bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictive value of CpG island methylator phenotype for tumor recurrence in hepatitis B virus-associated hepatocellular carcinoma following liver transplantation
Authors: Wu Li-Ming , Zhang Feng , Zhou Lin , Yang Zhe , Xie Hai-Yang , Zheng Shu-Sen
Published: August 2010

Background

CpG island methylator phenotype (CIMP), in which multiple genes concordantly methylated, has been demonstrated to be associated with progression, recurrence, as well as overall survival in some types of cancer.

Methods

We examined the promoter methylation status of seven genes includingP16, CDH1, GSTP1, DAPK, XAF1, SOCS1andSYKin 65 cases of HCC treated with LT by methylation-specific PCR. CIMP+ was defined as having three or more genes that are concordantly methylated. The relationship between CIMP status and clinicopathological parameters, as well as tumor recurrence was further analyzed.

Results

CIMP+ was more frequent in HCC with AFP > 400 ng/ml than those with AFP ≤ 400 ng/ml (P= 0.017). In addition, patients with CIMP+ were prone to have multiple tumor numbers than those with CIMP- (P= 0.007). Patients with CIMP+ tumors had significantly worse recurrence-free survival (RFS) than patients with CIMP-tumors by Kaplan-Meier estimates (P= 0.004). Multivariate analysis also revealed that CIMP status might be a novel independent prognostic factor of RFS for HCC patients treated with LT (HR: 3.581; 95% CI: 1.473-8.710,P= 0.005).

Conclusion

Our results suggested that CIMP could serve as a new prognostic biomarker to predict the risk of tumor recurrence in HCC after transplantation.
Siah1 proteins enhance radiosensitivity of human breast cancer cells
Authors: He Hai-Tao , Fokas Emmanouil , You An , Engenhart-Cabillic Rita , An Han-Xiang
Published: August 2010

Background

Siah proteins play an important role in cancer progression. We evaluated the effect of Siah1, its splice variants Siah1L and the Siah1 mutant with the RING finger deleted (Siah1ΔR) on radiosensitization of human breast cancer cells.

Methods

The status of Siah1 and Siah1L was analysed in five breast cancer cell lines. To establish stable cells, SKBR3 cells were transfected with Siah1, Siah-1L and Siah1ΔR. Siah1 function was suppressed by siRNA in MCF-7 cells. The impact of Siah1 overexpression and silencing on apoptosis, proliferation, survival, invasion ability and DNA repair was assessed in SKBR3 and MCF-7 cells, also in regards to radiation.

Results

Siah1 and Siah1L mRNA expression was absent in four of five breast cancer cells lines analysed. Overexpression of Siah1 and Siah1L enhanced radiation-induced apoptosis in stable transfected SKBR3 cells, while Siah1ΔR failed to show this effect. In addition, Siah1 and Siah1L significantly reduced cell clonogenic survival and proliferation. Siah1L sensitization enhancement ratio values were over 1.5 and 4.0 for clonogenic survival and proliferation, respectively, pointing to a highly cooperative and potentially synergistic fashion with radiation. Siah1 or Siah1L significantly reduced invasion ability of SKBR3 and suppressed Tcf/Lef factor activity. Importantly, Siah1 siRNA demonstrated opposite effects in MCF-7 cells. Siah1 and Siah1L overexpression resulted in inhibition of DNA repair as inferred by increased levels of DNA double-strand breaks in irradiated SKBR3 cells.

Conclusion

Our results reveal for the first time how overexpression of Siah1L and Siah1 can determine radiosensitivity of breast cancer cells. These findings suggest that development of drugs augmenting Siah1 and Siah1L activity could be a novel approach in improving tumor cell kill.
CRIMALDDI: a co-ordinated, rational, and integrated effort to set logical priorities in anti-malarial drug discovery initiatives
Authors: Boulton Ian C , Nwaka Solomon , Bathurst Ian , Lanzer Michael , Taramelli Donatella , Vial Henri , Doerig Christian , Chibale Kelly , Ward Steve A
Published: August 2010

Despite increasing efforts and support for anti-malarial drug R&D, globally anti-malarial drug discovery and development remains largely uncoordinated and fragmented. The current window of opportunity for large scale funding of R&D into malaria is likely to narrow in the coming decade due to a contraction in available resources caused by the current economic difficulties and new priorities (e.g. climate change). It is, therefore, essential that stakeholders are given well-articulated action plans and priorities to guide judgments on where resources can be best targeted.

The CRIMALDDI Consortium (a European Union funded initiative) has been set up to develop, through a process of stakeholder and expert consultations, such priorities and recommendations to address them. It is hoped that the recommendations will help to guide the priorities of the European anti-malarial research as well as the wider global discovery agenda in the coming decade.
Cadmium down-regulates expression of XIAP at the post-transcriptional level in prostate cancer cells through an NF-κB-independent, proteasome-mediated mechanism
Authors: Golovine Konstantin , Makhov Peter , Uzzo Robert G , Kutikov Alexander , Kaplan David J , Fox Eric , Kolenko Vladimir M
Published: August 2010

Background

Cadmium has been classified as a human carcinogen, affecting health through occupational and environmental exposure. Cadmium has a long biological half-life (>25 years), due to the flat kinetics of its excretion. The prostate is one of the organs with highest levels of cadmium accumulation. Importantly, patients with prostate cancer appear to have higher levels of cadmium both in the circulation and in prostatic tissues.

Results

In the current report, we demonstrate for the first time that cadmium down-regulates expression of the X-linked inhibitor of apoptosis protein (XIAP) in prostate cancer cells. Cadmium-mediated XIAP depletion occurs at the post-transcriptional level via an NF-κB-independent, proteasome-mediated mechanism and coincides with an increased sensitivity of prostate cancer cells to TNF-α-mediated apoptosis. Prolonged treatment with cadmium results in selection of prostate cancer cells with apoptosis-resistant phenotype. Development of apoptosis-resistance coincides with restoration of XIAP expression in cadmium-selected PC-3 cells.

Conclusions

Selection of cadmium-resistant cells could represent an adaptive survival mechanism that may contribute to progression of prostatic malignancies.
Regulation of the Aurora-A gene following topoisomerase I inhibition: implication of the Myc transcription Factor
Authors: Courapied Sandy , Cherier Julia , Vigneron Arnaud , Troadec Marie-Bérangère , Giraud Sandrine , Valo Isabelle , Prigent Claude , Gamelin Erick , Coqueret Olivier , Barré Benjamin
Published: August 2010

During the G2 phase of the cell cycle, the Aurora-A kinase plays an important role in centrosome maturation and progression to mitosis. In this study, we show in colorectal cell lines that Aurora-A expression is downregulated in response to topoisomerase I inhibition. Using chromatin immunoprecipitation assays, we have observed that the Myc transcription factor and its Max binding partner are associated with the Aurora-A promoter during the G2 phase of the cell cycle. RNA interference experiments indicated that Myc is involved in the regulation of the Aurora-A gene. Following topoisomerase I inhibition, the expression of Myc decreased whereas Mad was upregulated, and the association of Myc and Max with the promoter of the kinase was inhibited. In parallel, an increased association of Mad and Miz-1 was detected on DNA, associated with an inhibition of the recruitment of transcriptional coactivators. Interestingly, a gain of H3K9 trimethylation and HP1γ recruitment was observed on the Aurora-A promoter following sn38 treatment, suggesting that this promoter is located within SAHF foci following genotoxic treatment. Since Aurora-A is involved in centrosome maturation, we observed as expected that topoisomerase I inhibition prevented centrosome separation but did not affect their duplication. As a consequence, this led to G2 arrest and senescence induction.

These results suggest a model by which the Aurora-A gene is inactivated by the G2 checkpoint following topoisomerase I inhibition. We therefore propose the hypothesis that the coordinated overexpression of Myc and Aurora-A, together with a downregulation of Mad and Miz-1 should be tested as a prognosis signature of poor responses to topoisomerase I inhibitors.
Anti-oxidant effect of gold nanoparticles restrains hyperglycemic conditions in diabetic mice
Authors: BarathManiKanth Selvaraj , Kalishwaralal Kalimuthu , Sriram Muthuirulappan , Pandian SureshBabu Ram Kumar , Youn Hyung-seop , Eom SooHyun , Gurunathan Sangiliyandi
Published: August 2010

Background

Oxidative stress is imperative for its morbidity towards diabetic complications, where abnormal metabolic milieu as a result of hyperglycemia, leads to the onset of several complications. A biological antioxidant capable of inhibiting oxidative stress mediated diabetic progressions; during hyperglycemia is still the need of the era. The current study was performed to study the effect of biologically synthesized gold nanoparticles (AuNPs) to control the hyperglycemic conditions in streptozotocin induced diabetic mice.

Results

The profound control of AuNPs over the anti oxidant enzymes such as GSH, SOD, Catalase and GPx in diabetic mice to normal, by inhibition of lipid peroxidation and ROS generation during hyperglycemia evidence their anti-oxidant effect during hyperglycemia. The AuNPs exhibited an insistent control over the blood glucose level, lipids and serum biochemical profiles in diabetic mice near to the control mice provokes their effective role in controlling and increasing the organ functions for better utilization of blood glucose. Histopathological and hematological studies revealed the non-toxic and protective effect of the gold nanoparticles over the vital organs when administered at dosage of 2.5 mg/kilogram.body.weight/day. ICP-MS analysis revealed the biodistribution of gold nanoparticles in the vital organs showing accumulation of AuNPs in the spleen comparatively greater than other organs.

Conclusion

The results obtained disclose the effectual role of AuNPs as an anti-oxidative agent, by inhibiting the formation of ROS, scavenging free radicals; thus increasing the anti-oxidant defense enzymes and creating a sustained control over hyperglycemic conditions which consequently evoke the potential of AuNPs as an economic therapeutic remedy in diabetic treatments and its complications.
Key role for spinal dorsal horn microglial kinin B1receptor in early diabetic pain neuropathy
Authors: Talbot Sébastien , Chahmi Emna , Dias Jenny Pena , Couture Réjean
Published: August 2010

Background

The pro-nociceptive kinin B1receptor (B1R) is upregulated on sensory C-fibres, astrocytes and microglia in the spinal cord of streptozotocin (STZ)-diabetic rat. This study aims at defining the role of microglial kinin B1R in diabetic pain neuropathy.

Methods

Sprague-Dawley rats were made diabetic with STZ (65 mg/kg, i.p.), and 4 days later, two specific inhibitors of microglial cells (fluorocitrate, 1 nmol, i.t.; minocycline, 10 mg/kg, i.p.) were administered to assess the impact on thermal hyperalgesia, allodynia and mRNA expression (qRT-PCR) of B1R and pro-inflammatory markers. Spinal B1R binding sites ((125I)-HPP-desArg10-Hoe 140) were also measured by quantitative autoradiography. Inhibition of microglia was confirmed by confocal microscopy with the specific marker Iba-1. Effects of intrathecal and/or systemic administration of B1R agonist (des-Arg9-BK) and antagonists (SSR240612 and R-715) were measured on neuropathic pain manifestations.

Results

STZ-diabetic rats displayed significant tactile and cold allodynia compared with control rats. Intrathecal or peripheral blockade of B1R or inhibition of microglia reversed time-dependently tactile and cold allodynia in diabetic rats without affecting basal values in control rats. Microglia inhibition also abolished thermal hyperalgesia and the enhanced allodynia induced by intrathecal des-Arg9-BK without affecting hyperglycemia in STZ rats. The enhanced mRNA expression (B1R, IL-1β, TNF-α, TRPV1) and Iba-1 immunoreactivity in the STZ spinal cord were normalized by fluorocitrate or minocycline, yet B1R binding sites were reduced by 38%.

Conclusion

The upregulation of kinin B1R in spinal dorsal horn microglia by pro-inflammatory cytokines is proposed as a crucial mechanism in early pain neuropathy in STZ-diabetic rats.
Central Administration of Lipopolysaccharide Induces Depressive-like Behavior in Vivo and Activates Brain Indoleamine 2,3 Dioxygenase In Murine Organotypic Hippocampal Slice Cultures
Authors: Fu Xin , Zunich Samantha M , O'Connor Jason C , Kavelaars Annemieke , Dantzer Robert , Kelley Keith W
Published: August 2010

Background

Transient stimulation of the innate immune system by an intraperitoneal injection of lipopolysaccharide (LPS) activates peripheral and central expression of the tryptophan degrading enzyme indoleamine 2,3 dioxygenase (IDO) which mediates depressive-like behavior. It is unknown whether direct activation of the brain with LPS is sufficient to activate IDO and induce depressive-like behavior.

Methods

Sickness and depressive-like behavior in C57BL/6J mice were assessed by social exploration and the forced swim test, respectively. Expression of cytokines and IDO mRNA was measured by real-time RT-PCR and cytokine protein was measured by enzyme-linked immunosorbent assays (ELISAs). Enzymatic activity of IDO was estimated as the amount of kynurenine produced from tryptophan as determined by high pressure liquid chromatography (HPLC) with electrochemical detection.

Results

Intracerebroventricular (i.c.v.) administration of LPS (100 ng) increased steady-state transcripts of TNFα, IL-6 and the inducible isoform of nitric oxide synthase (iNOS) in the hippocampus in the absence of any change in IFNγ mRNA. LPS also increased IDO expression and induced depressive-like behavior, as measured by increased duration of immobility in the forced swim test. The regulation of IDO expression was investigated using in situ organotypic hippocampal slice cultures (OHSCs) derived from brains of newborn C57BL/6J mice. In accordance with the in vivo data, addition of LPS (10 ng/ml) to the medium of OHSCs induced steady-state expression of mRNA transcripts for IDO that peaked at 6 h and translated into increased IDO enzymatic activity within 8 h post-LPS. This activation of IDO by direct application of LPS was preceded by synthesis and secretion of TNFα and IL-6 protein and activation of iNOS while IFNγ expression was undetectable.

Conclusion

These data establish that activation of the innate immune system in the brain is sufficient to activate IDO and induce depressive-like behavior in the absence of detectable IFNγ. Targeting IDO itself may provide a novel therapy for inflammation-associated depression.
Chronic leucine supplementation improves glycemic control in etiologically distinct mouse models of obesity and diabetes mellitus
Authors: Guo Kaiying , Yu Yi-Hao , Hou Jue , Zhang Yiying
Published: August 2010

Background

Leucine may function as a signaling molecule to regulate metabolism. We have previously shown that dietary leucine supplementation significantly improves glucose and energy metabolism in diet-induced obese mice, suggesting that leucine supplementation could potentially be a useful adjuvant therapy for obesity and type 2 diabetes. Since the underlying cause for obesity and type 2 diabetes is multifold, we further investigated metabolic effects of leucine supplementation in obese/diabetes mouse models with different etiologies, and explored the underlying molecular mechanisms.

Methods

Leucine supplementation was carried out in NONcNZO10/LtJ (RCS10) - a polygenic model predisposed to beta cell failure and type 2 diabetes, and in B6.Cg-Ay/J (A

y
) - a monogenic model for impaired central melanocortin receptor signaling, obesity, and severe insulin resistance. Mice in the treatment group received the drinking water containing 1.5% leucine for up to 8 months; control mice received the tap water. Body weight, body composition, blood HbA1c levels, and plasma glucose and insulin levels were monitored throughout and/or at the end of the study period. Indirect calorimetry, skeletal muscle gene expression, and adipose tissue inflammation were also assessed in A

y
mice.

Results

Leucine supplementation significantly reduced HbA1c levels throughout the study period in both RCS10 and A

y
mice. However, the treatment had no long term effect on body weight or adiposity. The improvement in glycemic control was associated with an increased insulin response to food challenge in RCS10 mice and decreased plasma insulin levels in A

y
mice. In leucine-treated A

y
mice, energy expenditure was increased by ~10% (p < 0.05) in both dark and light cycles while the physical activity level was unchanged. The expression levels of UCP3, CrAT, PPAR-alpha, and NRF-1, which are known to regulate mitochondrial oxidative function, were significantly increased in the soleus muscle of leucine-treated Ay mice whereas the expression levels of MCP-1 and TNF-alpha and macrophage infiltration in adipose tissue were significantly reduced.

Conclusions

Chronic leucine supplementation significantly improves glycemic control in multiple mouse models of obesity and diabetes with distinct etiologies. The metabolic benefits of leucine supplementation are likely mediated via multiple mechanisms in different tissues, but are not necessarily dependent of weight reduction.
Bone Cancer Induces a Unique Central Sensitization through Synaptic Changes in a Wide Area of the Spinal Cord
Authors: Yanagisawa Yoshikazu , Furue Hidemasa , Kawamata Tomoyuki , Uta Daisuke , Yamamoto Jun , Furuse Shingo , Katafuchi Toshihiko , Imoto Keiji , Iwamoto Yukihide , Yoshimura Megumu
Published: August 2010

Background:

Chronic bone cancer pain is thought to be partly due to central sensitization. Although murine models of bone cancer pain revealed significant neurochemical changes in the spinal cord, it is not known whether this produces functional alterations in spinal sensory synaptic transmission. In this study, we examined excitatory synaptic responses evoked in substantia gelatinosa (SG, lamina II) neurons in spinal cord slices of adult mice bearing bone cancer, using whole-cell voltage-clamp recording techniques.

Results:

Mice at 14 to 21 days after sarcoma implantation into the femur exhibited hyperalgesia to mechanical stimuli applied to the skin of the ipsilateral hind paw, as well as showing spontaneous and movement evoked pain-related behaviors. SG neurons exhibited spontaneous excitatory postsynaptic currents (EPSCs). The amplitudes of spontaneous EPSCs were significantly larger in cancer-bearing than control mice without any changes in passive membrane properties of SG neurons. In the presence of TTX, the amplitude of miniature EPSCs in SG neurons was increased in cancer-bearing mice and this was observed for cells sampled across a wide range of lumbar segmental levels. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor- and N-methyl- D-aspartate (NMDA) receptor-mediated EPSCs evoked by focal stimulation were also enhanced in cancer-bearing mice. Dorsal root stimulation elicited mono- and/or polysynaptic EPSCs that were caused by the activation of Aδ and/or C afferent fibers in SG neurons from both groups of animals. The number of cells receiving monosynaptic inputs from Aδ and C fibers was not different between the two groups. However, the amplitude of the monosynaptic C fiber-evoked EPSCs and the number of SG neurons receiving polysynaptic inputs from Aδ and C fibers were increased in cancer-bearing mice.

Conclusions:

These results show that spinal synaptic transmission mediated through Aδ and C fibers is enhanced in the SG across a wide area of lumbar levels following sarcoma implantation in the femur. This widespread spinal sensitization may be one of the underlying mechanisms for the development of chronic bone cancer pain.
Overexpression of candidate tumor suppressor ECRG4 inhibits glioma proliferation and invasion
Authors: Li Wei , Liu Xinrui , Zhang Bo , Qi Dongxue , Zhang Lihong , Jin Yuhong , Yang Hongfa
Published: August 2010

Background

ECRG4 has been shown to be a candidate tumor suppressor in several tumors, but its role in glioma remains poorly understood. In this study, we examined the mRNA expression of ECRG4 and investigated its biological role in glioma cells.

Methods

Real-time PCR was used to examine expression of ECRG4 in gliomas and their matched brain tissues. The effect of ECRG4 expression on cell proliferation, invasion, and migration was investigated in human U251 glioma cells. Finally, the regulation of transcription factor NF-kB by ECRG4 was evaluated by western blotting.

Results

Of the 10 paired samples analyzed, 9 glioma tissues displayed the decreased expression of ECRG4 compared to matched normal brain tissues. Cells transfected with ECRG4 showed significantly decreased cell proliferation as evaluated by MTT and colony formation assays. Furthermore, overexpression inhibited cell migration and invasion in transwell and Boyden chamber experiments and retarded the cell cycle progression from G1 to S phase by FACSCaliber cytometry. Protein levels of nuclear transcription factor NF-kB, which is involved in cell proliferation, inversely correlated with ECRG4 expression.

Conclusion

Our data suggest that ECRG4 serves as a tumor suppressor in glioma.
Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib
Authors: Jain Lokesh , Sissung Tristan M , Danesi Romano , Kohn Elise C , Dahut William L , Kummar Shivaani , Venzon David , Liewehr David , English Bevin C , Baum Caitlin E , Yarchoan Robert , Giaccone Giuseppe , Venitz Jürgen , Price Douglas K , Figg William D
Published: August 2010

Background

Hypertension (HT) and hand-foot skin reactions (HFSR) may be related to the activity of bevacizumab and sorafenib. We hypothesized that these toxicities would correspond to favorable outcome in these drugs, that HT and HFSR would coincide, and thatVEGFR2genotypic variation would be related to toxicity and clinical outcomes.

Methods

Toxicities (≥ grade 2 HT or HFSR), progression-free survival (PFS), and overall survival (OS) following treatment initiation were evaluated. Toxicity incidence and VEGFR2 H472Q and V297I status were compared to clinical outcomes.

Results

Individuals experiencing HT had longer PFS following bevacizumab therapy than those without this toxicity in trials utilizing bevacizumab in patients with prostate cancer (31.5 vs 14.9 months,n= 60,P= 0.0009), and bevacizumab and sorafenib in patients with solid tumors (11.9 vs. 3.7 months,n= 27,P= 0.052). HT was also linked to a > 5-fold OS benefit after sorafenib and bevacizumab cotherapy (5.7 versus 29.0 months,P= 0.0068). HFSR was a marker for prolonged PFS during sorafenib therapy (6.1 versus 3.7 months respectively,n= 113,P= 0.0003). HT was a risk factor for HFSR in patients treated with bevacizumab and/or sorafenib (OR(95%CI) = 3.2(1.5-6.8),P= 0.0024). Carriers of variant alleles at VEGFR2 H472Q experienced greater risk of developing HT (OR(95%CI) = 2.3(1.2 - 4.6),n= 170,P= 0.0154) and HFSR (OR(95%CI) = 2.7(1.3 - 5.6),n= 170,P= 0.0136).

