bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Dynamics of HIV-1 Adaptation in Early Infection
Authors: da Silva Jack 
Published: December 2011

AbstractHuman immunodeficiency virus type 1 (HIV-1) undergoes a severe population bottleneck during sexual transmission and yet adapts extremely rapidly to the earliest immune responses. The bottleneck has been inferred to typically consist of a single genome, and typically eight amino acid mutations in viral proteins spread to fixation by the end of the early chronic phase of infection in response to selection by CD8+ T cells. Stochastic simulation was used to examine the effects of the transmission bottleneck and of potential interference among spreading immune-escape mutations on the adaptive dynamics of the virus in early infection. If major viral population genetic parameters are assigned realistic values that permit rapid adaptive evolution, then a bottleneck of a single genome is not inconsistent with the observed pattern of adaptive fixations. One requirement is strong selection by CD8+ T cells that decreases over time. Such selection may reduce effective population sizes at linked loci through genetic hitchhiking. However, this effect is predicted to be minor in early infection because the transmission bottleneck reduces the effective population size to such an extent that the resulting strong selection and weak mutation cause beneficial mutations to fix sequentially and thus avoid interference.
Extended Linkage Disequilibrium in Noncoding Regions in a Conifer, Cryptomeria japonica
Authors: Moritsuka Etsuko , Hisataka Yosuke , Tamura Miho , Uchiyama Kentaro , Watanabe Atsushi , Tsumura Yoshihiko , Tachida Hidenori 
Published: December 2011

Abstract
We measured linkage disequilibrium in mostly noncoding regions of Cryptomeria japonica, a conifer belonging to Cupressaceae. Linkage disequilibrium was extensive and did not decay even at a distance of 100 kb. The average estimate of the population recombination rate per base pair was 1.55 × 10−5 and was &lt;1/70 of that in the coding regions. We discuss the impact of low recombination rates in a large part of the genome on association studies.
Notch Signaling Is Antagonized by SAO-1, a Novel GYF-Domain Protein That Interacts with the E3 Ubiquitin Ligase SEL-10 in Caenorhabditis elegans
Authors: Hale Valerie A , Guiney Evan L , Goldberg Lindsey Y , Haduong Josephine H , Kwartler Callie S , Scangos Katherine W , Goutte Caroline 
Published: December 2011

Abstract
Notch signaling pathways can be regulated through a variety of cellular mechanisms, and genetically compromised systems provide useful platforms from which to search for the responsible modulators. The Caenorhabditis elegans gene aph-1 encodes a component of γ-secretase, which is essential for Notch signaling events throughout development. By looking for suppressors of the incompletely penetrant aph-1(zu147) mutation, we identify a new gene, sao-1 (suppressor of aph-one), that negatively regulates aph-1(zu147) activity in the early embryo. The sao-1 gene encodes a novel protein that contains a GYF protein–protein interaction domain and interacts specifically with SEL-10, an Fbw7 component of SCF E3 ubiquitin ligases. We demonstrate that the embryonic lethality of aph-1(zu147) mutants can be suppressed by removing sao-1 activity or by mutations that disrupt the SAO-1–SEL-10 protein interaction. Decreased sao-1 activity also influences Notch signaling events when they are compromised at different molecular steps of the pathway, such as at the level of the Notch receptor GLP-1 or the downstream transcription factor LAG-1. Combined analysis of the SAO-1–SEL-10 protein interaction and comparisons of sao-1 and sel-10 genetic interactions suggest a possible role for SAO-1 as an accessory protein that participates with SEL-10 in downregulation of Notch signaling. This work provides the first mutant analysis of a GYF-domain protein in either C. elegans or Drosophila and introduces a new type of Fbw7-interacting protein that acts in a subset of Fbw7 functions.
A Simple Method for Finding Explicit Analytic Transition Densities of Diffusion Processes with General Diploid Selection
Authors: Song Yun S , Steinrücken Matthias 
Published: December 2011

Abstract
The transition density function of the Wright–Fisher diffusion describes the evolution of population-wide allele frequencies over time. This function has important practical applications in population genetics, but finding an explicit formula under a general diploid selection model has remained a difficult open problem. In this article, we develop a new computational method to tackle this classic problem. Specifically, our method explicitly finds the eigenvalues and eigenfunctions of the diffusion generator associated with the Wright–Fisher diffusion with recurrent mutation and arbitrary diploid selection, thus allowing one to obtain an accurate spectral representation of the transition density function. Simplicity is one of the appealing features of our approach. Although our derivation involves somewhat advanced mathematical concepts, the resulting algorithm is quite simple and efficient, only involving standard linear algebra. Furthermore, unlike previous approaches based on perturbation, which is applicable only when the population-scaled selection coefficient is small, our method is nonperturbative and is valid for a broad range of parameter values. As a by-product of our work, we obtain the rate of convergence to the stationary distribution under mutation–selection balance.
Current Status of Autologous Stem Cell Transplantation in Relapsed and Refractory Hodgkin's Lymphoma
Authors: Colpo Anna , Hochberg Ephraim , Chen Yi-Bin 
Published: December 2011

