1137 bp) was deleted and from the human NTCP promoter when three putative Stat5REs (-2898 bp, - 2164 bp, and -691 bp) were deleted. Chromatin immunoprecipitation demonstrated that berberine decreased binding of phospho-Stat5 protein to the -2164 bp and -691 bp Stat5REs in the human NTCP promoter. In summary, berberine-disrupted Stat5 signaling promoted mouse and human Ntcp/NTCP expression, resulting in enhanced bile-acid uptake. Therefore, berberine may be a therapeutic candidate compound for maintaining bile-acid homeostasis.

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Green Tea Polyphenol Epigallocatechin-3-gallate Suppresses Toll-like Receptor 4 Expression via Upregulation of E3 Ubiquitin-protein Ligase RNF216 [Metabolism]

Toll-like receptor 4 (TLR4) plays an essential role in innate immunity through inflammatory cytokine induction. Recent studies demonstrated that the abnormal activation of TLR4 has a pivotal role in obesity-induced inflammation, which is associated with several diseases, including hyperinsulinemia, hypertriglyceridemia, and cardiovascular disease. Here we demonstrate that (−)-epigallocatechin-3-O-gallate, a natural agonist of the 67-kDa laminin receptor (67LR), suppressed TLR4 expression through E3 ubiquitin-protein ring finger protein 216 (RNF216) upregulation. Our data indicate cyclic GMP mediates 67LR agonist-dependent RNF216 upregulation. Moreover, we show that the highly absorbent 67LR agonist (−)-epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3″Me) significantly attenuated TLR4 expression in the adipose tissue. EGCG3″Me completely inhibited the high-fat/high-sucrose (HF/HS)-induced upregulation of tumor necrosis factor α in adipose tissue and serum monocyte chemoattractant protein-1 increase. Furthermore, this agonist intake prevented HF/HS-induced hyperinsulinemia and hypertriglyceridemia. Taken together, 67LR presents an attractive target for the relief of obesity-induced inflammation.

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Novel Molecular Insights into the Catalytic Mechanism of Marine Bacterial Alginate Lyase AlyGC from Polysaccharide Lyase Family 6 [Enzymology]

Alginate lyases that degrade alginate via a β-elimination reaction fall into seven polysaccharide lyase (PL) families. While the structures and catalytic mechanisms of alginate lyases in the other PL families have been clarified, those in family PL6 are yet unrevealed. Here, the crystal structure of AlyGC, a PL6 alginate lyase from marine bacterium Glaciecola chathamensis S18K6T, was solved, and its catalytic mechanism was illustrated. AlyGC is a homodimeric enzyme and adopts a structure distinct from other alginate lyases. Each monomer contains a catalytic N-terminal domain and a function-unknown C-terminal domain. A combined structural and mutational analysis using the structures of AlyGC and of an inactive mutant R241A in complex with an alginate tetrasaccharide indicates that conformational changes occur in AlyGC when a substrate is bound and that the two active centers in AlyGC may not bind substrates simultaneously. The C-terminal domain is shown to be essential for the dimerization and the catalytic activity of AlyGC. Residues Tyr130, Arg187, His242, Arg265 and Tyr304 in the active center are also important for the activity of AlyGC. In catalysis, Lys220 and Arg241 function as the brØnsted base and acid, respectively, and a Ca2+ in the active center neutralizes the negative charge of C5 carboxyl group of the substrate. Finally, based on our data, we propose a metal ion-assisted catalytic mechanism of AlyGC for alginate cleavage with a state change mode, which provides a better understanding for polysaccharide lyases and alginate degradation.

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Metabolic alterations contribute to enhanced inflammatory cytokine production in Irgm1-deficient macrophages [Metabolism]

The Immunity-Related GTPases (IRG) are a family of proteins that are induced by interferon (IFN)-gamma and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes, and promote remodeling and trafficking of those membranes. Prior studies have shown that loss of Irgm1 in mice leads to increased lethality to bacterial infections, as well as enhanced inflammation to non-infectious stimuli; however, the mechanisms underlying these phenotypes are unclear. In the studies reported here, we found uninfected Irgm1-deficient mice to display high levels of serum cytokines typifying profound autoinflammation. Similar increases in cytokine production were also seen in cultured, IFN-gamma-primed macrophages that lacked Irgm1. A series of metabolic studies indicated that the enhanced cytokine production was associated with marked metabolic changes in the Irgm1-deficient macrophages, including increased glycolysis and an accumulation of long chain acylcarnitines. Cells were exposed to the glycolytic inhibitor, 2-deoxyglucose, or fatty acid synthase inhibitors to perturb the metabolic alterations, which resulted in dampening of the excessive cytokine production. These results suggest that Irgm1-deficiency drives metabolic dysfunction in macrophages in a manner that is cell autonomous and independent of infectious triggers. This may be a significant contributor to excessive inflammation seen in Irgm1-deficient mice in different contexts.

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Critical role of the cAMP-PKA pathway in hyperglycemia-induced epigenetic activation of fibrogenic program in the kidney [Research]

Hyperglycemia is a major pathogenic factor that promotes diabetic nephropathy, but the underlying mechanism remains incompletely understood. Here, we show that high glucose induced cAMP response element-binding protein (CREB)-binding protein (CBP)–mediated H3K9/14 hyperacetylation in approximately 5000 gene promoters in glomerular mesangial cells, including those of Tgfb1, Tgfb3, and Ctgf, the major profibrotic factors that are known to drive diabetic renal fibrogenesis. In these promoters, H3K9/14 hyperacetylation was closely associated with NF-B or CREB motifs. Chromatin immunoprecipitation assays confirmed that hyperglycemia promoted phospho-p65 or phospho-CREB and CBP bindings and RNA polymerase II recruitment to these promoters in mesangial cells as well as in glomeruli that were purified from type I and type II diabetic mice. Under hyperglycemia, cAMP production and PKA activity were markedly increased as a result of glucose transporter 1–mediated glucose influx that drives glucose metabolism and ATP production, which led to increased phosphorylation of p65 and CREB. Inhibition of adenylyl cyclase or PKA activity blocked p65 and CREB phosphorylation, CBP recruitment, and histone acetylation in these promoters. Collectively, these data demonstrate that the cAMP-PKA pathway plays a key role in epigenetic regulation of key profibrotic factors in diabetes.—Deb, D. K., Bao, R., Li, Y. C. Critical role of the cAMP-PKA pathway in hyperglycemia-induced epigenetic activation of fibrogenic program in the kidney.



