bluuebunny/crossref_metadata_2025 huggingface dataset:
A Conserved Suppressor Mutation in a Tryptophan Auxotroph Results in Dysregulation of Pseudomonas Quinolone Signal Synthesis
Authors: Knoten Claire A. , Wells Greg , Coleman James P. , Pesci Everett C.
Published: April 2014

Pseudomonas aeruginosa
is a common nosocomial pathogen that relies on three cell-to-cell signals to regulate multiple virulence factors. The
Pseudomonas
quinolone signal (PQS; 2-heptyl-3-hydroxy-4-quinolone) is one of these signals, and it is known to be important for
P. aeruginosa
pathogenesis. PQS is synthesized in a multistep reaction that condenses anthranilate and a fatty acid. In
P. aeruginosa
, anthranilate is produced via the kynurenine pathway and two separate anthranilate synthases, TrpEG and PhnAB, the latter of which is important for PQS synthesis. Others have previously shown that a
P. aeruginosa
tryptophan auxotroph could grow on tryptophan-depleted medium with a frequency of 10
−5
to 10
−6
. These revertants produced more pyocyanin and had increased levels of
phnA
transcript. In this study, we constructed similar tryptophan auxotroph revertants and found that the reversion resulted from a synonymous G-to-A nucleotide mutation within
pqsC
. This change resulted in increased pyocyanin and decreased PQS, along with an increase in the level of the
pqsD
,
pqsE
, and
phnAB
transcripts. Reporter fusion and reverse transcriptase PCR studies indicated that a novel transcript containing
pqsD
,
pqsE
, and
phnAB
occurs in these revertants, and quantitative real-time PCR experiments suggested that the same transcript appears in the wild-type strain under nutrient-limiting conditions. These results imply that the PQS biosynthetic operon can produce an internal transcript that increases anthranilate production and greatly elevates the expression of the PQS signal response protein PqsE. This suggests a novel mechanism to ensure the production of both anthranilate and PQS-controlled virulence factors.
Tenosynovitis of the peroneal tendons associated with a hypertrophic peroneal tubercle: radiography and MRI findings
Authors: Celikyay Fatih , Yuksekkaya Ruken , Almus Ferdag , Bilgic Erkal
Published: April 2014

An enlarged peroneal tubercle can cause a peroneal tendon tear and/or tenosynovitis due to chronic friction. We present the case of a 45-year-old man with tenosynovitis in the peroneus longus and brevis tendons associated with a hypertrophic peroneal tubercle. On admission to our facility, the patient presented with pain while walking and had a fixed mass on the lateral aspect of his right foot. In addition, an osseous prominence corresponding to a hypertrophic peroneal tubercle was seen on the lateral side of the right calcaneus on radiography. MRI confirmed the hypertrophic peroneal tubercle and revealed high-signal intensity within the peroneus longus and brevis tendons along with fluid in their sheaths.
Scalp fibroma: a rare cutaneous manifestation of tuberous sclerosis
Authors: Sharma Bhawna , Prakash Swayam , Sannegowda Raghavendra Bakki , Panagariya Ashok
Published: April 2014

We report a case of a 23-year-old woman with a history of generalised tonic–clonic seizures, reddish brown maculopapular swelling over the face and an enlarging swelling over the scalp. Physical examinations revealed angiofibroma of the face and other typical cutaneous lesions of tuberous sclerosis, for example, shagreen patch and periungual fibroma. Scalp swelling was labelled as fibroma by dermatologists, which was further supported by the histopathological findings. Fibroma of the face is one of the commonest lesions, however, fibroma of the scalp is a rarely described entity.
The great masquerader: Behçet's disease
Authors: Nordstrom Edra , Fischer Monika
Published: April 2014

This report describes the case of a 44-year-old Caucasian woman of Northern European descent with a medical history of pyoderma gangrenosum, chronic abdominal pain and erythema nodosum which required intermittent use of high-dose steroids that failed to improve her symptoms. The patient was initially diagnosed with Crohn's disease and most recently with sclerosing mesenteritis. She presented to the hospital with worsening abdominal pain. She was found to have recurrent painful aphthous oral, genital and perianal ulcers and a clinical diagnosis of Behçet's disease was made. Her hospitalisation was complicated by haemoptysis, and bronchoscopy revealed alveolar haemorrhage. Treatment was initiated with three days of pulse intravenous solumedrol 1 g/day and cyclophosphamide at 700 mg/m2. The case had a favourable outcome despite the initial diagnostic challenges. This report emphasises that systemic diseases, including Behçet's disease, can have variable presentations and can be frequently misdiagnosed.
An unusual presentation of miliary tuberculosis
Authors: Sundaralingam A , Potter J L , White V L C , Emmanuel J
Published: April 2014

A young Bangladeshi woman presented to the emergency department with vaginal discharge on a history of fevers and rigours. Although initially treated for pelvic inflammatory disease, the patient rapidly developed respiratory failure with acute respiratory distress syndrome. An axillary biopsy and a high-resolution CT of the chest confirmed miliary tuberculosis (TB). She was initiated on anti-TB medication and made a rapid recovery.
A case of recurrent gallstone ileus: the fate of the residual gallstone remains unknown
Authors: Aslam Jamil , Patel Prashant , Odogwu Steve
Published: April 2014