AbstractDespite the relatively high long-term disease-free survival (DFS) rate for patients with Hodgkin lymphoma (HL) with modern combination chemotherapy or combined modality regimens, ∼20% of patients die from progressive or relapsed disease. The standard treatment for relapsed and primary refractory HL is salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT), which has shown a 5-year progression-free survival rate of ∼50%–60%. Recent developments in a number of diagnostic and therapeutic modalities have begun to improve these results. Functional imaging, refinement of clinical prognostic factors, and development of novel biomarkers have improved the predictive algorithms, allowing better patient selection and timing for ASCT. In addition, these algorithms have begun to identify a group of patients who are candidates for more aggressive treatment beyond standard ASCT. Novel salvage regimens may potentially improve the rate of complete remission prior to ASCT, and the use of maintenance therapy after ASCT has become a subject of current investigation. We present a summary of developments in each of these areas.
Phase II Trial of Erlotinib and Docetaxel in Advanced and Refractory Hepatocellular and Biliary Cancers: Hoosier Oncology Group GI06-101
Authors: Chiorean E. Gabriela , Ramasubbaiah Rashmi , Yu Menggang , Picus Joel , Bufill Jose A. , Tong Yan , Coleman Nicki , Johnston Erica L. , Currie Colleen , Loehrer Patrick J. 
Published: December 2011

Abstract

Background.
Patients with advanced hepatocellular (HCC) and biliary tract carcinomas (BTC) have poor prognosis. While the EGFR pathway is overactive in HCC and BTC, single agent anti-EGFR therapies confer modest activity. Preclinical data showed synergistic antiproliferative and proapoptotic effects between anti-EGFR therapies and taxanes. We conducted a phase I study of erlotinib and docetaxel in solid tumors, and noted good tolerability and sustained complete (5 years +) and partial responses in patients with HCC and BTC. This trial evaluated the efficacy of erlotinib with docetaxel in refractory hepatobiliary cancers.

Methods.
Eligible patients were allowed to have two prior systemic therapies. Docetaxel 30 mg/m2 i.v. was administered on days 1, 8, 15, and erlotinib 150 mg was dosed orally on days 2–7, 9–14, 16–28 of each 28-day cycle. The primary endpoint was 16 weeks progression-free survival (PFS), and secondary endpoints included response, stable disease, and overall survival. Tumor samples were analyzed for KRAS gene mutations and E-cadherin expression by immunohistochemistry (IHC). Patients with BTC and HCC were accrued and assessed in separate strata for the efficacy endpoints, but for the two-stage initial design of the study, combined PFS was considered. A Simon optimal two-stage design tested the hypothesis that the 16-week PFS is ≤ 15% (clinically inactive) versus the alternative of ≥ 30% (warranting further study).

Results.
Twenty-five patients, 14 with HCC and 11 with BTC, were enrolled. Common toxicities were rash (76%), diarrhea (56%), and fatigue (52%), mostly grade 1 or 2. No objective responses were seen. Seven BTC (64%) and 6 HCC patients (46%) had stable disease as best response, with a median duration of 16.1 weeks (95% CI 3.7–56.3) for BTC, and 17.6 weeks (95% CI 8.1–49.8) for HCC. The 16-week PFS was 64% for BTC (95% CI 29.7–84.5), and 38% for HCC (95% CI 14.1–62.8). Median overall survival was 5.7 and 6.7 months for BTC and HCC patients, respectively. BTC patients with grade ≥ 2 rash had higher median PFS (6.2 vs 2.2 months) and OS (14.2 vs 4.2 months). HCC patients with negative/low E-cadherin expression had higher median PFS (6.7 vs 2.1 months) and OS (14.5 vs 4 months).

Conclusion.
Erlotinib with docetaxel met the 16-week PFS ≥ 30% endpoint,but overall survival was comparable to that seen with single-agent erlotinib. With the limitation of small numbers of patients, grade ≥ 2 rash (in BTC), and negative/low E-cadherin expression (HCC) were associated with higher PFS and OS.
Panitumumab in Patients with KRAS Wild-Type Colorectal Cancer after Progression on Cetuximab
Authors: Wadlow Raymond C. , Hezel Aram F. , Abrams Thomas A. , Blaszkowsky Lawrence S. , Fuchs Charles S. , Kulke Matthew H. , Kwak Eunice L. , Meyerhardt Jeffrey A. , Ryan David P. , Szymonifka Jackie , Wolpin Brian M. , Zhu Andrew X. , Clark Jeffrey W. 
Published: December 2011

Abstract

Purpose.
Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type metastatic colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab.

Patients and Methods.
We used a two-stage study design to treat patients with panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve patients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies.

Results.
We treated twenty patients for a median of two cycles (range 1–4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months. Panitumumab was well tolerated. Thirteen patients (65%) had grade 1–2 dry skin or rash, and three patients had treatment-related grade 3 toxicities (one each with hyperglycemia, hyperbilirubinemia, and hypokalemia). No patients had detectable anti-cetuximab antibodies at any time point; one patient developed anti-panitumumab antibodies.