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Blockade of RAGE ameliorates elastase-induced emphysema development and progression via RAGE-DAMP signaling [Research]

The receptor for advanced glycan end products (RAGE) has been identified as a susceptibility gene for chronic obstructive pulmonary disease (COPD) in genome-wide association studies (GWASs). However, less is known about how RAGE is involved in the pathogenesis of COPD. To determine the molecular mechanism by which RAGE influences COPD in experimental COPD models, we investigated the efficacy of the RAGE-specific antagonist FPS-ZM1 administration in in vivo and in vitro COPD models. We injected elastase intratracheally and the RAGE antagonist FPS-ZM1 in mice, and the infiltrated inflammatory cells and cytokines were assessed by ELISA. Cellular expression of RAGE was determined in protein, serum, and bronchoalveolar lavage fluid of mice and lungs and serum of human donors and patients with COPD. Downstream damage-associated molecular pattern (DAMP) pathway activation in vivo and in vitro and in patients with COPD was assessed by immunofluorescence staining, Western blot analysis, and ELISA. The expression of membrane RAGE in initiating the inflammatory response and of soluble RAGE acting as a decoy were associated with up-regulation of the DAMP-related signaling pathway via Nrf2. FPS-ZM1 administration significantly reversed emphysema in the lung of mice. Moreover, FPS-ZM1 treatment significantly reduced lung inflammation in Nrf2+/+, but not in Nrf2–/– mice. Thus, our data indicate for the first time that RAGE inhibition has an essential protective role in COPD. Our observation of RAGE inhibition provided novel insight into its potential as a therapeutic target in emphysema/COPD.—Lee, H., Park, J.-R., Kim, W. J., Sundar, I. K., Rahman, I., Park, S.-M., Yang. S.-R. Blockade of RAGE ameliorates elastase-induced emphysema development and progression via RAGE-DAMP signaling.



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Pirfenidone exerts antifibrotic effects through inhibition of GLI transcription factors [Research]

Pirfenidone is an antifibrotic drug, recently approved for the treatment of patients suffering from idiopathic pulmonary fibrosis (IPF). Although pirfenidone exhibits anti-inflammatory, antioxidant, and antifibrotic properties, the molecular mechanism underlying its protective effects remains unknown. Here, we link pirfenidone action with the regulation of the profibrotic hedgehog (Hh) signaling pathway. We demonstrate that pirfenidone selectively destabilizes the glioma-associated oncogene homolog (GLI)2 protein, the primary activator of Hh-mediated gene transcription. Consequently, pirfenidone decreases overall Hh pathway activity in patients with IPF and in patient-derived primary lung fibroblasts and leads to diminished levels of Hh target genes such as GLI1, Hh receptor Patched-1, α-smooth muscle actin, and fibronectin and to reduced cell migration and proliferation. Interestingly, Hh-triggered TGF-β1 expression potentiated Hh responsiveness of primary lung fibroblasts by elevating the available pool of glioma-associated oncogene homolog (GLI)1/GLI2, thus creating a vicious cycle of amplifying fibrotic processes. Because GLI transcription factors are not only crucial for Hh-mediated changes but are also required as mediators of TGF-β signaling, our findings suggest that pirfenidone exerts its clinically beneficial effects through dual Hh/TGF-β inhibition by targeting the GLI2 protein.—Didiasova, M., Singh, R., Wilhelm, J., Kwapiszewska, G., Wujak, L., Zakrzewicz, D., Schaefer, L., Markart, P., Seeger, W., Lauth, M., Wygrecka, M. Pirfenidone exerts antifibrotic effects through inhibition of GLI transcription factors.



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Imaging the digestive tract in infants and children by S. Stafrace and J. G. (Hans) Blickman (eds)



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Gaucher disease in the liver on hepatocyte specific contrast agent enhanced MR imaging

Abstract

Gaucher disease is a hereditary lipid storage disorder that affects the enzyme beta glucocerebrosidase, causing accumulation of glucocerebroside in macrophages of the reticuloendothelial system. Accumulation can occur in the liver and spleen, manifesting as hepatosplenomegaly, as well as within the bone marrow. Hepatic involvement is usually diffuse but can occasionally manifest as focal liver lesions. We present a case of a 2-year-old boy with Gaucher disease and an infiltrating liver lesion detected on imaging, which was pathologically shown to be focal changes related to the disease. Imaging characteristics of this lesion using hepatocyte specific contrast agent enhanced MRI, which have not been previously discussed in the literature, are described.



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Absolute Configuration Determination through the Unique Intramolecular Excitonic Coupling in the Circular Dichroisms of o,p'-DDT and o,p'-DDD. A Combined Experimental and Theoretical Study

Photochem. Photobiol. Sci., 2017, Accepted Manuscript
DOI: 10.1039/C6PP00438E, Paper
Hiroki Tanaka, Yoshihisa Inoue, Takeshi Nakano, Tadashi Mori
Circular dichroisms (CDs) of the o,p'-isomers of 1,1,1-trichloro- and 1,1-dichloro-2,2-bis(chlorophenyl)ethanes (DDT and DDD) were investigated experimentally and theoretically. A series of strong Cotton effect peaks in a characteristic negative-negative-positive-negative, or...
The content of this RSS Feed (c) The Royal Society of Chemistry


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Loss of Function Mutations in KIF15 Underlying a Braddock-Carey Genocopy

ABSTRACT

Braddock-Carey Syndrome (BCS) is characterized by microcephaly, congenital thrombocytopenia the Pierre-Robin sequence (PRS) and agenesis of the corpus callosum. BCS has been shown to be caused by a 21q22.11 microdeletion that encompasses multiple genes. Here we report a BCS genocopy characterized by congenital thrombocytopenia and PRS that is caused by a loss of function mutation in KIF15 in a consanguineous Saudi Arabian family. Mutations of mitotic kinesins are a well established cause of microcephaly. To our knowledge KIF15 is the first kinesin to be associated with congenital thrombocytopenia.