Gallstone ileus is a serious complication of cholelithiasis where mechanical small bowel obstruction occurs. The recurrence of gallstone ileus is rare. The 67-year-old woman in this case report had three known gallstones transit her small bowel with two causing obstruction and the third causing a ‘tumbling phenomenon’. As we have an ageing population, and gallstone ileus has a higher incidence in the over 65 age group, associated with increased comorbidities and hence greater mortality rates, it is imperative to establish the best surgical intervention for it. This case report highlights the difference CT of the abdomen has made to the diagnosis of gallstone ileus and the pros and cons of the surgical management options.
Severe depression masquerading as Creutzfeldt-Jakob disease
Authors: Shiner Elizabeth , Taylor Lauren , Mohan Adith , Watson Shaun , Sachdev Perminder Singh
Published: April 2014

We report a case of melancholic depression with catatonic features presenting as a rapidly progressive organic brain syndrome, initially thought to be probable Creutzfeldt-Jakob disease. The case highlights the fundamental importance of thorough exclusion of treatable pathology masquerading as an irreversible syndrome.
Breast cancer, DPYD mutations and capecitabine-related ileitis: description of two cases and a review of the literature
Authors: Mokrim Maha , Aftimos Philippe G , Errihani Hassan , Piccart-Gebhart Martine
Published: April 2014

Despite many treatment advances, metastatic breast cancer remains an incurable disease and is the third leading cause of cancer-related deaths in Europe. Capecitabine has become a standard treatment option for metastatic breast cancer, as a single agent or in combination. Hand–foot syndrome and diarrhoea are the most frequently reported side effects, while capecitabine-related ileitis is very rare. Deficiency of dihydropyrimidine dehydrogenase activity leads to severe toxicities after administration of 5-fluorouracil or its prodrugs. We report two cases of patients with metastatic breast cancer who developed ileitis after treatment with capecitabine. One patient had a DPYD gene abnormality.
Hyperbilirubinaemia and haemolytic anaemia in acute alcoholic hepatitis: there's oil in them thar veins
Authors: Hashmi Salman , Allison Michael G , McCurdy Michael T , Reed Robert M
Published: April 2014

A Caucasian woman in her late 30s was evaluated after a period of binge drinking and found to have hyperbilirubinaemia for which she was referred for consideration of cholecystectomy. After exclusion of other possibilities, Zieve's syndrome was diagnosed. This is a condition of hyperbilirubinaemia, Coombs’ negative haemolytic anaemia and hyperlipidaemia associated with alcoholism. Abstinence from alcohol remains the only known effective treatment, and appreciation of the entity can prevent unnecessary biliary procedures. The patient improved with supportive measures and was discharged in stable condition.
Cell biology of bordered-pit formation in balsam-fir trees
Authors: Savidge Rodney Arthur
Published: April 2014

A mature bordered pit in secondary xylem of Pinaceae comprises a circular border of secondary-wall material that protrudes into the tracheid lumen and is punctuated by a centralized aperture through which sap flows. The overarching border encloses a pit chamber within which is a “membrane”, or diaphragm, consisting of a central torus and margo strands. Bordered-pit pairs are abundantly present in all woods, and their membranes serve as swinging-diaphragm check valves regulating sap flow between adjoining tracheary elements, simultaneously trapping emboli and particulates in water as it moves from roots to leaves. The cell biology of bordered-pit formation in cambial derivatives of Abies balsamea (L.) Mill. was investigated by light and scanning electron microscopy during early stages of cellular differentiation of cambial derivatives into secondary xylem tracheids. A bordered-pit template (BPT), a bordered-pit organelle (BPO), a bordered-pit basal disk, and additional novel structures were found to be associated with bordered-pit formation. Evidence was found that the membrane does not comprise residual compound middle lamella; rather, the membrane forms de novo as BPO remnants. A cell-biology model and new terminology are introduced to explain how BPTs, BPOs, and basal disks contribute to successive stages in formation of bordered-pit pairs.
Exercise and vascular function: how much is too much?
Authors: Durand Matthew J. , Gutterman David D.
Published: April 2014

Exercise is a powerful therapy for preventing the onset of and slowing the progression of cardiovascular disease. Increased shear stress during exercise improves vascular homeostasis by both decreasing reactive oxygen species and increasing nitric oxide bioavailability in the endothelium. While these observations are well accepted as they apply to individuals at risk for cardiovascular disease, less is known about how exercise, especially intense exercise, affects vascular function in healthy individuals. This review highlights examples of how vascular function can paradoxically be impaired in otherwise healthy individuals by extreme levels of exercise, with a focus on the causative role that reactive oxygen species play in this impairment.
Sex-specific differences in the physiological basis of water conservation in the fruit flyDrosophila hydeifrom the western Himalayas
Authors: Parkash Ravi , Singh Divya , Lambhod Chanderkala
Published: April 2014