Conclusions.
Panitumumab has minimal benefit in patients with KRAS wild-type metastatic colorectal cancer that has progressed on prior cetuximab.
Effects of Low‐Dose Doxycycline and Bisphosphonate Clodronate on Alveolar Bone Loss and Gingival Levels of Matrix Metalloproteinase‐9 and Interleukin‐1β in Rats With Diabetes: A Histomorphometric and Immunohistochemical Study
Authors: Özdemir Selin P. , Kurtiş Bülent , Tüter Gülay , Bozkurt Şeyma , Gültekin Sibel Elif , Sengüven Burcu , Watanabe Keiko , Aydın Sevtap 
Published: January 2012

Background: Bisphosphonates (BPs) and low‐dose doxycycline (LDD) have been shown to inhibit bone resorption and to improve the levels of proinflammatory mediators and destructive enzymes in gingival tissues, respectively. The purpose of this study is to evaluate the effect of mono and combined BP clodronate and LDD therapies in reducing gingival levels of matrix metalloproteinase‐9 (MMP‐9), interleukin‐1β (IL‐1β), and alveolar bone loss in rats with diabetes.Methods: Fifty adult Wistar rats were divided into five study groups as follows: 1) group 1 = diabetes control; 2) group 2 = diabetes + periodontitis; 3) group 3 = diabetes + periodontitis + LDD; 4) group 4 = diabetes + periodontitis + clodronate; and 5) group 5 = diabetes + periodontitis + LDD + clodronate. LDD and clodronate were given as a single agent or as combination therapy during the 7 days of the post‐experimental periodontitis period. On day 7, the rats were sacrificed, the mobility of the tooth was recorded, and block biopsies were removed. The gingival tissues were analyzed histologically and immunohistochemically for expression of MMP‐9 and IL‐1β. Alveolar bone loss was evaluated morphometrically under a light microscope. Data analysis was performed statistically by Kruskal‐Wallis and post hoc Tukey and Spearman correlation tests.Results: Alveolar bone loss was significantly greater in groups 2 through 5 than group 1 (P <0.05) but was not significantly different among groups 2 through 5 (P >0.05). Animals with periodontitis (group 2) expressed significantly higher levels of MMP‐9 and IL‐1β compared with those without periodontitis (group 1) (P <0.05). MMP‐9 expression was significantly lower in group 3 than groups 1, 2, and 5 (P <0.05). IL‐1β expression was significantly lower in the groups 1, 3, 4, and 5 than 2 (P <0.01) but was not significantly different among groups 1, 3, 4, and 5. Positive correlations were found between alveolar bone loss and density of inflammation (ρ = 0.319, P = 0.021) and between MMP‐9 and IL‐1β (ρ = 0.418, P = 0.002), respectively.Conclusion: Our findings suggest that ligature‐induced periodontitis in animals with diabetes results in significantly higher levels of MMP‐9 and IL‐1β expression in gingiva. The use of mono and combined clodronate and LDD administrations may significantly reduce levels of MMP‐9 and IL‐1β expression. However, drug administration did not affect alveolar bone levels during the study period.
The Impact of Household Investments on Early Child Neurodevelopment and on Racial and Socioeconomic Developmental Gaps: Evidence from South America
Authors: Wehby George L. , McCarthy Ann Marie , Castilla Eduardo , Murray Jeffrey C. 
Published: December 2011

Abstract
This paper assesses the effects of household investments through child educating activities on child neurodevelopment between the ages of 3 and 24 months, and evaluates whether investments explain racial and socioeconomic developmental gaps in South America. Quantile regression is used to evaluate the heterogeneity in investment effects by unobserved developmental endowments. The study finds large positive investment effects on early child neurodevelopment, with generally larger effects among children with low developmental endowments (children at the left margin of the development distribution). Investments explain part of the observed racial gaps and the whole socioeconomic developmental gap. Investments may compensate for low endowments and policy interventions to increase investments may reduce early development gaps and result in high social and economic returns.
The Economics of the Long Tail
Authors: Kendall Todd D. , Tsui Kevin 
Published: December 2011

Abstract
Anderson (2006) argues that e-commerce and other new technologies improve efficiency by encouraging the entry of new producers and innovations, creating a “long tail” of niche products while reducing the market share of previously popular products. We study the strategic interaction between hits and niches in their pricing, entry, and innovation decisions using a model of competition under product differentiation and generalized cost structure. In contrast to the popular view, we show that improvements in information and communication technology can lead to either the long tail effect or an opposite “superstar” effect (Rosen, 1981), depending on (a) how the structure (not simply the level) of producer costs changes, and (b) how disparate are consumer preferences. These two factors also determine whether there is excessive or insufficient product diversity. Post-entry product and technology innovation incentives may be inefficient in the long tail market structure because producers can soften price competition by engaging in excessive product differentiation and adopting technologies with high variable costs. These results have implications for various competition-related policies.
“Incorporating” American Colonialism: Accounting and the Alaska Native Claims Settlement Act
Authors: Thornburg Steven W. , