bluuebunny/crossref_metadata_2025_split huggingface dataset:
Calcineurin Controls Growth, Morphology, and Pathogenicity in
Aspergillus fumigatus
Authors: Steinbach William J. , Cramer Robert A. , Perfect B. Zachary , Asfaw Yohannes G. , Sauer Theodor C. , Najvar Laura K. , Kirkpatrick William R. , Patterson Thomas F. , Benjamin Daniel K. , Heitman Joseph , Perfect John R. 
Published: July 2006

ABSTRACT

Calcineurin is implicated in a myriad of human diseases as well as homeostasis and virulence in several major human pathogenic microorganisms. The fungus
Aspergillus fumigatus
is a leading cause of infectious death in the rapidly expanding immunocompromised patient population. Current antifungal treatments for invasive aspergillosis are often ineffective, and novel therapeutic approaches are urgently needed. We demonstrate that a mutant of
A. fumigatus
lacking the calcineurin A (
cnaA
) catalytic subunit exhibited defective hyphal morphology related to apical extension and polarized growth, which resulted in drastically decreased filamentation. The Δ
cnaA
mutant lacked the extensive lattice of invading hyphae seen with the wild-type and complemented strains. Sporulation was also affected in the Δ
cnaA
mutant, including morphological conidial defects with the absence of surface rodlets and the added presence of disjunctors creating long conidial chains. Infection with the Δ
cnaA
mutant in several distinct animal models with different types of immunosuppression and inoculum delivery led to a profound attenuation of pathogenicity compared to infection with the wild-type and complemented strains. Lung tissue from animals infected with the Δ
cnaA
mutant showed a complete absence of hyphae, in contrast to tissue from animals infected with the wild-type and complemented strains. Quantitative fungal burden and pulmonary infarct scoring confirmed these findings. Our results support the clinical observation that substantially decreasing fungal growth can prevent disease establishment and decrease mortality. Our findings reveal that calcineurin appears to play a globally conserved role in the virulence of several pathogenic fungi and yet plays specialized roles in each and can be an excellent target for therapeutic intervention.
Transcription Factor Nrg1 Mediates Capsule Formation, Stress Response, and Pathogenesis inCryptococcus neoformans
Authors: Cramer Kari L. , Gerrald Quincy D. , Nichols Connie B. , Price Michael S. , Alspaugh J. Andrew 
Published: July 2006

ABSTRACTTheCryptococcus neoformans NRG1gene was identified using gene microarrays to define putative transcription factor genes regulated by the cyclic AMP (cAMP) signal transduction pathway. Disruption ofNRG1results in delayed capsule formation and mating, two phenotypes that are directly controlled by cAMP signaling. Putative targets of the Nrg1 transcription factor were identified using a second genome microarray to define differences in the transcriptomes of the wild-type andnrg1mutant strains. These experiments implicate Nrg1 in the transcriptional control of multiple genes involved in carbohydrate metabolism and substrate oxidation, as well as theUGD1gene encoding a UDP-glucose dehydrogenase required for polysaccharide capsule production and cell wall integrity. In addition to being under transcriptional control of the cAMP pathway, Nrg1 contains a putative protein kinase A phosphorylation site; mutation of this motif results in reduced Nrg1 activity. Consistent with prior studies in hypocapsular mutants, thenrg1mutant strain is attenuated in an animal model of disseminated cryptococcal disease.
EppA, a Putative Substrate of DdERK2, Regulates Cyclic AMP Relay and Chemotaxis in
Dictyostelium discoideum
Authors: Chen Songyang , Segall Jeffrey E. 
Published: July 2006

ABSTRACT

The
mitogen-activated protein kinase DdERK2 is critical for
cyclic AMP (cAMP) relay and chemotaxis to cAMP and folate, but the
details downstream of DdERK2 are unclear. To search for targets of
DdERK2 in
Dictyostelium discoideum
,
32
PO
4
3−
-labeled protein
samples from wild-type and Dd
erk2
−
cells
were resolved by 2-dimensional electrophoresis. Mass spectrometry was
used to identify a novel 45-kDa protein, named EppA (ERK2-dependent
phosphoprotein A), as a substrate of DdERK2 in
Dictyostelium
.
Mutation of potential DdERK2 phosphorylation sites demonstrated that
phosphorylation on serine 250 of EppA is DdERK2 dependent. Changing
serine 250 to alanine delayed development of
Dictyostelium
and
reduced
Dictyostelium
chemotaxis to cAMP. Although
overexpression of EppA had no significant effect on the development or
chemotaxis of
Dictyostelium
, disruption of the
eppA
gene led to delayed development and reduced chemotactic responses to
both cAMP and folate. Both
eppA
gene disruption and
overexpression of EppA carrying the serine 250-to-alanine mutation led
to inhibition of intracellular cAMP accumulation in response to
chemoattractant cAMP, a pivotal process in
Dictyostelium
chemotaxis and development. Our studies indicate that EppA regulates
extracellular cAMP-induced signal relay and chemotaxis of
Dictyostelium
.
Atypia and Ki-67 Expression from Ductal Lavage in Women at Different Risk for Breast Cancer
Authors: Cazzaniga Massimiliano , Severi Gianluca , Casadio Chiara , Chiapparini Laura , Veronesi Umberto , Decensi Andrea 
Published: July 2006

Abstract
Purpose: Ductal lavage provides adequate material and detects atypical cells from ducts in women at increased risk of breast cancer, but the clinical significance of this finding is unclear. We studied the prevalence and predictors of atypia in addition to the proliferation-associated antigen Ki-67 expression in ductal lavage done in women at different risk of breast cancer.
Results: Ductal lavage was attempted in 202 women at increased risk and in 16 at average risk. Lavage could not be done in 20 women at increased risk because of anatomic impediments. Seven average-risk women (44%) had samples with inadequate cytology versus 30 women at higher risk (16%; P = 0.014). Atypia was observed in two average-risk women [22%; 95% confidence interval (95% CI), 3-60%]. The prevalence of atypia was 33% in women with a 5-year risk of ≥1.3% according to the Gail model (25 of 75; 95% CI, 23-45%), 36% in women with an increased probability of or ascertained BRCA mutation (9 of 25; 95% CI, 18-57%), and 52% in women with contralateral breast cancer (27 of 52; 95% CI, 38-66%). Ki-67 expression measured in a consecutive series of 80 women at increased risk was higher in atypical samples (P = 0.0001) and was positively associated with total cell count per slide (P = 0.002).
Conclusions: Atypia is frequent in women at increased risk of breast cancer but it can also be found in average-risk women. Ki-67 expression is associated with atypia and cell yield and it might be assessed as a surrogate biomarker in early-phase chemoprevention trials. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1311–5)
Incidence of Non-Hodgkin's Lymphoma in Sweden, Denmark, and Finland from 1960 through 2003: an Epidemic That Was
Authors: Sandin Sven , Hjalgrim Henrik , Glimelius Bengt , Rostgaard Klaus , Pukkala Eero , Askling Johan 
Published: July 2006

Abstract
Background: Reports during the early 1990s indicated non-Hodgkin's lymphoma (NHL) as one of the most rapidly increasing malignancies. More recent trends remain poorly characterized, as do the underlying reasons for NHL time trends, in particular, the effect of changes in classification and registration of lymphoproliferative malignancies. Insights into the descriptive epidemiology of NHL may shed light upon its elusive etiology.
Methods: We used data from the Swedish, Danish, and Finnish national cancer registers to assess the incidences of NHL and other lymphoproliferative malignancies between 1960 and 2004. Using Poisson regression, we estimated the annual rate of change in NHL incidence per decade by sex, age, and country.
Results: In Sweden, Denmark, and Finland, the NHL incidence increased in both genders and all age categories by about 4% every year up until the early 1990s. Thereafter, the incidence increased at a slower rate (ages 60-79 years), stabilized (ages 50-59 and ≥80 years), and decreased (ages 0-49 years), respectively, similarly for males and females in the three countries. Time trends of NHL were not reciprocated and explained by trends for other lymphoproliferative malignancies nor explained by trends in NHL as secondary primaries or NHL diagnosed postmortem.
Conclusions: The epidemic increase of NHL has recently subsided. Changes in the classification of lymphoproliferative malignancies, or occurrence of NHL as second primaries, only offer a marginal explanation. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1295–300)
A Role for XRCC4 in Age at Diagnosis and Breast Cancer Risk
Authors: Allen-Brady Kristina , Cannon-Albright Lisa A. , Neuhausen Susan L. , Camp Nicola J. 
Published: July 2006

