bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends of stage, grade, histology and tumour necrosis in renal cell carcinoma in a European centre surgical series from 1984 to 2010
Authors: Pichler Martin , Hutterer Georg C , Chromecki Thomas F , Jesche Johanna , Kampel-Kettner Karin , Eberhard Katharina , Hoefler Gerald , Pummer Karl , Zigeuner Richard
Published: May 2012

Aims

To analyse renal cell carcinoma (RCC) stage, grade, histology and necrosis migration in a large European centre series over the last 27 years.

Methods

The pathology reports of 2739 consecutive patients with RCC who underwent nephrectomy from 1984 to 2010 at the institution of the authors were systematically re-evaluated. Patients were pooled into five time groups according to the date of surgery: group 1: 1984–1989, group 2: 1990–1994, group 3: 1995–1999, group 4: 2000–2004 and group 5: 2005–2010, respectively. Changes in pT categories according to WHO 2010 classification, tumour grade, histological subtype and presence of tumour necrosis (TN) were evaluated.

Results

Small pT1a tumours were found in 62/485 (12.8%) and 312/639 (48.8%) patients in groups 1 and 5, respectively (p<0.001). Advanced tumour stages (pT3a-4) were found in 306/485 (63.1%) and 171/639 (26.8%) patients in groups 1 and 5, respectively (p<0.001). The number of grade 3/4 tumours increased from 62/485 (12.7%) and 130/639 (20.3%) in groups 1 and 5, respectively, whereas the number of grade 1 tumours decreased over time (p<0.001). There has been a significant histological migration for the chromophobe subtype from 1.1% to 4.3% (p=0.002). The frequency of the presence TN decreased from 41.7% in group 1 to 32.7% in group 5 (p<0.001).

Conclusions

In contrast to data from Australia but similar to data from US cohorts, a statistically significant stage migration towards small RCCs was observed in this European cohort. Significant changes in tumour grade, histological subtype and TN were also observed.
SUBCONSCIOUS ENVIRONMENTAL INFORMATION PERCEIVING BEHAVIOR AND ITS ATTENUATION IN INFORMATION-BASED EVACUATION EXPERIMENT
Authors: YANG LIZHONG , LIU SHAOBO , RAO PING , ZHU KONGJIN
Published: May 2012

An evacuation was studied from a classroom by means of experiment and simulation. In the experiments, evacuation with and without visibility was mimicked by requiring the evacuees to wear eye masks or not. The distribution of evacuees' egress times against initial positions and the flow rate at exits were studied. It was found that when masks were used, evacuees' egress strategies were highly dependent on their pre-perceived environmental information in subconsciousness which might affect the egress process. Thus we call this phenomenon the "subconscious environmental information perceiving behavior." In the simulation, a cellular automata model considering the influence of sound information and the subconscious behavior was used to simulate the experiments. Both the experimental and the simulation results show that the sound information plays a more important role in evacuation without visibility than in normal condition, and the pre-perceived environmental information is also very important when people have poor visibility because of the subconscious environmental information perceiving behavior. The simulation results consist with the experimental results well. This study is useful for understanding the human behaviors during emergency evacuation with poor visibility under the guide of sound signal.
Relative contribution of SKCa and TREK1 channels in purinergic and nitrergic neuromuscular transmission in the rat colon
Authors: Gil V. , Gallego D. , Moha Ou Maati H. , Peyronnet R. , Martínez-Cutillas M. , Heurteaux C. , Borsotto M. , Jiménez M.
Published: May 2012

Purinergic and nitrergic neurotransmission predominantly mediate inhibitory neuromuscular transmission in the rat colon. We studied the sensitivity of both purinergic and nitrergic pathways to spadin, a TWIK-related potassium channel 1 (TREK1) inhibitor, apamin, a small-conductance calcium-activated potassium channel blocker and 1H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one (ODQ), a specific inhibitor of soluble guanylate cyclase. TREK1 expression was detected by RT-PCR in the rat colon. Patch-clamp experiments were performed on cells expressing hTREK1 channels. Spadin (1 μM) reduced currents 1) in basal conditions 2) activated by stretch, and 3) with arachidonic acid (AA; 10 μM). l-Methionine (1 mM) or l-cysteine (1 mM) did not modify currents activated by AA. Microelectrode and muscle bath studies were performed on rat colon samples. l-Methionine (2 mM), apamin (1 μM), ODQ (10 μM), and Nω-nitro-l-arginine (l-NNA; 1 mM) depolarized smooth muscle cells and increased motility. These effects were not observed with spadin (1 μM). Purinergic and nitrergic inhibitory junction potentials (IJP) were studied by incubating the tissue with l-NNA (1 mM) or MRS2500 (1 μM). Both purinergic and nitrergic IJP were unaffected by spadin. Apamin reduced both IJP with a different potency and maximal effect for each. ODQ concentration dependently abolished nitrergic IJP without affecting purinergic IJP. Similar effects were observed in hyperpolarizations induced by sodium nitroprusside (1 μM) and nitrergic relaxations induced by electrical stimulation. We propose a pharmacological approach to characterize the pathways and function of purinergic and nitrergic neurotransmission. Nitrergic neurotransmission, which is mediated by cyclic guanosine monophosphate, is insensitive to spadin, an effective TREK1 channel inhibitor. Both purinergic and nitrergic neurotransmission are inhibited by apamin but with different relative sensitivity.
Increased hemoglobin O2affinity protects during acute hypoxia
Authors: Yalcin Ozlem , Cabrales Pedro
Published: May 2012

