bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of the presence and extent of loss of heterozygosity mutations with histological classifications of Barrett’s esophagus
Authors: Ellsworth Eric , Jackson Sara A , Thakkar Shyam J , Smith Dennis M , Finkelstein Sydney
Published: December 2012

Background

Recent advances in the management of Barrett’s Esophagus (BE) have placed greater emphasis on accurate diagnosis of BE as well as better prediction of risk for progression to esophageal adenocarcinoma (EAC). Histological evaluation of BE is particularly challenging with significant inter-observer variability. We explored the presence and extent of genomic instability in BE biopsy specimens as a means to add supplementary information to the histological classification and clinical decision-making related to early disease.

Methods

We reviewed histology slides from 271 patients known to have BE. Using histological features as a guide, we microdissected target cell populations with various histological classifications of BE (intestinal metaplasia, “indefinite for dysplasia”, low grade dysplasia, or high grade dysplasia). DNA was extracted from microdissected targets and analyzed for loss of heterozygosity (LOH) using a panel of 16 LOH mutational markers associated with tumor suppressor genes at chromosomal loci 1p, 3p, 5q, 9p, 10q, 17p, 17q, 18q, 21q, 22q. The presence or absence of mutations and the clonality of each mutation were determined for each marker.

Results

The presence and clonal expansion of LOH mutations was formulated into mutational load (ML) for each microdissected target analyzed. ML correlated with the histological classification of microdissected targets, with increasingly severe histology having higher ML. Three levels of mutation load (no ML, low ML, and high ML) were defined based on the population of microdissected targets histologically classified as intestinal metaplasia. All microdissected targets with dysplasia had mutations, with a high ML consistently present in high grade dysplasia targets. Microdissected targets histologically classified as intestinal metaplasia or “indefinite for dysplasia” spanned a range of no, low, and high ML.

Conclusions

The results of this study reinforce the association of genomic instability with disease progression in BE. The presence and extent (clonality) of genomic instability, as assessed by mutational load, may assist histology in defining early stages of BE that are potentially at greater risk for disease progression. Assessment of mutational load using our panel of LOH mutational markers may be a useful adjunct to microscopic inspection of biopsy specimens, and thereby, improve patient management.
The risk allele of SNP rs3803662 and the mRNA level of its closest genes TOX3 and LOC643714predict adverse outcome for breast cancer patients
Authors: Gudmundsdottir Eydis Th , Barkardottir Rosa B , Arason Adalgeir , Gunnarsson Haukur , Amundadottir Laufey Th , Agnarsson Bjarni A , Johannsson Oskar Th , Reynisdottir Inga
Published: December 2012

Background

The minor allele of SNP rs3803662 has been shown to correlate with increased breast cancer risk and with lower expression ofTOX3. The SNP is closely located toTOX3residing within an uncharacterised geneLOC643714. The aim of the study was to examine the association of the risk allele with expression ofTOX3andLOC643714,and of mRNA levels and genotype with clinical and pathological characteristics.

Methods

The SNP was genotyped in DNA isolated from blood and normal tissue from 160 breast cancer patients and mRNA levels were measured by microarrays and quantitative real-time (qRT)-PCR in breast tumours. Association with clinical and pathological characteristics was analysed by parametric tests.

Results

An association of the risk allele of rs3803662 with lowerTOX3expression was confirmed in oestrogen receptor (ER) positive tumours. It was more often observed in lobular tumours (p = 0.04), and carriers of the risk allele who had been diagnosed with luminal A tumours had shorter overall survival (OS) than carriers of the non-risk allele (p = 0.01). Positive correlation between the mRNA levels ofTOX3andLOC643714was observed (r = 0.44 and p < 0.001). Association analysis with tumour pathology showed that lowTOX3andLOC643714expression correlated with high Ki67 levels (p = 0.026 and p = 0.002) and the basal subtype (p < 0.001 and p < 0.001), whereas high expression correlated with ER (p = 0.004 and p < 0.001) and progesterone receptor (PgR) (p = 0.005 and p < 0.001) expression. Furthermore, high TOX3 and LOC643714 correlated with positive lymph nodes (p < 0.001 and p = 0.01). Patients with ER positive tumours and high levels ofTOX3mRNA had shorter overall- and distant metastasis free-survival (p = 0.017 and p = 0.021), an effect mostly attributable to patients with luminal B tumours.

Conclusions

The results suggest that the effect of the risk allele of rs3803662 is strongest in luminal A tumours and that the expression levels ofTOX3and/orLOC643714affect the progression of breast cancer. The effect may vary depending on the subtype and developmental stage of the tumour.
Autophagy-independent enhancing effects of Beclin 1 on cytotoxicity of ovarian cancer cells mediated by proteasome inhibitors
Authors: Liu Chuan , Yan Xu , Wang Hua-Qin , Gao Yan-Yan , Liu Juanjuan , Hu Zhenhua , Liu Dawo , Gao Jian , Lin Bei
Published: December 2012

Background

The ubiquitin-proteasome system and macroautophagy (hereafter referred to autophagy) are two complementary pathways for protein degradation. Emerging evidence suggests that proteasome inhibition might be a promising approach for tumor therapy. Accumulating data suggest that autophagy is activated as a compensatory mechanism upon proteasome activity is impaired.

Method

Autophagy activation was measured using acridine orange staining and LC3 transition. Cell viability and apoptosis were measured using MTT assay and flow cytometry, respectively. Beclin 1 expression vectors or shRNA against Beclin 1 (shBeclin 1) were transfected to investigate the role of Beclin 1 in autophagy activation and cytotoxicity of ovarian cancer cells induced by proteasome inhibitors.