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An emerging Female Phenotype with Loss of Function Mutations in the Aristaless-Related Homeodomain Transcription Factor ARX

ABSTRACT

The devastating clinical presentation of X-linked lissencephaly with abnormal genitalia (XLAG) is invariably caused by loss of function mutations in the Aristaless-related homeobox (ARX) gene. Mutations in this X-chromosome gene contribute to intellectual disability (ID) with co-morbidities including seizures and movement disorders such as dystonia in affected males. The detection of affected females with mutations in ARX is increasing. We present a family with multiple affected individuals, including two females. Two male siblings presenting with XLAG were deceased prior to full term gestation or within the first few weeks of life. Of the two female siblings, one presented with behavioural disturbances, mild ID, a seizure disorder and complete agenesis of the corpus callosum, similar to the mother's phenotype. A novel insertion mutation in Exon 2 of ARX was identified, c.982delCinsTTT predicted to cause a frameshift at p.(Q328Ffs*37). Our finding is consistent with loss-of-function mutations in ARX causing XLAG in hemizygous males and extends the findings of ID and seizures in heterozygous females. We review the reported phenotypes of females with mutations in ARX and highlight the importance of screening ARX in male and female patients with ID, seizures and in particular with complete agenesis of the corpus callosum.

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Impact of rapid ultrafiltration rate on changes in the echocardiographic left atrial volume index in patients undergoing haemodialysis: a longitudinal observational study

Objective

Optimal fluid management is essential when caring for a patient on haemodialysis (HD). However, if the fluid removal is too rapid, the resultant higher ultrafiltration rate (UFR) disadvantageously promotes haemodynamic instability and cardiac injury. We evaluated the effects of a rapid UFR on changes in the echocardiographic left atrial volume index (LAVI) over a period of time.

Design

Longitudinal observational study.

Setting and participants

A total of 124 new patients on HD.

Interventions

Echocardiography was performed at baseline and repeated after 19.7 months (range 11.3–23.1 months). Changes in LAVI (LAVI/year, mL/m2/year) were calculated. The UFR was expressed in mL/hour/kg, and we used the mean UFR over 30 days (~12–13 treatments).

Main outcome measures

The 75th centile of the LAVI/year distribution was regarded as a ‘pathological’ increment.

Results

The mean interdialytic weight gain was 1.73±0.94 kg, and the UFR was 8.01±3.87 mL/hour/kg. The significant pathological increment point in LAVI/year was 4.89 mL/m2/year. Correlation analysis showed that LAVI/year was closely related to the baseline blood pressure, haemoglobin level, residual renal function and UFR. According to the receiver operating characteristics curve, the ‘best’ cut-off value of UFR for predicting the pathological increment was 10 mL/hour/kg, with an area under the curve of 0.712. In multivariate analysis, systolic blood pressure, a history of coronary artery disease, haemoglobin <10 g/dL and high UFR were significant predictors. An increase of 1 mL/hour/kg in the UFR was associated with a 22% higher risk of a worsening LAVI (OR 1.22, 95% CI 1.05 to 1.41).

Conclusions

An increased haemodynamic load could affect left atrial remodelling in incident patients on HD. Thus, close monitoring and optimal control of UFR are needed.



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Single-visit or multiple-visit root canal treatment: systematic review, meta-analysis and trial sequential analysis

Objectives

Single-visit root canal treatment has some advantages over conventional multivisit treatment, but might increase the risk of complications. We systematically evaluated the risk of complications after single-visit or multiple-visit root canal treatment using meta-analysis and trial-sequential analysis.

Data

Controlled trials comparing single-visit versus multiple-visit root canal treatment of permanent teeth were included. Trials needed to assess the risk of long-term complications (pain, infection, new/persisting/increasing periapical lesions ≥1 year after treatment), short-term pain or flare-up (acute exacerbation of initiation or continuation of root canal treatment).

Sources

Electronic databases (PubMed, EMBASE, Cochrane Central) were screened, random-effects meta-analyses performed and trial-sequential analysis used to control for risk of random errors. Evidence was graded according to GRADE.

Study selection

29 trials (4341 patients) were included, all but 6 showing high risk of bias. Based on 10 trials (1257 teeth), risk of complications was not significantly different in single-visit versus multiple-visit treatment (risk ratio (RR) 1.00 (95% CI 0.75 to 1.35); weak evidence). Based on 20 studies (3008 teeth), risk of pain did not significantly differ between treatments (RR 0.99 (95% CI 0.76 to 1.30); moderate evidence). Risk of flare-up was recorded by 8 studies (1110 teeth) and was significantly higher after single-visit versus multiple-visit treatment (RR 2.13 (95% CI 1.16 to 3.89); very weak evidence). Trial-sequential analysis revealed that firm evidence for benefit, harm or futility was not reached for any of the outcomes.

Conclusions

There is insufficient evidence to rule out whether important differences between both strategies exist.

Clinical significance

Dentists can provide root canal treatment in 1 or multiple visits. Given the possibly increased risk of flare-ups, multiple-visit treatment might be preferred for certain teeth (eg, those with periapical lesions).