Conclusions

This study suggests that HT and HFSR may be markers for favorable clinical outcome, HT development may be a marker for HFSR, andVEGFR2alleles may be related to the development of toxicities during therapy with bevacizumab and/or sorafenib.
Prevalence and risk factors of vertebral compression fractures in female SLE patients
Authors: Almehed Katarina , Hetényi Szabolcs , Ohlsson Claes , Carlsten Hans , Forsblad-d'Elia Helena
Published: August 2010

Introduction

Our objective was to determine the frequency of and factors associated with prevalent vertebral compression fractures in female systemic lupus erythematosus (SLE) patients attending rheumatologists in western Sweden.

Methods

In this cross sectional study 150 women were included. They were examined with x-ray of thoracic and lumbar spine (Th4 to L4). A reduction of at least 20% of any vertebral height, assessed by Genant's semiquantitative method, was defined as a fracture. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DXA).

Results

Median patient age was 47 years (20 to 82) and disease duration 11 years (1 to 41). Only 6 (4%) women had a history of clinical compressions whereas 43 (29%) had at least one radiological fracture each. The patients with at least one fracture at any site were characterized by older age (P < 0.001), being postmenopausal (P < 0.01), higher Systemic Lupus International Collaborative Clinics Damage Index (P < 0.05), lower BMD total hip and femoral neck (P < 0.05), more peripheral fractures (P < 0.01), medication with bisphosphonates (P <0.05) and calcium and vitamin D3 (P < 0.05). There were no significant differences regarding current or cumulative glucocorticosteroid dose between the groups. In logistic regression analyses high age remained as a risk factor of at least one vertebral fracture at any site whereas low BMD in total hip was associated with vertebral fracture in the lumbar spine.

Conclusions

Radiological compression fractures are common but seldom diagnosed in SLE patients. High age and low BMD in total hip, but not in spine, was associated with vertebral fractures.
HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer
Authors: Da Silva Leonard , Simpson Peter T , Smart Chanel E , Cocciardi Sibylle , Waddell Nic , Lane Annette , Morrison Brian J , Vargas Ana Cristina , Healey Sue , Beesley Jonathan , Pakkiri Pria , Parry Suzanne , Kurniawan Nyoman , Reid Lynne , Keith Patricia , Faria Paulo , Pereira Emilio , Skalova Alena , Bilous Michael , Balleine Rosemary L , Do Hongdo , Dobrovic Alexander , Fox Stephen , Franco Marcello , Reynolds Brent , Khanna Kum Kum , Cummings Margaret , Chenevix-Trench Georgia , Lakhani Sunil R
Published: August 2010

Introduction

Metastases to the brain from breast cancer have a high mortality, and basal-like breast cancers have a propensity for brain metastases. However, the mechanisms that allow cells to colonize the brain are unclear.

Methods

We used morphology, immunohistochemistry, gene expression and somatic mutation profiling to analyze 39 matched pairs of primary breast cancers and brain metastases, 22 unmatched brain metastases of breast cancer, 11 non-breast brain metastases and 6 autopsy cases of patients with breast cancer metastases to multiple sites, including the brain.

Results

Most brain metastases were triple negative and basal-like. The brain metastases over-expressed one or more members of the HER family and in particular HER3 was significantly over-expressed relative to matched primary tumors. Brain metastases from breast and other primary sites, and metastases to multiple organs in the autopsied cases, also contained somatic mutations in EGFR, HRAS, KRAS, NRAS or PIK3CA. This paralleled the frequent activation of AKT and MAPK pathways. In particular, activation of the MAPK pathway was increased in the brain metastases compared to the primary tumors.

Conclusions

Deregulated HER family receptors, particularly HER3, and their downstream pathways are implicated in colonization of brain metastasis. The need for HER family receptors to dimerize for activation suggests that tumors may be susceptible to combinations of anti-HER family inhibitors, and may even be effective in the absence of HER2 amplification (that is, in triple negative/basal cancers). However, the presence of activating mutations in PIK3CA, HRAS, KRAS and NRAS suggests the necessity for also specifically targeting downstream molecules.
Breast cancer incidence and overdiagnosis in Catalonia (Spain)
Authors: Martinez-Alonso Montserrat , Vilaprinyo Ester , Marcos-Gragera Rafael , Rue Montserrat
Published: August 2010

Introduction

Early detection of breast cancer (BC) with mammography may cause overdiagnosis and overtreatment, detecting tumors which would remain undiagnosed during a lifetime. The aims of this study were: first, to model invasive BC incidence trends in Catalonia (Spain) taking into account reproductive and screening data; and second, to quantify the extent of BC overdiagnosis.

Methods

We modeled the incidence of invasive BC using a Poisson regression model. Explanatory variables were: age at diagnosis and cohort characteristics (completed fertility rate, percentage of women that use mammography at age 50, and year of birth). This model also was used to estimate the background incidence in the absence of screening. We used a probabilistic model to estimate the expected BC incidence if women in the population used mammography as reported in health surveys. The difference between the observed and expected cumulative incidences provided an estimate of overdiagnosis.