Results

Proteasome inhibitors suppressed proliferation and induced autophagy in ovarian cancer cells. Neither phosphoinositide 3-kinase (PI3K) inhibitors nor shRNA against Beclin 1 could abolish the formation of acidic vacuoles and the processing of LC3 induced by proteasome inhibitors. Moreover, Beclin 1 overexpression enhanced anti-proliferative effects of proteasome inhibitors in ovarian cancer cells.

Conclusions

For the first time, the current study demonstrated that proteasome inhibitors induced PI3K and Beclin 1-independent autophagy in ovarian cancer cells. In addition, this study revealed autophagy-independent tumor suppressive effects of Beclin 1 in ovarian cancer cells.
Predictors of malaria-association with rubber plantations in Thailand
Authors: Satitvipawee Pratana , Wongkhang Warunnee , Pattanasin Sarika , Hoithong Penprapai , Bhumiratana Adisak
Published: December 2012

Background

The national Global Fund-supported malaria (GFM) program in Thailand, which focuses on the household-level implementation of vector control via insecticide-treated nets (ITNs)/long-lasting insecticidal nets (LLINs) combined with indoor residual spraying (IRS), has been combating malaria risk situations in different provinces with complex epidemiological settings. By using the perception of malaria villagers (MVs), defined as villagers who recognized malaria burden and had local understanding of mosquitoes, malaria, and ITNs/LLINs and practiced preventive measures, this study investigated the predictors for malaria that are associated with rubber plantations in an area of high household-level implementation coverage of IRS (2007–2010) and ITNs/LLINs (2008–2010) in Prachuap Khiri Khan Province.

Methods

A structured questionnaire addressing socio-demographics, household characteristics and health behavioral factors (knowledge, perceptions and practices) regarding the performed interventions was administered to the 313 households (70 malaria-affected and 243 malaria-unaffected) that had respondents aged ≥18 years of both genders. In the univariate and multivariate analyses, only 246 (78.6%) MV respondents (62 malaria-affected and 184 malaria-unaffected) were analyzed to determine the predictors for risk (morbidity).

Results

The majority (70%) of households were covered by IRS. For a combination of ITNs/LLINs, there were 74% of malaria-affected households covered and 46% of malaria-unaffected households. In a logistic regression analysis using odds ratios (aORs) adjusted on the variables and a 95% confidence interval (CI), malaria affecting MVs was associated with daily worker (i.e., earning daily income by normally practicing laborious activities mostly in agriculture such as rubber tapping and rubber sheet processing at the smallholdings of rubber plantations) (aOR = 2.9, 95% CI: 1.1-7.4), low-moderate level of malaria knowledge (aOR = 2.4, 95% CI: 1.1-5.0) and sleeping under mosquito-nets (nets/ITNs/LLINs intermittently and ITNs/LLINs only) (aOR = 2.0, 95% CI: 1.0-3.7).

Conclusions

The MV predictors for malaria-association with rubber plantations included occupation (daily worker), misconceptions about malaria (mosquito and prevention) and the use of mosquito-nets. Human practices such as revisiting rubber plantations while exposed to multiple bites at multiple locations are more likely to apply to daily workers than to rubber farmers/tappers and others. The promotion and use of ITNs/LLINs depends substantially on cultural factors and defensive behaviors relevant to their occupational risk despite the perceived threats of malaria and the perceived benefits of ITNs/LLINs. This information supports the conclusion that GFM program implementation in Thailand or elsewhere for malaria-associated with rubber plantations would benefit from the potential use of ITNs/LLINs and changes in personal protection behaviors.
Clinical significance of troponin elevations in acute decompensated diabetes without clinical acute coronary syndrome
Authors: Eubanks Anthony , Raza Farhan , Alkhouli Mohamad , Glenn April N , Homko Carol , Kashem Abul , Bove Alfred
Published: December 2012

Background

Elevation of cardiac troponin has been documented in multiple settings without acute coronary syndrome. However, its impact on long-term cardiac outcomes in the context of acute decompensated diabetes remains to be explored.

Methods

We performed a retrospective analysis of 872 patients admitted to Temple University Hospital from 2004–2009 with DKA or HHS. Patients were included if they had cardiac troponin I (cTnI) measured within 24 hours of hospital admission, had no evidence of acute coronary syndrome and had a follow up period of at least 18 months. Of the 264 patients who met the criteria, we reviewed the baseline patient characteristics, admission labs, EKGs and major adverse cardiovascular events during the follow up period. Patients were categorized into two groups with normal and elevated levels of cardiac enzymes. The composite end point of the study was the occurrence of a major cardiovascular event (MACE) during the follow up period and was compared between the two groups.

Results

Of 264 patients, 24 patients were found to have elevated cTnI. Compared to patients with normal cardiac enzymes, there was a significant increase in incidence of MACE in patients with elevated cTnI. In a regression analysis, which included prior history of CAD, HTN and ESRD, the only variable that independently predicted MACE was an elevation in cTnI (p = 0.044). Patients with elevated CK-MB had increased lengths of hospitalization compared to the other group (p < 0.001).