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Cohort profile: the Scottish Research register SHARE. A register of people interested in research participation linked to NHS data sets

Purpose

Recruitment to trials is often difficult. Many trials fail to meet recruitment targets resulting in underpowered studies which waste resources and the time of those who participated. While there is evidence that many people are willing to take part in research, particularly if it involves a condition from which they suffer, researchers are unable to easily contact such people often relying on busy clinicians to identify them. Many clinicians perceive themselves as too busy to take part in research activities. The Scottish Health Research Register SHARE adopts an approach which asks the public to consent to their data held in National Health Service databases to be used to determine their suitability for research projects. Additionally, participants can consent for spare blood, left after routine venepuncture to be automatically identified in the laboratory and stored for future research studies.

Participants

Anyone over the age of 16 years in Scotland can participate. Participants are approached through a range of methods including directly at outpatient clinics and general practitioners practices, leaflets with hospital letters and personal email from employers.

Findings to date

SHARE has recruited around 130 000 people. SHARE has demonstrated that it can quickly and efficiently recruit to studies, over 20 until now. In addition, it can be used to administer questionnaire studies by email and recruit to patient and public involvement groups.

Future plans

SHARE continues to steadily recruit with the ambition of eventually achieving 1 000 000 people in Scotland. We are steadily increasing the number of data sets we use for identifying participants. We are adding a mobile app which will facilitate dissemination about research and allow the collection of physiological and activity data if desired. We anticipate that SHARE will soon become the main source of health research recruitment in Scotland.



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Primary healthcare usage and use of medications among immigrant children according to age of arrival to Norway: a population-based study

Background

Morbidity, use of healthcare and medication use have been reported to vary across groups of migrants and according to the different phases of migration, but little is known about children with immigrant background. In this study, we investigate whether the immigrant children's age of arrival predicts differences in usage of primary healthcare (PHC) and in use of prescribed medication.

Methods

This nationwide, population-based study used information for children under 18 years of age in 2008 from three linked registers in Norway. Use of medication was assessed with logistic regression analyses presented with ORs with 95% CIs.

Results

Of 1 168 365 children, 119 251 had immigrant background. The mean number of PHC visits among children aged 10–18 years, was 1.19 for non-immigrants, 1.17 among second generation immigrants, 1.12, 1.05 and 0.83 among first immigrant children who were <5, 5–9 and ≥10 years at arrival in Norway, respectively. Patterns were similar for younger immigrants, and were confirmed with regression models adjusting for age and sex. First generation immigrant children used less of nearly all groups of prescribed medication compared to non-immigrants when adjusting for age and sex (overall OR 0.48 (0.47 to 0.49)), and medication was also generally less used among second generation immigrant children (overall OR 0.92 (0.91 to 0.94)).

Conclusions

Age of arrival predicted PHC usage among children among first-generation children. First-generation immigrant children, particularly those arriving later in adolescence, used PHC less than age corresponding non-immigrant children. Immigrant children used less prescribed medication compared to non-immigrants after adjustment for age and sex.



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Intermittent hypoxia during recovery from neonatal hyperoxic lung injury causes long-term impairment of alveolar development: A new rat model of BPD

Bronchopulmonary dysplasia (BPD) is a chronic lung injury characterized by impaired alveologenesis that may persist into adulthood. Rat models of BPD using varying degrees of hyperoxia to produce injury either cause early mortality or spontaneously recover following removal of the inciting stimulus, thus limiting clinical relevance. We sought to refine an established rat model induced by exposure to 60% O2 from birth by following hyperoxia with intermittent hypoxia (IH). Rats exposed from birth to air or 60% O2 until day 14 were recovered in air with or without IH (FIO2 = 0.10 for 10 min every 6 h) until day 28. Animals exposed to 60% O2 and recovered in air had no evidence of abnormal lung morphology on day 28 or at 10–12 wk. In contrast, 60% O2-exposed animals recovered in IH had persistently increased mean chord length, more dysmorphic septal crests, and fewer peripheral arteries. Recovery in IH also increased pulmonary vascular resistance, Fulton index, and arterial wall thickness. IH-mediated abnormalities in lung structure (but not pulmonary hypertension) persisted when reexamined at 10–12 wk, accompanied by increased pulmonary vascular reactivity and decreased exercise tolerance. Increased mean chord length secondary to IH was prevented by treatment with a peroxynitrite decomposition catalyst [5,10,15,20-Tetrakis(4-sulfonatophenyl)-21H,23H-porphyrin iron (III) chloride, 30 mg/kg/day, days 1428], an effect accompanied by fewer inflammatory cells. We conclude that IH during recovery from hyperoxia-induced injury prevents recovery of alveologenesis and leads to changes in lung and pulmonary vascular function lasting into adulthood, thus more closely mimicking contemporary BPD.



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Cartilage rings contribute to the proper embryonic tracheal epithelial differentiation, metabolism, and expression of inflammatory genes

The signaling cross talk between the tracheal mesenchyme and epithelium has not been researched extensively, leaving a substantial gap of knowledge in the mechanisms dictating embryonic development of the proximal airways by the adjacent mesenchyme. Recently, we reported that embryos lacking mesenchymal expression of Sox9 did not develop tracheal cartilage rings and showed aberrant differentiation of the tracheal epithelium. Here, we propose that tracheal cartilage provides local inductive signals responsible for the proper differentiation, metabolism, and inflammatory status regulation of the tracheal epithelium. The tracheal epithelium of mesenchyme-specific Sox9/ mutant embryos showed altered mRNA expression of various epithelial markers such as Pb1fa1, surfactant protein B (Sftpb), secretoglobulin, family 1A, member 1 (Scgb1a1), and trefoil factor 1 (Tff1). In vitro tracheal epithelial cell cultures confirmed that tracheal chondrocytes secrete factors that inhibit club cell differentiation. Whole gene expression profiling and ingenuity pathway analysis showed that the tumor necrosis factor-α (TNF-α), interferon- (IFN-), and transforming growth factor-β (TGF-β) signaling pathways were significantly altered in the Sox9 mutant trachea. TNF-α and IFN- interfered with the differentiation of tracheal epithelial progenitor cells into mature epithelial cell types in vitro. Mesenchymal knockout of Tgf-β1 in vivo resulted in altered differentiation of the tracheal epithelium. Finally, mitochondrial enzymes involved in fat and glycogen metabolism, cytochrome c oxidase subunit VIIIb (Cox8b) and cytochrome c oxidase subunit VIIa polypeptide 1 (Cox7a1), were strongly upregulated in the Sox9 mutant trachea, resulting in increases in the number and size of glycogen storage vacuoles. Our results support a role for tracheal cartilage in modulation of the differentiation and metabolism and the expression of inflammatory-related genes in the tracheal epithelium by feeding into the TNF-α, IFN-, and TGF-β signaling pathways.



