bluuebunny/crossref_metadata_2025_split huggingface dataset:
MR/PET quantification tools: Registration, segmentation, classification, and MR‐based attenuation correction
Authors: Fei Baowei , Yang Xiaofeng , Nye Jonathon A. , Aarsvold John N. , Raghunath Nivedita , Cervo Morgan , Stark Rebecca , Meltzer Carolyn C. , Votaw John R. 
Published: October 2012

Purpose:Combined MR/PET is a relatively new, hybrid imaging modality. A human MR/PET prototype system consisting of a Siemens 3T Trio MR and brain PET insert was installed and tested at our institution. Its present design does not offer measured attenuation correction (AC) using traditional transmission imaging. This study is the development of quantification tools including MR‐based AC for quantification in combined MR/PET for brain imaging.Methods:The developed quantification tools include image registration, segmentation, classification, and MR‐based AC. These components were integrated into a single scheme for processing MR/PET data. The segmentation method is multiscale and based on the Radon transform of brain MR images. It was developed to segment the skull on T1‐weighted MR images. A modified fuzzy C‐means classification scheme was developed to classify brain tissue into gray matter, white matter, and cerebrospinal fluid. Classified tissue is assigned an attenuation coefficient so that AC factors can be generated. PET emission data are then reconstructed using a three‐dimensional ordered sets expectation maximization method with the MR‐based AC map. Ten subjects had separate MR and PET scans. The PET with [11C]PIB was acquired using a high‐resolution research tomography (HRRT) PET. MR‐based AC was compared with transmission (TX)‐based AC on the HRRT. Seventeen volumes of interest were drawn manually on each subject image to compare the PET activities between the MR‐based and TX‐based AC methods.Results:For skull segmentation, the overlap ratio between our segmented results and the ground truth is 85.2 ± 2.6%. Attenuation correction results from the ten subjects show that the difference between the MR and TX‐based methods was <6.5%.Conclusions:MR‐based AC compared favorably with conventional transmission‐based AC. Quantitative tools including registration, segmentation, classification, and MR‐based AC have been developed for use in combined MR/PET.
Role of
CTR4
in the Virulence of Cryptococcus neoformans
Authors: Waterman Scott R. , Park Yoon-Dong , Raja Meera , Qiu Jin , Hammoud Dima A. , O’Halloran Thomas V. , Williamson Peter R. 
Published: October 2012

ABSTRACT

While research has identified an important contribution for metals, such as iron, in microbial pathogenesis, the roles of other transition metals, such as copper, remain mostly unknown. Recent evidence points to a requirement for copper homeostasis in the virulence of
Cryptococcus neoformans
based on a role for a
CUF1
copper regulatory factor in mouse models and in a human patient cohort.
C. neoformans
is an important fungal pathogen that results in an estimated 600,000 AIDS-related deaths yearly. In the present studies, we found that a
C. neoformans
mutant lacking the
CUF1
-dependent copper transporter,
CTR4
, grows normally in rich medium at 37°C but has reduced survival in macrophages and attenuated virulence in a mouse model. This reduced survival and virulence were traced to a growth defect under nutrient-restricted conditions. Expression studies using a full-length
CTR4
-fluorescent fusion reporter construct demonstrated robust expression in macrophages, brain, and lung, the latter shown by
ex vivo
fluorescent imaging. Inductively coupled mass spectroscopy (ICP-MS) was used to probe the copper quota of fungal cells grown in defined medium and recovered from brain, which suggested a role for a copper-protective function of
CTR4
in combination with cell metallothioneins under copper-replete conditions. In summary, these data suggest a role for
CTR4
in copper-related homeostasis and subsequently in fungal virulence.

IMPORTANCE
Crytococcus neoformans
is a significant global fungal pathogen, and copper homeostasis is a relatively unexplored aspect of microbial pathogenesis that could lead to novel therapeutics. Previous studies correlated expression levels of a Ctr4 copper transporter to development of meningoencephalitis in a patient cohort of solid-organ transplants, but a direct role for Ctr4 in mammalian pathogenesis has not been demonstrated. The present studies utilize a Δ
ctr4
mutant strain which revealed an important role for
CTR4
in
C. neoformans
infections in mice and relate the gene product to homeostatic control of copper and growth under nutrient-restricted conditions. Robust expression levels of
CTR4
during fungal infection were exploited to demonstrate expression and lung cryptococcal disease using
ex vivo
fluorescence imaging. In summary, these studies are the first to directly demonstrate a role for a copper transporter in fungal disease and provide an
ex vivo
imaging tool for further study of cryptococcal gene expression and pathogenesis.
Inhibition of LpxC Protects Mice from Resistant Acinetobacter baumannii by Modulating Inflammation and Enhancing Phagocytosis
Authors: Lin Lin , Tan Brandon , Pantapalangkoor Paul , Ho Tiffany , Baquir Beverlie , Tomaras Andrew , Montgomery Justin I. , Reilly Usa , Barbacci Elsa G. , Hujer Kristine , Bonomo Robert A. , Fernandez Lucia , Hancock Robert E. W. , Adams Mark D. , French Samuel W. , Buslon Virgil S. , Spellberg Brad 
Published: October 2012