In the cosmopolitan fruit fly Drosophila hydei Sturtevant, 1921 (Diptera: Drosophilidae), the relative abundance of males is significantly higher than females, but the physiological basis of such sex-specific differences are largely unknown. For wild populations of D. hydei, we found seasonal changes (summer versus autumn) in desiccation-related traits, but the desiccation tolerance of males was higher than that of females in all seasons. For desiccation-related traits, we tested whether thermal developmental acclimation at three temperatures (17, 21, and 28 °C) matched seasonal changes observed under wild conditions. Male flies showed significantly higher trait values for desiccation resistance, cuticular lipid mass, hemolymph content, carbohydrate content, and dehydration tolerance compared with females when reared at lower or higher temperatures despite the lack of significant sex-specific differences in the total body-water content of flies reared at a particular growth temperature. We observed plastic changes in the amount of cuticular lipids consistent with corresponding differences in the rate of water loss. Treatment of cuticular surface with organic solvent (hexane) supported the role of cuticular lipids in affecting transcuticular water loss. We found significant thermal plastic effects for desiccation-related traits of D. hydei, but the sexual dimorphism was in the opposite direction, i.e., males were more desiccation resistant than females in D. hydei, whereas the reverse is true for many other Drosophila species. Our results suggest that sex-specific differences in the level of desiccation resistance in D. hydei are good predictors of relative abundance levels of male and female flies under wild conditions.
Reduction of Na/K-ATPase affects cardiac remodeling and increases c-kit cell abundance in partial nephrectomized mice
Authors: Drummond Christopher A. , Sayed Moustafa , Evans Kaleigh L. , Shi Huilin , Wang Xiaoliang , Haller Steven T. , Liu Jiang , Cooper Christopher J. , Xie Zijian , Shapiro Joseph I. , Tian Jiang
Published: April 2014

The current study examined the role of Na/K-ATPase α1-subunit in animals subjected to 5/6th partial nephrectomy (PNx) using Na/K-ATPase α1-heterozygous (α1+/−) mice and their wild-type (WT) littermates. After PNx, both WT and α1+/−animals displayed diastolic dimension increases, increased blood pressure, and increased cardiac hypertrophy. However, in the α1+/−animals we detected significant increases in cardiac cell death in PNx animals. Given that reduction of α1elicited increased cardiac cell death with PNx, while at the same time these animals developed cardiac hypertrophy, an examination of cardiac cell number, and proliferative capabilities of those cells was carried out. Cardiac tissues were probed for the progenitor cell marker c-kit and the proliferation marker ki-67. The results revealed that α1+/−mice had significantly higher numbers of c-kit-positive and ki-67-positive cells, especially in the PNx group. We also found that α1+/−mice express higher levels of stem cell factor, a c-kit ligand, in their heart tissue and had higher circulating levels of stem cell factor than WT animals. In addition, PNx induced significant enlargement of cardiac myocytes in WT mice but has much less effect in α1+/−mice. However, the total cell number determined by nuclear counting is higher in α1+/−mice with PNx compared with WT mice. We conclude that PNx induces hypertrophic growth and high blood pressure regardless of Na/K-ATPase content change. However, total cardiac cell number as well as c-kit-positive cell number is increased in α1+/−mice with PNx.
Mechano-electrical coupling as framework for understanding functional remodeling during LBBB and CRT
Authors: Kuijpers Nico H. L. , Hermeling Evelien , Lumens Joost , ten Eikelder Huub M. M. , Delhaas Tammo , Prinzen Frits W.
Published: April 2014

It is not understood why, after onset of left bundle-branch block (LBBB), acute worsening of cardiac function is followed by a further gradual deterioration of function, whereas most adverse cardiac events lead to compensatory adaptations. We investigated whether mechano-electrical coupling (MEC) can explain long-term remodeling with LBBB and cardiac resynchronization therapy (CRT). To this purpose, we used an integrative modeling approach relating local ventricular electrophysiology, calcium handling, and excitation-contraction coupling to global cardiovascular mechanics and hemodynamics. Each ventricular wall was composed of multiple mechanically and electrically coupled myocardial segments. MEC was incorporated by allowing adaptation of L-type Ca2+ current aiming at minimal dispersion of local external work, an approach that we previously applied to replicate T-wave memory in a synchronous heart after a period of asynchronous activation. LBBB instantaneously decreased left-ventricular stroke work and increased end-diastolic volume. During sustained LBBB, MEC reduced intraventricular dispersion of mechanical workload and repolarization. However, MEC-induced reduction in contractility in late-activated regions was larger than the contractility increase in early-activated regions, resulting in further decrease of stroke work and increase of end-diastolic volume. Upon the start of CRT, stroke work increased despite a wider dispersion of mechanical workload. During sustained CRT, MEC-induced reduction in dispersion of workload and repolarization coincided with a further reduction in end-diastolic volume. In conclusion, MEC may represent a useful framework for better understanding the long-term changes in cardiac electrophysiology and contraction following LBBB as well as CRT.
The presence of the NOS3 gene polymorphism for intron 4 mitigates the beneficial effects of exercise training on ambulatory blood pressure monitoring in adults
Authors: Sponton Carlos H. , Esposti Rodrigo , Rodovalho Cynara M. , Ferreira Maycon J. , Jarrete Aline P. , Anaruma Chadi P. , Bacci Mauricio , Zanesco Angelina
Published: April 2014

The number of studies that have evaluated exercise training (ET) and nitric oxide synthase (NOS)3 gene polymorphisms is scarce. The present study was designed to evaluate the relationship between exercise training and NOS3 polymorphisms at −786T>C, 894G>T, and intron 4b/a on blood pressure (BP) using 24-h ambulatory BP monitoring (ABPM), nitrate/nitrite levels (NO x), and redox state. Eighty-six volunteers (51 ± 0.6 yr old) were genotyped into nonpolymorphic and polymorphic groups for each of the three positions of NOS3 polymorphisms. Auscultatory BP, ABPM, SOD activity, catalase activity, NO x levels, and malondialdehyde levels were measured. DNA was extracted from leukocytes, and PCR followed by sequencing was applied for genotype analysis. Aerobic ET consisted of 24 sessions for 3 days/wk for 40 min at moderate intensity. This study was performed in a double-blind and crossover format. ET was effective in lowering office BP (systolic BP: 3.2% and diastolic BP: 3%) as well as ABPM (systolic BP: 2% and diastolic BP: 1.3%). Increased SOD and catalase activity (42.6% and 15.1%, respectively) were also observed. The NOS3 polymorphism for intron 4 mitigated the beneficial effect of ET for systolic BP (nonpolymorphic group: −3.0% and polymorphic group: −0.6%) and diastolic BP (nonpolymorphic group: −3.2% and polymorphic group: −0.5%), but it was not associated with NO x level and redox state. Paradoxical responses were found for positions T786-C and G894T for the NOS3 gene. Consistently, the presence of the polymorphism for intron 4 blunted the beneficial effects of ET in middle-aged adults. Possibly, this effect might be as consequence of intron 4 acting as a short intronic repeat RNA controlling endothelial NOS activity epigenetically.
A-769662 potentiates the effect of other AMP-activated protein kinase activators on cardiac glucose uptake
Authors: Timmermans Aurélie D. , Balteau Magali , Gélinas Roselle , Renguet Edith , Ginion Audrey , de Meester Carole , Sakamoto Kei , Balligand Jean-Luc , Bontemps Françoise , Vanoverschelde Jean-Louis , Horman Sandrine , Beauloye Christophe , Bertrand Luc
Published: April 2014

AMP-activated protein kinase (AMPK), a key cellular sensor of energy, regulates metabolic homeostasis and plays a protective role in the ischemic or diabetic heart. Stimulation of cardiac glucose uptake contributes to this AMPK-mediated protection. The small-molecule AMPK activator A-769662, which binds and directly activates AMPK, has recently been characterized. A-769662-dependent AMPK activation protects the heart against an ischemia-reperfusion episode but is unable to stimulate skeletal muscle glucose uptake. Here, we tried to reconcile these conflicting findings by investigating the impact of A-769662 on cardiac AMPK signaling and glucose uptake. We showed that A-769662 promoted AMPK activation, resulting in the phosphorylation of several downstream targets, but was incapable of stimulating glucose uptake in cultured cardiomyocytes and the perfused heart. The lack of glucose uptake stimulation can be explained by A-769662's narrow specificity, since it selectively activates cardiac AMPK heterotrimeric complexes containing α2/β1-subunits, the others being presumably required for this metabolic outcome. However, when combined with classical AMPK activators, such as metformin, phenformin, oligomycin, or hypoxia, which impact AMPK heterotrimers more broadly via elevation of cellular AMP levels, A-769662 induced more profound AMPK phosphorylation and subsequent glucose uptake stimulation. The synergistic effect of A-769662 under such ischemia-mimetic conditions protected cardiomyocytes against ROS production and cell death. In conclusion, despite the fact that A-769662 activates AMPK, it alone does not significantly stimulate glucose uptake. However, strikingly, its ability of potentiating the action on other AMPK activators makes it a potentially useful participant in the protective role of AMPK in the heart.
Sustained hyperoxia-induced NF-κB activation improves survival and preserves lung development in neonatal mice
Authors: McKenna Sarah , Michaelis Katherine A. , Agboke Fadeke , Liu Thanh , Han Kristie , Yang Guang , Dennery Phyllis A. , Wright Clyde J.
Published: April 2014

Oxygen toxicity contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). Neonatal mice exposed to hyperoxia develop a simplified lung structure that resembles BPD. Sustained activation of the transcription factor NF-κB and increased expression of protective target genes attenuate hyperoxia-induced mortality in adults. However, the effect of enhancing hyperoxia-induced NF-κB activity on lung injury and development in neonatal animals is unknown. We performed this study to determine whether sustained NF-κB activation, mediated through IκBβ overexpression, preserves lung development in neonatal animals exposed to hyperoxia. Newborn wild-type (WT) and IκBβ-overexpressing (AKBI) mice were exposed to hyperoxia (>95%) or room air from day of life (DOL) 0–14, after which all animals were kept in room air. Survival curves were generated through DOL 14. Lung development was assessed using radial alveolar count (RAC) and mean linear intercept (MLI) at DOL 3 and 28 and pulmonary vessel density at DOL 28. Lung tissue was collected, and NF-κB activity was assessed using Western blot for IκB degradation and NF-κB nuclear translocation. WT mice demonstrated 80% mortality through 14 days of exposure. In contrast, AKBI mice demonstrated 60% survival. Decreased RAC, increased MLI, and pulmonary vessel density caused by hyperoxia in WT mice were significantly attenuated in AKBI mice. These findings were associated with early and sustained NF-κB activation and expression of cytoprotective target genes, including vascular endothelial growth factor receptor 2. We conclude that sustained hyperoxia-induced NF-κB activation improves neonatal survival and preserves lung development. Potentiating early NF-κB activity after hyperoxic exposure may represent a therapeutic intervention to prevent BPD.
Lung fibroblasts accelerate wound closure in human alveolar epithelial cells through hepatocyte growth factor/c-Met signaling
Authors: Ito Yoko , Correll Kelly , Schiel John A. , Finigan Jay H. , Prekeris Rytis , Mason Robert J.
Published: April 2014