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Factor XI deficiency enhances the pulmonary allergic response to house dust mite in mice independent of factor XII

Asthma is associated with activation of coagulation in the airways. The coagulation system can be initiated via the extrinsic tissue factor-dependent pathway or via the intrinsic pathway, in which the central player factor XI (FXI) can be either activated via active factor XII (FXIIa) or via thrombin. We aimed to determine the role of the intrinsic coagulation system and its possible route of activation in allergic lung inflammation induced by the clinically relevant human allergen house dust mite (HDM). Wild-type (WT), FXI knockout (KO), and FXII KO mice were subjected to repeated exposure to HDM via the airways, and inflammatory responses were compared. FXI KO mice showed increased influx of eosinophils into lung tissue, accompanied by elevated local levels of the main eosinophil chemoattractant eotaxin. Although gross lung pathology and airway mucus production did not differ between groups, FXI KO mice displayed an impaired endothelial/epithelial barrier function, as reflected by elevated levels of total protein and IgM in bronchoalveolar lavage fluid. FXI KO mice had a stronger systemic IgE response with an almost completely absent HDM-specific IgG1 response. The phenotype of FXII KO mice was, except for a higher HDM-specific IgG1 response, similar to that of WT mice. In conclusion, FXI attenuates part of the allergic response to repeated administration of HDM in the airways by a mechanism that is independent of activation via FXII.



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The role of nuclear factor-erythroid 2 related factor 2 (Nrf-2) in the protection against lung injury

Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a ubiquitous master transcription factor that upregulates antioxidant response elements (AREs)-mediated expression of antioxidant enzyme and cytoprotective proteins. Activation of Nrf2 has been shown to be protective against lung injury. In the lung, diverse stimuli including environmental oxidants, medicinal agents, and pathogens can activate Nrf2. Nrf2 translocates to the nucleus and binds to an ARE. Through transcriptional induction of ARE-bearing genes encoding antioxidant-detoxifying proteins, Nrf2 induces cellular rescue pathways against oxidative pulmonary injury, abnormal inflammatory and immune responses, and apoptosis. The Nrf2-antioxidant pathway has been shown to be important in the protection against various lung injuries including acute lung injury/acute respiratory distress syndrome and bronchopulmonary dysplasia, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, and allergy and was widely examined for new therapeutic targets. The present review explores the protective role of Nrf-2 against lung injury and the therapeutic potential in targeting Nrf-2.



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Posttranslational modification of {beta}-catenin is associated with pathogenic fibroblastic changes in bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a common complication of premature birth. The histopathology of BPD is characterized by an arrest of alveolarization with fibroblast activation. The Wnt/β-catenin signaling pathway is important in early lung development. When Wnt signaling is active, phosphorylation of β-catenin by tyrosine kinases at activating sites, specifically at tyrosine 489 (Y489), correlates with nuclear localization of β-catenin. We examined fetal lung tissue, lung tissue from term newborns, and lung tissue from infants who died with BPD; we found nuclear β-catenin phosphorylation at Y489 in epithelial and mesenchymal cells in fetal tissue and BPD tissue, but not in the lungs of term infants. Using a 3D human organoid model, we found increased nuclear localization of β-catenin phosphorylated at Y489 (p-β-cateninY489) after exposure to alternating hypoxia and hyperoxia compared with organoids cultured in normoxia. Exogenous stimulation of the canonical Wnt pathway in organoids was sufficient to cause nuclear localization of p-β-cateninY489 in normoxia and mimicked the pattern of α-smooth muscle actin (α-SMA) expression seen with fibroblastic activation from oxidative stress. Treatment of organoids with a tyrosine kinase inhibitor prior to cyclic hypoxia-hyperoxia inhibited nuclear localization of p-β-cateninY489 and prevented α-SMA expression by fibroblasts. Posttranslational phosphorylation of β-catenin is a transient feature of normal lung development. Moreover, the persistence of p-β-cateninY489 is a durable marker of fibroblast activation in BPD and may play an important role in BPD disease pathobiology.



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Alternative hematological and vascular adaptive responses to high-altitude hypoxia in East African highlanders

Elevation of hemoglobin concentration, a common adaptive response to high-altitude hypoxia, occurs among Oromo but is dampened among Amhara highlanders of East Africa. We hypothesized that Amhara highlanders offset their smaller hemoglobin response with a vascular response. We tested this by comparing Amhara and Oromo highlanders at 3,700 and 4,000 m to their lowland counterparts at 1,200 and 1,700 m. To evaluate vascular responses, we assessed urinary levels of nitrate (NO3) as a readout of production of the vasodilator nitric oxide and its downstream signal transducer cyclic guanosine monophosphate (cGMP), along with diastolic blood pressure as an indicator of vasomotor tone. To evaluate hematological responses, we measured hemoglobin and percent oxygen saturation of hemoglobin. Amhara highlanders, but not Oromo, had higher NO3 and cGMP compared with their lowland counterparts. NO3 directly correlated with cGMP (Amhara R2 = 0.25, P < 0.0001; Oromo R2 = 0.30, P < 0.0001). Consistent with higher levels of NO3 and cGMP, diastolic blood pressure was lower in Amhara highlanders. Both highland samples had apparent left shift in oxyhemoglobin saturation characteristics and maintained total oxyhemoglobin content similar to their lowland counterparts. However, deoxyhemoglobin levels were significantly higher, much more so among Oromo than Amhara. In conclusion, the Amhara balance minimally elevated hemoglobin with vasodilatory response to environmental hypoxia, whereas Oromo rely mainly on elevated hemoglobin response. These results point to different combinations of adaptive responses in genetically similar East African highlanders.



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Bronchodilatory effect of deep inspiration in freshly isolated sheep lungs

Taking a big breath is known to reverse bronchoconstriction induced by bronchochallenge in healthy subjects; this bronchodilatory effect of deep inspiration (DI) is diminished in asthmatics. The mechanism underlying the DI effect is not clear. Observations from experiments using isolated airway smooth muscle (ASM) preparations and airway segments suggest that straining of ASM due to DI could lead to bronchodilation, possibly due to strain-induced reduction in ASM contractility. However, factors external to the lung cannot be excluded as potential causes for the DI effect. Neural reflex initiated by stretch receptors in the lung are known to inhibit the broncho-motor tone and enhance vasodilatation; the former directly reduces airway resistance, and the latter facilitates removal of contractile agonists through the bronchial circulation. If the DI effect is solely mediated by factors extrinsic to the lung, the DI effect would be absent in isolated, nonperfused lungs. Here we examined the DI effect in freshly isolated, nonperfused sheep lungs. We found that imposition of DI on isolated lungs resulted in significant bronchodilation, that this DI effect was present only after the lungs were challenged with a contractile agonist (acetylcholine or histamine), and that the effect was independent of the difference in lung volume observed pre- and post-DI. We conclude that a significant portion of the bronchodilatory DI effect stems from factors internal to the lung related to the activation of ASM.



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Young family's heartbreak - The Maitland Mercury


The Maitland Mercury

Young family's heartbreak
The Maitland Mercury
Erin had metastatic tongue cancer a condition that was rare for her age and gender, highly aggressive and one that spread quickly throughout her body. Her diagnosis came shortly after twins Jorja and Charli were born, two months premature, in March.



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Dr. Schoenfeld on Low-Dose Radiation Plus Immunotherapy in Head and Neck Cancer - OncLive


OncLive

Dr. Schoenfeld on Low-Dose Radiation Plus Immunotherapy in Head and Neck Cancer
OncLive
Jonathan D. Schoenfeld, MD, MPhil, MPH, director, melanoma radiation oncology, physician, assistant professor of radiation oncology, Harvard Medical School, Dana-Farber Cancer Institute, discusses potential combination regimens of low-dose radiation ...



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Cellular phosphatases play an essential role in the inhibition of RAF-MEK-ERK signalling by sorafenib in Hepatocellular carcinoma cells

The RAS-RAF-MEK-ERK cascade is a key oncogenic signal transduction pathway activated in many types of tumours in humans. Sorafenib, the medical treatment of reference against advanced stages of hepatocellular carcinoma (HCC), inhibits the RAF-MEK-ERK cascade in HCC cells. Based on previous studies suggesting that this cascade is an important target of sorafenib in HCC cells, we explored its regulation using mathematical modeling and ordinary differential equations. We analyzed the dynamic regulation of the core components of the RAF-MEK-ERK cascade in three human HCC cell lines (Huh7, Hep3B and PLC/PRF5) with heterogeneous responses to sorafenib.

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Transforming growth factor-β-induced plasticity causes a migratory stemness phenotype in hepatocellular carcinoma

As part of its potential pro-tumorigenic actions, Transforming Growth Factor-(TGF)-β induces epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells. Whether EMT induces changes in tumor cell plasticity has not been fully explored yet. Here, we analyze the effects of TGF-β on the EMT and stem-related properties of HCC cells and the potential correlation among those processes. The translational aim of the study was to propose a TGF-β/EMT/stem gene signature that would help in recognizing HCC patients as good candidates for anti-TGF-β therapy.

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The dual specificity PI3K/mTOR inhibitor PKI-587 displays efficacy against T-cell acute lymphoblastic leukemia (T-ALL)

Although significant improvements have been made in the treatment of acute lymphoblastic leukemia (ALL), there is a substantial subset of high-risk T-cell ALL (T-ALL) patients with relatively poor prognosis. Like in other leukemia types, alterations of the PI3K/mTOR pathway are predominant in ALL which is also responsible for treatment failure and relapse. In this study, we showed that relapsed T-ALL patients display an enrichment of the PI3K/mTOR pathway. Using a panel of inhibitors targeting multiple components of the PI3K/mTOR pathway, we observed that the dual-specific PI3K/mTOR inhibitor PKI-587 was the most selective inhibitor for T-ALL cells dependent on the PI3K/mTOR pathway.

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Toxicological investigation of forensic cases related to the designer drug 3,4-methylenedioxypyrovalerone (MDPV): Detection, quantification and studies on human metabolism by GC-MS

In the recent years, among the increasing number of new psychoactive substances (NPS) synthetic cathinones have reached popularity as one of the most widely abused drugs [1,2]. This new group of recreational drugs is also known as “bath salts”, “plant food” or “research chemicals” and are taken by drug users for its psychostimulant effects. However, the abuse of synthetic chathinones can result in severe side effects including tachycardia, hyperthermia, agitation and violent behaviour [1,3–5].

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Acute intoxication caused by synthetic cannabinoids 5F-ADB and MMB-2201: a case series

In the recent past, cannabimimetic compounds, have been synthetically produced and initially offered commercially as a legal alternative to cannabis [1]. They are often inhaled via a pipe or rolled into a cigarette [2]. A variety of formulations of these “synthetic cannabinoids” are available on Internet web stores or in specialized “smart shops”, smoke shops and gas stations [2].

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Researchers: Fast food wrapped in chemically treated paper linked to cancers, thyroid disease - WFAA.com


WFAA.com

Researchers: Fast food wrapped in chemically treated paper linked to cancers, thyroid disease
WFAA.com
A recent study has found evidence that Americans may be consuming fast food wrapped in paper treated with chemicals linked to kidney and testicular cancers, thyroid disease, low birth rates and immunotoxicity in children. According to a new study ...
Researchers find 'another reason' to avoid fast food: Chemicals in the packagingWashington Post
Researchers find chemicals in fast food packaging sometimes leach into your foodWWMT-TV
Troubling chemicals found in wide range of fast-food wrappers - The ...The Verge
Gizmodo -ACS Publications - American Chemical Society -YouTube -Environmental Working Group
all 87 news articles »


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Fully-covered metallic stenting in an infant with tracheoesophageal fistula due to button battery ingestion

Previously, the main treatment options for tracheoesophageal fistula included surgery and conservative treatment. Herein, we report a child suffering from severe tracheoesophageal fistula due to button battery ingestion. The child relapsed soon after a repair surgery. Then, he was endotracheally implanted with a fully-covered metallic stent combined with a jejunal tube feeding. He recovered soon and the stent was removed five months later. The fistula was healed with no relapse during a 25-month follow-up.

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Methylphenidate effects on P300 responses from children and adolescents.

The attention deficit hyperactivity disorder (ADHD) is characterized by a lack of attention, by hyperactivity and impulsivity, by flawed academic performance, by problematic family and social relationships and by a need for psychosocial adjustment (1). Neuropsychological studies have suggested an association between ADHD and neural alterations in the prefrontal cortex and its projections in various subcortical structures (2, 3). Methylphenidate (MPH) is the most commonly prescribed central nervous system stimulant used to treat ADHD.

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A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now

Bladder cancer is the fifth most common cancer in the United States (US), and as of 2012, is the ninth most common cancer diagnosed worldwide, affecting 430,000 people and resulting in 165,000 deaths annually [1,2]. The greatest risk factor for bladder cancer is tobacco smoking and worldwide incidence rates correspond with smoking prevalence [2]. Although significant time, effort, and spend has been dedicated to bladder cancer research, overall incidence and mortality rates have changed little over the past 20 years [1–3].

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Immune checkpoint inhibitors and targeted therapies for metastatic melanoma: a network meta-analysis

Immune checkpoint inhibitors and targeted therapies, two new class of drugs for treatment of metastatic melanoma, have not been compared in randomized controlled trials (RCT). We quantitatively summarized the evidence and compared immune and targeted therapies in terms of both efficacy and toxicity.

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Transcanal endoscopic lateral skull base surgery

Presutti and Marchioni’s transcanal exclusive endoscopic transpromontorial approach represents a new surgical technique to remove diseases that involve cochlea and fundus of IAC in selected cases, thus avoiding extensive bone drilling, brain, meningeal and neurovascular manipulation. The advantage of this endoscopic technique is that direct access to IAC allows the creation of a minimally-invasive route through the cochlea with a consequent improved safety during intra and postoperative management.

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Effect of nebulized budesonide on decreasing the recurrence of allergic fungal rhinosinusitis

To evaluate the clinical efficacy and the effects on decreasing the recurrence of AFRS (allergic fungal rhinosinusitis) of a budesonide inhalation suspension delivered via transnasal nebulization to patients following endoscopic sinus surgery.

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Overview of Sinonasal and Ventral Skull Base Malignancy Management

Significant technological advances have fostered a movement toward minimally invasive surgical interventions for the management of ventral skull base malignancies. The care of patients with these lesions ideally involves an interdisciplinary skull base team that includes otolaryngologists, neurologic surgeons, radiation oncologists, and medical oncologists. This overview describes considerations essential for diagnosis, prognosis, and preoperative evaluation. Furthermore, surgical nuances, strategies for skull base reconstruction, and nonsurgical options are briefly discussed. Our hope is that this overview may be useful as an up-to-date description of the challenging clinical scenarios associated with these lesions.

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The Making of a Skull Base Team and the Value of Multidisciplinary Approach in the Management of Sinonasal and Ventral Skull Base Malignancies

The management of sinonasal and ventral skull base malignancies is best performed by a team. Although the composition of the team may vary, it is important to have multidisciplinary representation. There are multiple obstacles, both individual and institutional, that must be overcome to develop a highly functioning team. Adequate training is an important part of team-building and can be fostered with surgical telementoring. A quality improvement program should be incorporated into the activities of a skull base team.

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The Role of Chemotherapy in the Management of Sinonasal and Ventral Skull Base Malignancies

In most cases of advanced sinonasal and ventral skull base cancer, a multimodal treatment approach provides the best chance for improved outcomes. Depending on the tumor type and extent of disease, systemic chemotherapy has been shown to play an important role in neoadjuvant, concomitant, and adjuvant settings. The lack of randomized trials continues to limit its indications. Further high-quality studies are needed to understand ideal chemotherapeutic regimens and their role and sequential timing in sinonasal and ventral skull base cancer.

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Survival, Morbidity, and Quality-of-Life Outcomes for Sinonasal and Ventral Skull Base Malignancies

Sinonasal and ventral skull base malignancies are a rare, heterogeneous group of cancers. Although prognosis usually depends on many factors, long-term survival rates remain low despite recent advances. Population-based databases are powerful resources for studying survival outcomes. However, institutional retrospective chart-review studies have been able to provide more insight on recurrence patterns, morbidity, and quality-of-life metrics, as well as more details of the treatment information that may affect outcomes. This article discusses general considerations for understanding reported outcome data, summarizes the overall outcomes and their determinants, and provides histology-specific outcomes reported in the literature.

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How Do Adolescent Students Perceive Aging Teachers' Voices?

This study aims to analyze adolescent evaluations of aging teachers' perceived vocal age (PVA) and pleasantness, relative to actual vocal parameters.

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Computational Sensing Using Low-Cost and Mobile Plasmonic Readers Designed by Machine Learning

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b00105
ancac3?d=yIl2AUoC8zA


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Abrupt Size Partitioning of Multimodal Photoluminescence Relaxation in Monodisperse Silicon Nanocrystals

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.6b07285
ancac3?d=yIl2AUoC8zA


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Molecular Tuning of the Vibrational Thermal Transport Mechanisms in Fullerene Derivative Solutions

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.6b06499
ancac3?d=yIl2AUoC8zA


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High, Anisotropic, and Substrate-Independent Mobility in Polymer Field-Effect Transistors Based on Preassembled Semiconducting Nanofibrils

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.6b08184
ancac3?d=yIl2AUoC8zA


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Quasi-epitaxial Metal-Halide Perovskite Ligand Shells on PbS Nanocrystals

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.6b04721
ancac3?d=yIl2AUoC8zA


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Zeolite-Templated Carbon as an Ordered Microporous Electrode for Aluminum Batteries

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.6b07995
ancac3?d=yIl2AUoC8zA


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Nanocuvette: A Functional Ultrathin Liquid Container for Transmission Electron Microscopy

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.6b05007
ancac3?d=yIl2AUoC8zA


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A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now

Bladder cancer is the fifth most common cancer in the United States (US), and as of 2012, is the ninth most common cancer diagnosed worldwide, affecting 430,000 people and resulting in 165,000 deaths annually [1,2]. The greatest risk factor for bladder cancer is tobacco smoking and worldwide incidence rates correspond with smoking prevalence [2]. Although significant time, effort, and spend has been dedicated to bladder cancer research, overall incidence and mortality rates have changed little over the past 20 years [1–3].

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Immune checkpoint inhibitors and targeted therapies for metastatic melanoma: a network meta-analysis

Immune checkpoint inhibitors and targeted therapies, two new class of drugs for treatment of metastatic melanoma, have not been compared in randomized controlled trials (RCT). We quantitatively summarized the evidence and compared immune and targeted therapies in terms of both efficacy and toxicity.

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Upper Eyelid Reconstruction Using a Blepharoplasty Flap.

Purpose: The blepharoplasty flap is a relatively simple but under-recognized surgical technique for repairing defects that result from excision of broad-based lesions on the upper eyelid that lie between the eyelid crease and the eyelashes. As this has not been previously published in the literature, the authors aim to increase the awareness of this technique. Methods: The eyelid crease is marked. A line is drawn perpendicular to the crease line along the aspect of the lesion closest to the centre of the eyelid, dividing the eyelid into 4 quarters. The lesion is excised along with the area lying diagonally. An advancement flap is then fashioned from excess skin of the upper eyelid and moved inferiorly to close the defect. Results: The resulting cosmetic results seen postoperatively have been excellent. Conclusions: The blepharoplasty flap is a style of surgical advancement flap that utilizes the tissue that would normally be excised during blepharoplasty. This straightforward technique can prove useful in the surgical repertoire due to its potential to be widely adopted in surgical practice. (C) 2017 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

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Making Mouse Models That Reflect Human Immune Responses

Publication date: Available online 1 February 2017
Source:Trends in Immunology
Author(s): Lili Tao, Tiffany A. Reese
Humans are infected with a variety of acute and chronic pathogens over the course of their lives, and pathogen-driven selection has shaped the immune system of humans. The same is likely true for mice. However, laboratory mice we use for most biomedical studies are bred in ultra-hygienic environments, and are kept free of specific pathogens. We review recent studies that indicate that pathogen infections are important for the basal level of activation and the function of the immune system. Consideration of these environmental exposures of both humans and mice can potentially improve mouse models of human disease.



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Non-small cell lung cancer patients with Adenocarcinoma morphology have a better outcome compared to patients diagnosed with non-small cell lung cancer favor Adenocarcinoma

Non-small cell lung cancer patients are treated differently, depending largely on histology identification of squamous vs. adenocarcinoma subtypes. This distinction has been classically based on micro-morphology features, but immunohistochemistry (IHC) has become a major tool for this distinction in recent years. We retrospectively compared the outcome of adenocarcinoma patients considering their diagnosis being based on morphology versus IHC. We found the method of diagnosis to be an independent prognostic factor. We believe that identification of adenocarcinoma as based on morphology vs. IHC should be integrated into the evaluation of such patients and should be considered as a stratification factor in clinical trials.

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A Multimedia Self-Management Intervention to Prepare Cancer Patients and Family Caregivers for Lung Surgery and Post-Operative Recovery

This study pilot-tested a multimedia self-management (MSM) intervention for lung surgery patients and family caregivers. We administered the intervention to 60 patients/family caregivers from before surgery to 2-4 weeks after. Trends for improvements were observed in scores for self-efficacy, knowledge, activation, and emotional QOL. Patient-centered models of surgical care are needed to improve QOL and reduce undesirable healthcare resource use.

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The Controlling Nutritional Status Score is a Significant Independent Predictor of Poor Prognosis in Patients with Malignant Pleural Mesothelioma

The aim of this study was to clarify the clinical significance of the Controlling Nutritious Status (CONUT) in malignant pleural mesothelioma. The data of 83 patients were analyzed. The high CONUT group had significantly poorer overall survival (p<0.001) and disease or progression free survival (p<0.001). This score provides useful information for selecting patients who will benefit from the treatment.

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Early Results of Lung Cancer Screening and Radiation Dose Assessment by Low-Dose CT at a Community Hospital

Effective translation of low-dose computed tomography (LDCT) lung cancer screening from academic to community healthcare settings has been questioned. Records of 680 community healthcare patients who completed LDCT screening were reviewed and results compared to those of the National Lung Screen Trial. Successful implementation of LDCT lung cancer screening in a community healthcare setting was demonstrated.

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