bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Transporter Required for Biogenesis of
cbb
3
-Type Cytochrome
c
Oxidase in Rhodobacter capsulatus
Authors: Ekici Seda , Yang Honghui , Koch Hans-Georg , Daldal Fevzi 
Published: February 2012

ABSTRACT

The acquisition, delivery, and incorporation of metals into their respective metalloproteins are important cellular processes. These processes are tightly controlled in order to prevent exposure of cells to free-metal concentrations that could yield oxidative damage. Copper (Cu) is one such metal that is required as a cofactor in a variety of proteins. However, when present in excessive amounts, Cu is toxic due to its oxidative capability. Cytochrome
c
oxidases (Coxs) are among the metalloproteins whose assembly and activity require the presence of Cu in their catalytic subunits. In this study, we focused on the acquisition of Cu for incorporation into the heme-Cu binuclear center of the
cbb
3
-type Cox (
cbb
3
-Cox) in the facultative phototroph
Rhodobacter capsulatus
. Genetic screens identified a
cbb
3
-Cox defective mutant that requires Cu
2+
supplementation to produce an active
cbb
3
-Cox. Complementation of this mutant using wild-type genomic libraries unveiled a novel gene (
ccoA
) required for
cbb
3
-Cox biogenesis. In the absence of CcoA, the cellular Cu content decreases and
cbb
3
-Cox assembly and activity become defective. CcoA shows homology to major facilitator superfamily (MFS)-type transporter proteins. Members of this family are known to transport small solutes or drugs, but so far, no MFS protein has been implicated in
cbb
3
-Cox biogenesis. These findings provide novel insights into the maturation and assembly of membrane-integral metalloproteins and on a hitherto-unknown function(s) of MFS-type transporters in bacterial Cu acquisition.

IMPORTANCE
Biogenesis of energy-transducing membrane-integral enzymes, like the heme copper-containing cytochrome
c
oxidases, and the acquisition of transition metals, like copper, as their catalytic cofactors are vital processes for all cells. These widespread and well-controlled processes are poorly understood in all organisms, including bacteria. Defects in these processes lead to severe mitochondrial diseases in humans and poor crop yields in plants. In this study, using the facultative phototroph
Rhodobacter capsulatus
as a model organism, we report on the discovery of a novel major facilitator superfamily (MFS)-type transporter (CcoA) that affects cellular copper content and
cbb
3
-type cytochrome
c
oxidase production in bacteria.
Accuracy of the revised 2010 TNM classification in predicting the prognosis of patients treated for renal cell cancer in the north east of England
Authors: Veeratterapillay R , Simren R , El-Sherif A , Johnson M I , Soomro N , Heer R 
Published: January 2012

BackgroundThe TNM classification for renal cell cancer (RCC) should accurately predict and assign prognostic information for patients. In this study the recent 2010 revision to the TNM classification was compared with the previous 2002 classification with regard to survival outcomes.MethodsAll patients having radical nephrectomy for RCC in the 5-year period 2004–8 at a tertiary referral centre were included. Pathological and radiological records were reviewed to identify TNM stage (2002 and 2010 classification) and survival data were captured.Results345 patients with RCC were identified. Based on the 2002 TNM staging system and using outcomes in T1 staged tumours as a baseline, statistically significant differences in disease-specific survival were noted between patients with T1 and T3b tumours (log rank p<0.001) but not between those with T1 and T3a tumours (p=0.33). However, when tumour stage was reassigned according to the 2010 classification, patients with T3a tumours were also found to do statistically worse than T1 staged disease (p<0.001).ConclusionIn our cohort, the new 2010 TNM reclassification of T3 tumours showed better correlation with predicting worsening outcomes compared with localised disease.
Hereditary colorectal cancer diagnostics: morphological features of familial colorectal cancer type X versus Lynch syndrome
Authors: Klarskov Louise , Holck Susanne , Bernstein Inge , Nilbert Mef 
Published: January 2012