Abstract
Genetic variants in DNA repair genes influence the ability to repair damaged DNA. Unrepaired or improperly repaired DNA may lead to genetic instability and carcinogenesis. We evaluated the role of four tagging single nucleotide polymorphisms (tSNP) in the DNA repair gene, XRCC4, and its association with breast cancer risk and age at diagnosis of breast cancer in 464 cases and 576 controls selected to be BRCA1/2 mutation negative from high-risk Utah pedigrees. We observed a significant association for two 4-locus tSNP haplotypes and age at diagnosis. Carriage of one haplotype was associated with later diagnosis (haplotype frequency, 0.039; mean age at diagnosis, 67.17 years; P = 0.001), and carriage of the other was associated with earlier diagnosis (haplotype frequency, 0.214; mean age at diagnosis, 54.04 years; P = 0.0085). For breast cancer risk, two 2-locus tSNP haplotypes explained the observed association as well as extended four-locus haplotypes. The two 2-locus haplotypes were nominally associated with breast cancer risk, one for reduced risk (odds ratio, 0.57; 95% confidence interval, 0.36-0.90; P = 0.014) and one for increased risk (odds ratio, 1.30; 95% confidence interval, 1.02-1.67; P = 0.033). Moreover, one of the tSNPs is in strong linkage disequilibrium (D′ = 1.00) with an XRCC4 SNP found to be significantly associated with breast cancer risk in Taiwan, hence, confirming their findings. Our results suggest that XRCC4 may play a role in the age at diagnosis and risk of breast cancer in non-BRCA1/2, heritable breast cancer cases. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1306–10)
Clinical Use of p53 in Barrett's Esophagus
Authors: Keswani Rajesh N. , Noffsinger Amy , Waxman Irving , Bissonnette Marc 
Published: July 2006

Abstract
Barrett's esophagus is an established precursor to esophageal adenocarcinoma. Whereas most patients with Barrett's esophagus do not progress to adenocarcinoma, patients with progression have a poor prognosis. Current management strategies use frequent endoscopic surveillance and multiple nontargeted biopsies. This approach, however, may miss dysplastic areas. Furthermore, given the relatively high prevalence of Barrett's esophagus but low incidence of progression, this invasive and expensive approach has not been shown to be cost-effective. Thus, there is intense interest in using biomarkers to identify patients at increased risk of progressing to adenocarcinoma. This has included examination of mutations in the tumor suppressor gene, p53. In this report, we discuss the biology of p53 and the incidence of p53 mutations in Barrett's esophagus and review relevant studies regarding the ability of p53 to predict neoplastic progression. Additionally, we report our results of the expression of p53 by immunohistochemistry in a group of 18 patients that have undergone endoscopic esophageal mucosal resection for dysplasia. Although the presence of a p53 mutation increases the risk of neoplastic progression, the absence of this mutation does not abrogate the risk. Continuing efforts, therefore, are needed to define and prospectively validate a panel of biomarkers to risk-stratify patients with Barrett's esophagus. Determination of p53 mutational status may ultimately be a component of such a panel. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1243–9)
Residential History, Family Characteristics and Non–Hodgkin Lymphoma, A Population-Based Case-Control Study in the San Francisco Bay Area
Authors: Bracci Paige M. , Dalvi Tapashi B. , Holly Elizabeth A. 
Published: July 2006

Abstract
A population-based, case-control study (N = 1,593 cases, N = 2,515 controls) was conducted in the San Francisco Bay Area, California, to determine risk factors for non–Hodgkin lymphoma (NHL). This report examines residential characteristics, number of siblings, childhood infections, and allergic rhinitis to evaluate the association between NHL and the hygiene hypothesis. Adjusted unconditional logistic regression analyses included HIV-negative participants (N = 1,304 cases, N = 2,402 controls) ages 21 to 74 years, who completed in-person interviews. At childhood ages, odds ratios (OR) for NHL decreased with increasing number of household rooms (age 8 years, Ptrend = 0.08; age 15 years, Ptrend &lt; 0.0001) and increased with more crowded living conditions (quartiles of no. people/no. rooms; age 8 years, Ptrend &lt; 0.0001; age 15 years, Ptrend = 0.0004), whereas at older ages a greater number of people in the household and greater number of household rooms were positively associated with NHL. ORs increased with increasing number of siblings (Ptrend = 0.0003) and increasing birth order (Ptrend = 0.01). Participants with five or more younger siblings had a 50% increased OR for NHL. ORs for NHL decreased with an increasing number of different infections during childhood (age 8 years, Ptrend &lt; 0.0001; age 15 years, Ptrend = 0.0003) and with history of allergic rhinitis (P &lt; 0.0001). Our results are somewhat consistent with the hygiene hypothesis that less crowding and better sanitation results in fewer infections early in life and an increased incidence of immune-related conditions later in life. The role of the complex relationship between residential history, family characteristics, childhood infections, and immune function in the development of NHL warrants further investigation in pooled analyses. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1287–94)
Cell Cycle Regulators p105, p107, Rb2/p130, E2F4, p21CIP1/WAF1, Cyclin A in Predicting Cervical Intraepithelial Neoplasia, High-Risk Human Papillomavirus Infections and Their Outcome in Women Screened in Three New Independent States of the Former Soviet Union
Authors: Santopietro Rosa , Shabalova Irena , Petrovichev Nicolay , Kozachenko Vladimir , Zakharova Tatjana , Pajanidi Julia , Podistov Jurij , Chemeris Galina , Sozaeva Larisa , Lipova Elena , Tsidaeva Irena , Ivanchenko Olga , Pshepurko Alla , Zakharenko Sergej , Nerovjna Raisa , Kljukina Ludmila , Erokhina Oksana , Branovskaja Marina , Nikitina Maritta , Grunberga Valerija , Grunberg Alexandr , Juschenko Anna , Cintorino Marcella , Tosi Piero , Syrjänen Kari , Syrjänen Stina 
Published: July 2006

