bluuebunny/crossref_metadata_2025 huggingface dataset:
Depositional architecture and sequence stratigraphic correlation of Upper Ordovician glaciogenic deposits, Illizi Basin, Algeria
Authors: Lang Jörg , Dixon Richard J. , Le Heron Daniel P. , Winsemann Jutta
Published: March 2012

Upper Ordovician glaciogenic deposits are profoundly important as hydrocarbon reservoirs across North Africa, such as within the Illizi Basin of SE Algeria. In this study we present a new sedimentological and sequence stratigraphic model for Upper Ordovician glaciogenic deposits based on the analysis of core descriptions and wireline logs from 25 wells in the Tiguentourine Field. Within the glaciogenic succession, two ice advance–retreat cycles can be defined, consisting of glaciomarine ice-contact fan deposits and tillites. Deposits of the marine ice-contact fan systems generally show a retrogradational stacking pattern from ice-proximal to ice-distal deposits. This pattern is attributed to the deposition in front of a retreating ice sheet. The proximal marine ice-contact fan deposits consist of massive or low-angle cross-bedded pebbly sandstone. They are interpreted as the deposits of turbulent, high-energy plane-wall jets, emerging from subglacial meltwater conduits. These jet-efflux deposits are up to 60 m thick and interbedded with deposits of cohesive and non-cohesive debris flows. The jet-efflux deposits are overlain by fine-grained, thick-bedded massive sandstone. These mid-fan deposits build up the bulk of the glaciomarine fans and are interpreted as deposits of underflows, generated at the point of flow-detachment, where marine meltwater jets become buoyant and large volumes of sediment fall-out from suspension. In the upper part of the fan succession massive sandstones pass upwards into mud-prone massive sandstones, interpreted as deposits of cohesive sandy debris flows. The most ice-distal deposits are muddy sandstones and mudstones deposited by waning low-density turbulent flows and suspension fall-out. The best reservoir properties within the glaciogenic succession are attributed to the proximal and medial deposits of the ice-contact fans such as coarse-grained jet-efflux deposits and sustained high-density turbulent flow deposits. However, the mud content within the massive sandstones is highly variable and influences the reservoir quality. Both glacial depositional sequences infill 60–175 m deep, elongated depressions, which are interpreted as subglacial tunnel valleys. These tunnel valleys acted as depocentres for the glaciomarine fan deposits. After final deglaciation and post-glacial transgression, organic-rich shale was preferentially deposited in underfilled tunnel valleys.
Channelized sandstone bodies (‘cordons’) in the Tassili N'Ajjer (Algeria & Libya): snapshots of a Late Ordovician proglacial outwash plain
Authors: Girard F. , Ghienne J.-F. , Rubino J.-L.
Published: March 2012

The architecture, distribution and development of channelized sandstone bodies are described from Late Ordovician paraglacial successions of the Tassili N'Ajjer (SE Algeria and SW Libya) based on satellite images and field data (sedimentary logs, photomosaics). Sandstone bodies have a ribbon-like form at outcrop (often referred to as ‘cordons’ in the literature). They typify a fluvioglacial outwash plain deposited between a continental ice front and a marine delta-front zone. Channelized sandstone bodies are straight to sinuous, with widths (
W
) in the 60–600 m range, thicknesses (
T
) in the 5–30 m range and they have a mean
W
/
T
ratio of 16.5. They develop within an aggradational–progradational sand-dominated deltaic topset succession including at its distal end a terminal distributary channel and mouth-bar environments. The architecture of channel bodies and the related depositional facies, which includes climbing-dune cross-stratification, indicates that channelized sandstone bodies represent plugs of isolated channels related to high-magnitude flood events (glacier outbursts). These plugs form fossilized networks of both braided channels and interlaced anastomosed channels, offering snapshots of an outburst-related unconfined proglacial outwash braidplain constituted by the amalgamation of adjacent, elongated outwash fans.
Late Ordovician tunnel valleys in southern Jordan
Authors: Douillet G. , Ghienne J.-F. , Géraud Y. , Abueladas A. , Diraison M. , Al-Zoubi A.
Published: March 2012

The Upper Ordovician glacial record of southern Jordan (Ammar Fm.) essentially consists of palaeovalley infills and of a subordinate time-transgressive fluvial to shallow-marine succession overstepping both the palaeovalleys and interfluvial areas. Valley size (depth, 60–160 m; width, 1–3 km), steep (20–50°) margins, internal organization and depositional facies point to an origin as tunnel valleys. The tunnel valleys are infilled by either fluvioglacial sandstones or fluviodeltaic coarsening-upward successions including fine-grained clayey sediments. Re-occupation of previous valleys is evident in places. At least three generations of tunnel valleys are inferred from cross-cutting relationships, although they most probably only reflect temporary standstills and minor re-advances related to the overall recession following the main glacial advance recorded in Saudi Arabia. Petrophysical measurements indicate that higher permeabilities are located in the glacially related strata (1.5–3 darcy in fluvioglacial infills), with a somewhat reduced porosity (22–28%) relative to the preglacial sandstones owing to a higher clay content, probably of diagenetic origin. Sandstone amalgamation, however, gives the fluvioglacial sandstones a high reservoir quality.
The role of the superior laryngeal nerve in esophageal reflexes
Authors: Lang I. M. , Medda B. K. , Jadcherla S. , Shaker R.
Published: March 2012

The aim of this study was to determine the role of the superior laryngeal nerve (SLN) in the following esophageal reflexes: esophago-upper esophageal sphincter (UES) contractile reflex (EUCR), esophago-lower esophageal sphincter (LES) relaxation reflex (ELIR), secondary peristalsis, pharyngeal swallowing, and belch. Cats ( N = 43) were decerebrated and instrumented to record EMG of the cricopharyngeus, thyrohyoideus, geniohyoideus, and cricothyroideus; esophageal pressure; and motility of LES. Reflexes were activated by stimulation of the esophagus via slow balloon or rapid air distension at 1 to 16 cm distal to the UES. Slow balloon distension consistently activated EUCR and ELIR from all areas of the esophagus, but the distal esophagus was more sensitive than the proximal esophagus. Transection of SLN or proximal recurrent laryngeal nerves (RLN) blocked EUCR and ELIR generated from the cervical esophagus. Distal RLN transection blocked EUCR from the distal cervical esophagus. Slow distension of all areas of the esophagus except the most proximal few centimeters activated secondary peristalsis, and SLN transection had no effect on secondary peristalsis. Slow distension of all areas of the esophagus inconsistently activated pharyngeal swallows, and SLN transection blocked generation of pharyngeal swallows from all levels of the esophagus. Slow distension of the esophagus inconsistently activated belching, but rapid air distension consistently activated belching from all areas of the esophagus. SLN transection did not block initiation of belch but blocked one aspect of belch, i.e., inhibition of cricopharyngeus EMG. Vagotomy blocked all aspects of belch generated from all areas of esophagus and blocked all responses of all reflexes not blocked by SLN or RLN transection. In conclusion, the SLN mediates all aspects of the pharyngeal swallow, no portion of the secondary peristalsis, and the EUCR and ELIR generated from the proximal esophagus. Considering that SLN is not a motor nerve for any of these reflexes, the role of the SLN in control of these reflexes is sensory in nature only.
Enteropathogenic Escherichia coli inhibits ileal sodium-dependent bile acid transporter ASBT
Authors: Annaba Fadi , Sarwar Zaheer , Gill Ravinder K. , Ghosh Amit , Saksena Seema , Borthakur Alip , Hecht Gail A. , Dudeja Pradeep K. , Alrefai Waddah A.
Published: March 2012

Apical sodium-dependent bile acid transporter (ASBT) is responsible for the absorption of bile acids from the intestine. A decrease in ASBT function and expression has been implicated in diarrhea associated with intestinal inflammation. Whether infection with pathogenic microorganisms such as the enteropathogenic Escherichia coli (EPEC) affect ASBT activity is not known. EPEC is a food-borne enteric pathogen that translocates bacterial effector molecules via type three secretion system (TTSS) into host cells and is a major cause of infantile diarrhea. We investigated the effects of EPEC infection on ileal ASBT function utilizing human intestinal Caco2 cells and HEK-293 cells stably transfected with ASBT-V5 fusion protein (2BT cells). ASBT activity was significantly inhibited following 60 min infection with EPEC but not with nonpathogenic E. coli . Mutations in bacterial escN, espA, espB, and espD, the genes encoding for the elements of bacterial TTSS, ablated EPEC inhibitory effect on ASBT function. Furthermore, mutation in the bacterial BFP gene encoding for bundle-forming pili abrogated the inhibition of ASBT by EPEC, indicating the essential role for bacterial aggregation and the early attachment. The inhibition by EPEC was associated with a significant decrease in the Vmaxof the transporter and a reduction in the level of ASBT on the plasma membrane. The inhibition of ASBT by EPEC was blocked in the presence of protein tyrosine phosphatase inhibitors. Our studies provide novel evidence for the alterations in the activity of ASBT by EPEC infection and suggest a possible effect for EPEC in influencing intestinal bile acid homeostasis.
Effects of the combined administration of propranolol plus sorafenib on portal hypertension in cirrhotic rats
Authors: D'Amico M. , Mejías M. , García-Pras E. , Abraldes J. G. , García-Pagán J. C. , Fernández M. , Bosch J.
Published: March 2012

Low doses of sorafenib have been shown to decrease portal pressure (PP), portal-systemic shunts, and liver fibrosis in cirrhotic rats. Nonselective beta blockers (NSBB) are the only drugs recommended for the treatment of portal hypertension. The aim of our study was to explore whether the combination of propranolol and sorafenib might show an additive effect reducing PP in cirrhotic rats. Groups of common bile duct-ligated cirrhotic rats (CBDL) and sham-operated control rats were treated by gavage with vehicle, propranolol (30 mg·kg−1·day−1), sorafenib (1 mg·kg−1·day−1), or propranolol+sorafenib. Treatment began 2 wk after the CBDL or sham operation. Hemodynamic evaluation was performed after 2 wk of treatment. In cirrhotic rats, propranolol and sorafenib produced a significant ( P < 0.001) and similar reduction in PP (−19 and −15%, respectively). This was achieved through different mechanisms: whereas propranolol decreased PP by reducing portal blood flow (−35%; P = 0.03), sorafenib decreased PP without decreasing portal flow indicating decreased hepatic resistance. After propranolol+sorafenib, the fall in PP was significantly greater (−30%; P < 0.001) than with either drug alone, demonstrating an additive effect. However, the reduction in portal flow (−39%) under combined therapy was not significantly greater than after propranolol alone. Sorafenib, alone or in combination with propranolol, produced significant reduction in portal-systemic shunting (−25 and −33%, respectively), splanchnic vascularization (−37 and −41%, respectively), liver fibrosis (38%), and hepatic neovascularization (−42 and −51%, respectively). These effects were not observed after propranolol alone. In conclusion, the combination of propranolol+sorafenib causes a greater reduction in PP than either drug alone and decreases markedly the extent of portal-systemic shunting, splanchnic and hepatic neovascularization, and liver fibrosis, suggesting that this drug combination is a potentially useful strategy in the treatment of portal hypertension.
Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome
Authors: Camilleri Michael , Katzka David A.
Published: March 2012

The objectives of this review are twofold. Our first objective is to evaluate the evidence supporting a role for genetics in irritable bowel syndrome (IBS). Specific examples of the associations of genetic variation and symptoms, syndromes, and intermediate phenotypes, including neurotransmitter (serotonergic, α2-adrenergic, and cannabinoid) mechanisms, inflammatory pathways (IL-10, TNFα, GNβ3, and susceptibility loci involved in Crohn's disease), and bile acid metabolism, are explored. The second objective is to review pharmacogenetics in IBS, with the focus on cytochrome P-450 metabolism of drugs used in IBS, modulation of motor and sensory responses to serotonergic agents based on the 5-hydroxytryptamine (5-HT) transporter-linked polymorphic region ( 5-HTTLPR) and 5-HT3genetic variants, responses to a nonselective cannabinoid agonist (dronabinol) based on cannabinoid receptor ( CNR1) and fatty acid amide hydrolase ( FAAH) variation, and responses to a bile acid (sodium chenodeoxycholate) and bile acid binding (colesevelam) based on klothoβ ( KLB) and fibroblast growth factor receptor 4 ( FGFR4) variation. Overall, there is limited evidence of a genetic association with IBS; the most frequently studied association is with 5-HTTLPR, and the most replicated association is with TNF superfamily member 15. Most of the pharmacogenetic associations are reported with intermediate phenotypes in relatively small trials, and confirmation in large clinical trials using validated clinical end points is still required. No published genome-wide association studies in functional gastrointestinal or motility disorders have been published.
Intermittent hypoxia conditioning protects mitochondrial cytochrome c oxidase of rat cerebellum from ethanol withdrawal stress
Authors: Ju Xiaohua , Mallet Robert T. , Downey H. Fred , Metzger Daniel B. , Jung Marianna E.
Published: March 2012

Intermittent hypoxia (IH) conditioning minimizes neurocognitive impairment and stabilizes brain mitochondrial integrity during ethanol withdrawal (EW) in rats, but the mitoprotective mechanism is unclear. We investigated whether IH conditioning protects a key mitochondrial enzyme, cytochrome c oxidase (COX), from EW stress by inhibiting mitochondrially directed apoptotic pathways involving cytochrome c, Bax, or phosphor-P38 (pP38). Male rats completed two cycles of a 4-wk ethanol diet (6.5%) and 3 wk of EW. An IH program consisting of 5–10 bouts of 5–8 min of mild hypoxia (9.5–10% inspired O2) and 4 min of reoxygenation for 20 consecutive days began 3 days before the first EW period. For some animals, vitamin E replaced IH conditioning to test the contributions of antioxidant mechanisms to IH's mitoprotection. During the second EW, cerebellar-related motor function was evaluated by measuring latency of fall from a rotating rod (Rotarod test). After the second EW, COX activity in cerebellar mitochondria was measured by spectrophotometry, and COX, cytochrome c, Bax, and pP38 content were analyzed by immunoblot. Mitochondrial protein oxidation was detected by measuring carbonyl contents and by immunochemistry. Earlier IH conditioning prevented motor impairment, COX inactivation, depletion of COX subunit 4, protein carbonylation, and P38 phosphorylation during EW. IH did not prevent cytochrome c depletion during EW, and Bax content was unaffected by EW ± IH. Vitamin E treatment recapitulated IH protection of COX, and P38 inhibition attenuated protein oxidation during EW. Thus IH protects COX and improves cerebellar function during EW by limiting P38-dependent oxidative damage.
Adaptation of swallowing hyo-laryngeal kinematics is distinct in oral vs. pharyngeal sensory processing
Authors: Humbert Ianessa A. , Lokhande Akshay , Christopherson Heather , German Rebecca , Stone Alice
Published: March 2012

Before a bolus is pushed into the pharynx, oral sensory processing is critical for planning movements of the subsequent pharyngeal swallow, including hyoid bone and laryngeal (hyo-laryngeal) kinematics. However, oral and pharyngeal sensory processing for hyo-laryngeal kinematics is not fully understood. In 11 healthy adults, we examined changes in kinematics with sensory adaptation, sensitivity shifting, with oropharyngeal swallows vs. pharyngeal swallows (no oral processing), and with various bolus volumes and tastes. Only pharyngeal swallows showed sensory adaptation (gradual changes in kinematics with repeated exposure to the same bolus). Conversely, only oropharyngeal swallows distinguished volume differences, whereas pharyngeal swallows did not. No taste effects were observed for either swallow type. The hyo-laryngeal kinematics were very similar between oropharyngeal swallows and pharyngeal swallows with a comparable bolus. Sensitivity shifting (changing sensory threshold for a small bolus when it immediately follows several very large boluses) was not observed in pharyngeal or oropharyngeal swallowing. These findings indicate that once oral sensory processing has set a motor program for a specific kind of bolus (i.e., 5 ml water), hyo-laryngeal movements are already highly standardized and optimized, showing no shifting or adaptation regardless of repeated exposure (sensory adaptation) or previous sensory experiences (sensitivity shifting). Also, the oral cavity is highly specialized for differentiating certain properties of a bolus (volume) that might require a specific motor plan to ensure swallowing safety, whereas the pharyngeal cavity does not make the same distinctions. Pharyngeal sensory processing might not be able to adjust motor plans created by the oral cavity once the swallow has already been triggered.
Postnatal development and activation of L-type Ca2+ currents in locus ceruleus neurons: implications for a role for Ca2+ in central chemosensitivity
Authors: Imber Ann N. , Putnam Robert W.
Published: March 2012

Little is known about the role of Ca2+ in central chemosensitive signaling. We use electrophysiology to examine the chemosensitive responses of tetrodotoxin (TTX)-insensitive oscillations and spikes in neurons of the locus ceruleus (LC), a chemosensitive region involved in respiratory control. We show that both TTX-insensitive spikes and oscillations in LC neurons are sensitive to L-type Ca2+ channel inhibition and are activated by increased CO2/H+. Spikes appear to arise from L-type Ca2+ channels on the soma whereas oscillations arise from L-type Ca2+ channels that are distal to the soma. In HEPES-buffered solution (nominal absence of CO2/HCO3−), acidification does not activate either oscillations or spikes. When CO2 is increased while extracellular pH is held constant by elevated HCO3−, both oscillation and spike frequency increase. Furthermore, plots of both oscillation and spike frequency vs. intracellular [HCO3−]show a strong linear correlation. Increased frequency of TTX-insensitive spikes is associated with increases in intracellular Ca2+ concentrations. Finally, both the appearance and frequency of TTX-insensitive spikes and oscillations increase over postnatal ages day 3–16. Our data suggest that 1) L-type Ca2+ currents in LC neurons arise from channel populations that reside in different regions of the neuron, 2) these L-type Ca2+ currents undergo significant postnatal development, and 3) the activity of these L-type Ca2+ currents is activated by increased CO2 through a HCO3−-dependent mechanism. Thus the activity of L-type Ca2+ channels is likely to play a role in the chemosensitive response of LC neurons and may underlie significant changes in LC neuron chemosensitivity during neonatal development.
Stem-like Tumor-Initiating Cells Isolated from IL13Rα2 Expressing Gliomas Are Targeted and Killed by IL13-Zetakine–Redirected T Cells
Authors: Brown Christine E. , Starr Renate , Aguilar Brenda , Shami Andrew F. , Martinez Catalina , D'Apuzzo Massimo , Barish Michael E. , Forman Stephen J. , Jensen Michael C.
Published: March 2012

Purpose: To evaluate IL13Rα2 as an immunotherapeutic target for eliminating glioma stem–like cancer initiating cells (GSC) of high-grade gliomas, with particular focus on the potential of genetically engineered IL13Rα2-specific primary human CD8+ CTLs (IL13-zetakine+ CTL) to target this therapeutically resistant glioma subpopulation.

Experimental Design: A panel of low-passage GSC tumor sphere (TS) and serum-differentiated glioma lines were expanded from patient glioblastoma specimens. These glioblastoma lines were evaluated for expression of IL13Rα2 and for susceptibility to IL13-zetakine+ CTL-mediated killing in vitro and in vivo.

Results: We observed that although glioma IL13Rα2 expression varies between patients, for IL13Rα2pos cases this antigen was detected on both GSCs and more differentiated tumor cell populations. IL13-zetakine+ CTL were capable of efficient recognition and killing of both IL13Rα2pos GSCs and IL13Rα2pos differentiated cells in vitro, as well as eliminating glioma-initiating activity in an orthotopic mouse tumor model. Furthermore, intracranial administration of IL13-zetakine+ CTL displayed robust antitumor activity against established IL13Rα2pos GSC TS-initiated orthotopic tumors in mice.

Conclusions: Within IL13Rα2 expressing high-grade gliomas, this receptor is expressed by GSCs and differentiated tumor populations, rendering both targetable by IL13-zetakine+ CTLs. Thus, our results support the potential usefullness of IL13Rα2-directed immunotherapeutic approaches for eradicating therapeutically resistant GSC populations. Clin Cancer Res; 18(8); 2199–209. ©2012 AACR.
Survivin Is a Viable Target for the Treatment of Malignant Peripheral Nerve Sheath Tumors
Authors: Ghadimi Markus P. , Young Eric D. , Belousov Roman , Zhang Yiqun , Lopez Gonzalo , Lusby Kristelle , Kivlin Christine , Demicco Elizabeth G. , Creighton Chad J. , Lazar Alexander J. , Pollock Raphael E. , Lev Dina
Published: March 2012

Purpose: To examine the role of survivin as a therapeutic target in preclinical models of human malignant peripheral nerve sheath tumors (MPNST)

Experimental Design: Survivin protein expression levels and subcellular localization were examined immunohistochemically in an MPNST tissue microarray. Human MPNST cells were studied in vitro and in vivo; real-time PCR, Western blotting, and immunocytochemical analyses were used to evaluate survivin expression and localization activation. Cell culture assays were used to evaluate the impact of anti-survivin–specific siRNA inhibition on cell growth and cell-cycle progression and survival. The effect of the small-molecule survivin inhibitor YM155 on local and metastatic MPNST growth was examined in vivo.

Results: Survivin was found to be highly expressed in human MPNSTs; enhanced cytoplasmic subcellular localization differentiated MPNSTs from their plexiform neurofibroma premalignant counterparts. Human MPNST cell lines exhibited survivin mRNA and protein overexpression; expression in both nuclear and cytoplasmic compartments was noted. Survivin knockdown abrogated MPNST cell growth, inducing G2 cell-cycle arrest and marked apoptosis. YM155 inhibited human MPNST xenograft growth and metastasis in severe combined immunodeficient (SCID) mice. Antitumor effects were more pronounced in fast-growing xenografts.

Conclusions: Our studies show an important role for survivin in human MPNST biology. Patients with MPNSTs should be considered for ongoing or future clinical trials that evaluate anti-survivin therapeutic strategies. Most importantly, future investigations should evaluate additional pathways that can be targeted in combination with survivin for maximal synergistic anti-MPNST effects. Clin Cancer Res; 18(9); 2545–57. ©2012 AACR.
Analysis of Spontaneous Tumor-Specific CD4 T-cell Immunity in Lung Cancer Using Promiscuous HLA-DR Telomerase-Derived Epitopes: Potential Synergistic Effect with Chemotherapy Response
Authors: Godet Yann , Fabre Elizabeth , Dosset Magalie , Lamuraglia Michele , Levionnois Emeline , Ravel Patrice , Benhamouda Nadine , Cazes Aurélie , Le Pimpec-Barthes Françoise , Gaugler Beatrice , Langlade-Demoyen Pierre , Pivot Xavier , Saas Philippe , Maillère Bernard , Tartour Eric , Borg Christophe , Adotévi Olivier
Published: March 2012

Purpose: To investigate the presence and impact of spontaneous telomerase-specific CD4 T-cell responses in cancer patients.

Experimental Design: A multistep approach was used to design novel pan-HLA-DR–restricted peptides from telomerase. T-cell clones isolated from cancer patients were used to characterize the polarization of telomerase-specific CD4 response. The presence of spontaneous CD4 T-cell response against telomerase was monitored in 84 metastatic non–small cell lung cancer (NSCLC) patients before first-line chemotherapy (CT) using IFN-γ ELISPOT assay. Then we analyzed the impact of the pretherapeutic telomerase-specific CD4 T immunity on clinical outcome in patients according to their respective response to CT.

Results: We described four novel telomerase-derived CD4 epitopes referred as universal cancer peptides (UCP) that effectively bind to most commonly found human MHC class II alleles. UCP-specific CD4 T-cell repertoire is present in human and UCP-specific CD4 T-cell clones generated from cancer patients exhibited high avidity and are Th1 polarized. Significant frequency (38%) of naturally occurring UCP-specific T-cell responses were detected before CT in advanced NSCLC but not in healthy volunteers. This response was shown to significantly increase overall survival (OS) of patients responding to CT (Median OS: 53 vs. 40 weeks, P = 0.034).

Conclusions: These results show for the first time a potential synergistic effect of telomerase-specific CD4 T-cell response with CT response in NSCLC and underline the potential role of tumor-specific CD4 T-cell response on the efficiency of conventional anticancer therapy. Clin Cancer Res; 18(10); 2943–53. ©2012 AACR.
Hyperactivation of 4E-Binding Protein 1 as a Mediator of Biguanide-Induced Cytotoxicity during Glucose Deprivation
Authors: Matsuo Junichi , Tsukumo Yoshinori , Saito Sakae , Tsukahara Satomi , Sakurai Junko , Sato Shigeo , Kondo Hiromichi , Ushijima Masaru , Matsuura Masaaki , Watanabe Toshiki , Tomida Akihiro
Published: March 2012

Biguanides, including metformin, buformin, and phenformin, are potential antitumorigenic agents and induce cell death during glucose deprivation, a cell condition that occurs in the tumor microenvironment. Here, we show that this selective killing of glucose-deprived cells is coupled with hyperactivation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), a negative regulator of translation initiation. We found, in fact, that the 4E-BP1 hyperactivation led to failure of the unfolded protein response (UPR), an endoplasmic reticulum–originated stress signaling pathway for cell survival. We also found that the 4E-BP1–mediated UPR inhibition occurred through a strong inhibition of the mTOR signaling pathway, a proven antitumor target. Importantly, the 4E-BP1 hyperactivation can be also seen in xenografted cancer cells through an in vivo biguanide treatment. Our findings indicate that antitumor action of biguanides can be mediated by 4E-BP1 hyperactivation, which results in UPR inhibition and selective cell killing when glucose is withdrawn. Mol Cancer Ther; 11(5); 1082–91. ©2012 AACR.
ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors
Authors: Hatzivassiliou Georgia , Liu Bonnie , O'Brien Carol , Spoerke Jill M. , Hoeflich Klaus P. , Haverty Peter M. , Soriano Robert , Forrest William F. , Heldens Sherry , Chen Huifen , Toy Karen , Ha Connie , Zhou Wei , Song Kyung , Friedman Lori S. , Amler Lukas C. , Hampton Garret M. , Moffat John , Belvin Marcia , Lackner Mark R.
Published: March 2012

The RAS/RAF/MEK pathway is activated in more than 30% of human cancers, most commonly via mutation in the K-ras oncogene and also via mutations in BRAF. Several allosteric mitogen-activated protein/extracellular signal–regulated kinase (MEK) inhibitors, aimed at treating tumors with RAS/RAF pathway alterations, are in clinical development. However, acquired resistance to these inhibitors has been documented both in preclinical and clinical samples. To identify strategies to overcome this resistance, we have derived three independent MEK inhibitor–resistant cell lines. Resistance to allosteric MEK inhibitors in these cell lines was consistently linked to acquired mutations in the allosteric binding pocket of MEK. In one cell line, concurrent amplification of mutant K-ras was observed in conjunction with MEK allosteric pocket mutations. Clonal analysis showed that both resistance mechanisms occur in the same cell and contribute to enhanced resistance. Importantly, in all cases the MEK-resistant cell lines retained their addiction to the mitogen-activated protein kinase (MAPK) pathway, as evidenced by their sensitivity to a selective inhibitor of the ERK1/2 kinases. These data suggest that tumors with acquired MEK inhibitor resistance remain dependent on the MAPK pathway and are therefore sensitive to inhibitors that act downstream of the mutated MEK target. Importantly, we show that dual inhibition of MEK and ERK by small molecule inhibitors was synergistic and acted to both inhibit the emergence of resistance, as well as to overcome acquired resistance to MEK inhibitors. Therefore, our data provide a rationale for cotargeting multiple nodes within the MAPK signaling cascade in K-ras mutant tumors to maximize therapeutic benefit for patients. Mol Cancer Ther; 11(5); 1143–54. ©2012 AACR.
miRNA-29b Suppresses Prostate Cancer Metastasis by Regulating Epithelial–Mesenchymal Transition Signaling
Authors: Ru Peng , Steele Robert , Newhall Philip , Phillips Nancy J. , Toth Karoly , Ray Ratna B.
Published: March 2012