Conclusions

Elevated cardiac troponin I in patients admitted with decompensated diabetes and without evidence of acute coronary syndrome, strongly correlate with a later major cardiovascular event. Thus, elevated troponin I during metabolic abnormalities identify a group of patients at an increased risk for poor long-term outcomes. Whether these patients may benefit from early detection, risk stratification and preventive interventions remains to be investigated.
Synthesis, characterization and toxicological evaluation of maltodextrin capped cadmium sulfide nanoparticles in human cell lines and chicken embryos
Authors: Rodríguez-Fragoso Patricia , Reyes-Esparza Jorge , León-Buitimea Angel , Rodríguez-Fragoso Lourdes
Published: December 2012

Background

Semiconductor Quantum dots (QDs) have become quite popular thanks to their properties and wide use in biological and biomedical studies. However, these same properties entail new challenges in understanding, predicting, and managing potential adverse health effects following exposure. Cadmium and selenium, which are the major components of the majority of quantum dots, are known to be acutely and chronically toxic to cells and organisms. Protecting the core of nanoparticles can, to some degree, control the toxicity related to cadmium and selenium leakage.

Results

This study successfully synthesized and characterized maltodextrin coated cadmium sulfide semiconductor nanoparticles. The results show that CdS-MD nanoparticles are cytotoxic and embryotoxic. CdS-MD nanoparticles in low concentrations (4.92 and 6.56 nM) lightly increased the number of HepG2 cell. A reduction in MDA-MB-231 cells was observed with concentrations higher than 4.92 nM in a dose response manner, while Caco-2 cells showed an important increase starting at 1.64 nM. CdS-MD nanoparticles induced cell death by apoptosis and necrosis in MDA-MD-231 cells starting at 8.20 nM concentrations in a dose response manner. The exposure of these cells to 11.48-14.76 nM of CdS-MD nanoparticles induced ROS production. The analysis of cell proliferation in MDA-MB-231 showed different effects. Low concentrations (1.64 nM) increased cell proliferation (6%) at 7 days (p < 0.05). However, higher concentrations (>4.92 nM) increased cell proliferation in a dose response manner (15-30%) at 7 days. Exposures of chicken embryos to CdS-MD nanoparticles resulted in a dose-dependent increase in anomalies that, starting at 9.84 nM, centered on the heart, central nervous system, placodes, neural tube and somites. No toxic alterations were observed with concentrations of < 3.28 nM, neither in cells nor chicken embryos.

Conclusions

Our results indicate that CdS-MD nanoparticles induce cell death and alter cell proliferation in human cell lines at concentrations higher than 4.92 nM. We also demonstrated that they are embryotoxic. However, no toxic effects were observed with doses lower than 3.28 nM in neither cells nor chicken embryos. The CdS-MD nanoparticles used in this study can be potentially used in bio-imaging applications. However, further studies using mammalian species are required in order to discard more toxic effects.
A best proximity point theorem for Geraghty-contractions
Authors: Caballero J , Harjani J , Sadarangani K
Published: December 2012

The purpose of this paper is to provide sufficient conditions for the existence of a unique best proximity point for Geraghty-contractions.

Our paper provides an extension of a result due to Geraghty (Proc. Am. Math. Soc. 40:604-608, 1973).
Approximate perfect differential equations of second order
Authors: Abdollahpour Mohammad Reza , Najati Abbas , Park Choonkil , Rassias Themistocles M , Shin Dong Yun
Published: December 2012

In this paper we prove the Hyers-Ulam stability of the perfect linear differential equation

f
(
t
)

y
″

(
t
)
+

f
1

(
t
)

y
′

(
t
)
+

f
2

(
t
)
y
(
t
)
=
Q
(
t
)

, where

f
,
y
∈

C
2

[
a
,
b
]

,

Q
∈
C
[
a
,
b
]

,

f
2

(
t
)
=

f
1
′

(
t
)
−

f
″

(
t
)

and

−
∞
<
a
<
b
<
+
∞

.

MSC:34K20, 26D10, 39B82, 34K06, 39B72.
Application of iron nanaoparticles in landfill leachate treatment - case study: Hamadan landfill leachate
Authors: Kashitarash Zahra Esfahani , Taghi Samadi Mohammad , Kazem Naddafi , Abbass Afkhami , Alireza Rahmani
Published: December 2012

This study was performed with the objective of determining the efficiency of iron nanoparticles for reducing chemical oxygen demand (COD), 5-day biological oxygen demand (BOD5), total solids (TS) and color of Hamadan city landfill leachate. Experiments were performed in a batch reactor and the main effective factors of pH, reaction time and concentration of iron nanoparticles were investigated. The obtained data were analyzed with One-Way ANOVA statistical test and SPSS-13 software. Maximum removal efficiencies were 47.94%, 35%, 55.62% and 76.66% for COD, BOD5, TS and color, respectively (for 2.5 g/L iron nanoparticles dosage, pH = 6.5 and 10 min reaction time). The results showed that the removal of COD, BOD5 and color had reverse relationship with contact time and TS removal followed a direct relationship (P < 0.05). Iron nanoparticles could remove averagely 53% of leachate COD, BOD5, TS and color in a short contact time (10 min) increasing pH up to 6.5, increased the removal efficiency for COD, BOD5, TS and color and then removal efficiency decreased with increasing pH to 8.5. Increasing the dosage of nanoparticles to 2.5 g/L increased the efficiency of process. High compatibility and efficiency of this process was proven by landfill leachate pre-treatment or post-treatment, so this removal method may be recommended for municipal solid waste landfill leachate treatment plants.
Immunotherapy using slow-cycling tumor cells prolonged overall survival of tumor-bearing mice
Authors: Sun Qing , Zhong Yong , Wu Fan , Zhou Chunxia , Wang Dongmei , Ma Wenbo , Zhang Youhui , Zhang Shuren
Published: December 2012

Background

Despite considerable progress in the development of anticancer therapies, there is still a high mortality rate caused by cancer relapse and metastasis. Dormant or slow-cycling residual tumor cells are thought to be a source of tumor relapse and metastasis, and are therefore an obstacle to therapy. In this study, we assessed the drug resistance of tumor cells in mice, and investigated whether vaccination could promote survival.