ABSTRACTNew treatments are needed for extensively drug-resistant (XDR) Gram-negative bacilli (GNB), such asAcinetobacter baumannii. Toll-like receptor 4 (TLR4) was previously reported to enhance bacterial clearance of GNB, includingA. baumannii. However, here we have shown that 100% of wild-type mice versus 0% of TLR4-deficient mice died of septic shock due toA. baumanniiinfection, despite having similar tissue bacterial burdens. The strain lipopolysaccharide (LPS) content and TLR4 activation by extracted LPS did not correlate within vivovirulence, nor did colistin resistance due to LPS phosphoethanolamine modification. However, more-virulent strains shed more LPS during growth than less-virulent strains, resulting in enhanced TLR4 activation. Due to the role of LPS inA. baumanniivirulence, an LpxC inhibitor (which affects lipid A biosynthesis) antibiotic was tested. The LpxC inhibitor did not inhibit growth of the bacterium (MIC > 512 µg/ml) but suppressedA. baumanniiLPS-mediated activation of TLR4. Treatment of infected mice with the LpxC inhibitor enhanced clearance of the bacteria by enhancing opsonophagocytic killing, reduced serum LPS concentrations and inflammation, and completely protected the mice from lethal infection. These results identify a previously unappreciated potential for the new class of LpxC inhibitor antibiotics to treat XDRA. baumanniiinfections. Furthermore, they have far-reaching implications for pathogenesis and treatment of infections caused by GNB and for the discovery of novel antibiotics not detected by standardin vitroscreens.IMPORTANCENovel treatments are needed for infections caused byAcinetobacter baumannii, a Gram-negative bacterium that is extremely antibiotic resistant. The current study was undertaken to understand the immunopathogenesis of these infections, as a basis for defining novel treatments. The primary strain characteristic that differentiated virulent from less-virulent strains was shedding of Gram-negative lipopolysaccharide (LPS) during growth. A novel class of antibiotics, called LpxC inhibitors, block LPS synthesis, but these drugs do not demonstrate the ability to killA. baumanniiin vitro. We found that an LpxC inhibitor blocked the ability of bacteria to activate the sepsis cascade, enhanced opsonophagocytic killing of the bacteria, and protected mice from lethal infection. Thus, an entire new class of antibiotics which is already in development has heretofore-unrecognized potential to treatA. baumanniiinfections. Furthermore, standard antibiotic screens based onin vitrokilling failed to detect this treatment potential of LpxC inhibitors forA. baumanniiinfections.
EspZ of Enteropathogenic and Enterohemorrhagic Escherichia coli Regulates Type III Secretion System Protein Translocation
Authors: Berger Cedric N. , Crepin Valerie F. , Baruch Kobi , Mousnier Aurelie , Rosenshine Ilan , Frankel Gad 
Published: October 2012

ABSTRACT

Translocation of effector proteins via a type III secretion system (T3SS) is a widespread infection strategy among Gram-negative bacterial pathogens. Each pathogen translocates a particular set of effectors that subvert cell signaling in a way that suits its particular infection cycle. However, as effector unbalance might lead to cytotoxicity, the pathogens must employ mechanisms that regulate the intracellular effector concentration. We present evidence that the effector EspZ controls T3SS effector translocation from enteropathogenic (EPEC) and enterohemorrhagic (EHEC)
Escherichia coli
. Consistently, an EPEC
espZ
mutant is highly cytotoxic. Following ectopic expression, we found that EspZ inhibited the formation of actin pedestals as it blocked the translocation of Tir, as well as other effectors, including Map and EspF. Moreover, during infection EspZ inhibited effector translocation following superinfection. Importantly, while EspZ of EHEC O157:H7 had a universal “translocation stop” activity, EspZ of EPEC inhibited effector translocation from typical EPEC strains but not from EHEC O157:H7 or its progenitor, atypical EPEC O55:H7. We found that the N and C termini of EspZ, which contains two transmembrane domains, face the cytosolic leaflet of the plasma membrane at the site of bacterial attachment, while the extracellular loop of EspZ is responsible for its strain-specific activity. These results show that EPEC and EHEC acquired a sophisticated mechanism to regulate the effector translocation.

IMPORTANCE
Enteropathogenic
Escherichia coli
(EPEC) and enterohemorrhagic
E. coli
(EHEC) are important diarrheal pathogens responsible for significant morbidity and mortality in developing countries and the developed world, respectively. The virulence strategy of EPEC and EHEC revolves around a conserved type III secretion system (T3SS), which translocates bacterial proteins known as effectors directly into host cells. Previous studies have shown that when cells are infected in two waves with EPEC, the first wave inhibits effector translocation by the second wave in a T3SS-dependent manner, although the factor involved was not known. Importantly, we identified EspZ as the effector responsible for blocking protein translocation following a secondary EPEC infection. Interestingly, we found that while EspZ of EHEC can block protein translocation from both EPEC and EHEC strains, EPEC EspZ cannot block translocation from EHEC. These studies show that EPEC and EHEC employ a novel infection strategy to regulate T3SS translocation.
Unexpected Dissemination Patterns in Lymphoma Progression Revealed by Serial Imaging within a Murine Lymph Node
Authors: Ito Ken , Smith Bryan Ronain , Parashurama Natesh , Yoon Joon-Kee , Song Si Yeol , Miething Cornelius , Mallick Parag , Lowe Scott , Gambhir Sanjiv Sam 
Published: October 2012

Abstract
Non-Hodgkin lymphoma (NHL) is a heterogeneous and highly disseminated disease, but the mechanisms of its growth and dissemination are not well understood. Using a mouse model of this disease, we used multimodal imaging, including intravital microscopy (IVM) combined with bioluminescence, as a powerful tool to better elucidate NHL progression. We injected enhanced green fluorescent protein and luciferase-expressing Eμ-Myc/Arf−/− (Cdkn2a−/−) mouse lymphoma cells (EL-Arf−/−) into C57BL/6NCrl mice intravenously. Long-term observation inside a peripheral lymph node was enabled by a novel lymph node internal window chamber technique that allows chronic, sequential lymph node imaging under in vivo physiologic conditions. Interestingly, during early stages of tumor progression we found that few if any lymphoma cells homed initially to the inguinal lymph node (ILN), despite clear evidence of lymphoma cells in the bone marrow and spleen. Unexpectedly, we detected a reproducible efflux of lymphoma cells from spleen and bone marrow, concomitant with a massive and synchronous influx of lymphoma cells into the ILN, several days after injection. We confirmed a coordinated efflux/influx of tumor cells by injecting EL-Arf−/− lymphoma cells directly into the spleen and observing a burst of lymphoma cells, validating that the burst originated in organs remote from the lymph nodes. Our findings argue that in NHL an efflux of tumor cells from one disease site to another, distant site in which they become established occurs in discrete bursts. Cancer Res; 72(23); 6111–8. ©2012 AACR.
Establishment and Characterization of Novel Cell Lines from Sinonasal Undifferentiated Carcinoma
Authors: Takahashi Yoko , Kupferman Michael E. , Bell Diana , Jiffar Tilahun , Lee June Goo , Xie Tong-Xin , Li Ning-Wei , Zhao Mei , Frederick Mitchell J. , Gelbard Alexander , Myers Jeffrey N. , Hanna Ehab Y. 
Published: October 2012

Abstract
Purpose: Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive cancer. Despite the use of multimodality treatment, the overall prognosis remains poor. To better understand the biologic features of SNUC and help develop new therapies for the disease, we established SNUC cell lines and characterized their biologic behaviors.
Experimental Design: Cell lines were established from a patient with a T4N0M0 SNUC of the right maxillary sinus who was treated with surgical resection at our center. Tumor colonies were harvested and were sequentially replated onto larger plates. Two populations were developed and labeled MDA8788-6 and MDA8788-7. These cell lines were characterized with molecular, biomarker, functional, and histologic analyses.
Results: Short tandem repeat genotyping revealed that the cell line is isogenic to the parental tumor, and cytogenetic analysis identified 12 chromosomal translocations. The SNUC cell lines do not form colonies in soft agar but are tumorigenic and nonmetastatic in an orthotopic mouse model of sinonasal cancer. Western blot analysis revealed that both MDA8788 cell lines express epithelial markers but do not express mesenchymal markers or the endocrine marker synaptophysin.
Conclusions: This is the first report of the establishment of stable human-derived SNUC cell lines. The lines were highly tumorigenic and maintain the histologic and molecular features of the original tumor. These cell lines should serve as useful tools for the future study of SNUC biology and the development and testing of novel therapies for this deadly disease. Clin Cancer Res; 18(22); 6178–87. ©2012 AACR.
Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated Immune Response in Ovarian Cancer Patients
Authors: Sabbatini Paul , Tsuji Takemasa , Ferran Luis , Ritter Erika , Sedrak Christine , Tuballes Kevin , Jungbluth Achim A. , Ritter Gerd , Aghajanian Carol , Bell-McGuinn Katherine , Hensley Martee L. , Konner Jason , Tew William , Spriggs David R. , Hoffman Eric W. , Venhaus Ralph , Pan Linda , Salazar Andres M. , Diefenbach Catherine Magid , Old Lloyd J. , Gnjatic Sacha 
Published: October 2012

Abstract
Purpose: Long peptides are efficiently presented to both CD4+ and CD8+ T cells after intracellular processing by antigen-presenting cells. To investigate the safety and in vivo immunogenicity of synthetic overlapping long peptides (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations.
Experimental Design: Twenty-eight patients with advanced ovarian cancer in second or third remission were enrolled sequentially in three cohorts and received at least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2 (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP + 1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and cellular responses were evaluated by standardized immunomonitoring techniques (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining).
Results: The vaccine was generally well tolerated with injection site reactions and fatigue that resolved. NY-ESO-1–specific antibody and CD8+ T cells were undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%) and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide, and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1–specific CD4+ T cells were detected in all patients with greater frequency and polyclonality when Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant further accelerated the induction of NY-ESO-1–specific immune responses.
Conclusions: The current study shows that NY-ESO-1 OLP vaccine is safe and rapidly induces consistent integrated immune responses (antibody, CD8+ and CD4+) in nearly all vaccinated patients when given with appropriate adjuvants. Clin Cancer Res; 18(23); 6497–508. ©2012 AACR.
Acute Heart Failure
Authors: Ezekowitz Justin A. , Hu Jia , Delgado Diego , Hernandez Adrian F. , Kaul Padma , Leader Rolland , Proulx Guy , Virani Sean , White Michel , Zieroth Shelley , O’Connor Christopher , Westerhout Cynthia M. , Armstrong Paul W. 
Published: October 2012

Background—
Randomized controlled trials (RCT) are limited by their generalizability to the broader nontrial population. To provide a context for Acute Study of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial, we designed a complementary registry to characterize clinical characteristics, practice patterns, and in-hospital outcomes of acute heart failure patients.

Methods and Results—

Eligible patients for the registry included those with a principal diagnosis of acute heart failure (ICD-9-CM 402 and 428; ICD-10 I50.x, I11.0, I13.0, I13.2) from 8 sites participating in ASCEND-HF (n=697 patients, 2007–2010). Baseline characteristics, treatments, and hospital outcomes from the registy were compared with ASCEND-HF RCT patients from 31 Canadian sites (n=465, 2007–2010). Patients in the registry were older, more likely to be female, and have chronic respiratory disease, less likely to have diabetes mellitus: they had a similar incidence of ischemic HF, atrial fibrillation, and similar B-type natriuretic peptide levels. Registry patients had higher systolic blood pressure (registry: median 132 mm Hg [interquartile range 115–151 mm Hg]; RCT: median 120 mm Hg [interquartile range 110–135 mm Hg]) and ejection fraction (registry: median 40% [interquartile range 27–58%]; RCT: median 29% [interquartile range 20–40 mm Hg]) than RCT patients. Registry patients presented more often via ambulance and had a similar total length of stay as RCT patients. In-hospital mortality was significantly higher in the registry compared with the RCT patients (9.3% versus 1.3%,
P
<0.001), and this remained after multivariable adjustment (odds ratio 6.6, 95% CI 2.6–16.8,
P
<0.001).