Acclimatization to hypoxia requires time to complete the adaptation mechanisms that influence oxygen (O2) transport and O2utilization. Although decreasing hemoglobin (Hb) O2affinity would favor the release of O2to the tissues, increasing Hb O2affinity would augment arterial O2saturation during hypoxia. This study was designed to test the hypothesis that pharmacologically increasing the Hb O2affinity will augment O2transport during severe hypoxia (10 and 5% inspired O2) compared with normal Hb O2affinity. RBC Hb O2affinity was increased by infusion of 20 mg/kg of 5-hydroxymethyl-2-furfural (5HMF). Control animals received only the vehicle. The effects of increasing Hb O2affinity were studied in the hamster window chamber model, in terms of systemic and microvascular hemodynamics and partial pressures of O2(Po2). Pimonidazole binding to hypoxic areas of mice heart and brain was also studied. 5HMF decreased the Po2at which the Hb is 50% saturated with O2by 12.6 mmHg. During 10 and 5% O2hypoxia, 5HMF increased arterial blood O2saturation by 35 and 48% from the vehicle group, respectively. During 5% O2hypoxia, blood pressure and heart rate were 58 and 30% higher for 5HMF compared with the vehicle. In addition, 5HMF preserved microvascular blood flow, whereas blood flow decreased to 40% of baseline in the vehicle group. Consequently, perivascular Po2was three times higher in the 5HMF group compared with the control group at 5% O2hypoxia. 5HMF also reduced heart and brain hypoxic areas in mice. Therefore, increased Hb O2affinity resulted in hemodynamics and oxygenation benefits during severe hypoxia. This acute acclimatization process may have implications in survival during severe environmental hypoxia when logistic constraints prevent chronic acclimatization.
Mitofusins and the mitochondrial permeability transition: the potential downside of mitochondrial fusion
Authors: Papanicolaou Kyriakos N. , Phillippo Matthew M. , Walsh Kenneth
Published: May 2012

Mitofusins (Mfn-1 and Mfn-2) are transmembrane proteins that bind and hydrolyze guanosine 5′-triphosphate to bring about the merging of adjacent mitochondrial membranes. This event is necessary for mitochondrial fusion, a biological process that is critical for organelle function. The broad effects of mitochondrial fusion on cell bioenergetics have been extensively studied, whereas the local effects of mitofusin activity on the structure and integrity of the fusing mitochondrial membranes have received relatively little attention. From the study of fusogenic proteins, theoretical models, and simulations, it has been noted that the fusion of biological membranes is associated with local perturbations on the integrity of the membrane that present in the form of lipidic holes which open on the opposing bilayers. These lipidic holes represent obligate intermediates that make the fusion process thermodynamically more favorable and at the same time induce leakage to the fusing membranes. In this perspectives article we present the relevant evidence selected from a spectrum of membrane fusion/leakage models and attempt to couple this information with observations conducted with cardiac myocytes or mitochondria deficient in Mfn-1 and Mfn-2. More specifically, we argue in favor of a situation whereby mitochondrial fusion in cardiac myocytes is coupled with outer mitochondrial membrane destabilization that is opportunistically employed during the process of mitochondrial permeability transition. We hope that these insights will initiate research on this new hypothesis of mitochondrial permeability transition regulation, a poorly understood mitochondrial function with significant consequences on myocyte survival.
MRI-based prediction of adverse cardiac remodeling after murine myocardial infarction
Authors: Protti Andrea , Dong Xuebin , Sirker Alexander , Botnar Rene , Shah Ajay M.
Published: May 2012

Myocardial infarction (MI) results in adverse cardiac remodeling leading to heart failure and increased mortality. Experimental mouse models of MI are extensively used to identify mechanisms underlying adverse remodeling, but the extent of remodeling that occurs may be highly variable and can limit the utility to discover new disease pathways. The ability to predict the development of significant late post-MI remodeling would be invaluable in conducting such studies by increasing throughput and efficiency. This study aimed to identify potential thresholds of cardiac magnetic resonance imaging (MRI) parameters measured early after murine MI that would predict the development of significant adverse remodeling at 4 wk. MI was achieved by permanent coronary ligation and animals ( n = 84) were followed up for 4 wk subsequently. MRI was used to assess left ventricular (LV) volumes, mass and ejection fraction, as well as infarct size (IS). Late gadolinium enhancement cine-MRI was performed at 2 days with standard cine-MRI at 30 days post-MI. Utilizing multiple logistic regression, we found that IS >36%, at 2 days post-MI, was the overall best single predictor of adverse remodeling at 30 days (sensitivity 80.7%, specificity 88.9%; C-statistic of 0.939 from receiver-operating curve analysis). LV end-systolic volume (LVESV) >32 μl was also an excellent predictor comparable to IS. The combination of IS >36% and/or LVESV >32 μl provided the highest predictive values for late adverse remodeling among multiple predictors. This study demonstrates that MRI-based estimation of IS and ESV during the acute phase of murine MI are good predictors of subsequent adverse remodeling that may aid experimental design.
Cell-based therapy for prevention and reversal of myocardial remodeling
Authors: Karantalis Vasileios , Balkan Wayne , Schulman Ivonne H. , Hatzistergos Konstantinos E. , Hare Joshua M.
Published: May 2012

Although pharmacological and interventional advances have reduced the morbidity and mortality of ischemic heart disease, there is an ongoing need for novel therapeutic strategies that prevent or reverse progressive ventricular remodeling following myocardial infarction, the process that forms the substrate for ventricular failure. The development of cell-based therapy as a strategy to repair or regenerate injured tissue offers extraordinary promise for a powerful anti-remodeling therapy. In this regard, the field of cell therapy has made major advancements in the past decade. Accumulating data from preclinical studies have provided novel insights into stem cell engraftment, differentiation, and interactions with host cellular elements, as well as the effectiveness of various methods of cell delivery and accuracy of diverse imaging modalities to assess therapeutic efficacy. These findings have in turn guided rationally designed translational clinical investigations. Collectively, there is a growing understanding of the parameters that underlie successful cell-based approaches for improving heart structure and function in ischemic and other cardiomyopathies.
Angiotensin II enhances AT1-Nox1 binding and stimulates arterial smooth muscle cell migration and proliferation through AT1, Nox1, and interleukin-18
Authors: Valente Anthony J. , Yoshida Tadashi , Murthy Subramanyam N. , Sakamuri Siva S. V. P. , Katsuyama Masato , Clark Robert A. , Delafontaine Patrice , Chandrasekar Bysani
Published: May 2012

The redox-sensitive transcription factors NF-κB and activator protein-1 (AP-1) are critical mediators of ANG II signaling. The promitogenic and promigratory factor interleukin (IL)-18 is an NF-κB- and AP-1-responsive gene. Therefore, we investigated whether ANG II-mediated smooth muscle cell (SMC) migration and proliferation involve IL-18. ANG II induced rat carotid artery SMC migration and proliferation and IL-18 and metalloproteinase (MMP)-9 expression via ANG II type 1 (AT1) receptor. ANG II-induced superoxide generation, NF-κB and AP-1 activation, and IL-18 and MMP-9 induction were all markedly attenuated by losartan, diphenyleneiodonium chloride (DPI), and Nox1 knockdown. Similar to ANG II, addition of IL-18 also induced superoxide generation, activated NF-κB and AP-1, and stimulated SMC migration and proliferation, in part via Nox1, and both ANG II and IL-18 induced NOX1 transcription in an AP-1-dependent manner. AT1physically associates with Nox1 in SMC, and ANG II enhanced this binding. Interestingly, exogenous IL-18 neither induced AT1binding to Nox1 nor enhanced the ANG II-induced increase in AT1/Nox1 binding. Importantly, IL-18 knockdown, or pretreatment with IL-18 neutralizing antibodies, or IL-18 binding protein, all attenuated the migratory and mitogenic effects of ANG II. Continuous infusion of ANG II for 7 days induced carotid artery hyperplasia in rats via AT1and was associated with increased AT1/Nox1 binding (despite lower AT1levels); increased DPI-inhibitable superoxide production; increased phospho-IKKβ, JNK, p65, and c-Jun; and induction of IL-18 and MMP-9 in endothelium-denuded carotid arteries. These results indicate that IL-18 amplifies the ANG II-induced, redox-dependent inflammatory cascades by activating similar promitogenic and promigratory signal transduction pathways. The ANG II/Nox1/IL-18 pathway may be critical in hyperplastic vascular diseases, including atherosclerosis and restenosis.
Blockade of ATP-sensitive potassium channels prevents the attenuation of the exercise pressor reflex by tempol in rats with ligated femoral arteries
Authors: Yamauchi Katsuya , Stone Audrey J. , Stocker Sean D. , Kaufman Marc P.
Published: May 2012

We reported previously that tempol attenuated the exercise pressor and muscle mechanoreceptor reflexes in rats whose femoral arteries were ligated, whereas tempol did not attenuate these reflexes in rats whose femoral arteries were freely perfused. Although the mechanism whereby tempol attenuated these reflexes in rats whose femoral artery was ligated was independent of its ability to scavenge reactive oxygen species, its nature remains unclear. An alternative explanation for the tempol-induced attenuation of these reflexes involves ATP-sensitive potassium channels (KATP) and calcium-activated potassium channels (BKCa), both of which are opened by tempol. We tested the likelihood of this explanation by measuring the effects of either glibenclamide (0.1 mg/kg), which blocks KATP channels, or iberiotoxin (20 or 40 μg/kg), which blocks BKCa channels, on the tempol-induced attenuation of the exercise pressor and muscle mechanoreceptor reflexes in decerebrated rats whose femoral arteries were ligated. We found that glibenclamide prevented the tempol-induced attenuation of both reflexes, whereas iberiotoxin did not. We also found that the amount of protein comprising the pore of the KATP channel in the dorsal root ganglia innervating hindlimbs whose femoral artery was ligated was significantly greater than that in the dorsal root ganglia innervating hindlimbs whose femoral arteries were freely perfused. In contrast, the amounts of protein comprising the BKCa channel in the dorsal root ganglia innervating the ligated and freely perfused hindlimbs were not different. We conclude that tempol attenuated both reflexes by opening KATP channels, an effect that hyperpolarized muscle afferents stimulated by static contraction or tendon stretch.
The continuing evolution of the Langendorff and ejecting murine heart: new advances in cardiac phenotyping
Authors: Liao Ronglih , Podesser Bruno K. , Lim Chee Chew
Published: May 2012

The isolated retrograde-perfused Langendorff heart and the isolated ejecting heart have, over many decades, resulted in fundamental discoveries that form the underpinnings of our current understanding of the biology and physiology of the heart. These two experimental methodologies have proven invaluable in studying pharmacological effects on myocardial function, metabolism, and vascular reactivity and in the investigation of clinically relevant disease states such as ischemia-reperfusion injury, diabetes, obesity, and heart failure. With the advent of the genomics era, the isolated mouse heart preparation has gained prominence as an ex vivo research tool for investigators studying the impact of gene modification in the intact heart. This review summarizes the historical development of the isolated heart and provides a practical guide for the establishment of the Langendorff and ejecting heart preparations with a particular emphasis on the murine heart. In addition, current applications and novel methods of recording cardiovascular parameters in the isolated heart preparation will be discussed. With continued advances in methodological recordings, the isolated mouse heart preparation will remain physiologically relevant for the foreseeable future, serving as an integral bridge between in vitro assays and in vivo approaches.
Interactions among pulmonary surfactant, vernix caseosa, and intestinal enterocytes: intra-amniotic administration of fluorescently liposomes to pregnant rabbits
Authors: Nishijima Koji , Shukunami Ken-ichi , Yoshinari Hideo , Takahashi Jin , Maeda Hideyuki , Takagi Hitoshi , Kotsuji Fumikazu
Published: May 2012

Although vernix caseosa is known to be a natural biofilm at birth, human pulmonary surfactant commences to remove the vernix from fetal skin into the amniotic fluid at gestational week 34, i.e., well before delivery. To explain this paradox, we first produced two types of fluorescently labeled liposomes displaying morphology similar to that of pulmonary surfactant and vernix caseosa complexes. We then continuously administered these liposomes into the amniotic fluid space of pregnant rabbits. In addition, we produced pulmonary surfactant and vernix caseosa complexes and administered them into the amniotic fluid space of pregnant rabbits. The intra-amniotic infused fluorescently labeled liposomes were absorbed into the fetal intestinal epithelium. However, the liposomes were not transported to the livers of fetal rabbits. We also revealed that continuous administration of micelles derived from pulmonary surfactants and vernix caseosa protected the small intestine of the rabbit fetus from damage due to surgical intervention. Our results indicate that pulmonary surfactant and vernix caseosa complexes in swallowed amniotic fluid might locally influence fetal intestinal enterocytes. Although the present studies are primarily observational and further studies are needed, our findings elucidate the physiological interactions among pulmonary, dermal-epidermal, and gastrointestinal developmental processes.
CFTR is required for maximal transepithelial liquid transport in pig alveolar epithelia
Authors: Li Xiaopeng , Comellas Alejandro P. , Karp Philip H. , Ernst Sarah E. , Moninger Thomas O. , Gansemer Nicholas D. , Taft Peter J. , Pezzulo Alejandro A. , Rector Michael V. , Rossen Nathan , Stoltz David A. , McCray Paul B. , Welsh Michael J. , Zabner Joseph
Published: May 2012

A balance between alveolar liquid absorption and secretion is critical for maintaining optimal alveolar subphase liquid height and facilitating gas exchange in the alveolar space. However, the role of cystic fibrosis transmembrane regulator protein (CFTR) in this homeostatic process has remained elusive. Using a newly developed porcine model of cystic fibrosis, in which CFTR is absent, we investigated ion transport properties and alveolar liquid transport in isolated type II alveolar epithelial cells (T2AECs) cultured at the air-liquid interface. CFTR was distributed exclusively to the apical surface of cultured T2AECs. Alveolar epithelia from CFTR−/−pigs failed to increase liquid absorption in response to agents that increase cAMP, whereas cAMP-stimulated liquid absorption in CFTR+/−epithelia was similar to that in CFTR+/+epithelia. Expression of recombinant CFTR restored stimulated liquid absorption in CFTR−/−T2AECs but had no effect on CFTR+/+epithelia. In ex vivo studies of nonperfused lungs, stimulated liquid absorption was defective in CFTR−/−alveolar epithelia but similar between CFTR+/+and CFTR+/−epithelia. When epithelia were studied at the air-liquid interface, elevating cAMP levels increased subphase liquid height in CFTR+/+but not in CFTR−/−T2AECs. Our findings demonstrate that CFTR is required for maximal liquid absorption under cAMP stimulation, but it is not the rate-limiting factor. Furthermore, our data define a role for CFTR in liquid secretion by T2AECs. These insights may help to develop new treatment strategies for pulmonary edema and respiratory distress syndrome, diseases in which lung liquid transport is disrupted.
CCR5 Antagonist Blocks Metastasis of Basal Breast Cancer Cells
Authors: Velasco-Velázquez Marco , Jiao Xuanmao , De La Fuente Marisol , Pestell Timothy G. , Ertel Adam , Lisanti Michael P. , Pestell Richard G.
Published: May 2012

The roles of the chemokine CCL5 and its receptor CCR5 in breast cancer progression remain unclear. Here, we conducted microarray analysis on 2,254 human breast cancer specimens and found increased expression of CCL5 and its receptor CCR5, but not CCR3, in the basal and HER-2 genetic subtypes. The subpopulation of human breast cancer cell lines found to express CCR5 displayed a functional response to CCL5. In addition, oncogene transformation induced CCR5 expression, and the subpopulation of cells that expressed functional CCR5 also displayed increased invasiveness. The CCR5 antagonists maraviroc or vicriviroc, developed to block CCR5 HIV coreceptor function, reduced in vitro invasion of basal breast cancer cells without affecting cell proliferation or viability, and maraviroc decreased pulmonary metastasis in a preclinical mouse model of breast cancer. Taken together, our findings provide evidence for the key role of CCL5/CCR5 in the invasiveness of basal breast cancer cells and suggest that CCR5 antagonists may be used as an adjuvant therapy to reduce the risk of metastasis in patients with the basal breast cancer subtype. Cancer Res; 72(15); 3839–50. ©2012 AACR.
Wnt/Snail Signaling Regulates CytochromecOxidase and Glucose Metabolism
Authors: Lee Su Yeon , Jeon Hyun Min , Ju Min Kyung , Kim Cho Hee , Yoon Gyesoon , Han Song Iy , Park Hye Gyeong , Kang Ho Sung
Published: May 2012

Wnt signaling plays a critical role in embryonic development, and its deregulation is closely linked to the occurrence of a number of malignant tumors, including breast and colon cancer. The pathway also induces Snail-dependent epithelial-to-mesenchymal transition (EMT), which is responsible for tumor invasion and metastasis. In this study, we show that Wnt suppresses mitochondrial respiration and cytochrome C oxidase (COX) activity by inhibiting the expression of 3 COX subunits, namely, COXVIc, COXVIIa, and COXVIIc. We found that Wnt induced a glycolytic switch via increased glucose consumption and lactate production, with induction of pyruvate carboxylase (PC), a key enzyme of anaplerosis. In addition, Wnt-induced mitochondrial repression and glycolytic switching occurred through the canonical β-catenin/T-cell factor 4/Snail pathway. Short hairpin RNA–mediated knockdown of E-cadherin, a regulator of EMT, repressed mitochondrial respiration and induced a glycolytic switch via Snail activation, indicating that EMT may contribute to Wnt/Snail regulation of mitochondrial respiration and glucose metabolism. Together, our findings provide a new function for Wnt/Snail signaling in the regulation of mitochondrial respiration (via COX gene expression) and glucose metabolism (via PC gene expression) in tumor growth and progression. Cancer Res; 72(14); 3607–17. ©2012 AACR.
A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas
Authors: Hong David S. , Kurzrock Razelle , Supko Jeffrey G. , He Xiaoying , Naing Aung , Wheler Jennifer , Lawrence Donald , Eder Joseph Paul , Meyer Colin J. , Ferguson Deborah A. , Mier James , Konopleva Marina , Konoplev Sergej , Andreeff Michael , Kufe Donald , Lazarus Hillard , Shapiro Geoffrey I. , Dezube Bruce J.
Published: May 2012

Purpose: Bardoxolone methyl, a novel synthetic triterpenoid and antioxidant inflammation modulator, potently induces Nrf2 and inhibits NF-κB and Janus-activated kinase/STAT signaling. This first-in-human phase I clinical trial aimed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and appropriate dose for phase II studies; characterize pharmacokinetic and pharmacodynamic parameters; and assess antitumor activity.

Experimental Design: Bardoxolone methyl was administered orally once daily for 21 days of a 28-day cycle. An accelerated titration design was employed until a grade 2–related adverse event occurred. A standard 3 + 3 dose escalation was then employed until the MTD was reached. Single dose and steady-state plasma pharmacokinetics of the drug were characterized. Assessment of Nrf2 activation was examined in peripheral blood mononuclear cells (PBMC) by measuring NAD(P)H:quinone oxidoreductase (NQO1) mRNA levels. Immunohistochemical assessment of markers of inflammation, cell cycle, and apoptosis was carried out on tumor biopsies.

Results: The DLTs were grade 3 reversible liver transaminase elevations. The MTD was established as 900 mg/d. A complete tumor response occurred in a mantle cell lymphoma patient, and a partial response was observed in an anaplastic thyroid carcinoma patient. NQO1 mRNA levels increased in PBMCs, and NF-κB and cyclin D1 levels decreased in tumor biopsies. Estimated glomerular filtration rate (eGFR) was also increased.

Conclusions: Bardoxolone methyl was well tolerated with an MTD of 900 mg/d. The increase in eGFR suggests that bardoxolone methyl might be beneficial in chronic kidney disease. Objective tumor responses and pharmacodynamic effects were observed, supporting continued development of other synthetic triterpenoids in cancer. Clin Cancer Res; 18(12); 3396–406. ©2012 AACR.
Sustained Remission of Multicentric Castleman Disease in Children Treated with Tocilizumab, an Anti-Interleukin-6 Receptor Antibody
Authors: Galeotti Caroline , Boucheron Adeline , Guillaume Séverine , Koné-Paut Isabelle
Published: May 2012

Multicentric Castleman Disease (MCD) is an idiopathic lymphoproliferative disorder, reported exceptionally in children and generally believed to be an autoinflammatory disease resulting in an increase of interleukin-6 secretion. Previous studies in adult patients suggested a beneficial role of the anti-interleukin-6 receptor antibody tocilizumab on the clinical and biologic disease manifestations of MCD. Here, we describe the efficacy and safety of tocilizumab in two children with MCD, which was diagnosed on the basis of clinical and histologic findings. In both cases, tocilizumab was administered intravenously at a dose of 8 mg/kg every 2 weeks. The tocilizumab treatment alleviated fever and restored growth rate in both patients. The patients' hypergammaglobulinemia, high C-reactive protein, and high erythrocyte sedimentation rates normalized simultaneously. Nevertheless, splenomegaly persisted in the first patient, and a secondary hepatic node appeared in the second patient. The side effects, essentially sustained thrombocytopenia, were mild in both cases. For the first patient, following an initial 10-month period, the interval between infusions was increased. This patient benefited from sustained remission for a period of 3 years. Tocilizumab was effective and safe in these two children with MCD. Mol Cancer Ther; 11(8); 1623–6. ©2012 AACR.
Early to Intermediate Steps of Tumor Embolic Formation Involve Specific Proteolytic Processing of E-Cadherin Regulated by Rab7
Authors: Ye Yin , Gao Jian-Xin , Tian Honglin , Yearsley Kurtis , Lange Alicia R. , Robertson Fredika M. , Barsky Sanford H.
Published: May 2012

The lymphovascular embolus is an enigmatic entity adept at metastatic dissemination and chemotherapy resistance. Using MARY-X, a human breast cancer xenograft that exhibits florid lymphovascular emboli in mice and spheroids in vitro, we established a model where the in vitro transition stages from minced tumoral aggregates to well-formed spheroids served as a surrogate for in vivo emboli formation. MARY-X well-formed spheroids and emboli exhibited strong similarity of expression. The aggregate-to-spheroid transition stages were characterized by increased ExoC5, decreased Hgs and Rab7, increased calpains, increased full-length E-cadherin (E-cad/FL), and the transient appearance of E-cad/NTF2, a 95 kDa E-cadherin fragment and increased Notch3icd (N3icd), the latter two fragments produced by increased γ-secretase. Both transient and permanent knockdowns of Rab7 in MCF-7 cells increased protein but not transcription of E-cad/FL and resulted in the de novo appearance of E-cad/NTF2, the presence of nuclear E-cad/CTF2, and increased Notch1icd (N1icd). Overexpression of Rab7 conversely decreased E-cad/FL, γ-secretase (PS1/NTF), and E-cad/NTF2. Overexpression of calpains did not alter PS1/NTF but decreased E-cad/FL and E-cad/NTF2 and increased N1icd. Well-formed spheroids showed increased Rab7, absent E-cad/NTF2, decreased PS1/NTF, increased E-cad/NTF1, and increased N3icd, the latter two fragments being the direct and indirect consequences, respectively, of increased calpains (calpain 1 and calpain 2). Inhibition of calpains decreased E-cad/NTF1 but increased E-cad/NTF2 showing that calpains compete with γ-secretase (PS1) for closely located cleavage/binding sites on E-cadherin and that increased calpains can shuttle even decreased levels of γ-secretase to Notch 3, resulting in increased Notch 3 signaling in the well-formed spheroids. Mol Cancer Res; 10(6); 713–26. ©2012 AACR.
State of the Science: An Update on Renal Cell Carcinoma
Authors: Jonasch Eric , Futreal P. Andrew , Davis Ian J. , Bailey Sean T. , Kim William Y. , Brugarolas James , Giaccia Amato J. , Kurban Ghada , Pause Armin , Frydman Judith , Zurita Amado J. , Rini Brian I. , Sharma Pam , Atkins Michael B. , Walker Cheryl L. , Rathmell W. Kimryn
Published: May 2012

Renal cell carcinomas (RCC) are emerging as a complex set of diseases that are having a major socioeconomic impact and showing a continued rise in incidence throughout the world. As the field of urologic oncology faces these trends, several major genomic and mechanistic discoveries are altering our core understanding of this multitude of cancers, including several new rare subtypes of renal cancers. In this review, these new findings are examined and placed in the context of the well-established association of clear cell RCC (ccRCC) with mutations in the von Hippel-Lindau (VHL) gene and resultant aberrant hypoxia inducible factor (HIF) signaling. The impact of novel ccRCC-associated genetic lesions on chromatin remodeling and epigenetic regulation is explored. The effects of VHL mutation on primary ciliary function, extracellular matrix homeostasis, and tumor metabolism are discussed. Studies of VHL proteostasis, with the goal of harnessing the proteostatic machinery to refunctionalize mutant VHL, are reviewed. Translational efforts using molecular tools to elucidate discriminating features of ccRCC tumors and develop improved prognostic and predictive algorithms are presented, and new therapeutics arising from the earliest molecular discoveries in ccRCC are summarized. By creating an integrated review of the key genomic and molecular biological disease characteristics of ccRCC and placing these data in the context of the evolving therapeutic landscape, we intend to facilitate interaction among basic, translational, and clinical researchers involved in the treatment of this devastating disease, and accelerate progress toward its ultimate eradication. Mol Cancer Res; 10(7); 859–80. ©2012 AACR.
A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma
Authors: Collisson Eric A. , Trejo Christy L. , Silva Jillian M. , Gu Shenda , Korkola James E. , Heiser Laura M. , Charles Roch-Philippe , Rabinovich Brian A. , Hann Byron , Dankort David , Spellman Paul T. , Phillips Wayne A. , Gray Joe W. , McMahon Martin
Published: May 2012

KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDA) but remains an intractable pharmacologic target. Consequently, defining RAS effector pathway(s) required for PDA initiation and maintenance is critical to improve treatment of this disease. Here, we show that expression of BRAFV600E, but not PIK3CAH1047R, in the mouse pancreas leads to pancreatic intraepithelial neoplasia (PanIN) lesions. Moreover, concomitant expression of BRAFV600E and TP53R270H result in lethal PDA. We tested pharmacologic inhibitors of RAS effectors against multiple human PDA cell lines. Mitogen-activated protein (MAP)/extracellular signal–regulated (ERK) kinase (MEK) inhibition was highly effective both in vivo and in vitro and was synergistic with AKT inhibition in most cell lines tested. We show that RAF→MEK→ERK signaling is central to the initiation and maintenance of PDA and to rational combination strategies in this disease. These results emphasize the value of leveraging multiple complementary experimental systems to prioritize pathways for effective intervention strategies in PDA.