Methods

The mouse colon carcinoma cell line CT-26 was treated with 5-fluorouracil to assess its sensitivity to drug treatment. Mice with colon tumors were immunized with inactivated slow-cycling CT-26 cells to estimate the efficacy of this vaccine.

Results

We identified a small population of slow-cycling tumor cells in the mouse colon carcinoma CT-26 cell line, which was resistant to conventional chemotherapy. To inhibit tumor recurrence and metastasis more effectively, treatments that selectively target the slow-cycling tumor cells should be developed to complement conventional therapies. We found that drug-treated, slow-cycling tumor cells induced a more intense immune response in vitro. Moreover, vaccination with inactivated slow-cycling tumor cells caused a reduction in tumor volume and prolonged the overall survival of tumor-bearing mice.

Conclusions

These findings suggest that targeting of slow-cycling tumor cells application using immunotherapy is a possible treatment to complement traditional antitumor therapy.
Development of a loop-mediated isothermal amplification method to rapidly detect porcine circovirus genotypes 2a and 2b
Authors: Qiu Xiaohuo , Li Tian , Zhang Guorui , Cao Jingjing , Jin Yulan , Xing Gang , Liao Min , Zhou Jiyong
Published: December 2012

Background

Porcine circovirus type 2 (PCV2), is nowadays associated with a number of diseases known as porcine circovirus-associated diseases (PCVAD), especially postweaning multisystemic wasting syndrome (PMWS). The epidemiological investigation of PCV2 infection was usually conducted by PCR, nested PCR, PCR-RFLP, TaqMan-based assay and nucleotide sequencing. However, there is still no rapid, sensitive and practical method for detecting PCV2 genotypes. As a novel nucleic acid amplification method, the loop-mediated isothermal amplification method (LAMP) has been used to detect a variety of pathogenic microorganisms.

Results

Herein, a LAMP method is developed to detect the genotypes of PCV2. The diagnostic sensitivity of LAMP is 1 copy/reaction for differentiating genotypes PCV2a and PCV2b. The reaction process was completed at 65°C for 1 hour in a water bath. Cross-reactivity assay shows that this method is specific for PCV2a and PCV2b and no reactive for PCV2c and other swine-origin viruses (i.e. CSFV, PRRSV, BVDV, TGEV and PEDV, etc). Identity between LAMP and nested PCR was 92.3% on 52 field clinical samples.

Conclusions

LAMP method provides a rapid, sensitive, reliable way to detect PCV2a and PCV2b, and a better means for the large scale investigation of PCV2a and PCV2b infection.
Design of different strategies of multivalent DNA-based vaccination against rabies and canine distemper in mice and dogs
Authors: Touihri Leila , Ahmed Sami Belhaj , Chtourou Yacine , Daoud Rahma , Bahloul Chokri
Published: December 2012

Background

During the vaccination campaigns, puppies younger than 3 months old are not targeted and remain unvaccinated for at least the first year of their lives. Almost half of the reported rabid dogs are 6 months or younger. Hence, we should recommend the vaccination against rabies of young puppies. Unfortunately, owing to the exposure of puppies to infections with either canine parvovirus (CPV) or distemper virus (CDV) after the intervention of the vaccinators, owners are reluctant to vaccinate puppies against rabies. Therefore, it is necessary to include the CPV and CDV valences in the vaccine against rabies. Multivalent DNA-based vaccination in dogs, including rabies and distemper valences, could help in raising vaccine coverage.

Methods

We have designed monovalent and multivalent DNA-based vaccine candidates for in vitro and in vivo assays. These plasmids encode to the rabies virus glycoprotein and/or the canine distemper virus hemagglutinin. The first strategy of multivalent DNA-based vaccination is by mixing plasmids encoding to a single antigen each. The second is by simply fusing the genes of the antigens together. The third is by adding the foot and mouth disease virus (FMDV) 2A oligopeptide gene into the antigen genes. The last strategy is by the design and use of a bicistronic plasmid with an “Internal Ribosome Entry Site” (IRES) domain.

Results

The monovalent construct against canine distemper was efficiently validated by inducing higher humoral immune responses compared to cell-culture-derived vaccine both in mice and dogs. All multivalent plasmids efficiently expressed both valences after in vitro transfection of BHK-21 cells. In BALB/c mice, the bicistronic IRES-dependant construct was the most efficient inducer of virus-neutralizing antibodies against both valences. It was able to induce better humoral immune responses compared to the administration of either cell-culture-derived vaccines or monovalent plasmids. The FMDV 2A was also efficient in the design of multivalent plasmids.

Conclusions

In a single shot, the design of efficient multivalent plasmids will be very beneficial for DNA-based vaccination against numerous diseases.
Hypofractionated radiotherapy for primary or secondary oligometastatic lung cancer using Tomotherapy
Authors: Chang Heng-Jui , Ko Hui-Ling , Lee Cheng-Yen , Wu Ren-Hong , Yeh Yu-Wung , Jiang Jiunn-Song , Kao Shang-Jyh , Chi Kwan-Hwa
Published: December 2012

Background

To retrospectively review the outcome of patients with primary or secondary oligometastatic lung cancer, treated with hypofractionated Tomotherapy.

Methods

Between April 2007 and June 2011, a total of 33 patients with oligometastatic intrapulmonary lesions underwent hypofractionated radiotherapy by Tomotherapy along with appropriate systemic therapy. There were 24 primary, and 9 secondary lung cancer cases. The radiation doses ranged from 4.5 to 7.0 Gy per fraction, multiplied by 8–16 fractions. The median dose per fraction was 4.5 Gy (range, 4.5-7.0 Gy), and the median total dose was 49.5 Gy (range, 45–72 Gy). The median estimated biological effective dose at 10 Gy (BED10) was 71.8 Gy (range, 65.3–119.0 Gy), and that at 3 Gy (BED3) was 123.8 Gy (range, 112.5–233.3 Gy). The mean lung dose (MLD) was constrained mainly under 1200 cGy. The median gross tumor volume (GTV) was 27.9 cm3 (range: 2.5–178.1 cm3).

Results

The median follow-up period was 25.8 months (range, 3.0–60.7 months). The median overall survival (OS) time was 32.1 months for the 24 primary lung cancer patients, and >40 months for the 9 metastatic lung patients. The median survival time of the patients with extra-pulmonary disease (EPD) was 11.2 months versus >50 months (not reached) in the patients without EPD (p < 0.001). Those patients with smaller GTV (≦27.9 cm3) had a better survival than those with larger GTV (>27.9 cm3): >40 months versus 12.85 months (p = 0.047). The patients with ≦2 lesions had a median survival >40 months, whereas those with ≧3 lesions had 26 months (p = 0.065). The 2-year local control (LC) rate was 94.7%. Only 2 patients (6.1%) developed ≧grade 3 radiation pneumonitis.

Conclusion

Using Tomotherapy in hypofractionation may be effective for selected primary or secondary lung oligometastatic diseases, without causing significant toxicities. Pulmonary oligometastasis patients without EPD had better survival outcomes than those with EPD. Moreover, GTV is more significant than lesion number in predicting survival.
Preclinical models in radiation oncology
Authors: Kahn Jenna , Tofilon Philip J , Camphausen Kevin
Published: December 2012

As the incidence of cancer continues to rise, the use of radiotherapy has emerged as a leading treatment modality. Preclinical models in radiation oncology are essential tools for cancer research and therapeutics. Various model systems have been used to test radiation therapy, including in vitro cell culture assays as well as in vivo ectopic and orthotopic xenograft models. This review aims to describe such models, their advantages and disadvantages, particularly as they have been employed in the discovery of molecular targets for tumor radiosensitization. Ultimately, any model system must be judged by its utility in developing more effective cancer therapies, which is in turn dependent on its ability to simulate the biology of tumors as they exist in situ. Although every model has its limitations, each has played a significant role in preclinical testing. Continued advances in preclinical models will allow for the identification and application of targets for radiation in the clinic.
Metabolic Flux-Based Modularity using Shortest Retroactive distances
Authors: Sridharan GauthamVivek , Yi Michael , Hassoun Soha , Lee Kyongbum
Published: December 2012

Background

Graph-based modularity analysis has emerged as an important tool to study the functional organization of biological networks. However, few methods are available to study state-dependent changes in network modularity using biological activity data. We develop a weighting scheme, based on metabolic flux data, to adjust the interaction distances in a reaction-centric graph model of a metabolic network. The weighting scheme was combined with a hierarchical module assignment algorithm featuring the preservation of metabolic cycles to examine the effects of cellular differentiation and enzyme inhibitions on the functional organization of adipocyte metabolism.

Results

Our analysis found that the differences between various metabolic states primarily involved the assignment of two specific reactions in fatty acid synthesis and glycerogenesis. Our analysis also identified cyclical interactions between reactions that are robust with respect to metabolic state, suggesting possible co-regulation. Comparisons based on cyclical interaction distances between reaction pairs suggest that the modular organization of adipocyte metabolism is stable with respect to the inhibition of an enzyme, whereas a major physiological change such as cellular differentiation leads to a more substantial reorganization.

Conclusion

Taken together, our results support the notion that network modularity is influenced by both the connectivity of the network’s components as well as the relative engagements of the connections.
Mutation screen in the GWAS derived obesity gene SH2B1including functional analyses of detected variants
Authors: Volckmar Anna-Lena , Bolze Florian , Jarick Ivonne , Knoll Nadja , Scherag André , Reinehr Thomas , Illig Thomas , Grallert Harald , Wichmann Heinz-Erich , Wiegand Susanna , Biebermann Heike , Krude Heiko , Fischer-Posovszky Pamela , Rief Winfried , Wabitsch Martin , Klingenspor Martin , Hebebrand Johannes , Hinney Anke
Published: December 2012

Background

The SH2B1 gene (Src-homology 2B adaptor protein 1 gene) is a solid candidate gene for obesity. Large scale GWAS studies depicted markers in the vicinity of the gene; animal models suggest a potential relevance for human body weight regulation.

Methods

We performed a mutation screen for variants in the SH2B1 coding sequence in 95 extremely obese children and adolescents. Detected variants were genotyped in independent childhood and adult study groups (up to 11,406 obese or overweight individuals and 4,568 controls). Functional implications on STAT3 mediated leptin signalling of the detected variants were analyzed in vitro.

Results

We identified two new rare mutations and five known SNPs (rs147094247, rs7498665, rs60604881, rs62037368 and rs62037369) in SH2B1. Mutation g.9483C/T leads to a non-synonymous, non-conservative exchange in the beta (βThr656Ile) and gamma (γPro674Ser) splice variants of SH2B1. It was additionally detected in two of 11,206 (extremely) obese or overweight children, adolescents and adults, but not in 4,506 population-based normal-weight or lean controls. The non-coding mutation g.10182C/A at the 3’ end of SH2B1 was only detected in three obese individuals. For the non-synonymous SNP rs7498665 (Thr484Ala) we observed nominal over-transmission of the previously described risk allele in 705 obesity trios (nominal p = 0.009, OR = 1.23) and an increased frequency of the same allele in 359 cases compared to 429 controls (nominal p = 0.042, OR = 1.23). The obesity risk-alleles at Thr484Ala and βThr656Ile/γPro674Ser had no effect on STAT3 mediated leptin receptor signalling in splice variants β and γ.

Conclusion

The rare coding mutation βThr656Ile/γPro674Ser (g.9483C/T) in SH2B1 was exclusively detected in overweight or obese individuals. Functional analyzes did not reveal impairments in leptin signalling for the mutated SH2B1.
FGFR-1 amplification in metastatic lymph-nodal and haematogenous lobular breast carcinoma
Authors: Brunello Eleonora , Brunelli Matteo , Bogina Giuseppe , Caliò Anna , Manfrin Erminia , Nottegar Alessia , Vergine Marco , Molino Annamaria , Bria Emilio , Massari Francesco , Tortora Giampaolo , Cingarlini Sara , Pedron Serena , Chilosi Marco , Zamboni Giuseppe , Miller Keith , Martignoni Guido , Bonetti Franco
Published: December 2012

Background

Lobular breast carcinoma usually shows poor responsiveness to chemotherapies and often lacks targeted therapies. Since FGFR1 expression has been shown to play pivotal roles in primary breast cancer tumorigenesis, we sought to analyze the status of FGFR1 gene in a metastatic setting of lobular breast carcinoma, since promising FGFR1 inhibitors has been recently developed.

Methods

Fifteen tissue metastases from lobular breast carcinomas with matched primary infiltrative lobular breast carcinoma were recruited. Eleven cases showed loco-regional lymph-nodal and four haematogenous metastases.

FGFR-1 gene (8p12) amplification was evaluated by chromogenic in situ hybridization (CISH) analysis. Her-2/neu and topoisomerase-IIα gene status was assessed. E-cadherin and Hercept Test were also performed. We distinguished amplification (>6 or cluster of signals) versus gains (3–6 signals) of the locus specific FGFR-1 gene.

Results

Three (20%) primary lobular breast carcinomas showed >6 or cluster of FGFR1 signals (amplification), six cases (40%) had a mean of three (range 3–6) chromogenic signals (gains) whereas in 6 (40%) was not observed any abnormality. Three of 15 metastasis (20%) were amplified, 2/15 (13,4%) did not. The ten remaining cases (66,6%) showed three chromogenic signals.

The three cases with FGFR-1 amplification matched with those primary breast carcinomas showing FGFR-1 amplification. The six cases showing FGFR-1 gains in the primary tumour again showed FGFR-1 gains in the metastases. Four cases showed gains of FGFR-1 gene signals in the metastases and not in the primary tumours. Her-2/neu gene amplification was not observed in all cases but one (6%) case. Topoisomerase-IIα was not amplified in all cases.

Conclusions

1) a subset of metastatic lobular breast carcinoma harbors FGFR-1 gene amplification or gains of chromogenic signals; 2) a minor heterogeneity has been observed after matching primary and metastatic carcinomas; 3) in the era of tailored therapies, patients affected by the lobular subtype of breast carcinoma with FGFR1 amplification could be approached to the new target biological therapy such as emerging FGFR-1 inhibitors.
Delirium in the ICU: an overview
Authors: Cavallazzi Rodrigo , Saad Mohamed , Marik Paul E
Published: December 2012

Delirium is characterized by a disturbance of consciousness with accompanying change in cognition. Delirium typically manifests as a constellation of symptoms with an acute onset and a fluctuating course. Delirium is extremely common in the intensive care unit (ICU) especially amongst mechanically ventilated patients. Three subtypes have been recognized: hyperactive, hypoactive, and mixed. Delirium is frequently undiagnosed unless specific diagnostic instruments are used. The CAM-ICU is the most widely studied and validated diagnostic instrument. However, the accuracy of this tool may be less than ideal without adequate training of the providers applying it. The presence of delirium has important prognostic implications; in mechanically ventilated patients it is associated with a 2.5-fold increase in short-term mortality and a 3.2-fold increase in 6-month mortality. Nonpharmacological approaches, such as physical and occupational therapy, decrease the duration of delirium and should be encouraged. Pharmacological treatment for delirium traditionally includes haloperidol; however, more data for haloperidol are needed given the paucity of placebo-controlled trials testing its efficacy to treat delirium in the ICU. Second-generation antipsychotics have emerged as an alternative for the treatment of delirium, and they may have a better safety profile. Dexmedetomidine may prove to be a valuable adjunctive agent for patients with delirium in the ICU.
How quickly does structural reform pay off? An empirical analysis of the short-term effects of unemployment benefit reform
Authors: Bouis Romain , Causa Orsetta , Demmou Lilas , Duval Romain
Published: December 2012

While there is a fairly broad consensus regarding the potential adverse effects of generous unemployment benefit insurance on steady-state employment, the short-term effects of benefit reforms are not well-established. This paper contributes to fill this gap by estimating impulse responses to benefit reform “shocks” identified for a panel of OECD countries. Findings indicate that although it takes time for unemployment benefit reforms to pay off, such reforms do not appear to entail any negative short-run effects. There is however some suggestive evidence that reducing unemployment benefits could have negative short-run effects in “bad times”.

