bluuebunny/crossref_metadata_2025 huggingface dataset:
On growth, identities and free subsemigroups for inverse semigroups of deficiency one
Authors: Shneerson L. M.
Published: January 2015

For any positive integer n > 1 we construct an example of inverse semigroup with n generators and n - 1 defining relations which has cubic growth and at least n generators in any presentation. This semigroup has the same set of identities as the free monogenic inverse semigroup. In particular, we give the first example of a one relation nonmonogenic inverse semigroup having polynomial growth. We also prove that for any positive integer n there exists an inverse semigroup ϒnof deficiency 1 and rank n + 1 such that ϒnhas exponential growth and it does not contain nonmonogenic free inverse subsemigroups. Furthermore, ϒnsatisfies the identity [[x, y], [z, t]]2= [[x, y], [z, t]] of quasi-solvability and it contains a free subsemigroup of rank 2.
Factoring Euclidean isometries
Authors: Brady Noel , McCammond Jon
Published: January 2015

Every isometry of a finite-dimensional Euclidean space is a product of reflections and the minimum length of a reflection factorization defines a metric on its full isometry group. In this paper we identify the structure of intervals in this metric space by constructing, for each isometry, an explicit combinatorial model encoding all of its minimum length reflection factorizations. The model is largely independent of the isometry chosen in that it only depends on whether or not some point is fixed and the dimension of the space of directions that points are moved.
Palindromic words in simple groups
Authors: Fink Elisabeth , Thom Andreas
Published: January 2015

A palindrome is a word that reads the same left-to-right as right-to-left. We show that every simple group has a finite generating set X, such that every element of it can be written as a palindrome in the letters of X. Moreover, every simple group has palindromic width pw(G, X) = 1, where X only differs by at most one additional generator from any given generating set. On the contrary, we prove that all non-abelian finite simple groups G also have a generating set S with pw(G, S) > 1. As a by-product of our work we also obtain that every just-infinite group has finite palindromic width with respect to a finite generating set. This provides first examples of groups with finite palindromic width but infinite commutator width.
CARBON ION IRRADIATION EFFECTS ON PULSED LASER DEPOSITED TITANIUM NITRIDE THIN FILMS
Authors: MAHMOOD KHALIQ , BASHIR SHAZIA , AKRAM MAHREEN , HAYAT ASMA , FAIZAN-Ul-HAQ  , SAADAT SHAHZAD
Published: January 2015

Pulse laser deposited thin films of TiN are irradiated by 1 MeV carbon (C+) ions beam for various doses ranging 0.4 to 2.8 × 1014 ions/cm2. Atomic force microscopy (AFM) analysis reveals the formation of hillocks like structures after ion irradiation. X-ray diffraction (XRD) investigations show that the film crystallinity increases for lower doses ranging from 0.4 to 1.2 × 1014 ions/cm2 and decreases for higher doses (2 to 2.8 × 1014 ions/cm2) of ions. No new bands are identified from Raman spectroscopy. However, a noticeable change in microhardness has been observed. The hillock densities as well as hardness are strongly dependent upon ion dose.
Analytical and Experimental Aeroelastic Wing Flutter Analysis and Suppression
Authors: Alsaif Khalid A. , Foda Mosaad A. , Fellouah Hachimi
Published: January 2015

Aeroelastic response and control of airfoil-flap wing exposed to unsteady aerodynamic loads is addressed. The aim is to suppress flutter and to maintain stability of the system. The analytical aerodynamic model is featuring plunging–pitching–flapping coupled motion. Both linear and nonlinear models are developed. Linear quadratic regulator theory is used to design a full state feedback controller in state-space. The control law is implemented through the flap torque to suppress flutter instability and enhance the aeroelastic response. The system response is investigated when it is flying beyond the flutter speed and the control is delayed by a few seconds. The effects of aircraft propeller excitation and the variation of the aspect ratio on the intitiation of flutter are investigated. Numerical simulations are complemented by experimental measurements in a wind tunnel for NACA0012 airfoil.
A REVIEW OF THE EFFECTS OF BODY TEMPERATURE VARIATIONS ON RESPIRATORY MECHANICS: MEASUREMENTS BY THE END-INFLATION OCCLUSION METHOD IN THE RAT
Authors: RUBINI ALESSANDRO , CATENA VINCENZO , MONTE DANIELE DEL , CARNIEL EMANUELE LUIGI
Published: January 2015

The temperature of body fluids is expected to affect tissues mechanical properties, including respiratory system tissues. This is because of the changes in airway smooth muscle tone and contractile properties, influencing airway frictional resistance to airflow, and because of the temperature effects on the stress–strain relationships of elastin and collagen, which determinates the elastic behavior of the lungs as reflected by their pressure–volume relationship. Alveolar surfactant biological and physical properties have also been shown to be affected by temperature changes, suggesting influences on the respiratory system hysteretic properties.

Experimental works describing the effects of body temperature variations on respiratory mechanics are reviewed, including recent findings dealing with investigations on respiratory mechanics carried out by the end-inflation occlusion method in the rat. This method allows to determine, together with the elastance of the respiratory system, its resistive properties too. In particular, both the ohmic airway resistance due to frictional forces in the airway and the additional visco-elastic resistance exerted because of tissues stress-relaxation may be quantified.