BackgroundThe hereditary non-polyposis colorectal cancer (HNPCC) subset of tumours can broadly be divided into tumours caused by an underlying mismatch-repair gene mutation, referred to as Lynch syndrome, and those that develop in families with similar patterns of heredity but without disease-predisposing germline mismatch repair mutations, referred to as familial colorectal cancer type X (FCCTX). Recognition of HNPCC-associated colorectal cancers is central since surveillance programmes effectively reduce morbidity and mortality. The characteristic morphological features linked to Lynch syndrome can aid in the identification of this subset, whereas the possibility to use morphological features as an indicator of FCCTX is uncertain.Objective and methodsTo perform a detailed morphological evaluation of HNPCC-associated colorectal cancers and demonstrate significant differences between tumours associated with FCCTX and Lynch syndrome.ResultsThe morphological features associated with Lynch syndrome, that is, right-sided tumour location, poor differentiation, expansive growth pattern, tumour-infiltrating lymphocytes, peritumorous lymphocytes, Crohn-like reactions, and lack of dirty necrosis, were significantly less often observed in FCCTX tumours.DiscussionThe less typical morphology in FCCTX implies that family history of cancer needs to be taken into account since these tumours cannot readily be recognised based on histopathological features.
Current and future delivery of diagnostic electron microscopy in the UK: results of a national survey
Authors: de Haro Tracey , Furness Peter 
Published: January 2012

AimsElectron microscopy (EM) remains essential to delivering several specialist areas of diagnosis, especially the interpretation of native renal biopsies. However, there is anecdotal evidence of EM units struggling to survive, for a variety of reasons. The authors sought to obtain objective evidence of the extent and the causes of this problem.MethodsAn online survey was undertaken of Fellows of the Royal College of Pathologists who use EM in diagnosis.ResultsA significant number of EM units anticipate having to close and hence outsource their EM work in the coming years. Yet most existing units are working to full capacity and would be unable to take on the substantial amounts of extra work implied by other units outsourcing their needs. Equipment and staffing are identified by most EM units as the major barriers to growth and are also the main reasons cited for units facing potential closure.ConclusionsIn the current financial climate it seems unlikely that units will be willing to make the large investment in equipment and staff needed to take on extra work, unless they can be reasonably confident of an acceptable financial return as a result of increased external referral rates. The case is thus made for a degree of national coordination of the future provision of this specialist service, possibly through the National Commissioning Group or the new National Commissioning Board. Without this, the future of diagnostic EM services in the UK is uncertain. Its failure would pose a threat to good patient care.
Sphingosine-1-Phosphate Produced by Sphingosine Kinase 1 Promotes Breast Cancer Progression by Stimulating Angiogenesis and Lymphangiogenesis
Authors: Nagahashi Masayuki , Ramachandran Subramaniam , Kim Eugene Y. , Allegood Jeremy C. , Rashid Omar M. , Yamada Akimitsu , Zhao Renping , Milstien Sheldon , Zhou Huiping , Spiegel Sarah , Takabe Kazuaki 
Published: February 2012

Abstract
Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator that promotes breast cancer progression by diverse mechanisms that remain somewhat unclear. Here we report pharmacologic evidence of a critical role for sphingosine kinase 1 (SphK1) in producing S1P and mediating tumor-induced hemangiogenesis and lymphangiogenesis in a murine model of breast cancer metastasis. S1P levels increased both in the tumor and the circulation. In agreement, serum S1P levels were significantly elevated in stage IIIA human breast cancer patients, compared with age/ethnicity-matched healthy volunteers. However, treatment with the specific SphK1 inhibitor SK1-I suppressed S1P levels, reduced metastases to lymph nodes and lungs, and decreased overall tumor burden of our murine model. Both S1P and angiopoietin 2 (Ang2) stimulated hemangiogenesis and lymphangiogenesis in vitro, whereas SK1-I inhibited each process. We quantified both processes in vivo from the same specimen by combining directed in vivo angiogenesis assays with fluorescence-activated cell sorting, thereby confirming the results obtained in vitro. Notably, SK1-I decreased both processes not only at the primary tumor but also in lymph nodes, with peritumoral lymphatic vessel density reduced in SK1-I–treated animals. Taken together, our findings show that SphK1-produced S1P is a crucial mediator of breast cancer–induced hemangiogenesis and lymphangiogenesis. Our results implicate SphK1 along with S1P as therapeutic targets in breast cancer. Cancer Res; 72(3); 726–35. ©2012 AACR.
Modulation of Glucose Metabolism by CD44 Contributes to Antioxidant Status and Drug Resistance in Cancer Cells
Authors: Tamada Mayumi , Nagano Osamu , Tateyama Seiji , Ohmura Mitsuyo , Yae Toshifumi , Ishimoto Takatsugu , Sugihara Eiji , Onishi Nobuyuki , Yamamoto Takehiro , Yanagawa Hiroshi , Suematsu Makoto , Saya Hideyuki 
Published: February 2012