JEL classification

E02, E24, E60, J38, J58, J68
Payments for ecological restoration and internal migration in China: the sloping land conversion program in Ningxia
Authors: Démurger Sylvie , Wan Haiyuan
Published: December 2012

This paper analyzes the impact of the Sloping Land Conversion Program (SLCP) on rural labor migration in China. We use recent survey data from Ningxia Hui Autonomous Region and a difference-in-difference approach to assess the impact of the policy on labor migration decision. We find a significant effect of the policy: the migration probability increase due to the SLCP policy amounts to 17.5 percentage points in 2008. Furthermore, we highlight the role of policy duration in strengthening the impact of the program on migration. We also find that young, male and Hui nationality individuals are more likely to be impacted by the policy.

JEL codes

J22, J68, O13, Q23
Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia
Authors: Badoux Xavier C. , Keating Michael J. , Wen Sijin , Wierda William G. , O'Brien Susan M. , Faderl Stefan , Sargent Rachel , Burger Jan A. , Ferrajoli Alessandra
Published: December 2012

Purpose

Lenalidomide is an immunomodulatory drug active as salvage therapy for chronic lymphocytic leukemia (CLL). We combined lenalidomide with rituximab to improve response rates in patients with relapsed or refractory CLL.

Patients and Methods

Fifty-nine adult patients (age 42 to 82 years) with relapsed or refractory CLL were enrolled onto a phase II study of lenalidomide and rituximab. Patients had received prior fludarabine-based therapy or chemoimmunotherapy. Rituximab (375 mg/m2intravenously) was administered weekly during cycle one and on day 1 of cycles three to 12. Lenalidomide was started on day 9 of cycle one at 10 mg orally and administered daily continuously. Each cycle was 28 days. Rituximab was administered for 12 cycles; lenalidomide could continue indefinitely if patients benefitted clinically.

Results

The overall response rate was 66%, including 12% complete responses and 12% nodular partial remissions. Time to treatment failure was 17.4 months. Median overall survival has not been reached; estimated survival at 36 months is 71%. The most common grade 3 or 4 toxicity was neutropenia (73% of patients). Fourteen patients (24%) experienced a grade 3 to 4 infection or febrile episode. There was one episode of grade 3 tumor lysis; one patient experienced renal failure during the first cycle of therapy, and one venous thromboembolic event occurred during the study.

Conclusion

The combination of lenalidomide and rituximab is active in patients with recurrent CLL and warrants further investigation.
Radiofrequency Ablation With or Without Transcatheter Arterial Chemoembolization in the Treatment of Hepatocellular Carcinoma: A Prospective Randomized Trial
Authors: Peng Zhen-Wei , Zhang Yao-Jun , Chen Min-Shan , Xu Li , Liang Hui-Hong , Lin Xiao-Jun , Guo Rong-Ping , Zhang Ya-Qi , Lau Wan Yee
Published: December 2012

Purpose

To compare radiofrequency ablation (RFA) with or without transcatheter arterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC).

Patients and Methods

A randomized controlled trial was conducted on 189 patients with HCC less than 7 cm at a single tertiary referral center between October 2006 and June 2009. Patients were randomly asssigned to receive TACE combined with RFA (TACE-RFA; n = 94) or RFA alone (n = 95). The primary end point was overall survival. The secondary end point was recurrence-free survival, and the tertiary end point was adverse effects.

Results

At a follow-up of 7 to 62 months, 34 patients in the TACE-RFA group and 48 patients in the RFA group had died. Thirty-three patients and 52 patients had developed recurrence in the TACE-RFA group and RFA group, respectively. The 1-, 3-, and 4-year overall survivals for the TACE-RFA group and the RFA group were 92.6%, 66.6%, and 61.8% and 85.3%, 59%, and 45.0%, respectively. The corresponding recurrence-free survivals were 79.4%, 60.6%, and 54.8% and 66.7%, 44.2%, and 38.9%, respectively. Patients in the TACE-RFA group had better overall survival and recurrence-free survival than patients in the RFA group (hazard ratio, 0.525; 95% CI, 0.335 to 0.822; P = .002; hazard ratio, 0.575; 95% CI, 0.374 to 0.897; P = .009, respectively). There were no treatment-related deaths. On logistic regression analyses, treatment allocation, tumor size, and tumor number were significant prognostic factors for overall survival, whereas treatment allocation and tumor number were significant prognostic factors for recurrence-free survival.