The effects of body temperature variations were assessed, and experimentally induced temperature increments and/or decrements allowed to conclude that respiratory system tissues stiffness, both the ohmic and the stress-relaxation linked resistances, and the hysteretic behavior of the respiratory system, decrease with temperature increments. The mechanisms responsible for these effects are analyzed.
Centralizers of a monounary algebra
Authors: Jakubíková-Studenovská Danica , Šuličová Miroslava
Published: January 2015

The centralizer of an algebra is defined as the set of all transformations of the algebra which commute with all fundamental operations. Further, the second centralizer is the set of all transformations which commute with all elements of the (first) centralizer. The paper characterizes the monounary algebras having the property that the first and the second centralizers coincide.
On principally quasi-Baer skew power series rings
Authors: Moussavi A.
Published: January 2015

Let [Formula: see text] be a monomorphism of a ring [Formula: see text] which is not assumed to be surjective. It is shown that, for an [Formula: see text]-weakly rigid [Formula: see text], the skew power series ring [Formula: see text] is right p.q.-Baer if and only if the skew Laurent series ring [Formula: see text] is right p.q.-Baer if and only if [Formula: see text] is right p.q.-Baer and every countable subset of right semicentral idempotents has a generalized countable join.
Properties of Stone almost distributive lattices
Authors: Rao G. C. , Alamneh Mihret
Published: January 2015

In this paper, we study different properties of Stone almost distributive lattice (Stone ADL), prove basic facts on a Stone ADL and derive a necessary and sufficient conditions for an ADL L to be a Stone ADL.
Property (Sw) for bounded linear operators
Authors: Rashid M. H. M. , Prasad T.
Published: January 2015

In this paper, we define new variant of Weyl type theorems property (Sw) and the Browder version of property (Sw). We also obtain the inclusion relation among these new properties.
Human and mouse tissue-engineered small intestine both demonstrate digestive and absorptive function
Authors: Grant Christa N. , Mojica Salvador Garcia , Sala Frederic G. , Hill J. Ryan , Levin Daniel E. , Speer Allison L. , Barthel Erik R. , Shimada Hiroyuki , Zachos Nicholas C. , Grikscheit Tracy C.
Published: January 2015

Short bowel syndrome (SBS) is a devastating condition in which insufficient small intestinal surface area results in malnutrition and dependence on intravenous parenteral nutrition. There is an increasing incidence of SBS, particularly in premature babies and newborns with congenital intestinal anomalies. Tissue-engineered small intestine (TESI) offers a therapeutic alternative to the current standard treatment, intestinal transplantation, and has the potential to solve its biggest challenges, namely donor shortage and life-long immunosuppression. We have previously demonstrated that TESI can be generated from mouse and human small intestine and histologically replicates key components of native intestine. We hypothesized that TESI also recapitulates native small intestine function. Organoid units were generated from mouse or human donor intestine and implanted into genetically identical or immunodeficient host mice. After 4 wk, TESI was harvested and either fixed and paraffin embedded or immediately subjected to assays to illustrate function. We demonstrated that both mouse and human tissue-engineered small intestine grew into an appropriately polarized sphere of intact epithelium facing a lumen, contiguous with supporting mesenchyme, muscle, and stem/progenitor cells. The epithelium demonstrated major ultrastructural components, including tight junctions and microvilli, transporters, and functional brush-border and digestive enzymes. This study demonstrates that tissue-engineered small intestine possesses a well-differentiated epithelium with intact ion transporters/channels, functional brush-border enzymes, and similar ultrastructural components to native tissue, including progenitor cells, whether derived from mouse or human cells.
Distinct afferent innervation patterns within the human proximal and distal esophageal mucosa
Authors: Woodland Philip , Aktar Rubina , Mthunzi Engelbert , Lee Chung , Peiris Madusha , Preston Sean L. , Blackshaw L. Ashley , Sifrim Daniel
Published: January 2015

Little is known about the mucosal phenotype of the proximal human esophagus. There is evidence to suggest that the proximal esophagus is more sensitive to chemical and mechanical stimulation compared with the distal. This may have physiological relevance (e.g., in prevention of aspiration of gastroesophageal refluxate), but also pathological relevance (e.g., in reflux perception or dysphagia). Reasons for this increased sensitivity are unclear but may include impairment in mucosal barrier integrity or changes in sensory innervation. We assessed mucosal barrier integrity and afferent nerve distribution in the proximal and distal esophagus of healthy human volunteers. In 10 healthy volunteers baseline proximal and distal esophageal impedance was measured in vivo. Esophageal mucosal biopsies from the distal and proximal esophagus were taken, and baseline transepithelial electrical resistance (TER) was measured in Ussing chambers. Biopsies were examined immunohistochemically for presence and location of calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers. In a further four healthy volunteers we investigated for colocalization of CGRP and protein gene product (PGP) 9.5 immunoreactivity in nerve fibers. Baseline impedance was higher in the proximal than in the distal esophagus [2,936 Ω (SD578) vs. 2,229 Ω (SD821); P = 0.03], however, baseline TER was not significantly different between them. Mucosal CGRP-immunoreactive nerves were found in the epithelium of both proximal and distal esophagus, but were located more superficially in the proximal mucosa compared with the distal [11.5 (SD7) vs. 21.7 (SD5) cell layers from lumen, P = 0.002] 19% of proximal, and 10% of distal mucosal PGP-immunoreactive fibers colocalized with CGRP. PGP-immunoreactive fibers were also significantly closer to the luminal surface in the proximal compared with the distal esophagus ( P < 0.001). We conclude that mucosal barrier integrity is similar in proximal and distal esophagus, but proximal mucosal afferent nerves are in a more superficial location. The enhanced sensitivity to reflux-evoked symptoms of the proximal esophagus most likely has an anatomical basis.
Transcriptional corepressor MTG16 regulates small intestinal crypt proliferation and crypt regeneration after radiation-induced injury
Authors: Poindexter Shenika V. , Reddy Vishruth K. , Mittal Mukul K. , Williams Amanda M. , Washington M. Kay , Harris Elizabeth , Mah Amanda , Hiebert Scott W. , Singh Kshipra , Chaturvedi Rupesh , Wilson Keith T. , Lund P. Kay , Williams Christopher S.
Published: January 2015

Myeloid translocation genes (MTGs) are transcriptional corepressors implicated in development, malignancy, differentiation, and stem cell function. While MTG16 loss renders mice sensitive to chemical colitis, the role of MTG16 in the small intestine is unknown. Histological examination revealed that Mtg16−/−mice have increased enterocyte proliferation and goblet cell deficiency. After exposure to radiation, Mtg16−/−mice exhibited increased crypt viability and decreased apoptosis compared with wild-type (WT) mice. Flow cytometric and immunofluorescence analysis of intestinal epithelial cells for phospho-histone H2A.X also indicated decreased DNA damage and apoptosis in Mtg16−/−intestines. To determine if Mtg16 deletion affected epithelial cells in a cell-autonomous fashion, intestinal crypts were isolated from Mtg16−/−mice. Mtg16−/−and WT intestinal crypts showed similar enterosphere forming efficiencies when cultured in the presence of EGF, Noggin, and R-spondin. However, when Mtg16−/−crypts were cultured in the presence of Wnt3a, they demonstrated higher enterosphere forming efficiencies and delayed progression to mature enteroids. Mtg16−/−intestinal crypts isolated from irradiated mice exhibited increased survival compared with WT intestinal crypts. Interestingly, Mtg16 expression was reduced in a stem cell-enriched population at the time of crypt regeneration. This is consistent with MTG16 negatively regulating regeneration in vivo. Taken together, our data demonstrate that MTG16 loss promotes radioresistance and impacts intestinal stem cell function, possibly due to shifting cellular response away from DNA damage-induced apoptosis and towards DNA repair after injury.
Giardia duodenalis-induced alterations of commensal bacteria killCaenorhabditis elegans: a new model to study microbial-microbial interactions in the gut
Authors: Gerbaba Teklu K. , Gupta Pratyush , Rioux Kevin , Hansen Dave , Buret Andre G.
Published: January 2015

Giardia duodenalis is the most common cause of parasitic diarrhea worldwide and a well-established risk factor for postinfectious irritable bowel syndrome. We hypothesized that Giardia-induced disruptions in host-microbiota interactions may play a role in the pathogenesis of giardiasis and in postgiardiasis disease. Functional changes induced by Giardia in commensal bacteria and the resulting effects on Caenorhabditis elegans were determined. Although Giardia or bacteria alone did not affect worm viability, combining commensal Escherichia coli bacteria with Giardia became lethal to C. elegans. Giardia also induced killing of C. elegans with attenuated Citrobacter rodentium espF and map mutant strains, human microbiota from a healthy donor, and microbiota from inflamed colonic sites of ulcerative colitis patient. In contrast, combinations of Giardia with microbiota from noninflamed sites of the same patient allowed for worm survival. The synergistic lethal effects of Giardia and E. coli required the presence of live bacteria and were associated with the facilitation of bacterial colonization in the C. elegans intestine. Exposure to C. elegans and/or Giardia altered the expression of 172 genes in E. coli. The genes affected by Giardia included hydrogen sulfide biosynthesis (HSB) genes, and deletion of a positive regulator of HSB genes, cysB, was sufficient to kill C. elegans even in the absence of Giardia. Our findings indicate that Giardia induces functional changes in commensal bacteria, possibly making them opportunistic pathogens, and alters host-microbe homeostatic interactions. This report describes the use of a novel in vivo model to assess the toxicity of human microbiota.
Mixed lactate and caffeine compound increases satellite cell activity and anabolic signals for muscle hypertrophy
Authors: Oishi Yoshimi , Tsukamoto Hayato , Yokokawa Takumi , Hirotsu Keisuke , Shimazu Mariko , Uchida Kenji , Tomi Hironori , Higashida Kazuhiko , Iwanaka Nobumasa , Hashimoto Takeshi
Published: January 2015

We examined whether a mixed lactate and caffeine compound (LC) could effectively elicit proliferation and differentiation of satellite cells or activate anabolic signals in skeletal muscles. We cultured C2C12 cells with either lactate or LC for 6 h. We found that lactate significantly increased myogenin and follistatin protein levels and phosphorylation of P70S6K while decreasing the levels of myostatin relative to the control. LC significantly increased protein levels of Pax7, MyoD, and Ki67 in addition to myogenin, relative to control. LC also significantly increased follistatin expression relative to control and stimulated phosphorylation of mTOR and P70S6K. In an in vivo study, male F344/DuCrlCrlj rats were assigned to control (Sed, n = 10), exercise (Ex, n = 12), and LC supplementation (LCEx, n = 13) groups. LC was orally administered daily. The LCExand Ex groups were exercised on a treadmill, running for 30 min at low intensity every other day for 4 wk. The LCExgroup experienced a significant increase in the mass of the gastrocnemius (GA) and tibialis anterior (TA) relative to both the Sed and Ex groups. Furthermore, the LCExgroup showed a significant increase in the total DNA content of TA compared with the Sed group. The LCExgroup experienced a significant increase in myogenin and follistatin expression of GA relative to the Ex group. These results suggest that administration of LC can effectively increase muscle mass concomitant with elevated numbers of myonuclei, even with low-intensity exercise training, via activated satellite cells and anabolic signals.
No evidence of a role for neuronal nitric oxide synthase in the nucleus tractus solitarius in ventilatory responses to acute or chronic hypoxia in awake rats
Authors: Pamenter Matthew E. , Go Ariel , Fu Zhenxing , Powell Frank L.
Published: January 2015