Results

Incidence of invasive BC increased, especially in cohorts born from 1940 to 1955. The biggest increase was observed in these cohorts between the ages of 50 to 65 years, where the final BC incidence rates more than doubled the initial ones. Dissemination of mammography was significantly associated with BC incidence and overdiagnosis. Our estimates of overdiagnosis ranged from 0.4% to 46.6%, for women born around 1935 and 1950, respectively.

Conclusions

Our results support the existence of overdiagnosis in Catalonia attributed to mammography usage, and the limited malignant potential of some tumors may play an important role. Women should be better informed about this risk. Research should be oriented towards personalized screening and risk assessment tools.
Homeobox transcription factor muscle segment homeobox 2 (Msx2) correlates with good prognosis in breast cancer patients and induces apoptosis in vitro
Authors: Lanigan Fiona , Gremel Gabriela , Hughes Rowena , Brennan Donal J , Martin Finian , Jirström Karin , Gallagher William M
Published: August 2010

Introduction

The homeobox-containing transcription factor muscle segment homeobox 2 (Msx2) plays an important role in mammary gland development. However, the clinical implications of Msx2 expression in breast cancer are unclear. The aims of this study were to investigate the potential clinical value of Msx2 as a breast cancer biomarker and to clarify its functional role in vitro.

Methods

Msx2 gene expression was first examined in a well-validated breast cancer transcriptomic dataset of 295 patients. Msx2 protein expression was then evaluated by immunohistochemistry in a tissue microarray (TMA) containing 281 invasive breast tumours. Finally, to assess the functional role of Msx2 in vitro, Msx2 was ectopically expressed in a highly invasive breast tumour cell line (MDA-MB-231) and an immortalised breast cell line (MCF10a), and these cell lines were examined for changes in growth rate, cell death and cell signalling.

Results

Examination of Msx2 mRNA expression in a breast cancer transcriptomic dataset demonstrated that increased levels of Msx2 were associated with good prognosis (P = 0.011). Evaluation of Msx2 protein expression on a TMA revealed that Msx2 was detectable in both tumour cell nuclei and cytoplasm. Cytoplasmic Msx2 expression was associated with low grade tumours (P = 0.012) and Ki67 negativity (P = 0.018). Nuclear Msx2 correlated with low-grade tumours (P = 0.015), estrogen receptor positivity (P = 0.038), low Ki67 (P = 0.005) and high cyclin D1 expression (P = 0.037). Increased cytoplasmic Msx2 expression was associated with a prolonged breast cancer-specific survival (P = 0.049), recurrence-free survival (P = 0.029) and overall survival (P = 0.019). Ectopic expression of Msx2 in breast cell lines resulted in radically decreased cell viability mediated by induction of cell death via apoptosis. Further analysis of Msx2-expressing cells revealed increased levels of p21 and phosphorylated extracellular signal-regulated kinase (ERK) and decreased levels of Survivin and the 'split ends' (SPEN) protein family member RBM15.

Conclusions

We conclude that increased Msx2 expression results in improved outcome for breast cancer patients, possibly by increasing the likelihood of tumour cell death by apoptosis.
The impact of delirium on the prediction of in-hospital mortality in intensive care patients
Authors: van den Boogaard Mark , Peters Sanne AE , van der Hoeven Johannes G , Dagnelie Pieter C , Leffers Pieter , Pickkers Peter , Schoonhoven Lisette
Published: August 2010

Introduction

Predictive models, such as acute physiology and chronic health evaluation II (APACHE-II), are widely used in intensive care units (ICUs) to estimate mortality. Although the presence of delirium is associated with a higher mortality in ICU patients, delirium is not part of the APACHE-II model. The aim of the current study was to evaluate whether delirium, present within 24 hours after ICU admission, improves the predictive value of the APACHE-II score.

Methods

In a prospective cohort study 2116 adult patients admitted between February 2008 and February 2009 were screened for delirium with the confusion assessment method-ICU (CAM-ICU). Exclusion criteria were sustained coma and unable to understand Dutch. Logistic regression analysis was used to estimate the predicted probabilities in the model with and without delirium. Calibration plots and the Hosmer-Lemeshow test (HL-test) were used to assess calibration. The discriminatory power of the models was analyzed by the area under the receiver operating characteristics curve (AUC) and AUCs were compared using the Z-test.

Results

1740 patients met the inclusion criteria, of which 332 (19%) were delirious at the time of ICU admission or within 24 hours after admission. Delirium was associated with in-hospital mortality in unadjusted models, odds ratio (OR): 3.22 (95% confidence interval [CI]: 2.23 - 4.66). The OR between the APACHE-II and in-hospital mortality was 1.15 (95% CI 1.12 - 1.19) per point. The predictive accuracy of the APACHE-II did not improve after adding delirium, both in the total group as well as in the subgroup without cardiac surgery patients. The AUC of the APACHE model without delirium was 0.77 (0.73 - 0.81) and 0.78 (0.74 - 0.82) when delirium was added to the model. The z-value was 0.92 indicating no improvement in discriminative power, and the HL-test and calibration plots indicated no improvement in calibration.

Conclusions

Although delirium is a significant predictor of mortality in ICU patients, adding delirium as an additional variable to the APACHE-II model does not result in an improvement in its predictive estimates.
Treatment of hypophosphatemia in the intensive care unit: a review
Authors: Geerse Daniël A , Bindels Alexander J , Kuiper Michael A , Roos Arnout N , Spronk Peter E , Schultz Marcus J
Published: August 2010

Introduction

Currently no evidence-based guideline exists for the approach to hypophosphatemia in critically ill patients.