Abstract
An increased glycolytic flux accompanied by activation of the pentose phosphate pathway (PPP) is implicated in chemoresistance of cancer cells. In this study, we found that CD44, a cell surface marker for cancer stem cells, interacts with pyruvate kinase M2 (PKM2) and thereby enhances the glycolytic phenotype of cancer cells that are either deficient in p53 or exposed to hypoxia. CD44 ablation by RNA interference increased metabolic flux to mitochondrial respiration and concomitantly inhibited entry into glycolysis and the PPP. Such metabolic changes induced by CD44 ablation resulted in marked depletion of cellular reduced glutathione (GSH) and increased the intracellular level of reactive oxygen species in glycolytic cancer cells. Furthermore, CD44 ablation enhanced the effect of chemotherapeutic drugs in p53-deficient or hypoxic cancer cells. Taken together, our findings suggest that metabolic modulation by CD44 is a potential therapeutic target for glycolytic cancer cells that manifest drug resistance. Cancer Res; 72(6); 1438–48. ©2012 AACR.
Mechanisms of CHD5 Inactivation in Neuroblastomas
Authors: Koyama Hiroshi , Zhuang Tiangang , Light Jennifer E. , Kolla Venkatadri , Higashi Mayumi , McGrady Patrick W. , London Wendy B. , Brodeur Garrett M. 
Published: February 2012

Abstract
Purpose: Neuroblastomas (NBs) have genomic, biological, and clinical heterogeneity. High-risk NBs are characterized by several genomic changes, including MYCN amplification and 1p36 deletion. We identified the chromatin-remodeling gene CHD5 as a tumor suppressor gene that maps to 1p36.31. Low or absent CHD5 expression is associated with a 1p36 deletion and an unfavorable outcome, but the mechanisms of CHD5 inactivation in NBs are unknown.
Experimental Design: We examined (i) the CHD5 sequence in 188 high-risk NBs investigated through the TARGET initiative, (ii) the methylation status of the CHD5 promoter in 108 NBs with or without 1p36 deletion and/or MYCN amplification, and (iii) mRNA expression of CHD5 and MYCN in 814 representative NBs using TaqMan low-density array microfluidic cards.
Results: We found no examples of somatically acquired CHD5 mutations, even in cases with 1p36 deletion, indicating that homozygous genomic inactivation is rare. Methylation of the CHD5 promoter was common in the high-risk tumors, and it was generally associated with both 1p deletion and MYCN amplification. High CHD5 expression was a powerful predictor of favorable outcome, and it showed prognostic value even in multivariable analysis after adjusting for MYCN amplification, 1p36 deletion, and/or 11q deletion.
Conclusions: We conclude that (i) somatically acquired CHD5 mutations are rare in primary NBs, so inactivation probably occurs by deletion and epigenetic silencing; (ii) CHD5 expression and promoter methylation are associated with MYCN amplification, suggesting a possible interaction between these 2 genes; and (iii) high CHD5 expression is strongly correlated with favorable clinical/biological features and outcome. Clin Cancer Res; 18(6); 1588–97. ©2012 AACR.
A Phase 2 Cancer Chemoprevention Biomarker Trial of Isoflavone G-2535 (Genistein) in Presurgical Bladder Cancer Patients
Authors: Messing Edward , Gee Jason R. , Saltzstein Daniel R. , Kim KyungMann , diSant'Agnese Anthony , Kolesar Jill , Harris Linda , Faerber Adrienne , Havighurst Thomas , Young Jay M. , Efros Mitchell , Getzenberg Robert H. , Wheeler Marcia A. , Tangrea Joseph , Parnes Howard , House Margaret , Busby J. Erik , Hohl Raymond , Bailey Howard 
Published: February 2012