When exposed to a hypoxic environment, the body's first response is a reflex increase in ventilation, termed the hypoxic ventilatory response (HVR). With chronic sustained hypoxia (CSH), such as during acclimatization to high altitude, an additional time-dependent increase in ventilation occurs, which increases the HVR and is termed ventilatory acclimatization to hypoxia (VAH). This secondary increase persists after exposure to CSH and involves plasticity within the circuits in the central nervous system that control breathing. The mechanisms of HVR plasticity are currently poorly understood. We hypothesized that changes in neuronal nitric oxide synthase (nNOS) activity or expression in the nucleus tractus solitarius contribute to this plasticity and underlie VAH in rats. To test this, we treated rats held in normoxia or 10% O2(CSH, PiO2= 70 Torr) for 7–9 days and measured ventilation in conscious, unrestrained animals before and after microinjecting the general NOS antagonist L-NG-Nitroarginine methyl ester into the nucleus tractus solitarius (NTS) or systemically injecting the nNOS-specific antagonist S-methyl-l-thiocitrulline. Localization of injection sites in the NTS was confirmed by histology following the experiment. We found that 1) neither NTS-specific nor systemic nNOS antagonism had any effect on hypoxia-mediated changes in breathing or metabolism ( P > 0.05), but 2) nNOS protein expression was increased in the middle and caudal NTS by CSH. A persistent HVR after nNOS blockade in the NTS contrasts with results in awake mice, and our findings do not support the hypotheses that nNOS in the NTS contribute to the HVR or VAH in awake rats.
Gene expression changes controlling distinct adaptations in the heart and skeletal muscle of a hibernating mammal
Authors: Vermillion Katie L. , Anderson Kyle J. , Hampton Marshall , Andrews Matthew T.
Published: January 2015

Throughout the hibernation season, the thirteen-lined ground squirrel ( Ictidomys tridecemlineatus) experiences extreme fluctuations in heart rate, metabolism, oxygen consumption, and body temperature, along with prolonged fasting and immobility. These conditions necessitate different functional requirements for the heart, which maintains contractile function throughout hibernation, and the skeletal muscle, which remains largely inactive. The adaptations used to maintain these contractile organs under such variable conditions serves as a natural model to study a variety of medically relevant conditions including heart failure and disuse atrophy. To better understand how two different muscle tissues maintain function throughout the extreme fluctuations of hibernation we performed Illumina HiSeq 2000 sequencing of cDNAs to compare the transcriptome of heart and skeletal muscle across the circannual cycle. This analysis resulted in the identification of 1,076 and 1,466 differentially expressed genes in heart and skeletal muscle, respectively. In both heart and skeletal muscle we identified a distinct cold-tolerant mechanism utilizing peroxisomal metabolism to make use of elevated levels of unsaturated depot fats. The skeletal muscle transcriptome also shows an early increase in oxidative capacity necessary for the altered fuel utilization and increased oxygen demand of shivering. Expression of the fetal gene expression profile is used to maintain cardiac tissue, either through increasing myocyte size or proliferation of resident cardiomyocytes, while skeletal muscle function and mass are protected through transcriptional regulation of pathways involved in protein turnover. This study provides insight into how two functionally distinct muscles maintain function under the extreme conditions of mammalian hibernation.
RAGE Mediates S100A7-Induced Breast Cancer Growth and Metastasis by Modulating the Tumor Microenvironment
Authors: Nasser Mohd W. , Wani Nissar Ahmad , Ahirwar Dinesh K. , Powell Catherine A. , Ravi Janani , Elbaz Mohamad , Zhao Helong , Padilla Laura , Zhang Xiaoli , Shilo Konstantin , Ostrowski Michael , Shapiro Charles , Carson William E. , Ganju Ramesh K.
Published: January 2015

RAGE is a multifunctional receptor implicated in diverse processes including inflammation and cancer. In this study, we report that RAGE expression is upregulated widely in aggressive triple-negative breast cancer (TNBC) cells, both in primary tumors and in lymph node metastases. In evaluating the functional contributions of RAGE in breast cancer, we found that RAGE-deficient mice displayed a reduced propensity for breast tumor growth. In an established model of lung metastasis, systemic blockade by injection of a RAGE neutralizing antibody inhibited metastasis development. Mechanistic investigations revealed that RAGE bound to the proinflammatory ligand S100A7 and mediated its ability to activate ERK, NF-κB, and cell migration. In an S100A7 transgenic mouse model of breast cancer (mS100a7a15 mice), administration of either RAGE neutralizing antibody or soluble RAGE was sufficient to inhibit tumor progression and metastasis. In this model, we found that RAGE/S100A7 conditioned the tumor microenvironment by driving the recruitment of MMP9-positive tumor-associated macrophages. Overall, our results highlight RAGE as a candidate biomarker for TNBCs, and they reveal a functional role for RAGE/S100A7 signaling in linking inflammation to aggressive breast cancer development. Cancer Res; 75(6); 974–85. ©2015 AACR.
Effective Targeting of the P53–MDM2 Axis in Preclinical Models of Infant MLL-Rearranged Acute Lymphoblastic Leukemia
Authors: Richmond Jennifer , Carol Hernan , Evans Kathryn , High Laura , Mendomo Agnes , Robbins Alissa , Meyer Claus , Venn Nicola C. , Marschalek Rolf , Henderson Michelle , Sutton Rosemary , Kurmasheva Raushan T. , Kees Ursula R. , Houghton Peter J. , Smith Malcolm A. , Lock Richard B.
Published: January 2015