Conclusions—
Patients enrolled in a large RCT of acute heart failure differed significantly based on clinical characteristics, treatments, and inpatient outcomes from contemporaneous patients participating in a registry. These results highlight the need for context of RCTs to evaluate generalizability of results and especially the need to improve clinical outcomes in acute heart failure.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00475852.
Adenoid Ciliostimulation in Children with Chronic Otitis Media
Authors: Andreoli Steven M. , Schlosser Rodney J. , Wang Ling‐Feng , Mulligan Ryan M. , Discolo Christopher M. , White David R. 
Published: October 2012

ObjectiveAdenoid hypertrophy and chronic adenoiditis are associated with an increased incidence of chronic otitis media. This study intends to determine the relationship between chronic otitis media and dynamic ciliary beat frequency in children undergoing adenoidectomy.Study DesignProspective, controlled study.SettingPediatric tertiary care hospital.Subjects and MethodsChildren undergoing adenoidectomy were enrolled. Patients were stratified according to their indication for surgery, including adenotonsillar hypertrophy with obstructive sleep apnea, chronic otitis media with effusion, or recurrent episodes of acute otitis media. Adenoids were harvested using the curette. Tissue was sectioned and allowed to equilibrate in basal media for 24 hours. Cilia‐bearing tissue was then stimulated using isoproterenol or methacholine. Ciliary beat frequency was serially reordered and analyzed using the Sisson‐Ammons Video Analysis software program.ResultsBaseline ciliary beat frequency was similar in all groups (N = 47, total). Using isoproterenol, children with chronic otitis media with effusion demonstrated a blunted dynamic ciliary response at 2 and 3 hours relative to control (P =. 0176 and P =. 0282). Methacholine‐stimulated ciliary beat frequency was not different between each group.ConclusionAt 2 and 3 hours following isoproterenol stimulation, there was a significant blunting of dynamic ciliary beat frequency in children with chronic otitis media with effusion. This ciliary dysfunction may provide a physiological explanation related to chronic adenoiditis in children with chronic otitis media.
Use of a chemically induced-colon carcinogenesis-prone Apc-mutant rat in a chemotherapeutic bioassay
Authors: Yoshimi Kazuto , Hashimoto Takao , Niwa Yusuke , Hata Kazuya , Serikawa Tadao , Tanaka Takuji , Kuramoto Takashi 
Published: October 2012

Abstract

Background
Chemotherapeutic bioassay for colorectal cancer (CRC) with a rat model bearing chemically-induced CRCs plays an important role in the development of new anti-tumor drugs and regimens. Although several protocols to induce CRCs have been developed, the incidence and number of CRCs are not much enough for the efficient bioassay. Recently, we established the very efficient system to induce CRCs with a chemically induced-colon carcinogenesis-prone Apc-mutant rat, Kyoto Apc Delta (KAD) rat. Here, we applied the KAD rat to the chemotherapeutic bioassay for CRC and showed the utility of the KAD rat.

Methods
The KAD rat has been developed by the ENU mutagenesis and carries a homozygous nonsense mutation in the Apc gene (S2523X). Male KAD rats were given a single subcutaneous injection of AOM (20 mg/kg body weight) at 5 weeks of age. Starting at 1 week after the AOM injection, they were given 2% DSS in drinking water for 7 days. Tumor-bearing KAD rats were divided into experimental and control groups on the basis of the number of tumors observed by endoscopy at week 8. The 5-fluorouracil (5-FU) was administrated intravenously a dose of 50 or 75 mg/kg weekly at week 9, 10, and 11. After one-week interval, the 5-FU was given again at week 13, 14, and 15. At week 16, animals were sacrificed and tumor number and volume were measured macroscopically and microscopically.

Results
In total 48 tumors were observed in 27 KAD rats with a 100% incidence at week 8. The maximum tolerated dose for the KAD rat was 50 mg/kg of 5-FU. Macroscopically, the number or volume of tumors in the 5-FU treated rats was not significantly different from the control. Microscopically, the number of adenocarcinoma in the 5-FU treated rats was not significantly different (p < 0.02) from that of the control. However, the volume of adenocarcinomas was significantly lower than in the control. Anticancer effect of the 5-FU could be obtained only after the 16 weeks of experimental period.

Conclusion
The use of the AOM/DSS-treated tumor-bearing KAD rats could shorten the experimental period and reduce the number of animals examined in the chemotherapeutic bioassay. The efficient bioassay with the AOM/DSS-treated tumor-bearing KAD rats would promote the development of new anti-tumor drugs and regimens.