Abstract
The soy compound genistein has been observed preclinically to inhibit bladder cancer growth with one potential mechanism being the inhibition of epidermal growth factor receptor phosphorylation (p-EGFR). A phase 2 randomized, placebo-controlled trial investigated whether daily, oral genistein (300 or 600 mg/d as the purified soy extract G-2535) for 14 to 21 days before surgery alters molecular pathways in bladder epithelial tissue in 59 subjects diagnosed with urothelial bladder cancer (median age, 71 years). G-2535 treatment was well tolerated; observed toxicities were primarily mild to moderate gastrointestinal or metabolic and usually not attributed to study drug. Genistein was detected in plasma and urine of subjects receiving G-2535 at concentrations greater than placebo subjects' but were not dose-dependent. Reduction in bladder cancer tissue p-EGFR staining between the placebo arm and the combined genistein arms was significant at the protocol-specified significance level of 0.10 (P = 0.07). This difference was most prominent when comparing the 300-mg group with placebo (P = 0.015), but there was no significant reduction in p-EGFR staining between the 600-mg group and placebo. No difference in normal bladder epithelium p-EGFR staining was observed between treatment groups. No significant differences in tumor tissue staining between treatment groups were observed for COX-2, Ki-67, activated caspase-3, Akt, p-Akt, mitogen-activated protein kinase (MAPK), or p-MAPK. No significant differences in urinary survivin or BLCA-4 levels between treatment groups were observed. Genistein displayed a possible bimodal effect (more effective at the lower dose) on bladder cancer tissue EGFR phosphorylation that should be evaluated further, possibly in combination with other agents. Cancer Prev Res; 5(4); 621–30. ©2012 AACR.
Left Atrial Wall Stress Distribution and Its Relationship to Electrophysiologic Remodeling in Persistent Atrial Fibrillation
Authors: Hunter Ross J. , Liu Yankai , Lu Yiling , Wang Wen , Schilling Richard J. 
Published: February 2012

Background—
Atrial stretch causes remodeling that predisposes to atrial fibrillation. We tested the hypothesis that peaks in left atrial (LA) wall stress are associated with focal remodeling.

Methods and Results—

Nineteen patients underwent LA mapping before catheter ablation for persistent atrial fibrillation. Finite Element Analysis was used to predict wall stress distribution based on LA geometry from CT. The relationship was assessed between wall stress and (1) electrogram voltage and (2) complex fractionated atrial electrograms (CFAE), using CFAE mean (the mean interval between deflections). Wall stress varied widely within atria and between subjects (median, 36 kPa; interquartile range, 26–51 kP). Peaks in wall stress (≥90th percentile) were common at the pulmonary vein (PV) ostia (93%), the appendage ridge (100%), the high posterior wall (84%), and the anterior wall and septal regions (42–84%). Electrogram voltage showed an inverse relationship across quartiles for wall stress (19% difference across quartiles,
P
=0.016). There was no effect on CFAE mean across quartiles of wall stress. Receiver operating characteristic analysis showed high wall stress was associated with low voltage (ie, <0.5 mV) and electrical scar (ie, <0.05 mV; both
P
<0.0001) and with absence of CFAE (ie, CFAE mean <120 ms;
P
<0.0001). However, peaks in wall stress and CFAE were found at 88% of PV ostia.

Conclusions—
Peaks in wall stress were associated with areas of low voltage, suggestive of focal remodeling. Although peaks in wall stress were not associated with LA CFAE, the PV ostia may respond differently.
Genetic Analysis of Atherosclerosis and Glucose Homeostasis in an Intercross Between C57BL/6 and BALB/cJ Apolipoprotein E–Deficient Mice
Authors: Zhang Zhimin , Rowlan Jessica S. , Wang Qian , Shi Weibin 
Published: February 2012

Background—

Diabetic patients have an increased risk of developing atherosclerosis and related complications compared with nondiabetic individuals. The increased cardiovascular risk associated with diabetes is due in part to genetic variations that influence both glucose homeostasis and atherosclerotic lesion growth. Mouse strains C57BL/6J (B6) and BALB/cJ (BALB) exhibit distinct differences in fasting plasma glucose and atherosclerotic lesion size when deficient in apolipoprotein E (
Apoe
−/−
). Quantitative trait locus (QTL) analysis was performed to determine genetic factors influencing the 2 phenotypes.

Methods and Results—

Female F
2
mice (n=266) were generated from an intercross between B6.
Apoe
−/−
and BALB.
Apoe
−/−
mice and fed a Western diet for 12 weeks. Atherosclerotic lesions in the aortic root, fasting plasma glucose, and body weight were measured. 130 microsatellite markers across the entire genome were genotyped. Four significant QTLs,
Ath1
on chromosome (Chr) 1,
Ath41
on Chr2,
Ath42
on Chr5, and
Ath29
on Chr9, and 1 suggestive QTL on Chr4, were identified for atherosclerotic lesion size. Four significant QTLs,
Bglu3
and
Bglu12
on Chr1,
Bglu13
on Chr5,
Bglu15
on Chr12, and 2 suggestive QTLs on Chr9 and Chr15 were identified for fasting glucose levels on the chow diet. Two significant QTLs,
Bglu3
and
Bglu13
, and 1 suggestive locus on Chr8 were identified for fasting glucose on the Western diet. One significant locus on Chr1 and 2 suggestive loci on Chr9 and Chr19 were identified for body weight.
Ath1
and
Ath42
coincided with
Bglu3
and
Bglu13
, respectively, in the confidence interval.

Conclusions—
We have identified novel QTLs that have major influences on atherosclerotic lesion size and glucose homeostasis. The colocalization of QTLs for atherosclerosis and diabetes suggests possible genetic connections between the 2 diseases.
Lengthening z-Osteotomy of the Fibula to Correct Persistent Talar Shift Following Open Reduction Internal Fixation of Ankle Fractures
Authors: Thangarajah Tanujan , Lakdawala Ayaz , Battaloglu Emir , Malik Atul , Tillu Abhay 
Published: February 2012

Background: In cases where ankle fracture union has been compromised by persistent syndesmotic diastasis following open reduction internal fixation, both external rotation and shortening of the fibula have been identified as prominent features. Objective: This study reports a technique that uses a z-osteotomy to achieve both lengthening and internal rotation of the fibula to correct persistent talar shift following ankle fracture fixation. Methods: Four patients with persistent talar shift following open reduction internal fixation for an ankle fracture received z-osteotomy of the fibula to achieve both lengthening and internal rotation. Results: At the latest clinic review, all 4 ankles exhibited satisfactory clinical and radiological union. All patients have returned to full mobility and are satisfied with the outcome. Conclusions: This study demonstrates the effectiveness of lengthening z-osteotomy of the fibula in correcting persistent talar shift following internal fixation of ankle fractures. Level of evidence: Therapeutic Level V
A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes
Authors: Bryceson Yenan T. , Pende Daniela , Maul-Pavicic Andrea , Gilmour Kimberly C. , Ufheil Heike , Vraetz Thomas , Chiang Samuel C. , Marcenaro Stefania , Meazza Raffaella , Bondzio Ilka , Walshe Denise , Janka Gritta , Lehmberg Kai , Beutel Karin , zur Stadt Udo , Binder Nadine , Arico Maurizio , Moretta Lorenzo , Henter Jan-Inge , Ehl Stephan 
Published: February 2012

AbstractFamilial hemophagocytic lymphohistiocytosis (FHL) is a life-threatening disorder of immune regulation caused by defects in lymphocyte cytotoxicity. Rapid differentiation of primary, genetic forms from secondary forms of hemophagocytic lymphohistiocytosis (HLH) is crucial for treatment decisions. We prospectively evaluated the performance of degranulation assays based on surface up-regulation of CD107a on natural killer (NK) cells and cytotoxic T lymphocytes in a cohort of 494 patients referred for evaluation for suspected HLH. Seventy-five of 77 patients (97%) with FHL3-5 and 11 of 13 patients (85%) with Griscelli syndrome type 2 or Chediak-Higashi syndrome had abnormal resting NK-cell degranulation. In contrast, NK-cell degranulation was normal in 14 of 16 patients (88%) with X-linked lymphoproliferative disease and in 8 of 14 patients (57%) with FHL2, who were identified by diminished intracellular SLAM-associated protein (SAP), X-linked inhibitor of apoptosis protein (XIAP), and perforin expression, respectively. Among 66 patients with a clinical diagnosis of secondary HLH, 13 of 59 (22%) had abnormal resting NK-cell degranulation, whereas 0 of 43 had abnormal degranulation using IL-2–activated NK cells. Active disease or immunosuppressive therapy did not impair the assay performance. Overall, resting NK-cell degranulation below 5% provided a 96% sensitivity for a genetic degranulation disorder and a specificity of 88%. Therefore, degranulation assays allow a rapid and reliable classification of patients, benefiting treatment decisions.