Prostate cancer remains the second leading cause of cancer deaths among American men. Early diagnosis increases survival rate in patients; however, treatments for advanced disease are limited to hormone ablation techniques and palliative care. Thus, new methods of treatment are necessary for inhibiting prostate cancer disease progression. Here, we have shown that miRNA-29b (miR-29b) expression was lower in prostate cancer cells (PC3 and LNCaP) as compared with immortalized prostate epithelial cells. Between these two prostate cancer cell lines, metastatic prostate cancer PC3 cells displayed lower expression of miR-29b. We also observed a significant downregulation of miR-29b expression in human prostate cancer tissues as compared with patient-matched nontumor tissues. PC3 cells ectopically expressing miR-29b inhibited wound healing, invasiveness, and failed to colonize in the lungs and liver of severe combined immunodeficient mice after intravenous injection, while PC3 cells expressing a control miRNA displayed metastasis. Epithelial cell marker E-cadherin expression was enhanced miR-29b transfected in prostate cancer cells as compared with cells expressing control miRNA. On the other hand, N-cadherin, Twist, and Snail expression was downregulated in PC3 cells expressing miR-29b. Together these results suggested that miR-29b acts as an antimetastatic miRNA for prostate cancer cells at multiple steps in a metastatic cascade. Therefore, miR-29b could be a potentially new attractive target for therapeutic intervention in prostate cancer. Mol Cancer Ther; 11(5); 1166–73. ©2012 AACR.
The Synthetic Triterpenoid CDDO-Methyl Ester Delays Estrogen Receptor–Negative Mammary Carcinogenesis in Polyoma Middle T Mice
Authors: Tran Kim , Risingsong Renee , Royce Darlene , Williams Charlotte R. , Sporn Michael B. , Liby Karen
Published: March 2012

Novel drugs are needed for the prevention and treatment of breast cancer. Synthetic triterpenoids are a promising new class of compounds with activity in a variety of preclinical cancer models. We tested activity of the methyl ester derivative of the synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me), in a relevant model of estrogen receptor–negative breast cancer, the polyoma-middle T (PyMT), in which the oncoprotein drives carcinogenesis. The developing tumors recapitulate key features of the human disease. Mice were fed CDDO-Me (50 mg/kg diet), starting at 4 weeks of age. CDDO-Me significantly increased the age of mice at onset of first tumor (P < 0.001) by an average of 4.3 weeks and overall survival (P < 0.001) by 5.2 weeks. The drug also inhibited the infiltration of tumor-associated macrophages into mammary glands of PyMT mice at 12 weeks of age and reduced levels of the chemokines CXCL12 and CCL2 in primary PyMT mammary tumor cells. Treatment with this multifunctional drug also inhibited secretion of matrix metalloproteinase-9 in primary tumor cells from PyMT mice and decreased proliferation of these cells by inhibiting cyclin D1 and decreasing phosphorylation of epidermal growth factor receptor and STAT3. Cancer Prev Res; 5(5); 726–34. ©2012 AACR.
Clinical Profiles Predict Early Nonadherence to Adjuvant Endocrine Treatment in a Prospective Breast Cancer Cohort
Authors: Markkula Andrea , Hietala Maria , Henningson Maria , Ingvar Christian , Rose Carsten , Jernström Helena
Published: March 2012

Nonadherence to adjuvant endocrine breast cancer treatment adversely affects disease-free and overall survival. Clinical predictors of nonadherence may allow for specific interventions to reduce nonadherence and improve survival. The aim was to investigate whether clinical characteristics predict nonadherence. Clinical characteristics and information on adherence were obtained from 417 patients with breast cancer in a population-based prospective cohort from southern Sweden using patient charts, pathology reports, and questionnaires filled out at the 1- and 2-year follow-up visits. At the 1- and 2-year follow-up visits, 36 (8.6%) and 33 (9.7%) patients were nonadherent, respectively. Thirteen of the nonadherent patients declined treatment and were never prescribed endocrine treatment. A body mass index (BMI) < 25 kg/m2, preoperative current smoking, and drinking alcohol less often than twice a month predicted nonadherence at the 1-year [relative risk (RR), 5.24; 95% confidence interval (CI), 2.75–9.97] and the 2-year visits (RR, 4.07; 95% CI, 2.11–7.84) in patients with at least two of these clinical characteristics. When low histologic grade (I) was added to the model, having at least two of these four clinical characteristics predicted nonadherence at the 1-year (RR, 4.94; 95% CI, 2.46–10.00) and the 2-year visits (RR, 4.74; 95% CI, 2.28–9.87), the two profiles had a sensitivity ranging from 60.6% to 72.7%, whereas the specificity ranged from 68.0% to 78.4%. Nonadherence at the 1-year visit was associated with an increased risk for early breast cancer events (HR, 2.97; 95% CI, 1.08–8.15), adjusted for age and tumor characteristics. In conclusion, two clinical profiles predicted early nonadherence and may allow for targeted interventions to increase adherence if validated in an independent cohort. Cancer Prev Res; 5(5); 735–45. ©2012 AACR.
Prevalence of Water Pipe Use and Its Correlates in Iranian Women of Reproductive Age in Tehran: A Population-Based Study
Authors: Baheiraei Azam , Mirghafourvand Mojgan , Nedjat Saharnaz , Mohammadi Eesa , Mohammad-Alizadeh Charandabi Sakineh
Published: March 2012

Objective: The objective of this study was to determine the prevalence of water pipe smoking and its associated sociodemographic factors among Iranian women of reproductive age in Tehran. Subjects and Methods: This was a population-based cross-sectional study of 1,359 Iranian women aged 15–49 years. The multistage random cluster technique was used to obtain the sample. Questionnaire-based interviews with questions relating to water pipe smoking and sociodemographic variables were used to collect the data. The multivariate logistic regression model was used to analyse the relationships between the dependent variable (water pipe smoking) and the independent variables (sociodemographic characteristics). Results: The prevalence of water pipe smoking was 6.3% among Iranian women. Water pipe smoking was more likely in the age range of 15–24 years [odds ratio (OR) = 4.8, 95% confidence interval (95% CI) = 2.7–8.6] compared to the age range of 35 years or older, in women with a university education (OR = 1.9, 95% CI = 1.3–3.0) compared to women with a high-school diploma or lower, and in women with an average crowding index score (OR = 4.7, 95% CI = 2.1–10.6) compared to women living in small families. Conclusion: The findings of this study show that Iranian women with a university education and the younger age group (15–24 years) were at most risk of water pipe smoking. The findings of this study about associated factors may contribute to the development of efficient health promotion programmes for the prevention and cessation of water pipe smoking.
The Two Different Effects of the Potential Neuroprotective Compound Minocycline on AMPA-Type Glutamate Receptors
Authors: Jin Ling-Jing , Schlesinger Friedrich , Guan Qiang , Song Yun-Ping , Nie Zhi-Yu
Published: March 2012

Background: Minocycline has demonstrated neuroprotective effects in experimental neurodegenerative diseases. The aim of this study was to investigate if there is any direct interaction between minocycline and the AMPA-type receptor channels, and to elucidate the underlying molecular pharmacological mechanisms. Methods: The patch-clamp technique was used combined with an ultrafast solution exchange system to investigate the interaction of minocycline with recombinant AMPA-type glutamate receptor channels (homomeric GluR2flipGQ or nondesensitizing GluR2L504Y). Results: Dose-dependent decreases in the relative peak current amplitude (rAmp) and the relative steady-state current (rCdes) were found in coapplication experiments with GluR2L504Y receptors, but not in preincubation experiments. Furthermore, coapplication of 1 or 3 mmol/l minocycline showed a decrease in the fast time constant of current decay, and reopening currents were observed. But in the test with GluR2flipGQ receptors, rAmp, relative area under the curve and rCdes increased with increasing concentrations of minocycline, and the steady-state time constant also increased when 3 µmol/l glutamate were used as agonist. Conclusion: Minocycline modulates AMPA-type receptor channels in a combination of a weaker open-channel block effect and a stronger potentiation effect, and the latter effect arises mainly from attenuating the extent of receptor desensitization.
Topical Treatment Habits in Psoriasis Patients Receiving Adalimumab
Authors: Kolios A.G.A. , Rusca F. , Reisenbauer K. , Cozzio A. , French L.E. , Navarini A.A.
Published: March 2012

Background: Biologics are used increasingly to treat moderate-to-severe psoriasis. Here the topical treatment habits (corticosteroids and vitamin D derivates) and moisturizer use of 97 Swiss patients (male 65, female 32) receiving adalimumab have been evaluated. Methods: Using a short cross-sectional survey the pharmacist asked patients during telephone contact about their topical treatment habits and psoriasis activity. Results: 47 patients with adalimumab monotherapy were still free of psoriatic lesions after a longer follow-up of 13 months of therapy; 8 of them still used topical treatment. In contrast, 38 of 50 patients with remaining lesions used topicals. More than 75% of patients indicated that the perceived efficacy of additional topical therapy was ≥5 on a visual analog scale (0–10). The use of moisturizers did not correlate with disease activity. Conclusion: Topical treatment use by adalimumab patients is associated with remaining disease activity. 83% of patients without residual plaques (40% of all adalimumab patients) are able to stop topical treatment completely.
PENS Syndrome: A New Neurocutaneous Phenotype
Authors: Tadini Gianluca , Restano Lucia , Happle Rudolph , Itin Peter
Published: March 2012

Background: The central nervous system originates ontogenetically from the ectoderm and therefore numerous neurocutaneous syndromes exist. Objective: We describe a novel neurocutaneous syndrome with characteristic epidermal papules and plaques associated with mild psychomotor retardation and epilepsy with a good prognosis. Methods: We investigated history, clinical features, laboratory parameters including karyotype, histopathological and immunohistological examination, electron microscopy, HPV infection, EEG and neurologic imaging in patients with an unusual symptom complex. Results: Six children are reported with characteristic keratotic papules and plaques of ‘gem-like’ appearance, randomly distributed on the trunk and the proximal part of the limbs. Four patients were unrelated and two were siblings. The cutaneous lesions appeared congenitally or developed soon after birth. The skin lesions were rounded or of an irregularly polycyclic shape, ranging from 0.5 to 1.5 cm in diameter. A few to eighteen lesions were present. The lesional surface was rough and of white or yellowish color. Histopathological examination showed acanthokeratosis, but immunostaining for keratins and melanocytes, electron microscopy and laboratory results were within normal range. During the natural course of the disease the lesions were stable and asymptomatic. All but one of our six patients developed neurologic signs and symptoms during the first year of life, in the form of epilepsy and psychomotor delay. Five children had low intellectual performance together with EEG abnormalities and some had MRI changes of the brain. One patient had marked language impairment. The central nervous system involvement had a peculiar benign and self-limiting course and total normalization occurred in one case. Limitations: We present only a small series of patients. Conclusion: Cutaneous lesions showing identical clinical and microscopical features, but without any extracutaneous abnormalities, have recently been described by Torrelo et al. [J Am Acad Dermatol 2011;64:888–892] under the designation ‘papular epidermal nevus with “skyline” basal cell layer (PENS)’. An association of such nevi with neurologic abnormalities had so far only been published in the ‘Atlas of Genodermatoses’ edited by Caputo and Tadini. We believe that this unique and otherwise undescribed symptom complex is a new neurocutaneous phenotype that may be called PENS syndrome. Whether this new syndrome can be categorized as a distinct phenotype within the group of epidermal nevus syndromes remains speculative and has to be clarified by further investigations.
Topical and Systemic Cannabidiol Improves Trinitrobenzene Sulfonic Acid Colitis in Mice
Authors: Schicho Rudolf , Storr Martin
Published: March 2012

Background/Aims: Compounds of Cannabis sativa are known to exert anti-inflammatory properties, some of them without inducing psychotropic side effects. Cannabidiol (CBD) is such a side effect-free phytocannabinoid that improves chemically induced colitis in rodents when given intraperitoneally. Here, we tested the possibility whether rectal and oral application of CBD would also ameliorate colonic inflammation, as these routes of application may represent a more appropriate way for delivering drugs in human colitis. Methods: Colitis was induced in CD1 mice by trinitrobenzene sulfonic acid. Individual groups were either treated with CBD intraperitoneally (10 mg/kg), orally (20 mg/kg) or intrarectally (20 mg/kg). Colitis was evaluated by macroscopic scoring, histopathology and the myeloperoxidase (MPO) assay. Results: Intraperitoneal treatment of mice with CBD led to improvement of colonic inflammation. Intrarectal treatment with CBD also led to a significant improvement of disease parameters and to a decrease in MPO activity while oral treatment, using the same dose as per rectum, had no ameliorating effect on colitis. Conclusion: The data of this study indicate that in addition to intraperitoneal application, intrarectal delivery of cannabinoids may represent a useful therapeutic administration route for the treatment of colonic inflammation.
Interaction Between NFκB and NFAT Coordinates Cardiac Hypertrophy and Pathological Remodeling
Authors: Liu Qinghang , Chen Yi , Auger-Messier Mannix , Molkentin Jeffery D.
Published: March 2012

Rationale:

Both nuclear factors of activated T cells (NFAT) and nuclear factor-κB (NFκB) are Rel homology domain (RHD)-containing transcription factors whose independent activities are critically involved in regulating cardiac hypertrophy and failure.

Objective:

To determine the potential functional interaction between NFAT and NFκB signaling pathways in cardiomyocytes and its role in cardiac hypertrophy and remodeling.

Methods and Results:

We identified a novel transcriptional regulatory mechanism whereby NFκB and NFAT directly interact and synergistically promote transcriptional activation in cardiomyocytes. We show that the p65 subunit of NFκB coimmunoprecipitates with NFAT in cardiomyocytes, and this interaction maps to the RHD within p65. Overexpression of the p65-RHD disrupts the association between endogenous p65 and NFATc1, leading to reduced transcriptional activity. Overexpression of IκB kinase β (IKKβ) or p65-RHD causes nuclear translocation of NFATc1, and expression of a constitutively nuclear NFATc1-SA mutant similarly facilitated p65 nuclear translocation. Combined overexpression of p65 and NFATc1 promotes synergistic activation of NFAT transcriptional activity in cardiomyocytes, whereas inhibition of NFκB with IκBαM or dominant negative IKKβ reduces NFAT activity. Importantly, agonist-induced NFAT activation is reduced in
p65
null mouse embryonic fibroblasts (MEFs) compared with wild-type MEFs. In vivo, cardiac-specific deletion of
p65
using a Cre-loxP system causes a ≈50% reduction in NFAT activity in luciferase reporter mice. Moreover, ablation of
p65
in the mouse heart decreases the hypertrophic response after pressure overload stimulation, reduces the degree of pathological remodeling, and preserves contractile function.

Conclusions:

Our results suggest a direct interaction between NFAT and NFκB that effectively integrates 2 disparate signaling pathways in promoting cardiac hypertrophy and ventricular remodeling.
Regulation of Cardiac MicroRNAs by Bone Marrow Mononuclear Cell Therapy in Myocardial Infarction
Authors: Iekushi Kazuma , Seeger Florian , Assmus Birgit , Zeiher Andreas M. , Dimmeler Stefanie
Published: March 2012

Background—

Cell therapy with bone marrow–derived mononuclear cells (BMCs) can improve recovery of cardiac function after ischemia; however, the molecular mechanisms are not yet fully understood. MicroRNAs (miRNAs) are key regulators of gene expression and modulate the pathophysiology of cardiovascular diseases.

Methods and Results—

We demonstrated that intramyocardial delivery of BMCs in infarcted mice regulates the expression of cardiac miRNAs and significantly downregulates the proapoptotic miR-34a. In vitro studies confirmed that the supernatant of BMC inhibited the expression of H
2
O
2
-induced miR-34a and cardiomyocytes apoptosis. These effects were blocked by neutralizing antibodies directed against insulin-like growth factor-1 (IGF-1). Indeed, IGF-1 significantly inhibited H
2
O
2
-induced miR-34a expression, and miR-34a overexpression abolished the antiapoptotic effect of IGF-1. Likewise, inhibition of IGF-1 signaling in vivo abolished the BMC-mediated inhibition of miR-34 expression and the protective effect on cardiac function and increased apoptosis and cardiac fibrosis. IGF-1 specifically blocked the expression of the precursor and the mature miR-34a, but did not interfere with the transcription of the primary miR-34a demonstrating that IGF-1 blocks the processing of miR-34a.

Conclusions—

Together, our data demonstrate that the paracrine regulation of cardiac miRNAs by transplanted BMCs contributes to the protective effects of cell therapy. BMCs release IGF-1, which inhibits the processing of miR-34a, thereby blocking cardiomyocyte apoptosis.