Purpose: Although the overall cure rate for pediatric acute lymphoblastic leukemia (ALL) approaches 90%, infants with ALL harboring translocations in the mixed-lineage leukemia (MLL) oncogene (infant MLL-ALL) experience shorter remission duration and lower survival rates (∼50%). Mutations in the p53 tumor-suppressor gene are uncommon in infant MLL-ALL, and drugs that release p53 from inhibitory mechanisms may be beneficial. The purpose of this study was to assess the efficacy of the orally available nutlin, RG7112, against patient-derived MLL-ALL xenografts.

Experimental Design: Eight MLL-ALL patient-derived xenografts were established in immune-deficient mice, and their molecular features compared with B-lineage ALL and T-ALL xenografts. The sensitivity of MLL-ALL xenografts to RG7112 was assessed in vitro and in vivo, and the ability of RG7112 to induce p53, cell-cycle arrest, and apoptosis in vivo was evaluated.

Results: Gene-expression analysis revealed that MLL-ALL, B-lineage ALL, and T-ALL xenografts clustered according to subtype. Moreover, genes previously reported to be overexpressed in MLL-ALL, including MEIS1, CCNA1, and members of the HOXA family, were significantly upregulated in MLL-ALL xenografts, confirming their ability to recapitulate the clinical disease. Exposure of MLL-ALL xenografts to RG7112 in vivo caused p53 upregulation, cell-cycle arrest, and apoptosis. RG7112 as a single agent induced significant regressions in infant MLL-ALL xenografts. Therapeutic enhancement was observed when RG7112 was assessed using combination treatment with an induction-type regimen (vincristine/dexamethasone/L-asparaginase) against an MLL-ALL xenograft.

Conclusions: The utility of targeting the p53–MDM2 axis in combination with established drugs for the management of infant MLL-ALL warrants further investigation. Clin Cancer Res; 21(6); 1395–405. ©2015 AACR.
A Phase I Study of CUDC-101, a Multitarget Inhibitor of HDACs, EGFR, and HER2, in Combination with Chemoradiation in Patients with Head and Neck Squamous Cell Carcinoma
Authors: Galloway Thomas J. , Wirth Lori J. , Colevas Alexander D. , Gilbert Jill , Bauman Julie E. , Saba Nabil F. , Raben David , Mehra Ranee , Ma Anna W. , Atoyan Ruzanna , Wang Jing , Burtness Barbara , Jimeno Antonio
Published: January 2015

Purpose: CUDC-101 is a small molecule that simultaneously inhibits the epidermal growth factor receptor (EGFR), human growth factor receptor 2 (HER2), and histone deacetylase (HDAC) with preclinical activity in head and neck squamous cell cancer (HNSCC). The primary objective of this investigation is to determine the maximum tolerated dose (MTD) of CUDC-101 with cisplatin–radiotherapy in the treatment of HNSCC.

Experimental Design: CUDC-101 monotherapy was administered intravenously three times weekly (Monday, Wednesday, Friday) for a one-week run-in, then continued with concurrent cisplatin (100 mg/m2 every 3 weeks) and external beam radiation (70 Gy to gross disease) over 7 weeks.

Results: Twelve patients with intermediate or high-risk HNSCC enrolled. Eleven were p16INKa (p16)-negative. The MTD of CUDC-101–based combination therapy was established at 275 mg/m2/dose. Five patients discontinued CUDC-101 due to an adverse event (AE); only one was considered a dose-limiting toxicity (DLT), at the MTD. Pharmacokinetic evaluation suggested low accumulation with this dosing regimen. HDAC inhibition was demonstrated by pharmacodynamic analyses in peripheral blood mononuclear cells (PBMC), tumor biopsies, and paired skin biopsies. Paired tumor biopsies demonstrated a trend of EGFR inhibition. At 1.5 years of median follow-up, there has been one recurrence and two patient deaths (neither attributed to CUDC-101). The remaining nine patients are free of progression.

Conclusions: CUDC-101, cisplatin, and radiation were feasible in intermediate-/high-risk patients with HNSCC, with no unexpected patterns of AE. Although the MTD was identified, a high rate of DLT-independent discontinuation of CUDC-101 suggests a need for alternate schedules or routes of administration. Clin Cancer Res; 21(7); 1566–73. ©2015 AACR.
Inhibition of p70S6K1 Activation by Pdcd4 Overcomes the Resistance to an IGF-1R/IR Inhibitor in Colon Carcinoma Cells
Authors: Zhang Yan , Wang Qing , Chen Li , Yang Hsin-Sheng
Published: January 2015