Abstract
Background: The growth-controlling functions of the high-risk human papillomaviruses (HPV) depend on their ability to interact with several cellular proteins, including the key regulatory proteins of the cell cycle. We have examined the value of cell cycle regulatory proteins as predictors of the intermediate end point markers in cervical carcinogenesis: (a) grade of cervical intraepithelial neoplasia (CIN), (b) high-risk HPV type, (c) clearance/persistence of high-risk HPV, and (d) disease outcome in women participating in a multicenter follow-up study in three New Independent States countries.
Methods: Totally, 232 biopsy samples tested high-risk HPV-positive and/or Papanicolaou smear–positive women were immunohistochemically stained for the following cell cycle markers: p105, p107, p130, E2F4, p21CIP1/WAF1/SDI1, cyclin A, and Ki-67. In addition, apoptotic index (AI) and mitotic index (MI) were determined in H&E-stained sections. Prospective follow-up data were available to disclose the clinical and virological outcome of the lesions.
Results: The expression of Ki-67, p21CIP1/WAF1/SDI1, and cyclin A and AI and MI values were markedly increased in high-grade lesions, but only MI was an independent predictor of CIN3 in multivariate analysis. Cyclin A was the only independent predictor of high-risk HPV (odds ratio, 1.09; 95% confidence interval, 1.01-1.18; P = 0.021), exceeding the predictive power of CIN grade and high-grade squamous intraepithelial lesion Papanicolaou smears. None of these markers provided any useful predictive information as to the clinical and virological outcomes during the follow-up. Highly significant correlations (P = 0.0001) were found between AI and MI as well as between MI and cyclin A, Ki-67 and p21CIP1/WAF1/SDI1, Ki-67 and cyclin A, and p21CIP1/WAF1/SDI1 and cyclin A followed by that between p105 and cyclin A (P = 0.001) and p105 and p130 (P = 0.002).
Conclusions: All tested factors related to cell cycle were increased, but only MI and cyclin A was an independent predictor of CIN3 and high-risk HPV carriage, respectively. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1250–6)
Number of Siblings and the Risk of Lymphoma, Leukemia, and Myeloma by Histopathology
Authors: Altieri Andrea , Castro Felipe , Bermejo Justo Lorenzo , Hemminki Kari 
Published: July 2006

AbstractEpidemiologic evidence indicates that several markers of exposure to childhood infections are inversely associated with the risk of childhood leukemia and lymphomas. We used the Swedish Family-Cancer Database to assess the effects of number of siblings on the risk of non-Hodgkin's (n = 7,007) and Hodgkin's lymphomas (n = 3,115), leukemias (n = 7,650), and multiple myeloma (n = 1,492) by histopathology. Poisson regression models included terms for age, sex, family history, period, and socioeconomic index. Having four or more siblings compared with none was associated with an excess risk of childhood acute lymphoblastic leukemia [ALL; rate ratio (RR), 2.11; Ptrend = 0.001], acute monocytic leukemia (RR, 2.51; Ptrend = 0.002), and multiple myeloma (RR, 1.34; Ptrend = 0.006). Having three or more older siblings compared with none decreased the risk of acute monocytic leukemia (RR, 0.35; Ptrend = 0.001) and childhood ALL (RR, 0.69; Ptrend = 0.01). The risk of Hodgkin's lymphoma for five or more older siblings compared with none was 0.41 (Ptrend = 0.003). Acute myeloid leukemia, chronic lymphocytic leukemia, and other lymphoproliferative malignancies were not associated with number of siblings. In conclusion, we found an excess risk of childhood ALL and acute monocytic leukemia in large families. However, for ALL, acute monocytic leukemia, and Hodgkin's lymphoma, younger siblings were strongly protected compared with older siblings. The remarkable protective effect of number of older siblings on acute monocytic leukemia is a novel finding of potential interest. Possible interpretations of our findings in the context of a putative infectious etiology are discussed. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1281–6)
p53 Alterations and Protein Accumulation in Benign Breast Tissue and Breast Cancer Risk: A Cohort Study
Authors: Rohan Thomas E. , Li Shu-Qiu , Hartwick Robert , Kandel Rita A. 
Published: July 2006

Abstract
Disruption of p53 gene function seems to have a pivotal role in carcinogenesis. p53 gene changes occur before the development of breast cancer and therefore might influence breast cancer risk. We investigated the association between p53 protein accumulation and p53 mutations detected in benign breast tissue and risk of subsequent breast cancer. We conducted a case-control study nested within the cohort of 4,888 women in the Canadian National Breast Screening Study who were diagnosed with biopsy-confirmed benign breast disease during active follow-up. Cases were women with benign breast disease who subsequently developed breast cancer; five controls were matched to each case. p53 protein accumulation was assessed immunohistochemically using sections of paraffin-embedded benign breast tissue from 104 cases and 385 controls; for 82 of these cases and 327 of the controls, DNA was successfully extracted from the breast tissue for p53 gene analysis using PCR-single-strand conformation polymorphism/direct sequencing. p53 protein accumulation was associated with a 2-fold increase in risk of progression to breast cancer [adjusted odds ratio (OR), 2.16; 95% confidence interval (95% CI), 1.08-4.30], whereas p53 nucleotide changes overall were not associated with altered risk (adjusted OR, 1.22; 95% CI, 0.68-2.19); those with both p53 immunopositivity and a p53 nucleotide change had an OR (95% CI) of 3.20 (1.21-8.50). Nonpolymorphic intronic changes were associated with a 2.8-fold increase in risk (OR, 2.84; 95% CI, 1.09-7.41). The results of this study suggest that p53 protein accumulation and nonpolymorphic intronic changes in p53 are associated with increased risk of progression to breast cancer in women with benign breast disease. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1316–23)
Patellofemoral Full-Thickness Chondral Defects Treated with Hyalograft-C
Authors: Gobbi Alberto , Kon Elisaveta , Berruto Massimo , Francisco Ramces , Filardo Giuseppe , Marcacci Maurilio 
Published: July 2006

Background Tissue engineering has emerged as a potential therapeutic option for cartilage regeneration. Hypothesis Hyaluronan-based scaffolds seeded with autologous chondrocytes are a viable treatment for damaged articular surface of the patellofemoral joint. Study Design Case series; Level of evidence, 4. Methods Thirty-two chondral lesions with a mean size of 4.7 cm2 were treated with Hyalograft-C. Twenty-two lesions were located in the patella and 10 in the trochlea. Sixteen patients had previous trauma, 3 had osteochondritis dissecans, and 13 had degenerative changes. Transplantations were carried out arthroscopically or through a miniarthrotomy incision. Eight patients had concomitant procedures, including patellar realignment (2), lateral release (3), and meniscectomy (3). Results were evaluated using the International Cartilage Repair Society–International Knee Documentation Committee scale, EuroQol EQ-5D form, and magnetic resonance imaging scans at 12 and 24 months. Six patients had second-look arthroscopy and biopsies. Statistical analysis was performed using the paired ttest and Wilcoxon signed rank test. Results The International Cartilage Repair Society–International Knee Documentation Committee and EuroQol EQ-5D scores demonstrated a statistically significant improvement (P <. 0001). Objective preoperative data improved from 6/32 (18.8%) with International Knee Documentation Committee A or B to 29/32 (90.7%) at 24 months after transplantation. Mean subjective scores improved from 43.2 points preoperatively to 73.6 points 24 months after implantation. Magnetic resonance imaging studies at 24 months revealed 71% to have an almost normal cartilage with positive correlation to clinical outcomes. Second-look arthroscopies in 6 cases revealed the repaired surface to be nearly normal with biopsy samples characterized as hyaline-like in appearance. Conclusion Biodegradable scaffolds seeded with autologous chondrocytes can be a viable treatment for chondral lesions. The type of tissue repair achieved demonstrated histologic characteristics similar to normal articular cartilage. Long-term investigations are needed to determine the durability of the repair produced with this technique.