There are 190,600 cases of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) each year in the United States, and the incidence and mortality of ALI/ARDS increase dramatically with age. Patients with ALI/ARDS have alveolar epithelial injury, which may be worsened by high-pressure mechanical ventilation. Alveolar type II (ATII) cells are the progenitor cells for the alveolar epithelium and are required to reestablish the alveolar epithelium during the recovery process from ALI/ARDS. Lung fibroblasts (FBs) migrate and proliferate early after lung injury and likely are an important source of growth factors for epithelial repair. However, how lung FBs affect epithelial wound healing in the human adult lung has not been investigated in detail. Hepatocyte growth factor (HGF) is known to be released mainly from FBs and to stimulate both migration and proliferation of primary rat ATII cells. HGF is also increased in lung tissue, bronchoalveolar lavage fluid, and serum in patients with ALI/ARDS. Therefore, we hypothesized that HGF secreted by FBs would enhance wound closure in alveolar epithelial cells (AECs). Wound closure was measured using a scratch wound-healing assay in primary human AEC monolayers and in a coculture system with FBs. We found that wound closure was accelerated by FBs mainly through HGF/c-Met signaling. HGF also restored impaired wound healing in AECs from the elderly subjects and after exposure to cyclic stretch. We conclude that HGF is the critical factor released from FBs to close wounds in human AEC monolayers and suggest that HGF is a potential strategy for hastening alveolar repair in patients with ALI/ARDS.
Inhibiting Tankyrases Sensitizes KRAS-Mutant Cancer Cells to MEK Inhibitors via FGFR2 Feedback Signaling
Authors: Schoumacher Marie , Hurov Kristen E. , Lehár Joseph , Yan-Neale Yan , Mishina Yuji , Sonkin Dmitriy , Korn Joshua M. , Flemming Daisy , Jones Michael D. , Antonakos Brandon , Cooke Vesselina G. , Steiger Janine , Ledell Jebediah , Stump Mark D. , Sellers William R. , Danial Nika N. , Shao Wenlin
Published: April 2014

Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis, and mitosis, offering attractive targets for anticancer treatment. Using unbiased combination screening in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors (MEKi) in KRAS-mutant cancer cells. Our study uncovers a novel function of TNKS in the relief of a feedback loop induced by MEK inhibition on FGFR2 signaling pathway. Moreover, dual inhibition of TNKS and MEK leads to more robust apoptosis and antitumor activity both in vitro and in vivo than effects observed by previously reported MEKi combinations. Altogether, our results show how a novel combination of TNKS and MEK inhibitors can be highly effective in targeting KRAS-mutant cancers by suppressing a newly discovered resistance mechanism. Cancer Res; 74(12); 3294–305. ©2014 AACR.
Enhancement of the T-cell Armamentarium as a Cell-Based Therapy for Prostate Cancer
Authors: Brennen W. Nathaniel , Drake Charles G. , Isaacs John T.
Published: April 2014

Prostate cancer is frequently characterized by a large inflammatory infiltrate that includes T cells. Although T cells traffic to cancer lesions in large numbers, they are unable to generate a therapeutic response because of the immunosuppressive microenvironment. Therefore, arming T cells with a cytotoxic agent that is capable of killing cancer cells independent of these immunosuppressive signals is a rational approach to enhance their potency. Essentially, the T cells would serve as a cell-based vector, or “Trojan Horse,” to selectively deliver a protoxin to disseminated prostate cancer lesions. The selective delivery of a protoxin using T cells represents an ideal method to maximize their therapeutic potency through a “field effect.” Because systemically infused T cells are expected to traffic to sites of inflammation other than cancer, an additional level of specificity may be needed to prevent toxicity to nontarget tissues. Toward this goal, genetic engineering can be used to make protoxin expression dependent upon T-cell recognition of the prostate-specific membrane antigen by a chimeric antigen receptor. Furthermore, selective activation of the protoxin using a tissue- or tumor-specific protease, such as PSA, can promote further specificity. Thus, T-cell potency can be enhanced by targeted protoxin secretion and greater specificity achieved using combinatorial antigen recognition and protoxin activation. Cancer Res; 74(13); 3390–5. ©2014 AACR.
Chronic Inflammation in Benign Prostate Tissue Is Associated with High-Grade Prostate Cancer in the Placebo Arm of the Prostate Cancer Prevention Trial
Authors: Gurel Bora , Lucia M. Scott , Thompson Ian M. , Goodman Phyllis J. , Tangen Catherine M. , Kristal Alan R. , Parnes Howard L. , Hoque Ashraful , Lippman Scott M. , Sutcliffe Siobhan , Peskoe Sarah B. , Drake Charles G. , Nelson William G. , De Marzo Angelo M. , Platz Elizabeth A.
Published: April 2014

Background: Chronic inflammation is hypothesized to influence prostate cancer development, although a definitive link has not been established.

Methods: Prostate cancer cases (N = 191) detected on a for-cause (clinically indicated) or end-of-study (protocol directed) biopsy, and frequency-matched controls (N = 209), defined as negative for cancer on an end-of-study biopsy, were sampled from the placebo arm of the Prostate Cancer Prevention Trial. Inflammation prevalence and extent in benign areas of biopsy cores were visually assessed using digital images of hematoxylin and eosin–stained sections. Logistic regression was used to estimate associations.

Results: Of note, 86.2% of cases and 78.2% of controls had at least one biopsy core (of three assessed) with inflammation in benign areas, most of which was chronic. Men who had at least one biopsy core with inflammation had 1.78 [95% confidence interval (CI), 1.04–3.06] times the odds of prostate cancer compared with men who had zero cores with inflammation. The association was stronger for high-grade disease (Gleason sum 7–10, N = 94; OR, 2.24; 95% CI, 1.06–4.71). These patterns were present when restricting to cases and controls in whom intraprostatic inflammation was the least likely to have influenced biopsy recommendation because their prostate-specific antigen (PSA) was low (<2 ng/mL at biopsy).

Conclusion: Inflammation, most of which was chronic, was common in benign prostate tissue, and was positively associated with prostate cancer, especially high grade. The association did not seem to be due to detection bias.

Impact: This study supports an etiologic link between inflammation and prostate carcinogenesis, and suggests an avenue for prevention by mitigating intraprostatic inflammation. Cancer Epidemiol Biomarkers Prev; 23(5); 847–56. ©2014 AACR.
Accelerated Approval for Pertuzumab in the Neoadjuvant Setting: Winds of Change?
Authors: Esserman Laura J. , DeMichele Angela
Published: April 2014

Accelerated approval for agents that improve the frequency of complete pathologic response in the primary breast cancer setting heralds a broadening of the opportunities to get effective agents to the market more quickly. However, these new pathways will require identifying the signature or subtype for which the agent is most effective, and evidence of enrollment of patients to a trial that enables the ascertainment of event-free survival. The recent approval of pertuzumab for use in the neoadjuvant setting is evidence that the FDA is committed to supporting the accelerated approval pathway. The situations in which approval is likely to be granted are discussed. Clin Cancer Res; 20(14); 3632–6. ©2014 AACR.
Centmitor-1, a Novel Acridinyl-Acetohydrazide, Possesses Similar Molecular Interaction Field and Antimitotic Cellular Phenotype as Rigosertib, ON 01910.Na
Authors: Mäki-Jouppila Jenni H.E. , Laine Leena J. , Rehnberg Jonathan , Narvi Elli , Tiikkainen Pekka , Hukasova Elvira , Halonen Pasi , Lindqvist Arne , Kallio Lila , Poso Antti , Kallio Marko J.
Published: April 2014

Mitosis is an attractive target for the development of new anticancer drugs. In a search for novel mitotic inhibitors, we virtually screened for low molecular weight compounds that would possess similar steric and electrostatic features, but different chemical structure than rigosertib (ON 01910.Na), a putative inhibitor of phosphoinositide 3-kinase (PI3K) and polo-like kinase 1 (Plk1) pathways. Highest scoring hit compounds were tested in cell-based assays for their ability to induce mitotic arrest. We identified a novel acridinyl-acetohydrazide, here named as Centmitor-1 (Cent-1), that possesses highly similar molecular interaction field as rigosertib. In cells, Cent-1 phenocopied the cellular effects of rigosertib and caused mitotic arrest characterized by chromosome alignment defects, multipolar spindles, centrosome fragmentation, and activated spindle assembly checkpoint. We compared the effects of Cent-1 and rigosertib on microtubules and found that both compounds modulated microtubule plus-ends and reduced microtubule dynamics. Also, mitotic spindle forces were affected by the compounds as tension across sister kinetochores was reduced in mitotic cells. Our results showed that both Cent-1 and rigosertib target processes that occur during mitosis as they had immediate antimitotic effects when added to cells during mitosis. Analysis of Plk1 activity in cells using a Förster resonance energy transfer (FRET)-based assay indicated that neither compound affected the activity of the kinase. Taken together, these findings suggest that Cent-1 and rigosertib elicit their antimitotic effects by targeting mitotic processes without impairment of Plk1 kinase activity. Mol Cancer Ther; 13(5); 1054–66. ©2014 AACR.
Ectodomain-Specific E-Cadherin Antibody Suppresses Skin SCC Growth and Reduces Tumor Grade: A Multitargeted Therapy Modulating RTKs and the PTEN–p53–MDM2 Axis
Authors: Brouxhon Sabine M. , Kyrkanides Stephanos , Raja Veena , Silberfeld Andrew , Teng Xiaofei , Trochesset Denise , Cohen Jason , Ma Li
Published: April 2014

Tumor cell survival consists of an intricate balance between cell growth and cell death pathways involving receptor tyrosine kinases [RTK; i.e., HER1-4, insulin-like growth factor-1 receptor (IGF-1R), etc.], MDM2, and the tumor suppressor proteins phosphatase and tensin homolog deleted on chromosome ten (PTEN) and p53. We recently demonstrated that shedded E-cadherin extracellular domain fragment (sEcad) is a valid oncogenic target that is significantly increased in human clinical skin squamous cell cancers (SCC) samples, UV-induced mouse tumors, and cells and promotes tumor cell proliferation, migration, and invasion by interacting and activating with the HER-phosphatidylinositol 3-kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) axis. In resected human SCC tumors, we reported enhanced sEcad-HER1, sEcad-HER2, and sEcad-IGF-1R, but not FL–Ecad–RTK interactions. Here, we demonstrate that a sEcad antibody against the ectodomain of E-cadherin suppressed SCC growth and increased tumor differentiation in orthotopic cutaneous SCC xenografts by inhibiting proliferation and inducing apoptosis. A similar anti-sEcad antibody-induced inhibition of proliferation and induction of cell death was evident in PAM212 cells in vitro. Mechanistically, anti-sEcad administration upregulated an array of cell death pathways (i.e., Bad, active caspase-3, and cleaved PARP) and inhibited inhibitors of apoptosis (IAP; survivin, livin, etc.), RTKs (HER1, HER2, p95HER2, and IGF-1R), MAPK and PI3K/mTOR prosurvival signaling. Interestingly, in anti-sEcad mAb-treated tumors and PAM212 cells, this effect was associated with a profound increase in membrane, cytosolic, and nuclear levels of PTEN; enhanced cytosolic p53; and a decrease in MDM2 levels. Overall, our studies suggest that an antibody-based therapy against sEcad may be a novel therapeutic platform for cutaneous SCCs by hampering key proto-oncogenes (RTKs, IAPs, and MDM2) and activating potent tumor suppressor proteins (PTEN and p53) intricately linked to tumor growth and survival. Mol Cancer Ther; 13(7); 1791–802. ©2014 AACR.
Combination of Anti-HER3 Antibody MM-121/SAR256212 and Cetuximab Inhibits Tumor Growth in Preclinical Models of Head and Neck Squamous Cell Carcinoma
Authors: Jiang Ning , Wang Dongsheng , Hu Zhongliang , Shin Hyung Ju C. , Qian Guoqing , Rahman Mohammad Aminur , Zhang Hongzheng , Amin A.R.M. Ruhul , Nannapaneni Sreenivas , Wang Xiaojing , Chen Zhengjia , Garcia Gabriela , MacBeath Gavin , Shin Dong M. , Khuri Fadlo R. , Ma Jun , Chen Zhuo G. , Saba Nabil F.
Published: April 2014

The EGFR monoclonal antibody cetuximab is the only approved targeted agent for treating head and neck squamous cell carcinoma (HNSCC). Yet resistance to cetuximab has hindered its activity in this disease. Intrinsic or compensatory HER3 signaling may contribute to cetuximab resistance. To investigate the therapeutic benefit of combining MM-121/SAR256212, an anti-HER3 monoclonal antibody, with cetuximab in HNSCC, we initially screened 12 HNSCC cell lines for total and phosphorylated levels of the four HER receptors. We also investigated the combination of MM-121 with cetuximab in preclinical models of HNSCC. Our results revealed that HER3 is widely expressed and activated in HNSCC cell lines. MM-121 strongly inhibited phosphorylation of HER3 and AKT. When combined with cetuximab, MM-121 exerted a more potent antitumor activity through simultaneously inhibiting the activation of HER3 and EGFR and consequently the downstream PI3K/AKT and ERK pathways in vitro. Both high and low doses of MM-121 in combination with cetuximab significantly suppressed tumor growth in xenograft models and inhibited activations of HER3, EGFR, AKT, and ERK in vivo. Our work is the first report on this new combination in HNSCC and supports the concept that HER3 inhibition may play an important role in future therapy of HNSCC. Our results open the door for further mechanistic studies to better understand the role of HER3 in resistance to EGFR inhibitors in HNSCC. Mol Cancer Ther; 13(7); 1826–36. ©2014 AACR.
HIC2
Is a Novel Dosage-Dependent Regulator of Cardiac Development Located Within the Distal 22q11 Deletion Syndrome Region
Authors: Dykes Iain M. , van Bueren Kelly Lammerts , Ashmore Rebekah J. , Floss Thomas , Wurst Wolfgang , Szumska Dorota , Bhattacharya Shoumo , Scambler Peter J.
Published: April 2014

Rationale
:

22q11 deletion syndrome arises from recombination between low-copy repeats on chromosome 22. Typical deletions result in hemizygosity for
TBX1
associated with congenital cardiovascular disease. Deletions distal to the typically deleted region result in a similar cardiac phenotype but lack in extracardiac features of the syndrome, suggesting that a second haploinsufficient gene maps to this interval.

Objective
:

The transcription factor
HIC2
is lost in most distal deletions, as well as in a minority of typical deletions. We used mouse models to test the hypothesis that
HIC2
hemizygosity causes congenital heart disease.

Methods and Results
:

We created a genetrap mouse allele of
Hic2.
The genetrap reporter was expressed in the heart throughout the key stages of cardiac morphogenesis. Homozygosity for the genetrap allele was embryonic lethal before embryonic day E10.5, whereas the heterozygous condition exhibited a partially penetrant late lethality. One third of heterozygous embryos had a cardiac phenotype. MRI demonstrated a ventricular septal defect with over-riding aorta. Conditional targeting indicated a requirement for
Hic2
within the
Nkx2.5+
and
Mesp1
+ cardiovascular progenitor lineages. Microarray analysis revealed increased expression of
Bmp10
.

Conclusions
:

Our results demonstrate a novel role for
Hic2
in cardiac development.
Hic2
is the first gene within the distal 22q11 interval to have a demonstrated haploinsufficient cardiac phenotype in mice. Together our data suggest that
HIC2
haploinsufficiency likely contributes to the cardiac defects seen in distal 22q11 deletion syndrome.
On the Causality and Cause of Returns to Organizational Status
Authors: Malter Daniel
Published: April 2014

This paper identifies the causal symbolic effect of status on the prices organizations charge for their products. I exploit the classification of the châteaux of the Médoc, which sorted 61 wine producers into five growth classes in 1855, as a fixed hierarchical symbol of class status. The classification has defied attempts at revision for more than 150 years. This means that a château’s rank in the classification cannot be reversely affected by the quality or price of its wine, which greatly facilitates the estimation of the causal effect of status. To determine whether status serves as a signal of quality under uncertainty or satisfies the motive of conspicuous consumption, I study a period of time during which the uncertainty about quality has arguably declined because the Internet has made wine ratings ubiquitously available. I identify a symbolic effect of status on prices that increases in a time of decreasing uncertainty, which suggests the motive of conspicuous consumption as a driver of the effect. But the results caution that we might commonly overestimate the symbolic value of status if we underestimate the disproportional value that markets place on the pinnacle of quality, the enduring nature of reputation, and the effect of endogenous quality choices on estimates of status effects.
Disability and Income
Authors: Walls Richard T. , Dowler Denetta L.
Published: April 2014

It has long been recognized that people with disabilities usually have less earnings than workers who do not have disabilities. The Rehabilitation Services Administration (RSA)-911 data for 2012 were examined to determine the “true” income of workers with disabilities. The 2012 database included 579,312 cases closed during that year. The benefits and earnings of the whole data set and of 17 disability groups were examined. That is, the amount of earnings (at application for Vocational Rehabilitation [VR] services and at case closure) were combined with the amount of benefits to determine (a) whether total income increased from application for VR services to case closure, (b) the proportion of total income from benefits versus earnings, and (c) how total income for these consumers compared with the poverty level. Overall, those data revealed a 326% increase in total income from application to closure. At application, the proportion of total monthly income from earnings was 42%, whereas at closure, it had shifted to 83% of total income from earnings. Income relative to the poverty threshold was 57% for all clients at application, but had increased to 185% at closure. Results are also provided for each of the 17 disability groups.
Does Religiousness Increase Self-Control and Reduce Criminal Behavior?
Authors: Pirutinsky Steven
Published: April 2014

Previous research suggests that religiousness correlates with less criminal behavior and that this relationship is partially mediated by higher self-control. Because most studies are cross-sectional, causality remains uncertain as stable between-subject factors may influence self-control, religiousness, and offending, confounding their relationships. Moreover, directionality may be reversed with higher self-control leading to both higher religiousness and less offending. The current research aimed to directly exclude these possibilities using longitudinal data from 1,354 adolescents participating in the Pathways to Desistance Study. Results indicated that short-term, within-subject increased religiousness predicted decreased future criminal behavior and that this effect was partially mediated by increased self-control. A reversed model in which past self-control predicted future religiousness was not significant. These findings suggest that religiousness may be causally related to offending, and self-control is likely one of multiple mediating processes. Additional research in this area appears warranted and may yield effective strategies for reducing criminal behavior and improving self-control.
Implementing the PEP uP Protocol in Critical Care Units in Canada
Authors: Heyland Daren K. , Dhaliwal Rupinder , Lemieux Margot , Wang Miao , Day Andrew G.
Published: April 2014

Background: Previous studies have documented widespread iatrogenic underfeeding in intensive care unit (ICU) patients. In an experimental setting, we demonstrated the safety and efficacy of a novel enteral feeding protocol designed to overcome the main barriers to adequate delivery of enteral nutrition (EN), the Enhanced Protein‐Energy Provision via the Enteral Route Feeding Protocol (PEP uP protocol). The purpose of this article is to describe our experience with implementing this feeding protocol under “real‐world” settings in Canada. Materials and Methods: This study is a multicenter quality improvement initiative with a concurrent control group. Selected ICUs implemented the PEP uP protocol, and nutrition practices and outcomes were compared with a concurrent control group of ICUs. Results: In 2013, of the 24 ICUs from Canada that participated in the International Nutrition Survey, 8 implemented the PEP uP protocol and the remaining 16 served as concurrent control sites. Patients at PEP uP sites received 60.1% of their prescribed energy requirements from EN compared with 49.9% in patients from control hospitals (P = .02). In addition, patients in PEP uP protocol sites received more protein from EN (61.0% vs 49.7% of prescribed amounts; P = .01), were more likely to receive protein supplements (71.8% vs 47.7%; P = .01), and were more likely to receive >80% of their protein requirements by day 3 (46.1% vs 29.3%; P = .05) compared with patients in control hospitals. Conclusions: In the real‐life setting, the PEP uP protocol can improve the delivery of EN to critically ill patients.
Use of 3 Tools to Assess Nutrition Risk in the Intensive Care Unit
Authors: Coltman Anne , Peterson Sarah , Roehl Kelly , Roosevelt Hannah , Sowa Diane
Published: April 2014

Background: Identifying patients at nutrition risk proves difficult in the intensive care unit (ICU) due to the nature of critical illness. No consensus exists on the most appropriate method to identify these patients. Traditional screens and assessments are often limited due to their subjective nature. The purpose of the quality improvement project was to compare proportions of ICU patients deemed at nutrition risk using 3 different tools. Material and Methods: A convenience sample of 294 patients admitted to the ICU was used. Patients were assessed using the institution's routine nutrition screening method, the Subjective Global Assessment (SGA), and the NUTrition Risk in Critically ill (NUTRIC) score. Information was collected on demographics, severity of illness, hospital and ICU length of stay (LOS), and disposition. Descriptive statistics were used to examine counts/proportions of risk categories; means ± SD were used to summarize demographic and clinical variables. Results: A total of 139 patients (47%) were deemed at nutrition risk or malnourished by at least 1 tool. Patients identified were older and had a lower body mass index, more weight loss, more fat and muscle wasting, more fluid accumulation, and lower average handgrips than those not at nutrition risk; they also had longer hospital and ICU LOS, higher rates of requiring further rehabilitation upon discharge, and higher mortality during hospitalization. Conclusion: Traditional screening and assessment tools did not uniformly identify patients as malnourished or at nutrition risk in the ICU and therefore may be inappropriate for use in this population. Inclusion of physical assessment, functional status, and severity of illness may be useful in predicting nutrition risk in the ICU.