bluuebunny/crossref_metadata_2025_split huggingface dataset:
Near-infrared spectroscopy in the assessment of suspected sepsis in the emergency department
Authors: Macdonald Stephen P J , Brown Simon G A 
Published: October 2013

Background and aimsThe conventional approach to sepsis resuscitation involves early interventions targeting global oxygenation and macro-haemodynamic variables such as central venous and systemic arterial pressures. There is increasing recognition of the importance of microcirculatory changes in shock states, including sepsis, and the relationship of these to outcome. Near-infrared spectroscopy (NIRS) is a recently developed non-invasive technology that measures tissue oxygen saturations (StO2), which may be an indirect measure of the adequacy of the microcirculation. StO2measurements, therefore, have the potential to identify patients who are at risk of progressing to organ dysfunction and could be used to guide resuscitation. This article reviews the current state of knowledge of NIRS in the setting of sepsis, examining its application, validity and prognostic value.MethodsA search of the relevant literature was performed using Medline, Embase and Cochrane databases, and a qualitative analysis was undertaken.ResultsA limited number of observational studies, mostly conducted among patients with severe sepsis, have shown that NIRS may correlate with severity of illness but demonstrate a variable relationship between StO2and outcome.ConclusionsOutstanding questions still remain as to whether NIRS can help to risk-stratify patients with suspected sepsis in the emergency department and the utility of StO2as a resuscitation target.
Has health in Spain been declining since the economic crisis?
Authors: Regidor Enrique , Barrio Gregorio , Bravo María J , de la Fuente Luis 
Published: October 2013

BackgroundThe economic recession starting in 2008 may be having negative effects on health.PurposeWe aimed to identify and characterise changes in trends in 15 health indicators in Spain during the recession.MethodsJoinpoint regression and average annual percent change (AAPC) were used to compare trends.ResultsPremature mortality rates from several causes of death, except from cancer, showed statistically significant downward trends during the recession, as did poor self-reported health. HIV incidence was stable. No indicator declined significantly more slowly during the recession than in the preceding 4-year period, and two declined significantly faster.ConclusionHealth in Spain has continued to improve during the first four years of the economic recession at a rate equal to or higher than in previous years.
Modified balloon assisted coil embolization for the treatment of intracranial and cervical arterial aneurysms using coaxial dual lumen balloon microcatheters: initial experience
Authors: Jagadeesan Bharathi D , Siddiq Farhan , Grande Andrew W , Tummala Ramachandra P 
Published: October 2013

IntroductionTraditional balloon assisted coil embolization techniques for intracranial aneurysms require a single lumen balloon to remodel the aneurysm neck and a separate microcatheter to place coils. Here we report utilization of a single coaxial dual balloon microcatheter to achieve both coil placement and neck remodeling in a series of intracranial and cervical arterial aneurysms.Materials and methodsA series of five patients, including two with subarachnoid hemorrhage, presented to our institution with wide necked oblong aneurysms (8–30 mm maximum diameter). Coil embolization in four of these aneurysms was performed by advancing the tip of either a 4×10 mm Scepter C or a 4×11 mm Scepter XC balloon microcatheter (Microvention, Tustin, USA) into the aneurysm, inflating the balloon at the aneurysm neck, and placing the coils through the same microcatheter. In the fifth patient, who had a giant aneurysm at the top of the basilar artery, two Scepter XC balloon microcatheters were placed side by side and inflated simultaneously at the neck of the aneurysm; coil embolization was then successfully performed through both Scepter XC microcatheters.ResultsCoil embolization was successfully performed with this technique in all five aneurysms. There was no instance of aneurysm rupture, thromboembolic complications, occlusion of branch vessels near the aneurysm neck, or prolapse of coil loops into the parent vessel.ConclusionsAneurysmal neck remodeling and coil embolization can both be achieved using a single coaxial dual lumen balloon microcatheter in selected oblong intracranial and cervical arterial aneurysms.
Across-sectional survey of prevalence and correlates of couple sexual concurrency among married couples in fishing communities along Lake Victoria in Kisumu, Kenya
Authors: Kwena Zachary A , Mwanzo Isaac J , Bukusi Elizabeth A , Achiro Lilian F , Shisanya Chris A 
Published: October 2013

ObjectiveSexual concurrency has been associated with HIV infection. Since HIV in sub-Saharan Africa is mostly spread within the context of heterosexual couples, it is necessary that intervention is focused on such couples. We sought to establish the correlates of couple sexual concurrency in Kisumu, Kenya.MethodsWe conducted 1090 gender-matched interviews in 545 couples in a cross-sectional survey. A random sample of fishermen and their spouses from 33 fish-landing beaches along the shores of Lake Victoria in Kisumu were asked to enrol in the study. Couples were separated into different private rooms for simultaneous interviews that documented socioeconomic and behavioural characteristics, and information on number of sexual partnerships in the preceding 6 months and their status. Based on reported concurrency status of the spouses, a couple was categorised as either concurrent when at least one spouse reported a concurrent sexual relationship or non-concurrent.ResultsOverall, 32.1% of the men and 6.2% of the women had concurrent sexual relationships in the 6 months preceding the study, resulting in 37.6% of the couples being sexually concurrent. Unmet sexual desire, intra-spousal suspicions of infidelity, male dominance scripts, domestic violence, couples’ children and women's age were the correlates of couple sexual concurrency.ConclusionsUnmet sexual desires, inter-spousal infidelity suspicions, male dominance scripts and domestic violence were the main correlates of couple sexual concurrency in these fishing communities.
ΔNp63 Promotes Pediatric Neuroblastoma and Osteosarcoma by Regulating Tumor Angiogenesis
Authors: Bid Hemant K. , Roberts Ryan D. , Cam Maren , Audino Anthony , Kurmasheva Raushan T. , Lin Jiayuh , Houghton Peter J. , Cam Hakan 
Published: October 2013

Abstract
The tumor suppressor gene p53 and its family members p63/p73 are critical determinants of tumorigenesis. ΔNp63 is a splice variant of p63, which lacks the N-terminal transactivation domain. It is thought to antagonize p53-, p63-, and p73-dependent translation, thus blocking their tumor suppressor activity. In our studies of the pediatric solid tumors neuroblastoma and osteosarcoma, we find overexpression of ΔNp63; however, there is no correlation of ΔNp63 expression with p53 mutation status. Our data suggest that ΔNp63 itself endows cells with a gain-of-function that leads to malignant transformation, a function independent of any p53 antagonism. Here, we demonstrate that ΔNp63 overexpression, independent of p53, increases secretion of interleukin (IL)-6 and IL-8, leading to elevated phosphorylation of STAT3 (Tyr-705). We show that elevated phosphorylation of STAT3 leads to stabilization of hypoxia-inducible factor 1α (HIF-1α) protein, resulting in VEGF secretion. We also show human clinical data, which suggest a mechanistic role for ΔNp63 in osteosarcoma metastasis. In summary, our studies reveal the mechanism by which ΔNp63, as a master transcription factor, modulates tumor angiogenesis. Cancer Res; 74(1); 320–9. ©2013 AACR.
PTEN Loss Mitigates the Response of Medulloblastoma to Hedgehog Pathway Inhibition
Authors: Metcalfe Ciara , Alicke Bruno , Crow Ailey , Lamoureux Marlea , Dijkgraaf Gerrit J.P. , Peale Franklin , Gould Stephen E. , de Sauvage Frederic J. 
Published: October 2013

Abstract
Medulloblastoma is a cancer of the cerebellum, for which there is currently no approved targeted therapy. Recent transcriptomics approaches have demonstrated that medulloblastoma is composed of molecularly distinct subgroups, one of which is characterized by activation of the Hedgehog pathway, which in mouse models is sufficient to drive medulloblastoma development. There is thus considerable interest in targeting the Hedgehog pathway for therapeutic benefit in medulloblastoma, particularly given the recent approval of the Hedgehog pathway inhibitor vismodegib for metastatic and locally advanced basal cell carcinoma. Like other molecularly targeted therapies, however, there have been reports of acquired resistance to vismodegib, driven by secondary Hedgehog pathway mutations and potentially by activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Given that acquired resistance to vismodegib may occur as a result of inappropriate PI3K pathway activation, we asked if loss of the PI3K pathway regulator, phosphatase and tensin homologue (Pten), which has been reported to occur in patients within the Hedgehog subgroup, would constitute a mechanism of innate resistance to vismodegib in Hedgehog-driven medulloblastoma. We find that Hedgehog pathway inhibition successfully restrains growth of Pten-deficient medulloblastoma in this mouse model, but does not drive tumor regression, as it does in Pten-wild-type medulloblastoma. Combined inhibition of the Hedgehog and PI3K pathways may lead to superior antitumor activity in PTEN-deficient medulloblastoma in the clinic. Cancer Res; 73(23); 7034–42. ©2013 AACR.
TLR9 Signaling in the Tumor Microenvironment Initiates Cancer Recurrence after Radiotherapy
Authors: Gao Chan , Kozlowska Anna , Nechaev Sergey , Li Haiqing , Zhang Qifang , Hossain Dewan M.S. , Kowolik Claudia M. , Chu Peiguo , Swiderski Piotr , Diamond Don J. , Pal Sumanta K. , Raubitschek Andrew , Kortylewski Marcin 
Published: October 2013

Abstract
Cancer radiotherapy may be immunogenic, but it is unclear why its immunogenic effects are rarely sufficient to prevent tumor recurrence. Here, we report a novel Toll-like receptor 9 (TLR9)–dependent mechanism that initiates tumor regrowth after local radiotherapy. Systemic inhibition of TLR9, but not TLR4, delayed tumor recurrence in mouse models of B16 melanoma, MB49 bladder cancer, and CT26 colon cancer after localized high-dose tumor irradiation. Soluble factors in the microenvironment of regressing tumors triggered TLR9 signaling in freshly recruited myeloid cells appearing within four days of radiotherapy. The tumorigenic effects of TLR9 depended on MyD88/NF-κB–mediated upregulation of interleukin (IL)-6 expression, which in turn resulted in downstream activation of Jak/STAT3 signaling in myeloid cells. In comparing global gene expression in wild-type, TLR9-, or STAT3-deficient myeloid cells derived from irradiated tumors, we identified a unique set of TLR9/STAT3–regulated genes involved in tumor-promoting inflammation and revascularization. Blocking STAT3 function by two myeloid-specific genetic strategies corrected TLR9-mediated cancer recurrence after radiotherapy. Our results suggest that combining localized tumor irradiation with myeloid cell–specific inhibition of TLR9/STAT3 signaling may help eliminate radioresistant cancers. Cancer Res; 73(24); 7211–21. ©2013 AACR.
A Circadian Clock Transcription Model for the Personalization of Cancer Chronotherapy
Authors: Li Xiao-Mei , Mohammad-Djafari Ali , Dumitru Mircea , Dulong Sandrine , Filipski Elisabeth , Siffroi-Fernandez Sandrine , Mteyrek Ali , Scaglione Francesco , Guettier Catherine , Delaunay Franck , Lévi Francis 
Published: October 2013

Abstract
Circadian timing of anticancer medications has improved treatment tolerability and efficacy several fold, yet with intersubject variability. Using three C57BL/6-based mouse strains of both sexes, we identified three chronotoxicity classes with distinct circadian toxicity patterns of irinotecan, a topoisomerase I inhibitor active against colorectal cancer. Liver and colon circadian 24-hour expression patterns of clock genes Rev-erbα and Bmal1 best discriminated these chronotoxicity classes, among 27 transcriptional 24-hour time series, according to sparse linear discriminant analysis. An 8-hour phase advance was found both for Rev-erbα and Bmal1 mRNA expressions and for irinotecan chronotoxicity in clock-altered Per2m/m mice. The application of a maximum-a-posteriori Bayesian inference method identified a linear model based on Rev-erbα and Bmal1 circadian expressions that accurately predicted for optimal irinotecan timing. The assessment of the Rev-erbα and Bmal1 regulatory transcription loop in the molecular clock could critically improve the tolerability of chemotherapy through a mathematical model–based determination of host-specific optimal timing. Cancer Res; 73(24); 7176–88. ©2013 AACR.
APOBEC3B Upregulation and Genomic Mutation Patterns in Serous Ovarian Carcinoma
Authors: Leonard Brandon , Hart Steven N. , Burns Michael B. , Carpenter Michael A. , Temiz Nuri A. , Rathore Anurag , Vogel Rachel I. , Nikas Jason B. , Law Emily K. , Brown William L. , Li Ying , Zhang Yuji , Maurer Matthew J. , Oberg Ann L. , Cunningham Julie M. , Shridhar Viji , Bell Debra A. , April Craig , Bentley David , Bibikova Marina , Cheetham R. Keira , Fan Jian-Bing , Grocock Russell , Humphray Sean , Kingsbury Zoya , Peden John , Chien Jeremy , Swisher Elizabeth M. , Hartmann Lynn C. , Kalli Kimberly R. , Goode Ellen L. , Sicotte Hugues , Kaufmann Scott H. , Harris Reuben S. 
Published: October 2013

Abstract
Ovarian cancer is a clinically and molecularly heterogeneous disease. The driving forces behind this variability are unknown. Here, we report wide variation in the expression of the DNA cytosine deaminase APOBEC3B, with elevated expression in the majority of ovarian cancer cell lines (three SDs above the mean of normal ovarian surface epithelial cells) and high-grade primary ovarian cancers. APOBEC3B is active in the nucleus of several ovarian cancer cell lines and elicits a biochemical preference for deamination of cytosines in 5′-TC dinucleotides. Importantly, examination of whole-genome sequence from 16 ovarian cancers reveals that APOBEC3B expression correlates with total mutation load as well as elevated levels of transversion mutations. In particular, high APOBEC3B expression correlates with C-to-A and C-to-G transversion mutations within 5′-TC dinucleotide motifs in early-stage high-grade serous ovarian cancer genomes, suggesting that APOBEC3B-catalyzed genomic uracil lesions are further processed by downstream DNA "repair" enzymes including error-prone translesion polymerases. These data identify a potential role for APOBEC3B in serous ovarian cancer genomic instability. Cancer Res; 73(24); 7222–31. ©2013 AACR.
Hematopoietic Expression of Oncogenic BRAF Promotes Aberrant Growth of Monocyte-Lineage Cells Resistant to PLX4720
Authors: Kamata Tamihiro , Dankort David , Kang Jing , Giblett Susan , Pritchard Catrin A. , McMahon Martin , Leavitt Andrew D. 
Published: October 2013

Abstract
Mutational activation of BRAF leading to expression of the BRAFV600E oncoprotein was recently identified in a high percentage of specific hematopoietic neoplasms in monocyte/histiocyte and mature B-cell lineages. Although BRAFV600E is a driver oncoprotein and pharmacologic target in solid tumors such as melanoma, lung, and thyroid cancer, it remains unknown whether BRAFV600E is an appropriate therapeutic target in hematopoietic neoplasms. To address this critical question, we generated a mouse model expressing inducible BRAFV600E in the hematopoietic system, and evaluated the efficacy of pathway-targeted therapeutics against primary hematopoietic cells. In this model, BRAFV600E expression conferred cytokine-independent growth to monocyte/macrophage-lineage progenitors leading to aberrant in vivo and in vitro monocyte/macrophage expansion. Furthermore, transplantation of BRAFV600E-expressing bone marrow cells promoted an in vivo pathology most notable for monocytosis in hematopoietic tissues and visceral organs. In vitro analysis revealed that MAP–ERK kinase inhibition, but not RAF inhibition, effectively suppressed cytokine-independent clonal growth of monocyte/macrophage-lineage progenitors. However, combined RAF and phosphoinositide 3-kinase (PI3K) inhibition effectively inhibited cytokine-independent colony formation, suggesting autocrine PI3K pathway activation. Taken together, these results provide evidence that constitutively activated BRAFV600E drives aberrant proliferation of monocyte-lineage cells.
Implications: This study supports the development of pathway-targeted therapeutics in the treatment of BRAFV600E-expressing hematopoietic neoplasms in the monocyte/histiocyte lineage. Mol Cancer Res; 11(12); 1530–41. ©2013 AACR.
A Multiantigen Vaccine Targeting Neu, IGFBP-2, and IGF-IR Prevents Tumor Progression in Mice with Preinvasive Breast Disease
Authors: Disis Mary L. , Gad Ekram , Herendeen Daniel R. , Lai Vy Phan- , Park Kyong Hwa , Cecil Denise L. , O'Meara Megan M. , Treuting Piper M. , Lubet Ronald A. 
Published: October 2013

Abstract
A multiantigen multipeptide vaccine, targeting proteins expressed in preinvasive breast lesions, can stimulate type I CD4+ T cells which have been shown to be deficient in both patients with breast cancer and mice that develop mammary tumors. Transgenic mice (TgMMTV-neu) were immunized with a multiantigen peptide vaccine specific for neu, insulin—like growth factor-binding protein 2 and insulin-like growth factor receptor-I at a time when some of the animals already had preinvasive lesions (18 weeks of age). Although immunization with each individual antigen was partially effective in inhibiting tumor growth, immunization with the multiantigen vaccine was highly effective, blocking development of palpable lesions in 65% of mice and slowing tumor growth in the infrequent palpable tumors, which did arise. Protection was mediated by CD4+ T cells, and the few slow-growing tumors that did develop demonstrated a significant increase in intratumoral CD8+ T cells as compared with controls (P = 0.0007). We also combined the vaccine with agents that were, by themselves, partially effective inhibitors of tumor progression in this model; lapatinib and the RXR agonist bexarotene. Although the combination of lapatinib and vaccination performed similarly to vaccination alone (P = 0.735), bexarotene and vaccination significantly enhanced disease-free survival (P &lt; 0.0001), and approximately 90% of the mice showed no pathologic evidence of carcinomas at one year. The vaccine also demonstrated significant clinical efficacy in an additional transgenic model of breast cancer (TgC3(I)-Tag). Chemoimmunoprevention combinations may be an effective approach to breast cancer prevention even when the vaccine is administered in the presence of subclinical disease. Cancer Prev Res; 6(12); 1273–82. ©2013 AACR.
Ticagrelor versus prasugrel in diabetic patients with an acute coronary syndrome
Authors: Laine Marc , Frere Corinne , Toesca Richard , Berbis Julie , Barnay Pierre , Pansieri Michel , Michelet Pierre , Bessereau Jacques , Camilleri Elise , Ronsin Olivia , Helal Olfa , Paganelli Franck , Dignat-George Françoise , Bonello Laurent 
Published: October 2013

SummaryOptimal P2Y12 receptor blockade is critical to prevent ischaemic recurrence in patients undergoing percutaneous coronary intervention (PCI). We aimed to compare the level of platelet reactivity (PR) inhibition achieved by prasugrel and ticagrelor loading dose (LD) in diabetic acute coronary syndrome (ACS) patients undergoing PCI. We performed a single-center prospective open-label randomised trial. Patients with diabetes mellitus undergoing PCI for an ACS were randomised to receive prasugrel 60 mg or ticagrelor 180 mg. The primary endpoint of the study was the level of platelet reactivity (PR) assessed between 6 and 18 hours post-LD using the VASP index. We randomised 100 diabetic patients undergoing PCI for an ACS. No difference was observed in baseline characteristics between the two groups. In particular, the rate of patient receiving insulin therapy was identical (25 vs 28.6%; p =0.7). Ticagrelor achieved a significantly lower PR compared to prasugrel loading dose (17.3 ± 14.2 vs 27.7 ± 23.3%; p=0.009). In addition the rate of high on-treatment platelet reactivity, defined by a VASP ≥50%, tend to be lower in the ticagrelor group although the difference did not reach statistical significance (6 vs 16%; p=0.2). The rate of low on treatment PR was identical (60 vs 54%; p=0.8). The present study demonstrates that ticagrelor LD is superior to prasugrel LD to reduce PR in ACS patients with diabetes mellitus. Whether the higher potency of ticagrelor could translate into a clinical benefit should be investigated.
A model-based analysis of the clinical and economic impact of personalising P2Y12-receptor inhibition with platelet function testing in acute coronary syndrome patients
Authors: Straub Niels , Beivers Andreas , Lenk Ekaterina , Aradi Daniel , Sibbing Dirk 
Published: October 2013

SummaryAlthough some observational studies reported that the measured level of P2Y12-inhibition is predictive for thrombotic events, the clinical and economic benefit of incorporating PFT to personalize P2Y12-receptor directed antiplatelet treatment is unknown. Here, we assessed the clinical impact and cost-effectiveness of selecting P2Y12-inhibitors based on platelet function testing (PFT) in acute coronary syndrome (ACS) patients undergoing PCI. A decision model was developed to analyse the health economic effects of different strategies. PFT-guided treatment was compared with the three options of general clopidogrel, prasugrel or ticagrelor treatment. In the PFT arm, low responders to clopidogrel received prasugrel, while normal responders carried on with clopidogrel. The associated endpoints in the model were cardiovascular death, stent thrombosis and major bleeding. With a simulated cohort of 10,000 patients treated for one year, there were 93 less events in the PFT arm compared to general clopidogrel. In prasugrel and ticagrelor arms, 110 and 86 events were prevented compared to clopidogrel treatment, respectively. The total expected costs (including event costs, drug costs and PFT costs) for generic clopidogrel therapy were US$ 1,059/patient. In the PFT arm, total costs were US$ 1,494, while in the prasugrel and ticagrelor branches they were US$ 3,102 and US$ 3,771, respectively. The incrementalcost- effectiveness-ratio (ICER) was US$ 46,770 for PFT-guided therapy, US$ 185,783 for prasugrel and US$ 315,360 for ticagrelor. In this model-based analysis, a PFT-guided therapy may have fewer adverse outcomes than general treatment with clopidogrel and may be more cost-effective than prasugrel or ticagrelor treatment in ACS patients undergoing PCI.