Significance: PDA is difficult to treat, in large part, due to recurrent mutations in the KRAS gene. Here, we define rational treatment approaches for the disease achievable today with existing drug combinations by thorough genetic and pharmacologic dissection of the major KRAS effector pathways, RAF→MEK→ERK and phosphoinositide 3′-kinase (PI3′K)→AKT. Cancer Discov; 2(8); 685–93. ©2012 AACR.

Read the Commentary on this article by Hanrahan et al., p. 666.

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Layered Activation of Epicardial Scar in Arrhythmogenic Right Ventricular Dysplasia
Authors: Haqqani Haris M. , Tschabrunn Cory M. , Betensky Brian P. , Lavi Nimrod , Tzou Wendy S. , Zado Erica S. , Marchlinski Francis E.
Published: May 2012

Background—

Ventricular tachycardia ablation in arrhythmogenic right ventricular dysplasia (ARVD) is more successful when including epicardial ablation. Scarring may cause independent, layered epicardial activation and promote epicardially confined ventricular tachycardia circuits. We aimed to characterize transmural right ventricular activation in ARVD patients and to compare this with reference patients without structural heart disease.

Methods and Results—

Eighteen ARVD patients underwent detailed endocardial and epicardial sinus rhythm electroanatomic mapping. Bipolar activation was annotated at the sharpest intrinsic deflection including late potentials and compared with 6 patients with normal hearts. Total scar area was larger on the epicardium (97±78 cm
2
) than the endocardium (57±44 cm
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;
P
=0.04), with significantly more isolated potentials. Total epicardial activation time was longer than endocardial (172±54 versus 99±27 ms;
P
<0.01), and both were longer than in reference patients. Earliest endocardial site was the right ventricular anteroseptum in 17 of 18 ARVD patients versus 5 of 6 controls (
P
=0.446), and latest endocardial site was in the outflow tract in 13 of 18 ARVD patients versus 4 of 6 controls and tricuspid annulus in 5 of 18 ARVD patients versus 2 of 6 controls (
P
=1.00). In reference patients, epicardial activation directly opposite endocardial sites occurred in 5.2±1.9 ms, suggesting direct transmural activation. In contrast, ARVD patients had major activation delay to the epicardium with laminar central scar activation from the scar border, not by direct transmural spread from the endocardium.

Conclusions—

Transmural right ventricular activation is modified by ARVD scarring with a delayed epicardial activation sequence suggestive of independent rather than direct transmural activation. This may predispose ventricular tachycardia circuits contained entirely within the epicardium in ARVD and explains observations on the need for direct epicardial ablation to eliminate ventricular tachycardia.
Surgery for Primary Cardiac Tumors in Children
Authors: Padalino Massimo A. , Vida Vladimiro L. , Boccuzzo Giovanna , Tonello Marco , Sarris George E. , Berggren Hakan , Comas Juan V. , Di Carlo Duccio , Di Donato Roberto M. , Ebels Tjark , Hraska Viktor , Jacobs Jeffrey P. , Gaynor J. William , Metras Dominique , Pretre Rene , Pozzi Marco , Rubay Jean , Sairanen Heikki , Schreiber Christian , Maruszewski Bohdan , Basso Cristina , Stellin Giovanni
Published: May 2012

Background—

To evaluate indications and results of surgery for primary cardiac tumors in children.

Methods and Results—

Eighty-nine patients aged ≤18 years undergoing surgery for cardiac tumor between 1990 and 2005 from 16 centers were included retrospectively (M/F=41/48; median age 4.3 months, range 1 day to 18 years). Sixty-three patients (68.5%) presented with symptoms. Surgery consisted of complete resection in 62 (69.7%) patients, partial resection in 21 (23.6%), and cardiac transplant in 4 (4.5%). Most frequent histotypes (93.2%) were benign (rhabdomyoma, myxoma, teratoma, fibroma, and hemangioma). Postoperative complications occurred in 29.9%. Early and late mortality were 4.5% each (mean follow-up, 6.3±4.4 years); major adverse events occurred in 28.2% of the patients; 90.7% of patients are in New York Heart Association class I. There were no statistically significant differences in survival, postoperative complications, or adverse events after complete and partial resection in benign tumors other than myxomas. Cardiac transplant was associated significantly with higher mortality rate (
P=
0.006). Overall mortality was associated to malignancy (
P
=0.0008), and adverse events during follow-up (
P
=0.005).

Conclusions—

Surgery for primary cardiac tumors in children has good early and long-term outcomes, with low recurrence rate. Rhabdomyomas are the most frequent surgical histotypes. Malignant tumors negatively affect early and late survival. Heart transplant is indicated when conservative surgery is not feasible. Lack of recurrence after partial resection of benign cardiac tumors indicates that a less risky tumor debulking is effective for a subset of histotypes such as rhabdomyomas and fibromas.
Simple Score to Assess the Risk of Rejection After Orthotopic Heart Transplantation
Authors: Kilic Arman , Weiss Eric S. , Allen Jeremiah G. , Conte John V. , Shah Ashish S. , Baumgartner William A. , Yuh David D.
Published: May 2012

Background—

The aim of this study was to derive and validate a risk score for rejection after orthotopic heart transplantation.

Methods and Results—

The United Network for Organ Sharing registry was used to identify patients undergoing orthotopic heart transplantation between 1998 and 2008. A total of 14 265 eligible patients were randomly divided into derivation (80%; n=11 412) and validation (20%; n=2853) cohorts. The primary outcome was drug-treated rejection within 1 year of orthotopic heart transplantation. Covariates found to be associated (exploratory univariate
P
<0.2) with rejection were entered into a multivariable logistic regression model. Inclusion of each variable in the model was assessed by improvement in the McFadden pseudo-
R
2
, likelihood ratio test, and c index. A risk score was then generated through the use of relative magnitudes of the odds ratios from the derivation cohort, and its ability to predict rejection was tested independently in the validation cohort. A 13-point risk score incorporating 4 variables (age, race, sex, HLA matching) was created. The mean scores in the derivation and validation cohorts were 8.3±2.2 and 8.4±2.1, respectively. Predicted 1-year rejection rates based on the derivation cohort ranged from 16.2% (score=0) to 50.7% (score=13;
P
<0.001). In weighted regression analysis, there was a strong correlation between these predicted rates of rejection and actual, observed rejection rates in the validation cohort (
r
2
=0.96,
P
<0.001). Logistic regression analysis also demonstrated a significant association (odds ratio, 1.13;
P
<0.001). The c index of the composite score was equivalent in both the derivation and validation cohorts (c=0.67).

Conclusions—

This novel 13-point risk score is highly predictive of clinically significant rejection episodes within 1 year of orthotopic heart transplantation. It has potential utility in tailoring immunosuppressive regimens and in research stratification in orthotopic heart transplantation.
Remote Monitoring Reduces Healthcare Use and Improves Quality of Care in Heart Failure Patients With Implantable Defibrillators
Authors: Landolina Maurizio , Perego Giovanni B. , Lunati Maurizio , Curnis Antonio , Guenzati Giuseppe , Vicentini Alessandro , Parati Gianfranco , Borghi Gabriella , Zanaboni Paolo , Valsecchi Sergio , Marzegalli Maurizio
Published: May 2012

Background—

Heart failure patients with implantable cardioverter-defibrillators (ICDs) or an ICD for resynchronization therapy often visit the hospital for unscheduled examinations, placing a great burden on healthcare providers. We hypothesized that Internet-based remote interrogation systems could reduce emergency healthcare visits.

Methods and Results—

This multicenter randomized trial involving 200 patients compared remote monitoring with standard patient management consisting of scheduled visits and patient response to audible ICD alerts. The primary end point was the rate of emergency department or urgent in-office visits for heart failure, arrhythmias, or ICD-related events. Over 16 months, such visits were 35% less frequent in the remote arm (75 versus 117; incidence density, 0.59 versus 0.93 events per year;
P
=0.005). A 21% difference was observed in the rates of total healthcare visits for heart failure, arrhythmias, or ICD-related events (4.40 versus 5.74 events per year;
P
<0.001). The time from an ICD alert condition to review of the data was reduced from 24.8 days in the standard arm to 1.4 days in the remote arm (
P
<0.001). The patients' clinical status, as measured by the Clinical Composite Score, was similar in the 2 groups, whereas a more favorable change in quality of life (Minnesota Living With Heart Failure Questionnaire) was observed from the baseline to the 16th month in the remote arm (
P
=0.026).

Conclusions—

Remote monitoring reduces emergency department/urgent in-office visits and, in general, total healthcare use in patients with ICD or defibrillators for resynchronization therapy. Compared with standard follow-up through in-office visits and audible ICD alerts, remote monitoring results in increased efficiency for healthcare providers and improved quality of care for patients.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00873899.
Maternal Use of Hydroxychloroquine Is Associated With a Reduced Risk of Recurrent Anti-SSA/Ro-Antibody–Associated Cardiac Manifestations of Neonatal Lupus
Authors: Izmirly Peter M. , Costedoat-Chalumeau Nathalie , Pisoni Cecilia N. , Khamashta Munther A. , Kim Mimi Y. , Saxena Amit , Friedman Deborah , Llanos Carolina , Piette Jean-Charles , Buyon Jill P.
Published: May 2012

Background—

A recent case-control study suggested a benefit of hydroxychloroquine (HCQ) in lowering the risk of cardiac manifestations of neonatal lupus (cardiac-NL) in pregnancies of anti-SSA/Ro–positive patients with systemic lupus erythematosus. A historical cohort assembled from 3 international databases was used to evaluate whether HCQ reduces the nearly 10-fold increase in risk of recurrence of cardiac-NL independently of maternal health status.

Methods and Results—

Two hundred fifty-seven pregnancies of anti-SSA/Ro-positive mothers (40 exposed and 217 unexposed to HCQ) subsequent to the birth of a child with cardiac-NL were identified from 3 databases (United States, England, and France). Exposure was defined as the sustained use of HCQ throughout pregnancy with initiation before 10 weeks of gestation. The recurrence rate of cardiac-NL in fetuses exposed to HCQ was 7.5% (3 of 40) compared with 21.2% (46 of 217) in the unexposed group (
P
=0.050). Although there were no deaths in the exposed group, the overall case fatality rate of the cardiac-NL fetuses in the unexposed group was 21.7%. In a multivariable analysis that adjusted for database source, maternal race/ethnicity, and anti-SSB/La status, HCQ use remained significantly associated with a decreased risk of cardiac-NL (odds ratio, 0.23; 95% confidence interval, 0.06–0.92;
P
=0.037). Similar results were obtained with propensity score analysis, an alternative approach to adjust for possible confounding by indication.

Conclusion—

Aggregate data from a multinational effort show that in mothers at high risk of having a child with cardiac-NL, the use of HCQ may protect against recurrence of disease in a subsequent pregnancy.