Methods

We performed a narrative review of the medical literature to identify the incidence, symptoms, and treatment of hypophosphatemia in critically ill patients. Specifically, we searched for answers to the questions whether correction of hypophosphatemia is associated with improved outcome, and whether a certain treatment strategy is superior.

Results

Incidence: hypophosphatemia is frequently encountered in the intensive care unit; and critically ill patients are at increased risk for developing hypophosphatemia due to the presence of multiple causal factors. Symptoms: hypophosphatemia may lead to a multitude of symptoms, including cardiac and respiratory failure. Treatment: hypophosphatemia is generally corrected when it is symptomatic or severe. However, although multiple studies confirm the efficacy and safety of intravenous phosphate administration, it remains uncertain when and how to correct hypophosphatemia. Outcome: in some studies, hypophosphatemia was associated with higher mortality; a paucity of randomized controlled evidence exists for whether correction of hypophosphatemia improves the outcome in critically ill patients.

Conclusions

Additional studies addressing the current approach to hypophosphatemia in critically ill patients are required. Studies should focus on the association between hypophosphatemia and morbidity and/or mortality, as well as the effect of correction of this electrolyte disorder.
Mortality associated with administration of high-dose tranexamic acid and aprotinin in primary open-heart procedures: a retrospective analysis
Authors: Sander Michael , Spies Claudia D , Martiny Viktoria , Rosenthal Christoph , Wernecke Klaus-Dieter , von Heymann Christian
Published: August 2010

Introduction

Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding. Because of safety concerns, aprotinin was withdrawn from the market in 2007. Since then, tranexamic acid (TXA) has become the antifibrinolytic treatment of choice in many heart centers. The safety profile of TXA has not been extensively studied. Therefore, the aim of this study was to evaluate safety and efficiency of TXA compared with aprotinin in cardiac surgery.

Methods

Since July 1, 2006, TXA has been administered at a dose of 50 mg/kg tranexamic acid before cardiopulmonary bypass (CPB) and 50 mg/kg into the priming fluid of the CPB. Prior to this, all patients were treated with aprotinin at a dose of 50,000 KIU per kilogram body weight. Safety was evaluated with mortality, biomarkers, and the diagnosis of myocardial infarction, ischemic stroke, convulsive seizures, and acute renal failure in the intensive care unit (ICU), intermediate care unit (IMCU), and hospital stay. Efficiency was evaluated by the need for transfusion of blood products and total postoperative blood loss.

Results

After informed consent, 893 patients were included in our database (557 consecutive patients receiving aprotinin and 336 patients receiving TXA). A subgroup of 320 patients undergoing open-heart procedures (105 receiving TXA and 215 receiving aprotinin) was analyzed separately. In the aprotinin group, a higher rate of late events of ischemic stroke (3.4% versus 0.9%; P = 0.02) and neurologic disability (5.8% versus 2.4%; P = 0.02) was found. The rate of postoperative convulsive seizures was increased in tendency in patients receiving TXA (2.7% versus 0.9%; P = 0.05). The use of TXA was associated with higher cumulative drainage losses (PANOVA < 0.01; Ptime < 0.01) and a higher rate of repeated thoracotomy for bleeding (6.9% versus 2.4%; P < 0.01). In the subgroup of patients with open-chamber procedures, mortality was higher in the TXA group (16.2% TXA versus 7.5% aprotinin; P = 0.02). Multivariate logistic regression identified EURO score II and CPB time as additional risk factors for this increased mortality.

Conclusions

The use of high-dose TXA is questioned, as our data suggest an association between higher mortality and minor efficiency while the safety profile of this drug is not consistently improved. Further confirmatory prospective studies evaluating the efficacy and safety profile of TXA are urgently needed to find a safe dosage for this antifibrinolytic drug.
Phase II Trial of Anastrozole Plus Goserelin in the Treatment of Hormone Receptor–Positive, Metastatic Carcinoma of the Breast in Premenopausal Women
Authors: Carlson Robert. W. , Theriault Richard , Schurman Christine M. , Rivera Edgardo , Chung Cathie T. , Phan See-Chun , Arun Banu , Dice Kristine , Chiv Vivian Y. , Green Marjorie , Valero Vicente
Published: August 2010

Purpose

To explore the antitumor activity of the aromatase inhibitor, anastrozole, in the treatment of premenopausal women with hormone receptor–positive, metastatic breast cancer who have been rendered functionally postmenopausal with the use of the luteinizing hormone-releasing hormone agonist, goserelin.

Patients and Methods

Premenopausal women with estrogen and/or progesterone receptor–positive, metastatic or recurrent breast cancer were enrolled in this prospective, single-arm, multicenter phase II trial. Patients were treated with goserelin 3.6 mg subcutaneous monthly and began anastrozole 1-mg daily 21 days after the first injection of goserelin. Patients continued on treatment until disease progression or unacceptable toxicity.

Results

Thirty-five patients were enrolled of which 32 were evaluable for response and toxicity. Estradiol suppression was assessed, with mean estradiol levels of 18.7 pg/mL at 3 months and 14.8 pg/mL at 6 months. One participant (3.1%) experienced a complete response, 11 (34.4%) experienced partial response, and 11 (34.4%) experienced stable disease for 6 months or longer for a clinical benefit rate of 71.9%. Median time to progression was 8.3 months (range, 2.1 to 63+) and median survival was not been reached (range, 11.1 to 63+). The most common adverse events were fatigue (50%), arthralgias (53%), and hot flashes (59%). There were no grade 4 to 5 toxicities.