Conclusion

TACE-RFA was superior to RFA alone in improving survival for patients with HCC less than 7 cm.
Risk of Asynchronous Contralateral Breast Cancer in Noncarriers of BRCA1 and BRCA2 Mutations With a Family History of Breast Cancer: A Report From the Women's Environmental Cancer and Radiation Epidemiology Study
Authors: Reiner Anne S. , John Esther M. , Brooks Jennifer D. , Lynch Charles F. , Bernstein Leslie , Mellemkjær Lene , Malone Kathleen E. , Knight Julia A. , Capanu Marinela , Teraoka Sharon N. , Concannon Patrick , Liang Xiaolin , Figueiredo Jane C. , Smith Susan A. , Stovall Marilyn , Pike Malcolm C. , Haile Robert W. , Thomas Duncan C. , Begg Colin B. , Bernstein Jonine L.
Published: December 2012

Purpose

To fully characterize the risk of contralateral breast cancer (CBC) in patients with breast cancer with a family history who test negative for BRCA1 and BRCA2 mutations.

Patients and Methods

From our population-based case-control study comparing women with CBC to women with unilateral breast cancer (UBC), we selected women who tested negative for BRCA1 and BRCA2 mutations (594 patients with CBC/1,119 control patients with UBC). Rate ratios (RRs) and 95% CIs were estimated to examine the association between family history of breast cancer and risk of asynchronous CBC. Age- and family history–specific 10-year cumulative absolute risks of CBC were estimated.

Results

Family history of breast cancer was associated with increased CBC risk; risk was highest among young women (< 45 years) with first-degree relatives affected at young ages (< 45 years; RR, 2.5; 95% CI, 1.1 to 5.3) or women with first-degree relatives with bilateral disease (RR, 3.6; 95% CI, 2.0 to 6.4). Women diagnosed with UBC before age 55 years with a first-degree family history of CBC had a 10-year risk of CBC of 15.6%.

Conclusion

Young women with breast cancer who have a family history of breast cancer and who test negative for deleterious mutations in BRCA1 and BRCA2 are at significantly greater risk of CBC than other breast cancer survivors. This risk varies with diagnosis age, family history of CBC, and degree of relationship to an affected relative. Women with a first-degree family history of bilateral disease have risks of CBC similar to mutation carriers. This has important implications for the clinical management of patients with breast cancer with family history of the disease.
Medical Oncologists' Perceptions of Financial Incentives in Cancer Care
Authors: Malin Jennifer L. , Weeks Jane C. , Potosky Arnold L. , Hornbrook Mark C. , Keating Nancy L.
Published: December 2012

Purpose

The cost of cancer care continues to increase at an unprecedented rate. Concerns have been raised about financial incentives associated with the chemotherapy concession in oncology practices and their impact on treatment recommendations.

Methods

The objective of this study was to measure the physician-reported effects of prescribing chemotherapy or growth factors or making referrals to other cancer specialists, hospice, or hospital admissions on medical oncologists' income. US medical oncologists involved in the care of a population-based cohort of patients with lung or colorectal cancer from the Cancer Care Outcomes Research and Surveillance (CanCORS) study were surveyed regarding their perceptions of the impact of prescribing practices or referrals on their income.

Results

Although most oncologists reported that their incomes would be unaffected, compared with salaried oncologists, physicians in fee-for-service practice, and those paid a salary with productivity incentives were more likely to report that their income would increase from administering chemotherapy (odds ratios [ORs], 7.05 and 7.52, respectively; both P < .001) or administering growth factors (ORs, 5.60 and 6.03, respectively; both P < .001).

Conclusion

A substantial proportion of oncologists who are not paid a fixed salary report that their incomes increase when they administer chemotherapy and growth factors. Further research is needed to understand the impact of these financial incentives on both the quality and cost of care.
Intrinsic Molecular Subtypes of Glioma Are Prognostic and Predict Benefit From Adjuvant Procarbazine, Lomustine, and Vincristine Chemotherapy in Combination With Other Prognostic Factors in Anaplastic Oligodendroglial Brain Tumors: A Report From EORTC Study 26951
Authors: Erdem-Eraslan Lale , Gravendeel Lonneke A. , de Rooi Johan , Eilers Paul H.C. , Idbaih Ahmed , Spliet Wim G.M. , den Dunnen Wilfred F.A. , Teepen Johannes L. , Wesseling Pieter , Sillevis Smitt Peter A.E. , Kros Johan M. , Gorlia Thierry , van den Bent Martin J. , French Pim J.
Published: December 2012

Purpose

Intrinsic glioma subtypes (IGSs) are molecularly similar tumors that can be identified based on unsupervised gene expression analysis. Here, we have evaluated the clinical relevance of these subtypes within European Organisation for Research and Treatment of Cancer (EORTC) 26951, a randomized phase III clinical trial investigating adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study includes gene expression profiles of formalin-fixed, paraffin-embedded (FFPE) clinical trial samples.

Patients and Methods

Gene expression profiling was performed in 140 samples, 47 fresh frozen samples and 93 FFPE samples, on HU133_Plus_2.0 and HuEx_1.0_st arrays, respectively.

Results

All previously identified six IGSs are present in EORTC 26951. This confirms that different molecular subtypes are present within a well-defined histologic subtype. Intrinsic subtypes are highly prognostic for overall survival (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance status, and tumor location), molecular (1p/19q loss of heterozygosity [LOH], IDH1 mutation, and MGMT methylation), and histologic parameters. Combining known molecular (1p/19q LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (proportion of explained variation, 30% v 23% for each individual group of factors). Specific genetic changes (IDH1, 1p/19q LOH, and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p/19q LOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone versus 12.8 years after RT/PCV (P = .0349; hazard ratio, 2.18; 95% CI, 1.06 to 4.50).

Conclusion

Intrinsic subtypes are highly prognostic in EORTC 26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV.