bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stress Alters Rates and Types of Loss of Heterozygosity in Candida albicans
Authors: Forche A. , Abbey D. , Pisithkul T. , Weinzierl M. A. , Ringstrom T. , Bruck D. , Petersen K. , Berman J. 
Published: July 2011

ABSTRACT

Genetic diversity is often generated during adaptation to stress, and in eukaryotes some of this diversity is thought to arise via recombination and reassortment of alleles during meiosis.
Candida albicans
, the most prevalent pathogen of humans, has no known meiotic cycle, and yet it is a heterozygous diploid that undergoes mitotic recombination during somatic growth. It has been shown that clinical isolates as well as strains passaged once through a mammalian host undergo increased levels of recombination. Here, we tested the hypothesis that stress conditions increase rates of mitotic recombination in
C. albicans
, which is measured as loss of heterozygosity (LOH) at specific loci. We show that LOH rates are elevated during
in vitro
exposure to oxidative stress, heat stress, and antifungal drugs. In addition, an increase in stress severity correlated well with increased LOH rates. LOH events can arise through local recombination, through homozygosis of longer tracts of chromosome arms, or by whole-chromosome homozygosis. Chromosome arm homozygosis was most prevalent in cultures grown under conventional lab conditions. Importantly, exposure to different stress conditions affected the levels of different types of LOH events, with oxidative stress causing increased recombination, while fluconazole and high temperature caused increases in events involving whole chromosomes. Thus,
C. albicans
generates increased amounts and different types of genetic diversity in response to a range of stress conditions, a process that we term “stress-induced LOH” that arises either by elevating rates of recombination and/or by increasing rates of chromosome missegregation.

IMPORTANCE
Stress-induced mutagenesis fuels the evolution of bacterial pathogens and is mainly driven by genetic changes via mitotic recombination. Little is known about this process in other organisms.
Candida albicans
, an opportunistic fungal pathogen, causes infections that require adaptation to different host environmental niches. We measured the rates of LOH and the types of LOH events that appeared in the absence and in the presence of physiologically relevant stresses and found that stress causes a significant increase in the rates of LOH and that this increase is proportional to the degree of stress. Furthermore, the types of LOH events that arose differed in a stress-dependent manner, indicating that eukaryotic cells generate increased genetic diversity in response to a range of stress conditions. We propose that this “stress-induced LOH” facilitates the rapid adaptation of
C. albicans
, which does not undergo meiosis, to changing environments within the host.
A multinational randomised study comparing didactic lectures with case scenario in a severe sepsis medical simulation course
Authors: Li Chih-Huang , Kuan Win-Sen , Mahadevan Malcolm , Daniel-Underwood Lynda , Chiu Te-Fa , Nguyen H Bryant 
Published: July 2011

BackgroundMedical simulation has been used to teach critical illness in a variety of settings. This study examined the effect of didactic lectures compared with simulated case scenario in a medical simulation course on the early management of severe sepsis.MethodsA prospective multicentre randomised study was performed enrolling resident physicians in emergency medicine from four hospitals in Asia. Participants were randomly assigned to a course that included didactic lectures followed by a skills workshop and simulated case scenario (lecture-first) or to a course that included a skills workshop and simulated case scenario followed by didactic lectures (simulation-first). A pre-test was given to the participants at the beginning of the course, post-test 1 was given after the didactic lectures or simulated case scenario depending on the study group assignment, then a final post-test 2 was given at the end of the course. Performance on the simulated case scenario was evaluated with a performance task checklist.Results98 participants were enrolled in the study. Post-test 2 scores were significantly higher than pre-test scores in all participants (80.8±12.0% vs 65.4±12.2%, p<0.01). There was no difference in pre-test scores between the two study groups. The lecture-first group had significantly higher post-test 1 scores than the simulation-first group (78.8±10.6% vs 71.6±12.6%, p<0.01). There was no difference in post-test 2 scores between the two groups. The simulated case scenario task performance completion was 90.8% (95% CI 86.6% to 95.0%) in the lecture-first group compared with 83.8% (95% CI 79.5% to 88.1%) in the simulation-first group (p=0.02).ConclusionsA medical simulation course can improve resident physician knowledge in the early management of severe sepsis. Such a course should include a comprehensive curriculum that includes didactic lectures followed by simulation experience.
Subclinical diseases underlying poor performance in endurance horses: diagnostic methods and predictive tests
Authors: Fraipont A. , Van Erck E. , Ramery E. , Richard E. , Denoix J‐M. , Lekeux P. , Art T. 
Published: July 2011

Thirty‐eight endurance horses underwent clinical and ancillary examinations, including haematological and biochemical evaluation, standardised exercise tests both on a treadmill and in the field, Doppler echocardiography, impulse oscillometry, video endoscopy and collection of respiratory fluids. All of the examined poorly performing horses were affected by subclinical diseases, and most of them had multiple concomitant disorders. On the contrary, the well‐performing horses were free of any subclinical disease. The most frequently diagnosed diseases were respiratory disorders, followed by musculoskeletal and cardiac problems. Poor performers exhibited lower speeds at blood lactate concentration of 4 mmol/l (VLA4) and at heart rates of 160 (V160) and 200 bpm (V200) on the treadmill and in the field, as well as slower recovery of heart rate.
Nutrient fluxes and the recent collapse of coastal California salmon populations
Authors: Moore Jonathan W. , Hayes Sean A. , Duffy Walter , Gallagher Sean , Michel Cyril J. , Wright David 
Published: July 2011

Migratory salmon move nutrients both in and out of fresh waters during the different parts of their life cycle. We used a mass-balance approach to quantify recent changes in phosphorus (P) fluxes in six coastal California, USA, watersheds that have recently experienced dramatic decreases in salmon populations. As adults, semelparous Chinook ( Oncorhynchus tshawytscha ) and coho ( Oncorhynchus kisutch ) salmon imported 8.3 and 10.4 times more P from the ocean, respectively, than they exported as smolts, while iteroparous steelhead (i.e., sea-run rainbow trout, Oncorhynchus mykiss ) imported only 1.6 times more than they exported as kelts and smolts. Semelparous species whose life histories led them to import more nutrients were also the species whose populations decreased the most dramatically in California in recent years. In addition, the relationship between import and export was nonlinear, with export being proportionally more important at lower levels of import. This pattern was driven by two density-dependent processes — smolts were larger and disproportionately more abundant at lower spawner abundances. In fact, in four of our six streams we found evidence that salmon can drive net export of P at low abundance, evidence for the reversal of the “conveyor belt” of nutrients.
Ocean circulation, Stokes drift, and connectivity of western rock lobster (Panulirus cygnus) population
Authors: Feng Ming , Caputi Nick , Penn James , Slawinski Dirk , de Lestang Simon , Weller Evan , Pearce Alan 
Published: July 2011

An individual-based model, incorporating outputs of a data-assimilating hydrodynamic model, was developed to investigate the role of ocean circulation in the recruitment processes of western rock lobster ( Panulirus cygnus ) during its 9- to 11-month larval phase off the west coast of Australia. During austral summer, strong northward alongshore winds aid the offshore movement of early-stage model larvae from midshelf hatching sites into open ocean; during austral winter, eastward flows that feed the enhanced Leeuwin Current facilitate onshore movement of late-stage larvae towards nearshore habitats. Stokes drift induced by swells from the Southern Ocean is critical to retain larvae off the west coast. Diurnal migration and temperature-dependent growth are also important. Model larvae hatched in late spring – early summer grow faster because of longer exposure to warm summer temperature, which allows them to be transported towards the coast by the strong onshore flows in winter and reduces their natural mortality. Preliminary source–sink relationship indicates that the population was well mixed off the coast, with higher likelihood of settlement success from hatching sites in the north, mostly due to higher surface temperature. Weighted with the breeding stock distribution, the area between 27.5°S and 29.5°S, including the Abrolhos Islands, is the most important hatching area to the success of settlement.
The mitochondrial genome of the soybean cyst nematode,Heterodera glycines
Authors: Gibson Tracey , Farrugia Daniel , Barrett Jeff , Chitwood David J. , Rowe Janet , Subbotin Sergei , Dowton Mark 
Published: July 2011

We sequenced the entire coding region of the mitochondrial genome of Heterodera glycines. The sequence obtained comprised 14.9 kb, with PCR evidence indicating that the entire genome comprised a single, circular molecule of approximately 21–22 kb. The genome is the most T-rich nematode mitochondrial genome reported to date, with T representing over half of all nucleotides on the coding strand. The genome also contains the highest number of poly(T) tracts so far reported (to our knowledge), with 60 poly(T) tracts ≥ 12 Ts. All genes are transcribed from the same mitochondrial strand. The organization of the mitochondrial genome of H. glycines shows a number of similarities compared with Radopholus similis, but fewer similarities when compared with Meloidogyne javanica. Very few gene boundaries are shared with Globodera pallida or Globodera rostochiensis. Partial mitochondrial genome sequences were also obtained for Heterodera cardiolata (5.3 kb) and Punctodera chalcoensis (6.8 kb), and these had identical organizations compared with H. glycines. We found PCR evidence of a minicircular mitochondrial genome in P. chalcoensis, but at low levels and lacking a noncoding region. Such circularised genome fragments may be present at low levels in a range of nematodes, with multipartite mitochondrial genomes representing a shift to a condition in which these subgenomic circles predominate.
The Tumor Suppressive MicroRNAmiR-218Targets the mTOR ComponentRictorand Inhibits AKT Phosphorylation in Oral Cancer
Authors: Uesugi Atsushi , Kozaki Ken-ichi , Tsuruta Tomohiko , Furuta Mayuko , Morita Kei-ichi , Imoto Issei , Omura Ken , Inazawa Johji 
Published: July 2011

AbstractThe incidence of oral squamous cell carcinoma (OSCC) is rising rapidly in developed countries, posing a growing challenge due to the poor management of this type of malignancy at present. In this study, we profiled tumor suppressive microRNAs (miRNAs) that are silenced by DNA hypermethylation in OSCC using a function-based screening approach. This approach employed a cell proliferation assay for 327 synthetic miRNAs in two OSCC cell lines. Among the 110 miRNAs identified in this set that exhibited inhibitory properties, we compared DNA methylation and expression status in a wider panel of OSCC cell lines and primary tumor tissues, resulting in the identification of miR-218 and miR-585 as functionally significant miRNA genes that are frequently silenced in OSCC by DNA hypermethylation. Ectopic expression of miR-218 and miR-585 in OSCC cells lacking endogenous expression reduced cell growth in part through caspase-mediated apoptosis. Notably, miR-218 reduced levels of the rapamycin-insensitive component of mTOR, Rictor, in a manner associated with a suppression of Akt S473 phosphorylation. Together our findings define miR-585 as a tumor suppressive function that is often epigenetically silenced in OSCC, and they identify Rictor as a novel target of miR-218, suggesting that activation of the mTOR-Akt signaling pathway induced by Rictor contributes centrally to oral carcinogenesis. Cancer Res; 71(17); 5765–78. ©2011 AACR.
The National Institute for Health and Clinical Excellence and Its Role in Assessing the Value of New Cancer Treatments in England and Wales
Authors: Trowman Rebecca , Chung Helen , Longson Carole , Littlejohns Peter , Clark Peter 
Published: July 2011

Abstract
The boundaries of medical science in the treatment of cancer are constantly extending. Developments of existing treatments, innovative approaches, new discoveries, and more targeted therapeutic options are translating into practice. With advances come increasing costs, often of a magnitude that stretches finite financial resources. When decisions about funding are made on behalf of a population, standardized processes and methods are needed in order to produce robust guidance in a fair, consistent, and transparent way. The challenges of making these difficult decisions are brought into particularly stark relief when potentially life-extending treatments for patients with a short life expectancy are appraised. The National Institute for Health and Clinical Excellence (NICE) produces guidance on the clinical- and cost-effectiveness of medicines compared with current standard practice. Approximately 40% of the technologies appraised by NICE are indicated for cancer, and the majority of these are pharmaceuticals, mostly biological agents. This article provides an overview of the current role of NICE in making new technologies for cancer available in England and Wales. This includes a summary of experiences with end-of-life treatments and the supplementary advice regarding such treatments that was issued by NICE to its decision-making committees in 2009. Clin Cancer Res; 17(15); 4930–5. ©2011 AACR.
Interleukin-6 as a Therapeutic Target in Human Ovarian Cancer
Authors: Coward Jermaine , Kulbe Hagen , Chakravarty Probir , Leader David , Vassileva Vessela , Leinster D. Andrew , Thompson Richard , Schioppa Tiziana , Nemeth Jeffery , Vermeulen Jessica , Singh Naveena , Avril Norbert , Cummings Jeff , Rexhepaj Elton , Jirström Karin , Gallagher William M. , Brennan Donal J. , McNeish Iain A. , Balkwill Frances R. 
Published: July 2011

Abstract
Purpose: We investigated whether inhibition of interleukin 6 (IL-6) has therapeutic activity in ovarian cancer via abrogation of a tumor-promoting cytokine network.
Experimental Design: We combined preclinical and in silico experiments with a phase 2 clinical trial of the anti-IL-6 antibody siltuximab in patients with platinum-resistant ovarian cancer.
Results: Automated immunohistochemistry on tissue microarrays from 221 ovarian cancer cases showed that intensity of IL-6 staining in malignant cells significantly associated with poor prognosis. Treatment of ovarian cancer cells with siltuximab reduced constitutive cytokine and chemokine production and also inhibited IL-6 signaling, tumor growth, the tumor-associated macrophage infiltrate and angiogenesis in IL-6–producing intraperitoneal ovarian cancer xenografts. In the clinical trial, the primary endpoint was response rate as assessed by combined RECIST and CA125 criteria. One patient of eighteen evaluable had a partial response, while seven others had periods of disease stabilization. In patients treated for 6 months, there was a significant decline in plasma levels of IL-6–regulated CCL2, CXCL12, and VEGF. Gene expression levels of factors that were reduced by siltuximab treatment in the patients significantly correlated with high IL-6 pathway gene expression and macrophage markers in microarray analyses of ovarian cancer biopsies.
Conclusion: IL-6 stimulates inflammatory cytokine production, tumor angiogenesis, and the tumor macrophage infiltrate in ovarian cancer and these actions can be inhibited by a neutralizing anti-IL-6 antibody in preclinical and clinical studies. Clin Cancer Res; 17(18); 6083–96. ©2011 AACR.
ERG Status Is Unrelated to PSA Recurrence in Radically Operated Prostate Cancer in the Absence of Antihormonal Therapy
Authors: Minner Sarah , Enodien Malaika , Sirma Hüseyin , Luebke Andreas M. , Krohn Antje , Mayer Pascale S. , Simon Ronald , Tennstedt Pierre , Müller Julia , Scholz Laura , Brase Jan C. , Liu Alvin Y. , Schlüter Hartmut , Pantel Klaus , Schumacher Udo , Bokemeyer Carsten , Steuber Thomas , Graefen Markus , Sauter Guido , Schlomm Thorsten 
Published: July 2011

Abstract
Purpose: About 50% of prostate cancers have TMPRSS2–ERG fusions with concurrent ERG overexpression. The aim of this study was to determine whether clinical differences exist between ERG-positive and ERG-negative cancers in surgically treated patients not exposed to antihormonal therapy. A secondary aim was to search for differences between these tumor classes.
Experimental Design: A tissue microarray containing samples from more than 2,800 prostate cancers with clinical data was analyzed for ERG alterations by immunohistochemistry and FISH. Results were compared with tumor phenotype, biochemical recurrence, and molecular features considered important for prostate cancer. The effect of ERG on androgen receptor (AR)-dependent transcription was analyzed in cell lines.
Results: ERG expression was found in 52.4% of 2,805 cancers with a 95% concordance between ERG expression and ERG gene rearrangement detected by FISH. ERG expression was unrelated to clinical outcome and tumor phenotype. Differences in AMACR, Annexin A3, Bcl2, CD10, ALCAM, chromogranin A, epidermal growth factor receptor, HER2, mTOR, p53, and synaptophysin status were significant but minimal in absolute numbers. The most striking difference was found for AR expression, which was markedly higher in ERG-positive cancers. In vitro studies showed ERG-dependent impairment of AR-mediated transcriptional activity.
Conclusions: The striking similarities between these two types of prostate cancers rules out a major impact of ERG on tumor aggressiveness in early, not hormonally treated cancer. The marked difference in AR levels between ERG-positive and -negative cancers supports a systematic difference in potential response to hormonal therapy as previously observed in clinical trials. Clin Cancer Res; 17(18); 5878–88. ©2011 AACR.
Lapatinib, a Preventive/Therapeutic Agent against Mammary Cancer, Suppresses RTK-Mediated Signaling through Multiple Signaling Pathways
Authors: Li Jixia , Cho Yeon-Yong , Langfald Alyssa , Carper Andria , Lubet Ronald A. , Grubbs Clinton J. , Ericson Marna E. , Bode Ann M. 
Published: July 2011

AbstractActivation of receptor tyrosine kinases (RTK) plays a key role in the prognosis of mammary cancer. Lapatinib is a small molecule dual RTK inhibitor that targets epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Identifying the protein targets involved in the effects of lapatinib and other RTK inhibitors might help determine why preventive efficacy varies. In this study, female Sprague-Dawley rats were given methylnitrosourea (MNU) by intravenous injection resulting in the development of multiple estrogen receptor–positive tumors. Treatment with lapatinib beginning 5 days after MNU was highly effective in preventing cancer development. In addition, we treated rats with palpable mammary tumors with lapatinib daily. In these tumor-bearing animals, treatment continued for 42 days and therapeutic results were obtained. Some rats bearing cancers were treated for 5 days, and the resulting lesions were examined for biomarker modulation. Lapatinib effectively suppressed the abundance of HER2, phosphorylated HER2 (Tyr1221/1222), and phosphorylated EGFR (Tyr1173, Tyr1110) compared with tumors from untreated rats. Protein array analyses allowed parallel determination of the effect of lapatinib on the relative levels of protein phosphorylation and proteins associated with apoptosis. These results combined with immunoreactivity data indicated that, in addition to EGFR and HER2, lapatinib treatment was associated with changes in a number of other signaling molecules, including IGF-1R, Akt, and downstream targets such as GSK3, p27, p53, and cyclin D1 presumably leading to impaired proliferation, apoptosis, or cell-cycle arrest. Cancer Prev Res; 4(8); 1190–7. ©2011 AACR.
Phenylbutyl Isoselenocyanate Modulates Phase I and II Enzymes and Inhibits 4-(Methylnitrosamino)-1-(3-Pyridyl)- 1-Butanone–Induced DNA Adducts in Mice
Authors: Crampsie Melissa A. , Jones Nathan , Das Arunangshu , Aliaga Cesar , Desai Dhimant , Lazarus Philip , Amin Shantu , Sharma Arun K. 
Published: July 2011

Abstract
Lung cancer remains one of the most preventable forms of cancer with about 90% of cases attributed to cigarette smoking. Over the years, the development of chemopreventive agents that could inhibit, delay, or reverse the lung carcinogenesis process has been an active field of research, however, without much attainment. Through extensive structure–activity relationship studies, we recently identified a novel agent phenylbutyl isoselenocyanate (ISC-4), designed on the basis of naturally occurring isothiocyanates well known for their lung cancer prevention properties, as a potential chemopreventive agent. In this study, we used A/J mice to evaluate the lung cancer chemopreventive potential of ISC-4. A single intragastric dose of 1.25 μmol ISC-4 resulted in a time-dependent increase of selenium levels in serum, liver, and lung, suggesting that ISC-4 is orally bioavailable, a key requirement for a chemopreventive agent. This dose also resulted in a time-dependent inhibition of microsomal cytochrome P450 (Cyp450) activity and delayed increases in phase II UDP-glucuronyl transferase (Ugt) and glutathione-S-transferase (Gst) activity. ISC-4 was able to induce mRNA expression of Cyp, Ugt, and Gst enzyme isoforms in liver, but in lung, it inhibited Cyp isoforms while inducing Ugt and Gst isoforms. In addition, ISC-4 effectively inhibited methyl–DNA adduct formation in mice fed diet supplemented with ISC-4 for two weeks and then treated with the tobacco procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. These results suggest that ISC-4 is a strong candidate for development as a chemopreventive agent. Cancer Prev Res; 4(11); 1884–94. ©2011 AACR.