Conclusion

The combination of goserelin plus anastrozole has substantial antitumor activity in the treatment of premenopausal women with hormone receptor–positive metastatic breast cancer.
Trastuzumab-Induced Cardiotoxicity: Clinical and Prognostic Implications of Troponin I Evaluation
Authors: Cardinale Daniela , Colombo Alessandro , Torrisi Rosalba , Sandri Maria T. , Civelli Maurizio , Salvatici Michela , Lamantia Giuseppina , Colombo Nicola , Cortinovis Sarah , Dessanai Maria A. , Nolè Franco , Veglia Fabrizio , Cipolla Carlo M.
Published: August 2010

Purpose

Treatment of breast cancer with trastuzumab is complicated by cardiotoxicity in up to 34% of the patients. In most patients, trastuzumab-induced cardiotoxicity (TIC) is reversible: left ventricular ejection fraction (LVEF) improves after trastuzumab withdrawal and with, or sometimes without, initiation of heart failure (HF) therapy. The reversibility of TIC, however, is not foreseeable, and identification of patients at risk and of those who will not recover from cardiac dysfunction is crucial. The usefulness of troponin I (TNI) in the identification of patients at risk for TIC and in the prediction of LVEF recovery has never been investigated.

Patients and Methods

In total, 251 women were enrolled. TNI was measured before and after each trastuzumab cycle. LVEF was evaluated at baseline, every 3 months during trastuzumab therapy, and every 6 months afterward. In case of TIC, trastuzumab was discontinued, and HF treatment with enalapril and carvedilol was initiated. TIC was defined as LVEF decrease of > 10 units and below 50%. Recovery from TIC was defined as LVEF increase above 50%.

Results

TIC occurred in 42 patients (17%) and was more frequent in patients with TNI elevation (TNI+; 62% v 5%; P < .001). Twenty-five patients (60%) recovered from TIC. LVEF recovery occurred less frequently in TNI+ patients (35% v 100%; P < .001). At multivariate analysis, TNI+ was the only independent predictor of TIC (hazard ratio [HR], 22.9; 95% CI, 11.6 to 45.5; P < .001) and of lack of LVEF recovery (HR, 2.88; 95% CI,1.78 to 4.65; P < .001).

Conclusion

TNI+ identifies trastuzumab-treated patients who are at risk for cardiotoxicity and are unlikely to recover from cardiac dysfunction despite HF therapy.
Hepatocellular Carcinoma: Consensus Recommendations of the National Cancer Institute Clinical Trials Planning Meeting
Authors: Thomas Melanie B. , Jaffe Deborah , Choti Michael M. , Belghiti Jacques , Curley Steven , Fong Yuman , Gores Gregory , Kerlan Robert , Merle Phillipe , O'Neil Bert , Poon Ronnie , Schwartz Lawrence , Tepper Joel , Yao Francis , Haller Daniel , Mooney Margaret , Venook Alan
Published: August 2010

Hepatocelluar carcinoma (HCC) is the most common primary malignancy of the liver in adults and the third most common cause of cancer death worldwide. The incidence of HCC in the United States is rising steadily because of the prevalence of hepatitis C viral infection and other causes of hepatic cirrhosis. The majority of patients have underlying hepatic dysfunction, which complicates patient management and the search for safe and effective therapies. The Clinical Trials Planning Meeting (CTPM) in HCC was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to identify the key knowledge gaps in HCC and define clinical research priorities. The CTPM structured its review according to current evidence-based treatment modalities in HCC and prioritized the recommendations on the basis of the patient populations representing the greatest unmet medical need.
Relationship Between Tumor Gene Expression and Recurrence in Four Independent Studies of Patients With Stage II/III Colon Cancer Treated With Surgery Alone or Surgery Plus Adjuvant Fluorouracil Plus Leucovorin
Authors: O'Connell Michael J. , Lavery Ian , Yothers Greg , Paik Soonmyung , Clark-Langone Kim M. , Lopatin Margarita , Watson Drew , Baehner Frederick L. , Shak Steven , Baker Joffre , Cowens J. Wayne , Wolmark Norman
Published: August 2010

Purpose

These studies were conducted to determine the relationship between quantitative tumor gene expression and risk of cancer recurrence in patients with stage II or III colon cancer treated with surgery alone or surgery plus fluorouracil (FU) and leucovorin (LV) to develop multigene algorithms to quantify the risk of recurrence as well as the likelihood of differential treatment benefit of FU/LV adjuvant chemotherapy for individual patients.

Patients and Methods

We performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) on RNA extracted from fixed, paraffin-embedded (FPE) tumor blocks from patients with stage II or III colon cancer who were treated with surgery alone (n = 270 from National Surgical Adjuvant Breast and Bowel Project [NSABP] C-01/C-02 and n = 765 from Cleveland Clinic [CC]) or surgery plus FU/LV (n = 308 from NSABP C-04 and n = 508 from NSABP C-06). Overall, 761 candidate genes were studied in C-01/C-02 and C-04, and a subset of 375 genes was studied in CC/C-06.

Results

A combined analysis of the four studies identified 48 genes significantly associated with risk of recurrence and 66 genes significantly associated with FU/LV benefit (with four genes in common). Seven recurrence-risk genes, six FU/LV-benefit genes, and five reference genes were selected, and algorithms were developed to identify groups of patients with low, intermediate, and high likelihood of recurrence and benefit from FU/LV.

Conclusion

RT-qPCR of FPE colon cancer tissue applied to four large independent populations has been used to develop multigene algorithms for estimating recurrence risk and benefit from FU/LV. These algorithms are being independently validated, and their clinical utility is being evaluated in the Quick and Simple and Reliable (QUASAR) study.