bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic efficacy of early photobiomodulation therapy on the zones of stasis in burns: An experimental rat model study
Authors: Jin Jian , Zheng Xingfeng , He Fang , Zhang Yongcun , Zhou Hao , Luo Pengfei , Hu Xiaoyan , Xia Zhaofan
Published: August 2018

This study aimed to investigate the role of photobiomodulation therapy in preventing zones of stasis in burn wounds. We hypothesized that photobiomodulation therapy could promote tissue formation and release of nitric oxide (NO), and reduce inflammatory responses, thereby dilating local microvessels, reducing necrosis and apoptosis. Thirty rats were randomly divided into control group (CG) and laser group (LG). The zone of stasis was formed by applying a brass comb to the skin resulting in four rectangular burns separated by three unburned interspaces. The left side was laser wound (LW), while the right side was shielded wound (SW). The LW of LG was immediately subjected to photobiomodulation therapy, followed by once‐daily 30‐minutes photobiomodulation therapy sessions. Skin ultrasound and Doppler angiography analyses were used to evaluate the statuses of the zones of stasis at 1, 24, and 96 hours after injury. Harvested burn wound tissue was subjected to hematoxylin–eosin staining and HMGB1, caspase 3, and thrombomodulin immunohistochemistry, and the contents of NO and TNF‐α were measured in stasis tissue. Thrombomodulin, HMGB1, and caspase 3 immunohistochemistry revealed significantly lower positive staining rates in the LW of LG rats relative to the others at 96 hours (p < 0.05), as well as a significantly higher skin blood flow relative to the others (p < 0.05). The NO content was significantly higher in the LW of LG, compared with other wounds, at 24 and 96 hours after injury (p < 0.05). The TNF‐α level was significantly lower in the LW of LG than in other wounds at 96 hours (p < 0.05). Early, local photobiomodulation therapy can effectively ameliorate injury progression in the zone of stasis. However, these beneficial effects are limited to the directly irradiated sites.
Differences between patient‐ and proxy‐reported HRQoL using the Wound‐QoL
Authors: Sommer Rachel , Hampel‐Kalthoff Carsten , Kalthoff Brigitte , Neht Christopher , Scherfer Erwin , Winkler Manfred , Blome Christine
Published: August 2018

The purpose of this study was to examine the patient‐ and proxy‐report agreement on the Wound‐quality of life (QoL) questionnaire to assess health‐related QoL in patients with chronic wounds. Patients and their proxies (in this case, relatives) were recruited via different nursing services in Germany and asked to complete the Wound‐QoL. Intraclass correlation coefficients were calculated for each Wound‐QoL scale and the total score, and weighted Cohen's Kappa coefficients for individual items. Proxies tended to report lower health‐related QoL in the Wound‐QoL than their relatives with chronic wounds. Agreement between the two perspectives was moderate on single‐item level and excellent on scale level. Proxy‐reports can be helpful, if patients are unable to provide information, although caution remains when interpreting the results. However, the patient's own perspective remains preferable.
Patients’ prediction of their wound healing time
Authors: Borda Luis J. , Jaller Jose A. , Kallis Penelope J. , MacQuhae Flor E. , Herskovitz Ingrid , Fox Joshua D. , Baquerizo Katherine L. , Kirsner Robert S.
Published: August 2018

Understanding and managing patients’ expectations can help improve their adherence to treatment for chronic wounds; however, little is known concerning about their expectations regarding healing time. Recruited subjects were asked to predict how long their wounds would take to heal and their charts were reviewed to retrieve real time of healing. We recruited 100 subjects from which 77% have healed. Fifty‐three subjects (68.8%) had a longer healing time than they predicted (underestimated), and 17 (22.1%) had a shorter healing time than they predicted (overestimated). Subjects with shorter wound duration history tended to predict shorter healing time than subjects with longer wound duration (p < 0.01). However, wound duration did not affect prediction accuracy (p = 0.65). Subjects with chronic wounds seem more often to underestimate their time of healing. Wound duration significantly influenced patients’ prediction time, although it did not make their prediction more accurate. Patient education about expectations may be important as patients often expect their wounds to heal faster than they actually do.
Chronic oral rapamycin decreases adiposity, hepatic triglycerides and insulin resistance in male mice fed a diet high in sucrose and saturated fat
Authors: den Hartigh Laura J. , Goodspeed Leela , Wang Shari A. , Kenerson Heidi L. , Omer Mohamed , O'Brien Kevin D. , Ladiges Warren , Yeung Raymond , Subramanian Savitha
Published: August 2018

New Findings

What is the central question of this study?

Whether chronic oral rapamycin promotes beneficial effects on glucose/lipid metabolism and energy balance when administered to mice with an obesogenic diet rich in saturated fat and sucrose has not been explored.

What is the main finding and its importance?

Chronic oral rapamycin reduces body weight and fat gain, improves insulin sensitivity and reduces hepatic steatosis when administered to mice with a high‐fat, high‐sucrose diet. In addition, we make the new observation that there appear to be tissue‐specific effects of rapamycin. Although rapamycin appears to impart its effects mainly on visceral adipose tissue, its effects on insulin sensitivity are mediated by subcutaneous adipose tissue.

Excess adiposity is commonly associated with insulin resistance, which can increase the risk of cardiovascular disease. However, the exact molecular mechanisms by which obesity results in insulin resistance are yet to be understood clearly. The intracellular nutrient‐sensing protein, mechanistic target of rapamycin (mTOR), is a crucial signalling component in the development of obesity‐associated insulin resistance. Given that increased tissue activation of mTOR complex‐1 (mTORC1) occurs in obesity, diabetes and ageing, we hypothesized that pharmacological inhibition of mTORC1 would improve metabolic dysregulation in diet‐induced obesity. We administered continuous rapamycin, a specific mTORC1 inhibitor, orally to C57BL/6J mice concurrently with a high‐fat, high‐sucrose (HFHS) diet for 20 weeks. The control group received placebo microcapsules. Rapamycin‐treated mice showed significantly reduced weight gain and adiposity (33.6 ± 4.9 versus 40.4 ± 3.0% body fat, P < 0.001, n = 8 mice per group), despite increased or equivalent food intake compared with the placebo group. The rapamycin‐fed mice also demonstrated reduced plasma glucose (252 ± 57 versus 297 ± 67 mg dl−1, P < 0.001) and improved insulin sensitivity during insulin and glucose tolerance testing. Rapamycin‐treated mice also had lower plasma triglycerides (48 ± 13 versus 67 ± 11 mg/dL, P < 0.01) and hepatic triglyceride content (89 ± 15 versus 110 ± 19 mg/g liver, P < 0.05) compared with the placebo group. A moderately low dose of rapamycin decreased adiposity and improved the metabolic profile in a model of diet‐induced obesity. These data suggest that low‐grade chronic mTORC1 inhibition might be a potential strategy for anti‐obesity therapies.
Directing Attention Externally and Self-Controlled Practice Have Similar Effects on Motor Skill Performance
Authors: Asadi Ayoub , Farsi Alireza , Abdoli Behrouz , Saemi Esmaeel , Porter Jared M.
Published: August 2018

There were two aims to the present study. First, we sought to investigate how a form of self-controlled practice compared to a well-established strategy of explicitly directing a mover’s attention externally when performing the standing long jump. Those two forms of practice were also compared to conditions in which participants were instructed to focus their attention internally or neutrally (i.e., control condition). Second, we investigated if the skill level of the participants was a factor in the comparison of these two forms of training (i.e., directing attention externally and self-controlled practice). In the External condition, volunteers were told to focus on jumping toward a cone that was placed in front of them at a distance of 5-m. In the Internal condition, participants were told to focus on the extension of their knees. In the Self-control condition, volunteers were allowed to choose a distant target to focus their attention on while executing the jump. Participants also completed jumps in a Control condition in which no explicit instructions were provided. Results demonstrated that both skilled and low-skilled participants jumped significantly farther in the External and Self-control conditions compared to jumps completed in the Control and Internal conditions. The findings of this study demonstrate that providing instructions that direct attention externally, or allowing the participant to choose where to direct their attention, resulted in similar enhancements in jumping performance in both low- and high-skilled jumpers.
The Influence of Guided Practice on Overhand Throwing Competence in Preschool Children in a Mastery Motivational Climate
Authors: Johnson Jerraco L. , Rudisill Mary E. , Hastie Peter A. , Sassi Julia
Published: August 2018

The aim of this study was to determine the extent to which guided throwing practice volume influenced gains in throwing competency in young children during exposure to a mastery motivational climate physical play program. Fifty-four preschool children attended 13 biweekly 30-minute motor skill sessions over 7 weeks. Pre- and post-test throwing competency was measured in three ways (Test of Gross and Motor Development–Third Edition [TGMD-3], developmental sequence for throwing, and throwing velocity). Throwing practice behaviors (visits, time, and trials) were then coded for each participant using video recordings. Paired-samples t-tests revealed significant gains in throwing proficiency by the children from pre- to post-test on all three measures. Results from multiple hierarchical linear regressions highlighted that pre-test scores and guided throwing practice volume (a principle component analysis of throwing visits, time, and trials) accounted for 19% (TGMD), 52% (developmental sequence), and 60% (velocity) of the explained variance of post-test throwing competency, respectively. Results also revealed that although boys spent more time practicing throwing than girls, gender only appeared to be a significant predictor in the TGMD regression model. These findings provide empirical evidence of the importance of guided practice during mastery climate programs.
Enhancing the Evidence Base for Irish Female Youth Participation in Physical Activity—The Development of the Gaelic4Girls Program
Authors: Farmer Orlagh , Duffy Donna , Cahill Kevin , Lester Diarmuid , Belton Sarahjane , O’Brien Wesley
Published: August 2018

The purpose of the current research was to gather baseline data on female youth to inform the development of a targeted physical activity (PA) and sports-based intervention, specifically identified as “Gaelic4Girls”. Cross-sectional data on PA levels, psychological correlates of PA, anthropometric characteristics, and the fundamental movement skill (FMS) proficiency of female youth (n = 331; M age 10.92±1.22) were collected. A subsample (n = 37) participated in focus group (FG) interviews exploring perceptions of health/sport, and identifying barriers/motivators to participation. PA levels were assessed using self-report (PA Questionnaire for Older Children) and classified as low, moderate, and high active. One- and two-way ANOVAs (post hoc Tukey honest significant difference [HSD]) were used to analyze the data. The FGs were transcribed verbatim, coded, and thematically analyzed. Findings indicated that the majority of youth (71.8%) were not meeting the minimum daily PA recommendations for health, and that 98.1% did not achieve the FMS proficiency expected for their age. Low, moderately, and highly active participants differ significantly in terms of overall FMS (p = .03), and locomotor control scores (p = .03). FG findings report fun and friendship as key PA motivators, too much competitiveness as barriers, and positive outside encouragement from family/friends/coaches as facilitators encouraging PA engagement. Findings highlight the need for targeting low levels of PA, FMS proﬁciency in female youth sport interventions, through addressing self-efﬁcacy levels, inclusive of fun, and socially-stimulating PA environments.
Three-level spaser for next-generation luminescent nanoprobe
Authors: Song Pei , Wang Jian-Hua , Zhang Miao , Yang Fan , Lu Hai-Jie , Kang Bin , Xu Jing-Juan , Chen Hong-Yuan
Published: August 2018

Delayed spasing dots with ~3-nm spectral width, ~1 mJ cm
−2
threshold, and ~10
2
-μs lifetime were developed for a bionanoprobe.
Effect of Diabetes Mellitus on the Pharmacokinetics and Pharmacodynamics of Tuberculosis Treatment
Authors: Alfarisi Omamah , Mave Vidya , Gaikwad Sanjay , Sahasrabudhe Tushar , Ramachandran Geetha , Kumar Hemanth , Gupte Nikhil , Kulkarni Vandana , Deshmukh Sona , Atre Sachin , Raskar Swapnil , Lokhande Rahul , Barthwal Madhusudan , Kakrani Arjun , Chon Sandy , Gupta Amita , Golub Jonathan E. , Dooley Kelly E.
Published: August 2018

Diabetes mellitus (DM) and tuberculosis (TB) are two common diseases with increasing geographic overlap and clinical interactions. The effect of DM and hemoglobin A1c (HbA1c) values on the pharmacokinetics (PK) and pharmacodynamics (PD) of anti-TB drugs remains poorly characterized.
Tax harmonisation and tobacco product prices in the European Union, 2004–2015
Authors: López-Nicolás Ángel , Stoklosa Michal
Published: August 2018

Objectives

The European Commission has formally opened a process of revision of its tobacco tax directive. The purpose of this study is to analyse the evolution of cigarette and roll-your-own (RYO) tobacco prices in order to identify avenues for the improvement of public health goals.

Methods

Pooled cross-sectional data on prices and taxes on cigarettes and RYO tobacco in the Member States over 2004–2015 is used to track the distributions of the most popular price category and the weighted average price of these products and to relate them to the underlying tax structure.

Results

The inflation-adjusted prices for the two products have increased over the period, but the dispersion of prices across Member States has remained constant. Throughout the period, there was a pervasive price gap between cigarettes and RYO tobacco within the Member States. Such features are explained by the underlying tax design.

Discussion

The current tax stance has been successful at increasing both cigarette and RYO tobacco prices. To further enhance the public health impact of the European Union tax directive, the revision should promote the convergence of prices across Member States and aim at closing the price gap between cigarettes and RYO tobacco. These objectives call for increasing the mandatory minimum levels of excise duty on the two products, preferably linking them to the evolution of a European weighted average price. The pace of increase should be faster for RYO tobacco in order to close the gap with respect to cigarette prices.
Serological survey of British sheep flocks for evidence of exposure to ovine pestiviruses
Authors: Jennings Amy , Gascoigne Emily , Macrae Alastair , Burrough Elizabeth , Crilly James Patrick
Published: August 2018

Ovine pestiviruses have the potential to reduce productivity in the British sheep flock. However, their prevalence and impact are currently poorly understood. This study aimed to estimate the exposure to pestiviruses in adult breeding ewe stock. Blood samples collected for metabolic profiling before lambing were tested using an ELISA that detected antibodies raised to both bovine viral diarrhoea virus and Border disease virus. A group of 15 animals were tested per flock. A total of 34 farms were tested, of which 13 had at least one seropositive animal. In those positive flocks between one and nine of the animals tested antibody‐positive. Positive flocks were identified in all regions of Great Britain. This work suggests that exposure to ovine pestiviruses is widespread, and that it is timely to investigate flock‐level prevalence and possible production impacts of endemic infection.
British Veterinary Association Annual General Meeting York, 20 September 2018
Authors: Thorpe Derek
Published: August 2018

The 2018 Annual General Meeting of the British Veterinary Association will be held at the National STEM Learning Centre, Siwards Way, University of York, York, on Thursday, 20 September 2018, at 16.10.
Dynamics of the bacterial community in a channel catfish nursery pond with a cage–pond integration system
Authors: Zhong Liqiang , Li Daming , Wang Minghua , Chen Xiaohui , Bian Wenji , Zhu Guangwei
Published: August 2018

The changes in the bacterial community composition in a channel catfish nursery pond with a cage–pond integration system were investigated by sequencing of the 16S rRNA gene through Illumina MiSeq sequencing platforms. A total of 1 362 877 sequences and 1440 operational taxonomic units were obtained. Further analysis showed that the dominant phyla in the cage and pond groups were similar, including Actinobacteria, Cyanobacteria, Proteobacteria, and Bacteroidetes, although a significant difference was detected between them by ANOSIM (P < 0.05). Temporal changes and site variation were significantly related to the variation of the bacterial community. A comprehensive analysis of the diversity and evenness of the bacterial 16S rRNA gene, redundancy analysis (RDA), and partial Mantel test showed that the bacterial community composition in a cage–pond integration system was shaped more by temporal variation than by site variation. RDA also indicated that water temperature, total dissolved solids, and Secchi depth had the largest impact on bacterial populations.
Principal fibrations over noncommutative spheres
Authors: Dubois-Violette Michel , Han Xiao , Landi Giovanni
Published: August 2018

We present examples of noncommutative four-spheres that are base spaces of SU(2)-principal bundles with noncommutative seven-spheres as total spaces. The noncommutative coordinate algebras of the four-spheres are generated by the entries of a projection which is invariant under the action of SU(2). We give conditions for the components of the Connes–Chern character of the projection to vanish but the second (the top) one. The latter is then a non-zero Hochschild cycle that plays the role of the volume form for the noncommutative four-spheres.
First-principles study on the structures and electronic properties of the PbnI and PbnI2 (n = 1–6) clusters
Authors: Zhao Zhen , Li Zhi , Wang Qi , Qi Ji-Long
Published: August 2018

To investigate the configurations and the electrical performance of the Pb–I films, the geometries and electronic properties of the Pb[Formula: see text]I and Pb[Formula: see text]I2 (n = 1–6) clusters are calculated by density functional theory at the GGA/PBE functional. The results reveal that I atoms prefer to occupy the symmetrical positions which are far from the centers of the Pb[Formula: see text] clusters. The Pb2I2 clusters are more structurally stable than the neighbors by the average binding energy. The PbI, Pb3I, PbI2, Pb4I2 and Pb6I2 clusters are more dynamically stable than their neighbors by the HOMO–LUMO gaps. The adsorption capacity of an I atom on the Pb2 cluster is the strongest compared to those of the other Pb[Formula: see text] (n = 1–6) clusters. NBO analysis reveals that the 5p orbital of I atoms in the Pb–I clusters acquires more electrons than the 5s orbital loses.
Effect of the δ-doping on the magnetoresistance effect in a magnetically modulated nanostructure
Authors: Lu Jian-Duo
Published: August 2018

With the help of the transfer-matrix method, we theoretically investigate the effect of the [Formula: see text]-doping on the magnetoresistance (MR) effect in a magnetic nanostructure, which can be realized by depositing two ferromagnetic strips on the top and bottom of a nanostructure and using the atomic layer doping technique. It is shown that an obvious MR effect can be obtained in this device, and it can be tuned by the position and weight of the [Formula: see text]-doping. This device can be used as a [Formula: see text]-doping-dependent MR device for magneto electronics applications.
Hydrothermal synthesis MoO3@CoMoO4 hybrid as an anode material for high performance lithium rechargeable batteries
Authors: Wu Jinggao , Lai Qi , Zhong Canyu
Published: August 2018

MoO3@CoMoO4 hybrid is fabricated by a facile one-step hydrothermal method and is used as anode for lithium-ion battery (LIB). Compared to pristine MoO3, galvanostatic charge–discharge tests show that the hybrid electrode delivered a remarkable rate capability of 586.69[Formula: see text]mAh[Formula: see text]g[Formula: see text] at the high current density of 1000[Formula: see text]mA[Formula: see text]g[Formula: see text] and a greatly enhanced cyclic capacity of 887.36[Formula: see text]mA[Formula: see text]h[Formula: see text]g[Formula: see text] after 140 cycles at the current density of 200[Formula: see text]mA[Formula: see text]g[Formula: see text] (with capacity retention, 85.3%). The superior electrochemical properties could be ascribed to the synergistic effect of MoO3 and CoO nanostructure that results in the lower charge transfer resistance and the higher Li[Formula: see text] diffusion coefficient, thus leading to high performance Li[Formula: see text] reversibility storage.
Can Allocation-Based Water Rates Promote Conservation and Increase Welfare? A California Case Study
Authors: Baerenklau Kenneth A. , Pérez-Urdiales María
Published: August 2018

An allocation-based rate (ABR) is a special type of increasing block rate (IBR) price structure that is receiving increased attention from urban water suppliers in places like California where population growth and climate change continue to increase water scarcity. Previous work by Baerenklau et al. [Baerenklau, KA, KA Schwabe and A Dinar (2014a). Allocation-based water pricing promotes conservation while keeping user costs low. Agricultural and Resource Economics Update, 17(6), 1–14; Baerenklau, KA, KA Schwabe and A Dinar (2014b). The residential water demand effect of increasing block rate water budgets. Land Economics, 90(4), 683–699.] investigates the conservation potential of ABR and finds that consumption under ABR was 10–15% below that of a comparable uniform rate structure for a southern California case study. This paper extends that work by using the discrete–continuous choice framework to estimate household-level welfare effects of ABR for the same dataset. We find that despite the observed decrease in consumption, average household welfare actually increased under ABR due to its non-linear structure. We also find that similar results would have been achievable with a simpler standard IBR structure. While either of these block rate structures is welfare-preferred to uniform price and quantity instruments, neither clearly dominates the other.
Cybersecurity Research: A Review of Current Research Topics
Authors: Lu Yang
Published: August 2018

This paper presents a systematic review of empirical research on cybersecurity issues. 14 empirical articles about cybersecurity, published in the two top IS journals, MISQ (12) and ISR (2), between 2008 and 2017, were selected and analyzed, classified into three categories: individual level (non-work setting), employee level (work setting), and organization level (policy/regulation environment). This paper provides a holistic picture of cybersecurity issues, for instance, fundamental theories, impressive research methods, and influencing factors. More importantly, for the first time an integrative framework was developed by R Project, which potentially text-mines end-users’ behaviors and decision-making processes toward cybersecurity under the circumstance of security breach. Some explanations of extant empirical study and potential research are addressed and discussed as well.
Inhibition of autotaxin alleviates inflammation and increases the expression of sodium-dependent glucose cotransporter 1 and Na+/H+ exchanger 3 in SAMP1/Fc mice
Authors: He Peijian , Haque Abedul , Lin Songbai , Cominelli Fabio , Yun C. Chris
Published: August 2018

Crohn’s disease (CD) is a chronic, relapsing, inflammatory disease that is often associated with malnutrition because of inflammation in the small intestine. Autotaxin (ATX) is a secreted enzyme that produces extracellular lysophosphatidic acid. Increasing evidence suggests that ATX is upregulated during inflammation, and inhibition of ATX has been effective in attenuating chronic inflammatory conditions, such as arthritis and pulmonary fibrosis. This study aims to determine whether inhibition of ATX alleviates CD-associated inflammation and malnutrition by using SAMP1/Fc mice, a model of CD-like ileitis. SAMP1/Fc mice were treated the ATX inhibitor PF-8380 for 4 wk. Inhibition of ATX led to increased weight gain in SAMP1/Fc mice, decreased T helper 2 cytokine expression, including IL-4, IL-5, and IL-13, and attenuated immune cell migration. SAMP1/Fc mice have low expression of Na+-dependent glucose transporter 1 (SGLT1), suggesting impaired nutrient absorption associated with ileitis. PF-8380 treatment significantly enhanced SGLT1 expression in SAMP1/Fc mice, which could reflect the increased weight changes. However, IL-4 or IL-13 did not alter SGLT1 expression in Caco-2 cells, ruling out their direct effects on SGLT1 expression. Immunofluorescence analysis showed that the expression of sucrase-isomaltase, a marker for intestinal epithelial cell (IEC) differentiation, was decreased in inflamed regions of SAMP1/Fc mice, which was partially restored by PF-8380. Moreover, expression of Na+/H+ exchanger 3 was also improved by PF-8380, suggesting that suppression of inflammation by PF-8380 enhanced IEC differentiation. Our study therefore suggests that ATX is a potential target for treating intestinal inflammation and restoration of the absorptive function of the intestine.

NEW & NOTEWORTHY This study is the first, to our knowledge, to determine whether autotoxin (ATX) inhibition improves inflammation and body weights in SAMP1/Fc mice, a mouse model of ileitis. ATX inhibition increased body weights of SAMP1/Fc mice and increased Na+-dependent glucose transporter 1 (SGLT1) expression. Increased SGLT1 expression in the inflamed regions was not a direct effect of cytokines but an indirect effect of increased epithelial cell differentiation upon ATX inhibition.
Periodontal therapy favorably modulates the oral-gut-hepatic axis in cirrhosis
Authors: Bajaj Jasmohan S. , Matin Payam , White Melanie B. , Fagan Andrew , Deeb Janina Golob , Acharya Chathur , Dalmet Swati S. , Sikaroodi Masoumeh , Gillevet Patrick M. , Sahingur Sinem E.
Published: August 2018

Cirrhosis is associated with a systemic proinflammatory milieu, endotoxemia, and gut dysbiosis. The oral cavity could be an additional source of inflammation. We aimed to determine the effect of periodontal therapy in cirrhosis through evaluating endotoxemia, inflammation, cognition, and quality of life (QOL). Age-matched cirrhotic and noncirrhotic subjects exhibiting chronic gingivitis and/or mild or moderate periodontitis underwent periodontal therapy with follow-up at 30 days. Saliva/stool for microbial composition and serum for Model for End-stage Liver Disease (MELD) score, endotoxin and lipopolysaccharide binding protein (LBP) and immune-inflammatory markers (IL-1β; IL-6; histatins 1, 3, 5; and lysozyme) were collected at baseline and day 30. The cognitive function and QOL were also evaluated similarly. A separate group of cirrhotic patients were followed for the same duration without periodontal therapy. Cirrhotics, especially those with hepatic encephalopathy (HE), demonstrated improved dysbiosis in stool and saliva, and improved endotoxin, LBP, and salivary and serum inflammatory mediators following periodontal therapy. These parameters, which were higher in HE at baseline, became statistically similar posttherapy. Pretherapy vs. posttherapy QOL and cognition also improved in HE patients following oral interventions. On the other hand, LBP and endotoxin increased over time in cirrhotic patients not receiving therapy, but the rest of the parameters, including microbiota remained similar over time in the no-therapy group. This proof-of-concept study demonstrates that periodontal therapy in cirrhosis, especially in those with HE, is associated with improved oral and gut dysbiosis, systemic inflammation, MELD score, and cognitive function, which was not observed in those who did not receive therapy over the same time period.

NEW & NOTEWORTHY Systematic periodontal therapy in cirrhotic outpatients improved endotoxemia, as well as systemic and local inflammation, and modulated salivary and stool microbial dysbiosis over 30 days. This was associated with improved quality of life and cognition in patients with prior hepatic encephalopathy. In a cirrhotic group that was not provided periodontal therapy, there was an increase in endotoxin and lipopolysaccharide binding protein in the same duration. The oral cavity could be an important underdefined source of inflammation in cirrhosis.
Linaclotide improves gastrointestinal transit in cystic fibrosis mice by inhibiting sodium/hydrogen exchanger 3
Authors: McHugh Daniel R. , Cotton Calvin U. , Moss Fraser J. , Vitko Megan , Valerio Dana M. , Kelley Thomas J. , Hao Shuyu , Jafri Anjum , Drumm Mitchell L. , Boron Walter F. , Stern Robert C. , McBennett Kimberly , Hodges Craig A.
Published: August 2018

Gastrointestinal dysfunction in cystic fibrosis (CF) is a prominent source of pain among patients with CF. Linaclotide, a guanylate cyclase C (GCC) receptor agonist, is a US Food and Drug Administration-approved drug prescribed for chronic constipation but has not been widely used in CF, as the cystic fibrosis transmembrane conductance regulator (CFTR) is the main mechanism of action. However, anecdotal clinical evidence suggests that linaclotide may be effective for treating some gastrointestinal symptoms in CF. The goal of this study was to determine the effectiveness and mechanism of linaclotide in treating CF gastrointestinal disorders using CF mouse models. Intestinal transit, chloride secretion, and intestinal lumen fluidity were assessed in wild-type and CF mouse models in response to linaclotide. CFTR and sodium/hydrogen exchanger 3 (NHE3) response to linaclotide was also evaluated. Linaclotide treatment improved intestinal transit in mice carrying either F508del or null Cftr mutations but did not induce detectable Cl− secretion. Linaclotide increased fluid retention and fluidity of CF intestinal contents, suggesting inhibition of fluid absorption. Targeted inhibition of sodium absorption by the NHE3 inhibitor tenapanor produced improvements in gastrointestinal transit similar to those produced by linaclotide treatment, suggesting that inhibition of fluid absorption by linaclotide contributes to improved gastrointestinal transit in CF. Our results demonstrate that linaclotide improves gastrointestinal transit in CF mouse models by increasing luminal fluidity through inhibiting NHE3-mediated sodium absorption. Further studies are necessary to assess whether linaclotide could improve CF intestinal pathologies in patients. GCC signaling and NHE3 inhibition may be therapeutic targets for CF intestinal manifestations.

NEW & NOTEWORTHY Linaclotide’s primary mechanism of action in alleviating chronic constipation is through cystic fibrosis transmembrane conductance regulator (CFTR), negating its use in patients with cystic fibrosis (CF). For the first time, our findings suggest that in the absence of CFTR, linaclotide can improve fluidity of the intestinal lumen through the inhibition of sodium/hydrogen exchanger 3. These findings suggest that linaclotide could improve CF intestinal pathologies in patients.
Hypercapnia-induced shear-mediated dilation in the internal carotid artery is blunted in healthy older adults
Authors: Iwamoto Erika , Bock Joshua M. , Casey Darren P.
Published: August 2018

This study aimed to elucidate the effect of aging on shear-mediated dilation of the common and internal carotid arteries (CCA and ICA, respectively). Hypercapnia-induced shear-mediated dilation in the CCA and ICA were assessed in 10 young (5 women and 5 men, 23 ± 1 yr) and 10 older (6 women/4 men, 68 ± 1 yr) healthy adults. Shear-mediated dilation was induced by two levels of hypercapnia (target end-tidal Pco2, +5 and +10 mmHg from individual baseline values) and was calculated as the percent rise in peak diameter from baseline diameter. There were no differences in shear-mediated dilation between young and older adults in either artery under lower levels of hypercapnia (CCA: 2.8 ± 0.6 vs. 2.0 ± 0.3%, P = 0.35; ICA: 4.6 ± 0.8 vs 3.6 ± 0.4%, P = 0.37). However, shear-mediated dilation in response to higher levels of hypercapnia was attenuated in older compared with young adults in the ICA (4.5 ± 0.5 vs. 7.9 ± 1.2%, P < 0.01) but not in the CCA (3.7 ± 0.6 vs. 4.5 ± 0.8%, P = 0.35). Shear-mediated dilation was significantly correlated to the percent change in shear rate in the ICA (young: r = 0.55, P = 0.01; older: r = 0.49, P = 0.03) but not in the CCA in either young or older adults (young: r = −0.30, P = 0.90; older: r = 0.16, P = 0.50). These data indicate that aging attenuates shear-mediated dilation of the ICA in response to higher levels of hypercapnia, and shear rate is an important stimulus for hypercapnic vasodilation of the ICA in both young and older adults. The present results may provide insights into age-related changes in the regulation of cerebral circulation in healthy adults.

NEW & NOTEWORTHY We explored the effect of aging on shear-mediated dilation in the common and internal carotid arteries (CCA and ICA, respectively) in healthy adults. Our findings suggest that 1) aging attenuates shear-mediated dilation of the ICA but not the CCA and 2) shear rate is an important stimulus for hypercapnic vasodilation of the ICA in young and older adults. These findings may provide insights into the age-related changes in cerebrovascular regulation of healthy adults.
Exacerbation of dystrophic cardiomyopathy by phospholamban deficiency mediated chronically increased cardiac Ca2+ cycling in vivo
Authors: Law Michelle L. , Prins Kurt W. , Olander Megan E. , Metzger Joseph M.
Published: August 2018

Cardiomyopathy is a significant contributor to morbidity and mortality in Duchenne muscular dystrophy (DMD). Membrane instability, leading to intracellular Ca2+ mishandling and overload, causes myocyte death and subsequent fibrosis in DMD cardiomyopathy. On a cellular level, cardiac myocytes from mdx mice have dysregulated Ca2+ handling, including increased resting Ca2+ and slow Ca2+ decay, especially evident under stress conditions. Sarco(endo)plasmic reticulum Ca2+ ATPase and its regulatory protein phospholamban (PLN) are potential therapeutic targets for DMD cardiomyopathy owing to their key role in regulating intracellular Ca2+ cycling. We tested the hypothesis that enhanced cardiac Ca2+ cycling would remediate cardiomyopathy caused by dystrophin deficiency. We used a genetic complementation model approach by crossing dystrophin-deficient mdx mice with PLN knockout (PLNKO) mice [termed double-knockout (DKO) mice]. As expected, adult cardiac myocytes isolated from DKO mice exhibited increased contractility and faster relaxation associated with increased Ca2+ transient peak height and faster Ca2+ decay rate compared with control mice. However, compared with wild-type, mdx, and PLNKO mice, DKO mice unexpectedly had reduced in vivo systolic and diastolic function as measured by echocardiography. Furthermore, Evans blue dye uptake was increased in DKO hearts compared with control, mdx, and PLNKO hearts, demonstrating increased membrane damage, which subsequently led to increased fibrosis in the DKO myocardium in vivo. In conclusion, despite enhanced intracellular Ca2+ handling at the myocyte level, DMD cardiomyopathy was exacerbated owing to unregulated chronic increases in Ca2+ cycling in DKO mice in vivo. These findings have potentially important implications for ongoing therapeutic strategies for the dystrophic heart.

NEW & NOTEWORTHY This study examined the effects of phospholamban ablation on the pathophysiology of cardiomyopathy in dystrophin-deficient mice. In this setting, contractility and Ca2+ cycling were enhanced in isolated myocytes; however, in vivo heart function was diminished. Additionally, sarcolemmal integrity was compromised and fibrosis was increased. This is the first study, to our knowledge, examining unregulated Ca2+ cycling in the dystrophin-deficient heart. Results from this study have implications for potential therapies targeting Ca2+ handling in dystrophic cardiomyopathy.

Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/unregulated-ca2-cycling-exacerbates-dmd-cardiomyopathy/ .
Promoting Scientist–Advocate Collaborations in Cancer Research: Why and How
Authors: Salamone Jeannine M. , Lucas Wanda , Brundage Shelley B. , Holloway Jamie N. , Stahl Sherri M. , Carbine Nora E. , London Margery , Greenwood Naomi , Goyes Rosa , Chisholm Deborah Charles , Price Erin , Carlin Roberta , Winarsky Susan , Baker Kirsten B. , Maues Julia , Shajahan-Haq Ayesha N.
Published: August 2018

Advocates bring unique and important viewpoints to the cancer research process, ensuring that scientific and medical advances are patient-centered and relevant. In this article, we discuss the benefits of engaging advocates in cancer research and underscore ways in which both the scientific and patient communities can facilitate this mutually beneficial collaboration. We discuss how to establish and nurture successful scientist–advocate relationships throughout the research process. We review opportunities that are available to advocates who want to obtain training in the evaluation of cancer research. We also suggest practical solutions that can strengthen communication between scientists and advocates, such as introducing scientist–advocate interactions at the trainee level. Finally, we highlight the essential role social media can play in disseminating patient-supported cancer research findings to the patient community and in raising awareness of the importance of promoting cancer research. Our perspective offers a model that Georgetown Breast Cancer Advocates have found effective and which could be one option for those interested in developing productive, successful, and sustainable collaborations between advocates and scientists in cancer research. Cancer Res; 78(20); 5723–8. ©2018 AACR.
Abstract A142: Targeting FGFR to overcome EMT-related resistance in EGFR-mutated non-small cell lung cancer
Authors: Raoof Sana , Ruddy David , Timonia Daria , Damon Leah , Engelman Jeff , Hata Aaron
Published: August 2018

Epithelial-to-mesenchymal transition (EMT) has been identified as a mechanism of both adaptive and acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in in vitro models and clinical samples of EGFR-mutated non-small cell lung cancer (NSCLC). However, a therapeutic strategy for targeting this mechanism remains unknown. In the setting of adaptive resistance early in the course of EGFR treatment, we observed that FGFR3 upregulation coincided with increased expression of mesenchymal genes, and a pooled shRNA dropout screen identified FGFR3 as a top sensitizer to EGFR inhibitor treatment. Dual FGFR (BGJ398) and EGFR (gefitinib) inhibition suppressed the outgrowth of drug-tolerant persister clones compared to EGFR TKI alone in vitro. Finally, we observed that the combination of BGJ398 and gefitinib prevented the development of in vivo resistance in PC9 xenograft mouse models. These results suggest that dual FGFR-EGFR blockade may be an effective strategy for preventing resistance associated with EMT in EGFR mutant NSCLC.

Citation Format: Sana Raoof, David Ruddy, Daria Timonia, Leah Damon, Jeff Engelman, Aaron Hata. Targeting FGFR to overcome EMT-related resistance in EGFR-mutated non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A142.
Abstract A206: Small-molecule Cbl-b inhibitors as novel intracellular checkpoint inhibitors for cancer immunotherapy
Authors: Riling Christopher , Sokirniy Ivan , Cunnion Brigid , Todd Emily , Mattern Michael , Wu Jian , Kambayashi Taku , Kumar Suresh
Published: August 2018

Cancer cells evade destruction by co-opting checkpoint signaling in the immune system. Therapeutics aimed at preventing this, such as anti-PD1 and anti-CTLA4 antibodies, promote cytotoxic T lymphocyte (CTL)-mediated antitumor immune responses against advanced solid tumors. Harnessing the antitumor activity of CTLs, and that of their innate counterpart natural killer (NK) cells, is a promising approach. Activation of CTLs and NK cells is tightly regulated. CTLs require costimulatory signals, such as CD28, for robust activation. NK cell activation can be kept in check by a variety of inhibitory receptors, such as those of the TAM tyrosine kinase receptor family. Ultimately, these signaling events are orchestrated by the ubiquitin signaling system. One ubiquitin ligase in particular, Cbl-b (Casitas B-lineage lymphoma proto-oncogene b), is a negative regulator of both CTL and NK cell activation. In T cells, Cbl-b attenuates TCR signaling by negatively regulating several downstream signaling components, enforcing the requirement for costimulation. In NK cells, Cbl-b regulates TAM receptor internalization at the plasma membrane via ubiquitylation, and this process is important in enabling inhibitory signaling via the TAM receptors. Accordingly, mice deficient in active Cbl-b exhibit hyper-responsive immunity and reject a variety of implanted metastatic and nonmetastatic tumors. Outgrowth of spontaneous tumors in these mice is also significantly delayed. This tumor resistance is mediated by activated CD8+ T cells and NK cells. Thus, Cbl-b is a promising target for developing small-molecule cancer immunotherapy agents. Using proprietary HTS technologies, Progenra has discovered novel and selective Cbl-b inhibitors that decrease ubiquitylation of TAM receptor family members (Tyro3). These inhibitors also promote CD3-mediated activation of T cells in a CD28-independent manner, markedly increasing proliferation, IL-2 secretion, and TNFα production in T cells. Additionally, these Cbl-b inhibitors increase NK cell activation (as measured by IFNγ and degranulation) in ex vivo assays. ADME/DMPK as well as in vivo efficacy data will be discussed. These molecules are expected to synergize with other approved immunotherapy agents.

Citation Format: Christopher Riling, Ivan Sokirniy, Brigid Cunnion, Emily Todd, Michael Mattern, Jian Wu, Taku Kambayashi, Suresh Kumar. Small-molecule Cbl-b inhibitors as novel intracellular checkpoint inhibitors for cancer immunotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A206.
Abstract A207: Utilizing human OX40 knock-in mice (HuGEMMTM) to assess antitumor efficacy of OX40-agonistic antibodies
Authors: Huang Xuesong , Zheng Lei , Ouyang Wenyi , Zhang Mingkun , An Annie Xiaoyu , Zhao Jing , Gao Xiang , Wery Jean Pierre , Shi Qian
Published: August 2018

OX40 is a costimulatory molecule of TNF receptor family, primarily expressed on activated effector T cells and regulatory T cells. Engagement of OX40 by ligand leads to dramatic expansion, effector function, cytokine production, and survival of T cells. Several OX40-agonistic antibodies are in early stages of clinical development and some have shown promising antitumor immunity and improved tumor-free survival in the patients compared with standard-of-care therapies. Preclinical studies using surrogate OX40-agonistic antibodies have also shown robust tumor growth inhibition (TGI) efficacies, especially when combined with other checkpoint inhibitors like PD1 and CTLA-4 antibodies. However, we are lacking reliable preclinical models to assess the efficacy of human therapeutic antibodies. To address this need, we created a human OX40 knock-in GEMM (OX40 HuGEMM), where the entire 2.5 Kb mouse OX40 coding region is replaced by human OX40. We confirmed the expression of human OX40 in the 95% of activated T cells from the homozygous knock-in mice, while the mouse OX40 is completely eliminated. In the heterozygous knock-in mice, 58% of activated T cells express both mouse and human OX40. We then used both heterozygous and homozygous knock-in mice for efficacy studies of OX40 antibodies. In the heterozygous knock-in mice bearing MC38 syngeneic tumors, human and mouse OX40 antibody monotherapies led to 49% and 20% TGI, respectively, while their combination with PD1 antibody was synergistically effective, resulting in ~90% TGI with multiple complete tumor regressions. When we grafted the homozygous knock-in mice with B16F10 syngeneic tumors, single 5 mg/kg dose of an investigational human OX40 antibody led to 47% TGI. Tumor-killing efficacy of OX40 antibody is also correlated with significantly increased tumor infiltrated T cells and NK cells. Taken together, our OX40 HuGEMM provides an urgently needed tool for testing in vivo efficacy of human OX40 therapeutics, both as a single agent and as various combination strategies with other treatment modalities.

Citation Format: Xuesong Huang, Lei Zheng, Wenyi Ouyang, Mingkun Zhang, Annie Xiaoyu An, Jing Zhao, Xiang Gao, Jean Pierre Wery, Qian Shi. Utilizing human OX40 knock-in mice (HuGEMMTM) to assess antitumor efficacy of OX40-agonistic antibodies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A207.
Abstract B109: ASN004, a novel 5T4-targeted Dolaflexin ADC, causes complete and durable tumor regression in a variety of tumor xenograft models
Authors: Smith Roger A. , Zammit David J. , Reddy Sanjeeva P.
Published: August 2018

The 5T4 oncofetal antigen (trophoblast glycoprotein) is expressed in a wide range of malignant tumors, while showing very limited expression in normal adult tissues. This selective pattern of expression establishes 5T4 as an attractive therapeutic target for the Antibody-Drug Conjugate (ADC) strategy. ASN004 is an anti-5T4 ADC that incorporates a novel single-chain homo-dimer antibody, Fleximer® linker technology (Mersana Therapeutics), and cytotoxic dolastatin (auristatin) analog warheads, with a drug/antibody ratio of ~15:1. ASN004 shows high affinity for the 5T4 antigen (Kd < 30 pM), with selective binding and internalization to 5T4-expressing tumor cells. Potent, selective cytotoxicity has been determined for a diverse panel of tumor cell lines. ASN004 provides complete and durable tumor regression in multiple tumor xenograft models, derived from human lung, breast, cervical, and gastric tumor cell lines having a range of 5T4 expression levels. Tumor-free survivors could be achieved in tumor models with a single dose of ASN004, as low as 1 mg/kg iv. The broad, superior activity of ASN004 was demonstrated in a head-to-head study against trastuzumab-DM1, in a low-5T4/high-HER2 expressing tumor model. Finally, efficacy of ASN004 in patient-derived tumor xenograft (PDX) models will be presented. In summary, ASN004 has been established as a promising ADC therapeutic for multiple tumor types, encompassing a wide range of 5T4-expression levels. IND-enabling studies are ongoing in preparation for advancement to clinical development.

Citation Format: Roger A. Smith, David J. Zammit, Sanjeeva P. Reddy. ASN004, a novel 5T4-targeted Dolaflexin ADC, causes complete and durable tumor regression in a variety of tumor xenograft models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B109.