bluuebunny/crossref_metadata_2025 huggingface dataset:
Packing subgroups in solvable groups
Authors: Sardar Pranab
Published: July 2015

We show that any subgroup of a (virtually) nilpotent-by-polycyclic group satisfies the bounded packing property of Hruska–Wise [Packing subgroups in relatively hyperbolic groups, Geom. Topol. 13 (2009) 1945–1988]. In particular, the same is true for all finitely generated subgroups of metabelian groups and linear solvable groups. However, we find an example of a finitely generated solvable group of derived length 3 which admits a finitely generated metabelian subgroup without the bounded packing property. In this example the subgroup is a retract also. Thus we obtain a negative answer to Problem 2.27 of the above paper. On the other hand, we show that polycyclic subgroups of solvable groups satisfy the bounded packing property.
Regularity of random attractors for stochastic reaction-diffusion equations on unbounded domains
Authors: Tang Bao Quoc
Published: July 2015

The existence of a unique random attractors in [Formula: see text] for a stochastic reaction-diffusion equation with time-dependent external forces is proved. Due to the presence of both random and non-autonomous deterministic terms, we use a new theory of random attractors which is introduced in [B. Wang, J. Differential Equations 253 (2012) 1544–1583] instead of the usual one. The asymptotic compactness of solutions in [Formula: see text] is established by combining “tail estimate” technique and some new estimates on solutions. This work improves some recent results about the regularity of random attractors for stochastic reaction-diffusion equations.
Dielectric and conducting behavior of gadolinium–terbium fumarate heptahydrate crystals
Authors: Shah M. D. , Want B.
Published: July 2015

Gadolinium–terbium fumarate heptahydrate crystals were grown in silica gel by using single gel diffusion technique. The crystals were characterized by different physico-chemical techniques of characterization. Powder X-ray diffraction results showed that the grown material is purely crystalline in nature. Elemental analyses suggested the chemical formula of the compound to be Gd Tb [Formula: see text]. Energy dispersive X-ray analysis confirmed the presence of Gd and Tb in the title compound. The dielectric and conductivity studies of the grown compound were carried as function of frequency of applied field and the temperature. The grown material showed a dielectric anomaly which was correlated with its thermal behavior. The ac conductivity of the material showed Jonscher's power law behavior: [Formula: see text], with a temperature-dependent power exponent [Formula: see text]. The conductivity was found to be a function of temperature and frequency.
GR3027 antagonizes GABAAreceptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy
Authors: Johansson Maja , Agusti Ana , Llansola Marta , Montoliu Carmina , Strömberg Jessica , Malinina Evgenya , Ragagnin Gianna , Doverskog Magnus , Bäckström Torbjörn , Felipo Vicente
Published: July 2015

Hepatic encephalopathy (HE) is one of the primary complications of liver cirrhosis. Current treatments for HE, mainly directed to reduction of ammonia levels, are not effective enough because they cannot completely eliminate hyperammonemia and inflammation, which induce the neurological alterations. Studies in animal models show that overactivation of GABAAreceptors is involved in cognitive and motor impairment in HE and that reducing this activation restores these functions. We have developed a new compound, GR3027, that selectively antagonizes the enhanced activation of GABAAreceptors by neurosteroids such as allopregnanolone and 3α,21-dihydroxy-5α-pregnan-20-one (THDOC). This work aimed to assess whether GR3027 improves motor incoordination, spatial learning, and circadian rhythms of activity in rats with HE. GR3027 was administered subcutaneously to two main models of HE: rats with chronic hyperammonemia due to ammonia feeding and rats with portacaval shunts (PCS). Motor coordination was assessed in beam walking and spatial learning and memory in the Morris water maze and the radial maze. Circadian rhythms of ambulatory and vertical activity were also assessed. In both hyperammonemic and PCS rats, GR3027 restores motor coordination, spatial memory in the Morris water maze, and spatial learning in the radial maze. GR3027 also partially restores circadian rhythms of ambulatory and vertical activity in PCS rats. GR3027 is a novel approach to treatment of HE that would normalize neurological functions altered because of enhanced GABAergic tone, affording more complete normalization of cognitive and motor function than current treatments for HE.
Inflammation-induced abnormalities in the subcellular localization and trafficking of the neurokinin 1 receptor in the enteric nervous system
Authors: Poole Daniel P. , Lieu TinaMarie , Pelayo Juan Carlos , Eriksson Emily M. , Veldhuis Nicholas A. , Bunnett Nigel W.
Published: July 2015

Activated G protein-coupled receptors traffic to endosomes and are sorted to recycling or degradative pathways. Endosomes are also a site of receptor signaling of sustained and pathophysiologically important processes, including inflammation. However, the mechanisms of endosomal sorting of receptors and the impact of disease on trafficking have not been fully defined. We examined the effects of inflammation on the subcellular distribution and trafficking of the substance P (SP) neurokinin 1 receptor (NK1R) in enteric neurons. We studied NK1R trafficking in enteric neurons of the mouse colon using immunofluorescence and confocal microscopy. The impact of inflammation was studied in IL10−/−-piroxicam and trinitrobenzenesulfonic acid colitis models. NK1R was localized to the plasma membrane of myenteric and submucosal neurons of the uninflamed colon. SP evoked NK1R endocytosis and recycling. Deletion of β-arrestin2, which associates with the activated NK1R, accelerated recycling. Inhibition of endothelin-converting enzyme-1 (ECE-1), which degrades endosomal SP, prevented recycling. Inflammation was associated with NK1R endocytosis in myenteric but not submucosal neurons. Whereas the NK1R in uninflamed neurons recycled within 60 min, NK1R recycling in inflamed neurons was delayed for >120 min, suggesting defective recycling machinery. Inflammation was associated with β-arrestin2 upregulation and ECE-1 downregulation, which may contribute to the defective NK1R recycling. We conclude that inflammation evokes redistribution of NK1R from the plasma membrane to endosomes of myenteric neurons through enhanced SP release and defective NK1R recycling. Defective recycling may be secondary to upregulation of β-arrestin2 and downregulation of ECE-1. Internalized NK1R may generate sustained proinflammatory signals that disrupt normal neuronal functions.
Bimodal effect of oxidative stress in internal anal sphincter smooth muscle
Authors: Singh Jagmohan , Kumar Sumit , Rattan Satish
Published: July 2015

Changes in oxidative stress may affect basal tone and relaxation of the internal anal sphincter (IAS) smooth muscle in aging. We examined this issue by investigating the effects of the oxidative stress inducer 6-anilino-5,8-quinolinedione (LY-83583) in basal as well as U-46619-stimulated tone, and nonadrenergic, noncholinergic (NANC) relaxation in rat IAS. LY-83583, which works via generation of reactive oxygen species in living cells, produced a bimodal effect in IAS tone: lower concentrations (0.1 nM to 10 μM) produced a concentration-dependent increase, while higher concentrations (50–100 μM) produced a decrease in IAS tone. An increase in IAS tone by lower concentrations was associated with an increase in RhoA/Rho kinase (ROCK) activity. This was evident by the increase in RhoA/ROCK in the particulate fractions, in ROCK activity, and in the levels of phosphorylated (p)Thr696-myosin phosphatase target subunit 1 and pThr18/Ser19-20-kDa myosin light chain. Conversely, higher concentrations of LY-83583 produced inhibitory effects on RhoA/ROCK. Interestingly, both the excitatory and inhibitory effects of LY-83583 in the IAS were reversed by superoxide dismutase. The excitatory effects of LY-83583 were found to resemble those with neuronal nitric oxide synthase (nNOS) inhibition by l-NNA, since it produced a significant increase in the IAS tone and attenuated NANC relaxation. These effects of LY-83583 and l-NNA were reversible by l-arginine. This suggests the role of nNOS inhibition and RhoA/ROCK activation in the increase in IAS tone by LY-83583. These data have important implications in the pathophysiology and therapeutic targeting of rectoanal disorders, especially associated with IAS dysfunction.
Impact of ursodeoxycholic acid on a CCK1R cholesterol-binding site may contribute to its positive effects in digestive function
Authors: Desai Aditya J. , Dong Maoqing , Harikumar Kaleeckal G. , Miller Laurence J.
Published: July 2015

Dysfunction of the type 1 cholecystokinin (CCK) receptor (CCK1R) as a result of increased gallbladder muscularis membrane cholesterol has been implicated in the pathogenesis of cholesterol gallstones. Administration of ursodeoxycholic acid, which is structurally related to cholesterol, has been shown to have beneficial effects on gallstone formation. Our aims were to explore the possible direct effects and mechanism of action of bile acids on CCK receptor function. We studied the effects of structurally related hydrophobic chenodeoxycholic acid and hydrophilic ursodeoxycholic acid in vitro on CCK receptor function in the setting of normal and elevated membrane cholesterol. We also examined their effects on a cholesterol-insensitive CCK1R mutant (Y140A) disrupting a key site of cholesterol action. The results show that, similar to the impact of cholesterol on CCK receptors, bile acid effects were limited to CCK1R, with no effects on CCK2R. Chenodeoxycholic acid had a negative impact on CCK1R function, while ursodeoxycholic acid had no effect on CCK1R function in normal membranes but was protective against the negative impact of elevated cholesterol on this receptor. The cholesterol-insensitive CCK1R mutant Y140A was resistant to effects of both bile acids. These data suggest that bile acids compete with the action of cholesterol on CCK1R, probably by interacting at the same site, although the conformational impact of each bile acid appears to be different, with ursodeoxycholic acid capable of correcting the abnormal conformation of CCK1R in a high-cholesterol environment. This mechanism may contribute to the beneficial effect of ursodeoxycholic acid in reducing cholesterol gallstone formation.
DHA suppresses chronic apoptosis in the lung caused by perinatal inflammation
Authors: Ali Mehboob , Heyob Kathryn M. , Velten Markus , Tipple Trent E. , Rogers Lynette K.
Published: July 2015

We have previously shown that an adverse perinatal environment significantly alters lung growth and development and results in persistently altered cardiopulmonary physiology in adulthood. Our model of maternal LPS treatment followed by 14 days of neonatal hyperoxia exposure causes severe pulmonary disease characterized by permanent decreases in alveolarization and diffuse interstitial fibrosis. The current investigations tested the hypothesis that dysregulation of Notch signaling pathways contributes to the permanently altered lung phenotype in our model and that the improvements we have observed previously with maternal docosahexaenoic acid (DHA) supplementation are mediated through normalization of Notch-related protein expression. Results indicated that inflammation (IL-6 levels) and oxidation (F2a-isoprostanes) persisted through 8 wk of life in mice exposed to LPS/O2 perinatally. These changes were attenuated by maternal DHA supplementation. Modest but inconsistent differences were observed in Notch-pathway proteins Jagged 1, DLL 1, PEN2, and presenilin-2. We detected substantial increases in markers of apoptosis including PARP-1, APAF-1, caspase-9, BCL2, and HMGB1, and these increases were attenuated in mice that were nursed by DHA-supplemented dams during the perinatal period. Although Notch signaling is not significantly altered at 8 wk of age in mice with perinatal exposure to LPS/O2, our findings indicate that persistent apoptosis continues to occur at 8 wk of age. We speculate that ongoing apoptosis may contribute to persistently altered lung development and may further enhance susceptibility to additional pulmonary disease. Finally, we found that maternal DHA supplementation prevented sustained inflammation, oxidation, and apoptosis in our model.
Neutral sphingomyelinase 2 is required for cytokine-induced skeletal muscle calpain activation
Authors: Supinski Gerald S. , Alimov Alexander P. , Wang Lin , Song Xiao-Hong , Callahan Leigh A.
Published: July 2015

Calpain contributes to infection-induced diaphragm dysfunction but the upstream mechanism(s) responsible for calpain activation are poorly understood. It is known, however, that cytokines activate neutral sphingomyelinase (nSMase) and nSMase has downstream effects with the potential to increase calpain activity. We tested the hypothesis that infection-induced skeletal muscle calpain activation is a consequence of nSMase activation. We administered cytomix (20 ng/ml TNF-α, 50 U/ml IL-1β, 100 U/ml IFN-γ, 10 μg/ml LPS) to C2C12 muscle cells to simulate the effects of infection in vitro and studied mice undergoing cecal ligation puncture (CLP) as an in vivo model of infection. In cell studies, we assessed sphingomyelinase activity, subcellular calcium levels, and calpain activity and determined the effects of inhibiting sphingomyelinase using chemical (GW4869) and genetic (siRNA to nSMase2 and nSMase3) techniques. We assessed diaphragm force and calpain activity and utilized GW4869 to inhibit sphingomyelinase in mice. Cytomix increased cytosolic and mitochondrial calcium levels in C2C12 cells ( P < 0.001); addition of GW4869 blocked these increases ( P < 0.001). Cytomix also activated calpain, increasing calpain activity ( P < 0.02), and the calpain-mediated cleavage of procaspase 12 ( P < 0.001). Procaspase 12 cleavage was attenuated by either GW4869 ( P < 0.001), BAPTA-AM ( P < 0.001), or siRNA to nSMase2 ( P < 0.001) but was unaffected by siRNA to nSMase3. GW4869 prevented CLP-induced diaphragm calpain activation and diaphragm weakness in mice. These data suggest that nSMase2 activation is required for the development of infection-induced diaphragm calpain activation and muscle weakness. As a consequence, therapies that inhibit nSMase2 in patients may prevent infection-induced skeletal muscle dysfunction.
Cerebral blood velocity regulation during progressive blood loss compared with lower body negative pressure in humans
Authors: Rickards Caroline A. , Johnson Blair D. , Harvey Ronée E. , Convertino Victor A. , Joyner Michael J. , Barnes Jill N.
Published: July 2015

Lower body negative pressure (LBNP) is often used to simulate blood loss in humans. It is unknown if cerebral blood flow responses to actual blood loss are analogous to simulated blood loss during LBNP. Nine healthy men were studied at baseline, during three levels of LBNP (5 min at −15, −30, and −45 mmHg), and during three levels of blood loss (333, 667, and 1,000 ml). LBNP and blood loss conditions were randomized. Intra-arterial mean arterial pressure (MAP) during LBNP was similar to that during blood loss ( P ≥ 0.42). Central venous pressure (2.8 ± 0.7 vs. 4.0 ± 0.8, 1.2 ± 0.6 vs. 3.5 ± 0.8, and 0.2 ± 0.9 vs. 2.1 ± 0.9 mmHg for levels 1, 2, and 3, respectively, P ≤ 0.003) and stroke volume (71 ± 4 vs. 80 ± 3, 60 ± 3 vs. 74 ± 3, and 51 ± 2 vs. 68 ± 4 ml for levels 1, 2, and 3, respectively, P ≤ 0.002) were lower during LBNP than blood loss. Despite differences in central venous pressure, middle cerebral artery velocity (MCAv) and cerebrovascular conductance were similar between LBNP and blood loss at each level (MCAv at level 3: 62 ± 6 vs. 66 ± 5 cm/s, P = 0.37; cerebrovascular conductance at level 3: 0.72 ± 0.05 vs. 0.73 ± 0.05 cm·s−1·mmHg−1, P = 0.53). While the slope of the MAP-MCAv relationship was slightly different between LBNP and blood loss (0.41 ± 0.03 and 0.66 ± 0.04 cm·s−1·mmHg−1, respectively, P = 0.05), time domain gain between MAP and MCAv at maximal LBNP/blood loss ( P = 0.23) and low-frequency MAP-mean MCAv transfer function coherence, gain, and phase were similar ( P ≥ 0.10). Our results suggest that cerebral hemodynamic responses to LBNP to −45 mmHg and blood loss up to 1,000 ml follow a similar trajectory, and the arterial pressure-cerebral blood velocity relationship is not altered from baseline under these conditions.
Left atrial phasic function interacts to support left ventricular filling during exercise in healthy athletes
Authors: Wright Steve , Sasson Zion , Gray Taylor , Chelvanathan Anjala , Esfandiari Sam , Dimitry John , Armstrong Sarah , Mak Susanna , Goodman Jack M.
Published: July 2015

We studied the contribution of phasic left atrial (LA) function to left ventricular (LV) filling during exercise. We hypothesized that reduced LV filling time at moderate-intensity exercise limits LA passive emptying and increases LA active emptying. Twenty endurance-trained males (55 ± 6 yr) were studied at rest and during light- (∼100 beats/min) and moderate-intensity (∼130 beats/min) exercise. Two-dimensional and Doppler echocardiography were used to assess phasic volumes and diastolic function. LV end-diastolic volume increased from rest to light exercise (54 ± 6 to 58 ± 5 ml/m2, P < 0.01) and from light to moderate exercise (58 ± 5 to 62 ± 6 ml/m2, P < 0.01). LA maximal volume increased from rest to light exercise (26 ± 4 to 30 ± 5 ml/m2, P < 0.01) related to atrioventricular plane displacement ( r = 0.55, P < 0.005), without further change at moderate exercise. LA passive emptying increased at light exercise (9 ± 2 to 13 ± 3 ml/m2, P < 0.01) and then returned to baseline at moderate exercise, whereas LA active emptying increased appreciably only at moderate exercise (6 ± 2 to 14 ± 3 ml/m2, P < 0.01). Thus, the total atrial emptying volume did not increase beyond light exercise, and the increase in LV filling at moderate exercise could be attributed primarily to an increase in the conduit flow volume (19 ± 3 to 25 ± 5 ml/m2, P < 0.01). LA filling increases during exercise in relation to augmented LV longitudinal contraction. Conduit flow increases progressively with exercise in athletes, although this is driven by LV properties rather than intrinsic LA function. The pump function of the LA augments only at moderate exercise due to a reduced diastolic filling time and the Frank-Starling mechanism.
Identification of mouse gaits using a novel force-sensing exercise wheel
Authors: Smith Benjamin J. H. , Cullingford Lottie , Usherwood James R.
Published: July 2015

The gaits that animals use can provide information on neurological and musculoskeletal disorders, as well as the biomechanics of locomotion. Mice are a common research model in many fields; however, there is no consensus in the literature on how (and if) mouse gaits vary with speed. One of the challenges in studying mouse gaits is that mice tend to run intermittently on treadmills or overground; this paper attempts to overcome this issue with a novel exercise wheel that measures vertical ground reaction forces. Unlike previous instrumented wheels, this wheel is able to measure forces continuously and can therefore record data from consecutive strides. By concatenating the maximum limb force at each time point, a force trace can be constructed to quantify and identify gaits. The wheel was three dimensionally printed, allowing the design to be shared with other researchers. The kinematic parameters measured by the wheel were evaluated using high-speed video. Gaits were classified using a metric called “3S” (stride signal symmetry), which quantifies the half wave symmetry of the force trace peaks. Although mice are capable of using both symmetric and asymmetric gaits throughout their speed range, the continuum of gaits can be divided into regions based on the frequency of symmetric and asymmetric gaits; these divisions are further supported by the fact that mice run less frequently at speeds near the boundaries between regions. The boundary speeds correspond to gait transition speeds predicted by the hypothesis that mice move in a dynamically similar fashion to other legged animals.
The SMARCA2/4 ATPase Domain Surpasses the Bromodomain as a Drug Target in SWI/SNF-Mutant Cancers: Insights from cDNA Rescue and PFI-3 Inhibitor Studies
Authors: Vangamudi Bhavatarini , Paul Thomas A. , Shah Parantu K. , Kost-Alimova Maria , Nottebaum Lisa , Shi Xi , Zhan Yanai , Leo Elisabetta , Mahadeshwar Harshad S. , Protopopov Alexei , Futreal Andrew , Tieu Trang N. , Peoples Mike , Heffernan Timothy P. , Marszalek Joseph R. , Toniatti Carlo , Petrocchi Alessia , Verhelle Dominique , Owen Dafydd R. , Draetta Giulio , Jones Philip , Palmer Wylie S. , Sharma Shikhar , Andersen Jannik N.
Published: July 2015

The SWI/SNF multisubunit complex modulates chromatin structure through the activity of two mutually exclusive catalytic subunits, SMARCA2 and SMARCA4, which both contain a bromodomain and an ATPase domain. Using RNAi, cancer-specific vulnerabilities have been identified in SWI/SNF-mutant tumors, including SMARCA4-deficient lung cancer; however, the contribution of conserved, druggable protein domains to this anticancer phenotype is unknown. Here, we functionally deconstruct the SMARCA2/4 paralog dependence of cancer cells using bioinformatics, genetic, and pharmacologic tools. We evaluate a selective SMARCA2/4 bromodomain inhibitor (PFI-3) and characterize its activity in chromatin-binding and cell-functional assays focusing on cells with altered SWI/SNF complex (e.g., lung, synovial sarcoma, leukemia, and rhabdoid tumors). We demonstrate that PFI-3 is a potent, cell-permeable probe capable of displacing ectopically expressed, GFP-tagged SMARCA2-bromodomain from chromatin, yet contrary to target knockdown, the inhibitor fails to display an antiproliferative phenotype. Mechanistically, the lack of pharmacologic efficacy is reconciled by the failure of bromodomain inhibition to displace endogenous, full-length SMARCA2 from chromatin as determined by in situ cell extraction, chromatin immunoprecipitation, and target gene expression studies. Furthermore, using inducible RNAi and cDNA complementation (bromodomain- and ATPase-dead constructs), we unequivocally identify the ATPase domain, and not the bromodomain of SMARCA2, as the relevant therapeutic target with the catalytic activity suppressing defined transcriptional programs. Taken together, our complementary genetic and pharmacologic studies exemplify a general strategy for multidomain protein drug-target validation and in case of SMARCA2/4 highlight the potential for drugging the more challenging helicase/ATPase domain to deliver on the promise of synthetic-lethality therapy. Cancer Res; 75(18); 3865–78. ©2015 AACR.
Increased Expression of HER2, HER3, and HER2:HER3 Heterodimers in HPV-Positive HNSCC Using a Novel Proximity-Based Assay: Implications for Targeted Therapies
Authors: Pollock Netanya I. , Wang Lin , Wallweber Gerald , Gooding William E. , Huang Weidong , Chenna Ahmed , Winslow John , Sen Malabika , DeGrave Kara A. , Li Hua , Zeng Yan , Grandis Jennifer R.
Published: July 2015

Purpose: In other cancer types, HPV infection has been reported to coincide with overexpression of HER2 (ERBB2) and HER3 (ERBB3); however, the association between HER2 or HER3 expression and dimer formation in HNSCC has not been reported. Overexpression of HER2 and HER3 may contribute to resistance to EGFR inhibitors, including cetuximab, although the contribution of HPV in modulating cetuximab response remains unknown. Determination of heterodimerization of HER receptors is challenging and has not been reported in HNSCC. The present study aimed to determine the expression of HER proteins in HPV+ versus HPV− HNSCC tumors using a proximity-based protein expression assay (VeraTag), and to determine the efficacy of HER-targeting agents in HPV+ and HPV− HNSCC cell lines.

Experimental Design: Expression of total HER1, HER2, and HER3, p95HER2, p-HER3, HER1:HER1 homodimers, HER2:HER3 heterodimers, and the HER3–PI3K complex in 88 HNSCC was determined using VeraTag, including 33 baseline tumors from individuals treated in a trial including cetuximab. Inhibition of cell growth and protein activation with cetuximab and afatinib was compared in HPV+ and HPV− cetuximab-resistant cell lines.

Results: Expression of total HER2, total HER3, HER2:HER3 heterodimers, and the HER3:PI3K complex were significantly elevated in HPV+ HNSCC. Total EGFR was significantly increased in HPV− HNSCC where VeraTag assay results correlated with IHC. Afatinib significantly inhibited cell growth when compared with cetuximab in the HPV+ and HPV− cetuximab-resistant HNSCC cell lines.

Conclusions: These findings suggest that agents targeting multiple HER proteins may be effective in the setting of HPV+ HNSCC and/or cetuximab resistance. Clin Cancer Res; 21(20); 4597–606. ©2015 AACR.
CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in BRCA1-Deficient Ovarian Cancer
Authors: Higuchi Tomoe , Flies Dallas B. , Marjon Nicole A. , Mantia-Smaldone Gina , Ronner Lukas , Gimotty Phyllis A. , Adams Sarah F.
Published: July 2015

Immune checkpoint blockade has shown significant therapeutic efficacy in melanoma and other solid tumors, but results in ovarian cancer have been limited. With evidence that tumor immunogenicity modulates the response to checkpoint blockade, and data indicating that BRCA-deficient ovarian cancers express higher levels of immune response genes, we hypothesized that BRCA− ovarian tumors would be vulnerable to checkpoint blockade. To test this hypothesis, we used an immunocompetent BRCA1-deficient murine ovarian cancer model to compare treatment with CTLA-4 or PD-1/PD-L1 antibodies alone or combined with targeted cytotoxic therapy using a PARP inhibitor. Correlative studies were performed in vitro using human BRCA1− cells. We found that CTLA-4 antibody, but not PD-1/PD-L1 blockade, synergized therapeutically with the PARP inhibitor, resulting in immune-mediated tumor clearance and long-term survival in a majority of animals (P < 0.0001). The survival benefit of this combination was T-cell mediated and dependent on increases in local IFNγ production in the peritoneal tumor environment. Evidence of protective immune memory was observed more than 60 days after completion of therapy. Similar increases in the cytotoxic effect of PARP inhibition in the presence of elevated levels of IFNγ in human BRCA1− cancer cells support the translational potential of this treatment protocol. These results demonstrate that CTLA-4 blockade combined with PARP inhibition induces protective antitumor immunity and significant survival benefit in the BRCA1− tumor model, and support clinical testing of this regimen to improve outcomes for women with hereditary ovarian cancer. Cancer Immunol Res; 3(11); 1257–68. ©2015 AACR.
Clinical Features of Patients Treated with Endoscopic Sinus Surgery for Posttraumatic Paranasal Sinus Mucocele
Authors: Kojima Yusuke , Tsuzuki Kenzo , Yukitatsu Yoriko , Oka Hideki , Takebayashi Hironori , Sakagami Masafumi
Published: July 2015

Aim: The purpose of this study was to analyze the clinical features of patients with posttraumatic paranasal sinus mucocele (PSM). Subjects and Methods: Between 2009 and 2013, we performed endoscopic sinus surgery (ESS) on 68 patients with PSM at the Department of Otolaryngology - Head and Neck Surgery at Hyogo College of Medicine. Five male patients (age range, 45-76 years) with posttraumatic PSM were analyzed retrospectively. Diagnosis was based on the history of injury and radiological findings. Results: Posttraumatic PSM was found in 7% (5/68) of patients. The mean interval from injury to diagnosis was 28.4 years. All patients had frontal sinus mucocele. Four patients had symptoms of headache, diplopia, visual field defect, and forehead swelling, and 1 patient was asymptomatic. ESS was performed under general anesthesia in all cases, and the symptoms improved postoperatively. Reoperation was required in 1 patient (20%) because headache developed with obstruction of the frontal drainage route 7 months after ESS. Conclusions: Posttraumatic PSM was the least frequent form of PSM and was located predominantly in the frontal sinus, causing symptoms long after the forehead injury. The important lessons to be learned for treating posttraumatic PSM are to obtain a detailed history and to enlarge the route to the cyst to avoid its recurrence.
Serum Soluble Klotho Level Is Associated with Abdominal Aortic Calcification in Patients on Maintenance Hemodialysis
Authors: Cai Hong , Lu Renhua , Zhang Mingfang , Pang Huihua , Zhu Mingli , Zhang Weiming , Ni Zhaohui , Qian Jiaqi , Yan Yucheng
Published: July 2015

Background: Klotho is a single transmembrane protein originally identified as an ‘aging suppressor'. Emerging evidence reveals that soluble Klotho (sKl) in the circulation plays important roles in anti-aging, anti-oxidation, anti-apoptosis and Wnt signaling. However, the role of serum sKl in the vascular calcification in hemodialysis patients is not clear. The aim of this study was to determine the associations of sKl with abdominal aortic calcification in patients on maintenance hemodialysis (MHD). Methods: 129 MHD patients were enrolled prospectively. Serum sKl level was detected by ELISA. Abdominal aortic calcification was measured by abdomen lateral plain radiograph, and the abdominal aorta calcification (AAC) score was calculated. The sKl levels were observed in patients with different degrees of calcification. Logistic regression analysis was used to determine the risk factor of abdominal aortic calcification in MHD patients. The diagnostic value of sKl for abdominal aortic calcification was assessed using receiver operator characteristic (ROC). Results: Abdominal aortic calcification was seen in 87 of 129 patients. The median AAC score was 4.0 (0.00, 11.00) and the median sKl level was 616.29 (378.19, 821.61) pg/ml. Serum sKl levels were inversely associated with AAC. When evaluated as AAC categories (<5, 5-15, >15) with ordinal logistic regression, each SD higher sKl was associated with 37.1% lower odds of AAC severity (proportional odds ratio: 0.629; 95% confidence interval: 0.413-0.959, p = 0.031) in models adjusted for demographic data, lifestyle factors, traditional CVD risk factors and uremic risk factors. Multivariate logistic regression analysis showed that serum sKl levels and smoking were independent risk factors for severe AAC. The area under the receiver-operating characteristic curve (AUC) of serum sKl for severe abdominal aortic calcification was 0.746 (0.612-0.880, p = 0.001), sensitivity was 0.885, and specificity was 0.562 for a cutoff value of 265.39 pg/ml. Conclusions: Lower serum sKl levels are independently associated with severe AAC. Serum sKl might have a diagnostic value for the severe AAC in MHD patients.
MicroRNA-155 Promotes Atherosclerosis Inflammation via Targeting SOCS1
Authors: Yang Yang , Yang Lixia , Liang Xing , Zhu Guofu
Published: July 2015

Aims: Accumulating evidence suggests that atherosclerotic progression depends on persistent and chronic inflammation in the arterial walls. MicroRNA-155 is reportedly involved in cardiovascular disease and has been implicated as a pro-inflammation regulator. Although some researchers have focused on microRNA-155 as an atherosclerosis regulator, the mechanisms by which microRNA-155 functions as a putative pro-atherosclerosis microRNA are largely unknown. This study aims to analyze microRNA-155's effects on atherosclerotic inflammation and to explore its mechanism. Methods: MicroRNA-155's effects on atherosclerotic inflammation were observed along with the expression and activity levels of SOCS1, STAT3 and NF-κB though microRNA-155 inhibition or overexpression. Results: Highly expressions of microRNA-155 in oxLDL-stimulated macrophages and atherosclerosis mice were inversely correlated with SOCS1 expression. Ectopic microRNA-155 overexpression significantly promoted inflammatory cytokine and chemokine production and atherosclerosis progression. We then observed microRNA-155's functional role in the atherosclerotic pathophysiological process in vivo and in vitro. The observation revealed that by enhancing STAT3 and NF-κB signaling and facilitating immune inflammation by targeting SOCS1, microRNA-155 plays a promotable role in atherosclerosis progression. Conclusions: microRNA-155 works as a promoter in the atherosclerotic procession. Its mechanism may include enhancing inflammatory response in atherosclerosis by increasing STAT3 and NF-κB signaling via targeting SOCS1.
DNA Repair Gene Polymorphisms in Relation to Non-Small Cell Lung Cancer Survival
Authors: Su Yuliang , Zhang Huan , Xu Fangxiu , Kong Jinyu , Yu Herbert , Qian Biyun
Published: July 2015

Background: Single nucleotide polymorphisms (SNPs) in the DNA repair genes are suspected to be related to the survival of lung cancer patients due to their possible influence on DNA repair capacity (DRC). However, the study results are inconsistent. Methods: A follow-up study of 610 non-small cell lung cancer (NSCLC) patients was conducted to investigate genetic polymorphisms associated with the DNA repair genes in relation to NSCLC survival; 6 SNPs were genotyped, including XRCC1 (rs25487 G>A), hOGG1 (rs1052133 C>G), MUTYH (rs3219489 G>C), XPA (rs1800975 G>A), ERCC2 (rs1799793 G>A) and XRCC3 (rs861539 C>T). Kaplan-Meier survival curve and Cox proportional hazards regression analyses were performed. SNP-SNP interaction was also examined using the survival tree analysis. Results: Advanced disease stage and older age at diagnosis were associated with poor prognosis of NSCLC. Patients with the variant ‘G' allele of hOGG1 rs1052133 had poor overall survival compared with those with the homozygous wild ‘CC' genotype, especially in female patients, adenocarcinoma histology, early stage, light smokers and without family history of cancer. For never smoking female lung cancer patients, individuals carrying homozygous variant ‘AA' genotype of XPA had shorter survival time compared to those with wild ‘G' alleles. Furthermore, females carrying homozygous variant XPA and hOGG1 genotypes simultaneously had 2.78-fold increased risk for death. Among all 6 polymorphisms, the homozygous variant ‘AA' of XPA carriers had poor prognosis compared to the carriers of wild ‘G' alleles of XPA together with other base excision repair (BER) polymorphisms. Conclusions: Besides disease stage and age, the study found DNA repair gene polymorphisms were associated with lung cancer survival.
The Interaction Between MiR-141 and lncRNA-H19 in Regulating Cell Proliferation and Migration in Gastric Cancer
Authors: Zhou Xiaoying , Ye Feng , Yin Chengqiang , Zhuang Ya , Yue Ge , Zhang Guoxin
Published: July 2015

Background/Aims: Non-coding RNAs including miRNA and lncRNA had been reported to regulate gene expression and were both related to cancer progression. MicroRNA-141 (miR-141) has been reported to play a role in the epithelial to mesenchymal transition (EMT) process and H19 has also been demonstrated to promote malignancy in various cancers. We aimed to determine the correlation between miR-141 and H19 and their roles in gastric cancer in this study. Methods: H19 and miR-141 expression were detected by qRT-PCR. By bioinformatic analysis and luciferase assay we examined the correlation between H19 and miR-141 in vitro. Results: H19 expression was found to be inversely correlated to miR-141 expression in gastric cancer cells and tissues. H19 promotes malignancy including proliferation and invasion whereas miR-141 suppresses malignancy in human cancer cells. MiR-141 binds to H19 in a sequence specific manner, and suppresses H19 expression and functions including proliferation and invasion. MiR-141 could also regulate H19 target genes and miR-141 inhibitor restores H19 siRNA function, while H19 regulates miR-141 target gene ZEB1. Conclusion: These results were the first to demonstrate that H19 and miR-141 could compete with each other and affect their target genes in gastric cancer, which provide important clues for understanding the key roles of lncRNA-miRNA functional network in cancer.
BCR-ABL1 Transcript Levels at 3 and 6 Months Are Better for Identifying Chronic Myeloid Leukemia Patients with Poor Outcome in Response to Second-Line Second-Generation Tyrosine Kinase Inhibitors after Imatinib Failure: A Report from a Single Institution
Authors: Ribeiro Beatriz Felicio , Vergílio Bruna Rocha , Miranda Eliana Cristina Martins , Almeida Maria Helena , Delamain Marcia Torresan , da Silveira Rosana Antunes , de Souza Carmino Antonio , Albuquerque Dulcinéia Martins , Dos Santos Andrey , Duarte Vagner Oliveira , Oliveira-Duarte Gislaine Borba , Lorand-Metze Irene , Pagnano Katia Borgia Barbosa
Published: July 2015

Early reduction of BCR-ABL1 transcript levels has been associated with improved outcome in chronic myeloid leukemia (CML) treatment. We evaluated 54 chronic-phase CML patients treated with imatinib who switched therapy to dasatinib (n = 33) or nilotinib (n = 21). BCR-ABL1 transcript levels were measured in peripheral blood using real-time quantitative PCR (RQ-PCR) every 3 months from the start of second-line treatment. Patients with BCR-ABL transcript levels >10% at 3 months and >1% at 6 months had significantly inferior progression-free (PFS) and event-free survival (EFS) than patients with RQ-PCR <10% at 3 months and <1% at 6 months (66 vs. 100%, p = 0.01, and 33 vs. 73%, p = 0.02, respectively). Patients with RQ-PCR <10% at 3 months and >1% at 6 months also had inferior PFS and EFS than patients with RQ-PCR <10% at 3 months and <1% at 6 months (48 vs. 100%, p = 0.002, and 25 vs. 73%, p < 0.0001, respectively). Two measurements of BCR-ABL levels were better than a single one to stratify chronic-phase CML patients as failure after second-line therapy.
Smad Anchor for Receptor Activation Regulates High Glucose-Induced EMT via Modulation of Smad2 and Smad3 Activities in Renal Tubular Epithelial Cells
Authors: Tang Wen-bin , Ling Guang-hui , Sun Lin , Zhang Ke , Zhu Xuejing , Zhou Xun , Liu Fu-you
Published: July 2015

Background: SARA is an essential adaptor protein in TGF-β1 signaling and it is also involved in the process of Epithelial-mesenchymal transition (EMT) and fibrosis. Our aim was to investigate the effect of SARA on high glucose (HG)-induced EMT and extracellular matrix (ECM) synthesis in renal tubular epithelial cells. Methods: The cells were transfected with the following plasmids: wild-type SARA (SARA-WT), SARA-dSBD (SARA with Smad binding domain deletion) and then subjected to HG ambience (30 mM). The expression levels were assessed by Western-blot, real-time PCR and immunofluorescence. Results: HG-induced EMT phenotype with increased expression of ECM protein in HK-2 cells. This was associated with the decreased expression of SARA and Smad2. In comparison with the HG group, overexpression of SARA in HK-2 cells, a relatively high upregulation of ZO-1 expression was seen, while that of Vimentin, fibronectin and collagen I was decreased. The Smad2 protein expression was increased in HK-2 cells after transfection with SARA (WT) plasmid. Interestingly, the overexpression of SARA prolonged the activity period of Smad2 and shortened that of Smad3, which seemed consistent with the change of EMT phenotype and ECM changes in HK-2 cell induced by HG. Conclusions: SARA regulates HG-induced EMT and ECM excretion via modulation of the activation of Smad2 and Smad3 in renal tubular epithelial cells. In view of these findings, it is conceivable that SARA may serve as a potential novel target in pre-EMT states for the amelioration renal fibrosis seen in chronic kidney diseases.
A Set of Cytogenetic Markers Allows the Precise Identification of All A-Genome Chromosomes in Diploid and Polyploid Wheat
Authors: Badaeva Ekaterina D. , Amosova Alexandra V. , Goncharov Nikolay P. , Macas Jiri , Ruban Alevtina S. , Grechishnikova Irina V. , Zoshchuk Svyatoslav A. , Houben Andreas
Published: July 2015

Karyotypes of 3 diploid wheat species containing different variants of the A-genome, Triticum boeoticum (Ab), T. monococcum (Ab), and T. urartu (Au), were examined using C-banding and FISH with DNA probes representing 5S and 45S rDNA families, the microsatellite sequences GAAn and GTTn, the already known satellite sequences pSc119.2, Spelt52, Fat, pAs1, and pTa535, and a newly identified repeat called Aesp_SAT86. The C-banding patterns of the 3 species in general were similar; differences were observed in chromosomes 4A and 6A. Besides 2 major 45S rDNA loci on chromosomes 1A and 5A, 2 minor polymorphic NORs were observed in the terminal part of 5AL and in the distal part of 6AS in all species. An additional minor locus was found in the distal part of 7AbL of T. boeoticum and T. monococcum, but not in T. urartu. Two 5S rDNA loci were observed in 1AS and 5AS. The pTa535 probe displayed species- and chromosome-specific hybridization patterns, allowing complete chromosome identification and species discrimination. The distribution of pTa535 on the Au-genome chromosomes was more similar to that on the A-genome chromosomes of T. dicoccoides and T. araraticum, thus confirming the origin of these genomes from T. urartu. The probe pAs1 allowed the identification of 4 chromosomes of T. urartu and 2 of T. boeoticum or T. monococcum. The Aesp_SAT86-derived patterns were polymorphic; main clusters were observed on chromosomes 1Au and 3Au of T. urartu and chromosomes 3Ab and 6Ab of T. boeoticum. Thus, a set of probes, pTa535, pAs1, GAAn and GTTn, pTa71, pTa794, and Aesp_SAT86, proved to be most informative for the analysis of A-genomes in diploid and polyploid wheat species.
Resection of Obstructive Left-Sided Colon Cancer at a National Level: A Prospective Analysis of Short-Term Outcomes in 1,816 Patients
Authors: Tanis Pieter J. , Paulino Pereira Nuno R. , van Hooft Jeanin E. , Consten Esther C.J. , Bemelman Willem A. ,   on behalf of the Dutch Surgical Colorectal Audit
Published: July 2015

Background/Aims: The prematurely closed Stent-In II trial in patients with left-sided obstructive colon cancer may have influenced clinical decision making in The Netherlands. The aim of this study was to evaluate treatment of left-sided malignant colon obstruction at a population level since then. Methods: Short-term outcomes of all patients who underwent resection for left-sided obstructive colon cancer between 2009 and 2012 were assessed based on a prospective national registry. Results: In total, 1,816 evaluable patients were included; acute resection was performed in 1,485 (81.8%), and endoscopic stent or decompressing stoma followed by resection in 196 (10.8%) and 135 (7.4%), respectively. The use of endoscopic stenting significantly decreased from 18% (2009) to 6% (2012). Overall 30-day or in-hospital mortality rate was 6.9, 5.6, and 3.7%, respectively (p = 0.107). Mortality rate after acute resection was 2.9% in patients >70 years, but mortality rates up to 32.2% were observed in high-risk elderly patients. Conclusion: Acute resection as first choice treatment seems justified for patients >70 years of age given a mortality rate of 3%. For the elderly frail patients, mortality rates over 30% after acute resection stress the need for alternative treatment strategies.
Transcortical Transventricular Endoscopic Approach and Ommaya Reservoir Placement for Cystic Craniopharyngioma
Authors: Shukla Dhaval
Published: July 2015

The treatment of craniopharyngioma is varied. It ranges from radical excision to direct radiotherapy. As the morbidity of excision is high, more conservative approaches are used. Placement of a catheter and reservoir is one such option for cystic craniopharyngiomas. The positioning of catheters has been performed by various means. A method of endoscopic reservoir catheter placement is described. Three children with ages ranging from 5 to 12 years presented with clinical features of raised intracranial pressure. They did not have vision impairment. Imaging showed a predominantly cystic craniopharyngioma extending into the third ventricle with hydrocephalus. All underwent precoronal burr hole, transcortical transventricular endoscopic biopsy of craniopharyngioma, and Ommaya reservoir placement. There were no complications. All children did well after surgery and did not require further cyst aspiration.
Sleep and Cognitive Decline: A Strong Bidirectional Relationship. It Is Time for Specific Recommendations on Routine Assessment and the Management of Sleep Disorders in Patients with Mild Cognitive Impairment and Dementia
Authors: Guarnieri Biancamaria , Sorbi Sandro
Published: July 2015

Background: Sleep disturbances and disruption of the neural regulation of the sleep-wake rhythm appear to be involved in the cellular and molecular mechanisms of cognitive decline. Although sleep problems are highly prevalent in mild cognitive impairment (MCI) and many types of dementia, they have not been systematically investigated in the clinical setting and are often only investigated by sleep specialists upon individual request. Summary: This review discusses sleep disorders in the context of cognitive decline and provides an overview of the clinical diagnosis and management of these disorders in patients with dementia and MCI. Key Messages: Sleep disorders are largely underestimated and do not receive sufficient attention in the global management of dementia patients. Sleep disturbances have a significant impact on cognitive and physical functions in individuals with cognitive decline and may be associated with important psychological distress and depression. They are positively associated with the severity of behavioral problems and cognitive impairment. Clinical Implications: The recent recommendations by the Sleep Study Group of the Italian Dementia Research Association can be used as a guideline for the clinical assessment and management of sleep disorders in MCI and dementia patients. Sleep disorders should be carefully investigated using an in-depth sleep history, physical examination, questionnaires and clinical scales and should be validated with the support of a direct caregiver. The recommendations for older adults can be used as a framework to guide the diagnosis and treatment of sleep disorders in individuals with dementia and MCI. The management strategy should be based on the choice of different treatments for each sleep problem present in the same patient, while avoiding adverse interactions between treatments.
Genetic Variations in Esophageal Cancer
Authors: Qian Jin , Fang Jing-Yuan
Published: July 2015

Background: Esophageal cancer is one of the most prevalent cancers worldwide, and occurs at a relatively high frequency in China and other Asian countries. The etiology of esophageal cancer remains unclear, making its early diagnosis and treatment difficult. Summary: In recent decades, efforts using candidate gene approaches have been made to identify genetic susceptibility factors for esophageal cancer in a series of genome-wide association studies. Here, we review the latest progress in research on genetic variations in esophageal cancer cases. Key Message: Genetic variations partially account for esophageal cancer incidence and mortality rates. A comparative genomic analysis of esophageal squamous cell carcinomas and esophageal adenocarcinomas suggests little overlap genetically. Current integrated studies using high-throughput approaches have unmasked a number of novel genetic lesions in both esophageal cancer and its precursor lesions, although distinct results obtained from different regions and cohorts remain to be investigated. Practical Implications: Pooled analyses of genome-wide association studies should be conducted to establish unique susceptibility loci for specific districts and nationalities. Meanwhile, the identification of ‘driver mutations' or mutations associated with prognosis in long-term follow-up studies is critical for the development of therapeutic and prognostic strategies.