Agents targeting insulin-like growth factor 1 receptor (IGF-1R) are being actively examined in clinical trials. Although there has been some initial success of single-agent targeting IGF-1R, attempts in later studies failed because of resistance. This study aimed to understand the effects of programmed cell death 4 (Pdcd4) on the chemosensitivity of the IGF-1R inhibitor OSI-906 in colorectal cancer cells and the mechanism underlying this impact. Using OSI-906–resistant and –sensitive colorectal cancer cells, we found that the Pdcd4 level directly correlates with cell chemosensitivity to OSI-906. In addition, tumors derived from Pdcd4 knockdown cells resist the growth inhibitory effect of OSI-906 in a colorectal cancer xenograft mouse model. Moreover, Pdcd4 enhances the antiproliferative effect of OSI-906 in resistant cells through suppression of p70S6K1 activation. Knockdown of p70S6K1, but not p70S6K2, significantly increases the chemosensitivity of OSI-906 in cultured colorectal cancer cells. Furthermore, the combination of OSI-906 and PF-4708671, a p70S6K1 inhibitor, efficiently suppresses the growth of OSI-906–resistant colon tumor cells in vitro and in vivo. Taken together, activation of p70S6K1 that is inhibited by Pdcd4 is essential for resistance to the IGF-1R inhibitor in colon tumor cells, and the combinational treatment of OSI-906 and PF-4708671 results in enhanced antiproliferation effects in colorectal cancer cells in vitro and in vivo, providing a novel venue to overcome the resistance to the IGF-1R inhibitor in treating colorectal cancer. Mol Cancer Ther; 14(3); 799–809. ©2015 AACR.
Mutant p53 Amplifies Epidermal Growth Factor Receptor Family Signaling to Promote Mammary Tumorigenesis
Authors: Yallowitz Alisha R. , Li Dun , Lobko Anthony , Mott Daniel , Nemajerova Alice , Marchenko Natalia
Published: January 2015

The EGFR family (ErbB2/Her2 and EGFR/ErbB1/Her1) often modulates the transcriptional program involved in promoting mammary tumorigenesis. In humans, the majority of ErbB2-positive sporadic breast cancers harbor p53 mutations, which correlate with poor prognosis. Also, the extremely high incidence of ErbB2-positive breast cancer in women with p53 germline mutations (Li–Fraumeni syndrome) suggests a key role of mutant p53 specifically in ErbB2-mediated mammary tumorigenesis. To examine the role of mutant p53 during ErbB2-mediated mammary tumorigenesis, a mutant p53 allele (R172H) was introduced into the (MMTV)-ErbB2/Neu mouse model system. Interestingly, we show in heterozygous p53 mice that mutant p53 R172H is a more potent activator of ErbB2-mediated mammary tumorigenesis than simple loss of p53. The more aggressive disease in mutant p53 animals was reflected by earlier tumor onset, increased mammary tumor multiplicity, and shorter survival. These in vivo and in vitro data provide mechanistic evidence that mutant p53 amplifies ErbB2 and EGFR signaling to promote the expansion of mammary stem cells and induce cell proliferation.

Implications: This study identifies mutant p53 as an essential player in ErbB2 and EGFR-mediated mammary tumorigenesis and indicates the potential translational importance of targeting mutant p53 in this subset of patients with breast cancer. Mol Cancer Res; 13(4); 743–54. ©2015 AACR.
Autophagy Supports Breast Cancer Stem Cell Maintenance by Regulating IL6 Secretion
Authors: Maycotte Paola , Jones Kenneth L. , Goodall Megan L. , Thorburn Jacqueline , Thorburn Andrew
Published: January 2015

Autophagy is a mechanism by which cells degrade cellular material to provide nutrients and energy for survival during stress. The autophagy is thought to be a critical process for cancer stem cell (CSC) or tumor-initiating cell maintenance but the mechanisms by which autophagy supports survival of CSCs remain poorly understood. In this study, inhibition of autophagy by knockdown of ATG7 or BECN1 modified the CD44+/CD24low/− population in breast cancer cells by regulating CD24 and IL6 secretion. In a breast cancer cell line that is independent of autophagy for survival, autophagy inhibition increased IL6 secretion to the media. On the other hand, in an autophagy-dependent cell line, autophagy inhibition decreased IL6 secretion, cell survival, and mammosphere formation. In these cells, IL6 treatment or conditioned media from autophagy-competent cells rescued the deficiency in mammosphere formation induced by autophagy inhibition. These results reveal that autophagy regulates breast CSC maintenance in autophagy-dependent breast cancer cells by modulating IL6 secretion implicating autophagy as a potential therapeutic target in breast cancer.

Implications: Modulation of autophagy in breast cancer has different and even opposite effects, indicating the need for a selection strategy when trying to manipulate autophagy in the context of cancer therapy. Mol Cancer Res; 13(4); 651–8. ©2015 AACR.
The Antigenic Repertoire of Premalignant and High-Risk Lesions
Authors: Marquez Juan Pablo , Stanton Sasha E. , Disis Mary L.
Published: January 2015

Prophylactic vaccines have been a major advance in preventing the development of infections after exposure to pathogens. When contemplating an effective approach to cancer prevention, vaccines offer unique advantages over other more standard approaches: First, once appropriately stimulated, antigen-specific T cells will travel to all sites of disease and eradicate cells bearing the proteins to which the T cells have been primed by vaccination. Second, successful immunization will further result in the development of immunologic memory, providing lifelong immunologic surveillance. There is evidence of an adaptive tumor immune infiltrate even at the earliest stages of breast and colon cancer development. Furthermore, there is measurable immunity to lesion-associated antigens present in patients who will eventually develop malignancy even before cancer is clinically evident. Recent studies are beginning to unmask the preinvasive antigenic repertoire for these two malignancies. Preliminary experiments in transgenic mouse models of mammary and intestinal tumors suggest that immunization against antigens expressed in preinvasive and high-risk lesions may be effective in preventing the development of invasive malignancy. Cancer Prev Res; 8(4); 266–70. ©2015 AACR.
JAK–STAT Pathway Activation in Malignant and Nonmalignant Cells Contributes to MPN Pathogenesis and Therapeutic Response
Authors: Kleppe Maria , Kwak Minsuk , Koppikar Priya , Riester Markus , Keller Matthew , Bastian Lennart , Hricik Todd , Bhagwat Neha , McKenney Anna Sophia , Papalexi Efthymia , Abdel-Wahab Omar , Rampal Raajit , Marubayashi Sachie , Chen Jonathan J. , Romanet Vincent , Fridman Jordan S. , Bromberg Jacqueline , Teruya-Feldstein Julie , Murakami Masato , Radimerski Thomas , Michor Franziska , Fan Rong , Levine Ross L.
Published: January 2015

The identification of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) has led to the clinical development of JAK kinase inhibitors, including ruxolitinib. Ruxolitinib reduces splenomegaly and systemic symptoms in myelofibrosis and improves overall survival; however, the mechanism by which JAK inhibitors achieve efficacy has not been delineated. Patients with MPN present with increased levels of circulating proinflammatory cytokines, which are mitigated by JAK inhibitor therapy. We sought to elucidate mechanisms by which JAK inhibitors attenuate cytokine-mediated pathophysiology. Single-cell profiling demonstrated that hematopoietic cells from myelofibrosis models and patient samples aberrantly secrete inflammatory cytokines. Pan-hematopoietic Stat3 deletion reduced disease severity and attenuated cytokine secretion, with similar efficacy as observed with ruxolitinib therapy. In contrast, Stat3 deletion restricted to MPN cells did not reduce disease severity or cytokine production. Consistent with these observations, we found that malignant and nonmalignant cells aberrantly secrete cytokines and JAK inhibition reduces cytokine production from both populations.

Significance: Our results demonstrate that JAK–STAT3-mediated cytokine production from malignant and nonmalignant cells contributes to MPN pathogenesis and that JAK inhibition in both populations is required for therapeutic efficacy. These findings provide novel insight into the mechanisms by which JAK kinase inhibition achieves therapeutic efficacy in MPNs. Cancer Discov; 5(3); 316–31. ©2015 AACR.

See related commentary by Belver and Ferrando, p. 234

This article is highlighted in the In This Issue feature, p. 213
Multiparametric Magnetic Resonance Imaging/Transrectal Ultrasound Fusion Targeted Biopsy of the Prostate: Preliminary Results of a Prospective Single-Centre Study
Authors: Junker Daniel , Schäfer Georg , Heidegger Isabel , Bektic Jasmin , Ladurner Michael , Jaschke Werner , Aigner Friedrich
Published: January 2015

Purpose: To evaluate multiparametric magnetic resonance imaging/transrectal ultrasound (mpMRI/TRUS) fusion targeted biopsy (TB) of the prostate for prostate cancer (PCa) diagnosis. Patients and Methods: From April 2013 to January 2014, 53 men were included in this prospective single-centre study. The degree of PCa suspicion from mpMRI findings was classified according to the PI-RADS scoring system. Of these, 50 patients underwent both an mpMRI/TRUS fusion TB and a 10-core systematic biopsy (SB) of the prostate and were eligible for analysis. Results: 225 targeted and 500 systematic cores were included in this study. PCa was histologically confirmed in 52.0% of patients (26/50), whereas TB revealed PCa in 46.0% (23/50) and SB in 36.0% (18/50). TB identified PCa in 16.0% of all patients (8/50) that were missed by SB. All told, the targeted core was 2.8 times more likely to be PCa-positive than the systematic core (29.3 vs. 10.4%). Conclusions: mpMRI/TRUS fusion TB of the prostate is safe, practicable and may improve PCa diagnosis using fewer biopsy cores compared to SB.
Longitudinal Monitoring of the Serotonin Transporter Gene Expression to Assess Major Depressive Episode Evolution
Authors: Belzeaux Raoul , Loundou Anderson , Azorin Jean-Michel , Naudin Jean , Ibrahim El Chérif
Published: January 2015

Background: Mood disorders are frequently characterized by uncertain prognosis and studying mRNA expression variations in blood cells represents a promising avenue of identifying biomarkers for mood disorders. State-dependent gene expression variations have been described during a major depressive episode (MDE), in particular for SLC6A4 mRNA, but how this transcript varies in relation to MDE evolution remains unclear. In this study, we prospectively assessed time trends of SCL6A4 mRNA expression in responder and nonresponder patients. Methods: We examined SLC6A4 mRNA expression in blood samples from 13 patients treated for severe MDE and their matched controls by reverse transcription and quantitative PCR. All subjects were followed for 30 weeks. Patients were classified as either responders or nonresponders based on improvement of depression according to the 17-item Hamilton Depression Rating Scale. Using a longitudinal design, we ascertained mRNA expression at baseline, 2, 8, and 30 weeks and compared mRNA expression between responder and nonresponder patients, and matched controls. Results: We observed a decrease of SLC6A4 mRNA expression in responder patients across a 30-week follow-up, while nonresponder patients exhibited up-regulated SLC6A4 mRNA. Conclusion: Peripheral SLC6A4 mRNA expression could serve as a biomarker for monitoring and follow-up during an MDE and may help to more appropriately select individualized treatments.
Susceptibility of Enamel to Initial Erosion in Relation to Tooth Type, Tooth Surface and Enamel Depth
Authors: Carvalho Thiago S. , Lussi A.
Published: January 2015

This study aimed at assessing the susceptibility of different tooth types (molar/premolar), surfaces (buccal/lingual) and enamel depths (100, 200, 400 and 600 µm) to initial erosion measured by surface microhardness loss (ΔSMH) and calcium (Ca) release. Twenty molars and 20 premolars were divided into experimental and control groups, cut into lingual/buccal halves, and ground/polished, removing 100 µm of enamel. The initial surface microhardness (SMH₀) was measured on all halves. The experimental group was subjected to 3 consecutive erosive challenges (30 ml/tooth of 1% citric acid, pH 3.6, 25°C, 1 min). After each challenge, ΔSMH and Ca release were measured. The same teeth were consecutively ground to 200, 400 and 600 µm depths, and the experimental group underwent 3 erosive challenges at each depth. No difference was found in SMH₀ between experimental and control groups. Multivariate nonparametric ANOVA showed no significant differences between lingual and buccal surfaces in ΔSMH (p = 0.801) or Ca release (p = 0.370). ΔSMH was significantly greater in premolars than in molars (p < 0.05), but not different with respect to enamel depth. Ca release decreased significantly with increasing depth. Regression between Ca release and ΔSMH at 100 µm depth showed lower slope and r2 value, associated with greater Ca release values. At 200-600 µm depths, moderately large r2 values were observed (0.651-0.830). In conclusion, different teeth and enamel depths have different susceptibility to erosion, so when Ca release is used to measure erosion, the depth of the test facet in enamel should be standardized, whereas this is less important if ΔSMH is used.
Impact of Prophylactic Mastectomy in BRCA1/2 Mutation Carriers
Authors: Rhiem Kerstin , Schmutzler Rita
Published: January 2015

Unlike the general decrease in invasive oncologic care, the trend for prophylactic bilateral mastectomy in healthy women and prophylactic contralateral mastectomy in women with unilateral breast cancer is steadily rising. This is even more surprising when considering that for e.g. prophylactic contralateral mastectomy no clear survival benefit has been demonstrated so far. The decision-making process around risk-reducing surgery may be influenced by several conflicting parameters such as the patient's fears and desire to achieve a survival advantage, the surgeon's financial motivations, or the oncologist's paternalistic approach to the above trend. Physicians should support their patients throughout the decision-making process, guide them through the dense fog of information, and encourage them to reconsider all options and alternatives before embarking on an irreversible surgical intervention. Healthy and diseased women should be comprehensively informed about their absolute individual risks for cancer, the benefits and harms of the surgery, alternative preventive strategies, and last but not least the competing risks of preceding carcinomas and cancer in general. Within the framework of non-directive counseling in the specialized centers of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), decision-making aids are being developed with grants from the Federal Ministry of Health and the German Cancer Aid to support women in making conclusive and satisfactory decisions.
Morning Serum Basal Cortisol Levels Are Affected by Age and Pubertal Maturation in School-Aged Children and Adolescents
Authors: Barra Cristina Botelho , Silva Ivani Novato , Rodrigues Tânia Maria Barreto , Santos Jovita Lane Soares , Colosimo Enrico Antônio
Published: January 2015

Background: The same reference values for cortisol have been used for adults and children, but laboratory results obtained from an adult population might not be suitable for pediatric patients. Aims: To determine morning serum basal cortisol levels in children and adolescents. Methods: The study was conducted on 120 suitable reference individuals, healthy Brazilian children and adolescents from both genders aged 4-19 years old. The method used for cortisol assessment was the chemiluminescent enzyme immunoassay (VITROS® 5600 MicroWell; Johnson & Johnson, High Wycombe, UK, 2009), and the kit reference interval was 4.46-22.7 μg/dl (122.7-626.2 nmol/l). The setting limits were calculated according to the Clinical Laboratory Standards Institute guidelines. Results: The morning serum basal cortisol levels increased with age and pubertal maturation, but there were no differences based on gender. The cortisol reference values were established based on the 2.5th and 97.5th percentiles as 2.97 μg/dl [81.9 nmol/l, 90% confidence interval (CI) 1.44-3.69 μg/dl] and 23.4 μg/dl (645.5 nmol/l; 90% CI 16.3-26.4 μg/dl), respectively. Conclusions: The assessment of the morning serum basal cortisol levels showed a unique pattern, with a different lower limit for the cohort compared to current values established for adult subjects.
Foetal Thyroid Dysfunction: Treat the Mother First!
Authors: Khater Carine , Ceccaldi Pierre François , Poujade Olivier , Banigé Maïa , Ottenwalter Annick , Luton Dominique
Published: January 2015

A case is presented of foetal compensated hypothyroidism due to persisting low maternal serum FT4 at the beginning of pregnancy. Diagnosis was made by means of foetal ultrasound followed by foetal blood sampling because of atypical findings. Foetal thyroid hypertrophy resolved progressively as exogenous thyroxine was administered to the mother. This case highlights once again the importance of adequate thyroid function during pregnancy.
Transarterial Onyx Embolization of an Orbital Solitary Fibrous Tumor
Authors: Hashemi Nafiseh , Ling Jeanie D. , Soparkar Charles , Sami Mirwat , Ellezam Benjamin , Klucznik Richard , Lee Andrew G. , Chévez-Barrios Patricia
Published: January 2015

Solitary fibrous tumor (SFT) is an uncommon mesenchymal neoplasm sometimes found in the orbit. We report a case of an aggressive orbital SFT with enlarged feeding vessels that was successfully resected immediately after transarterial embolization with Onyx (ethylene vinyl alcohol copolymer). To our knowledge, this is the first report showing the histopathology of Onyx embolization material in an orbital SFT.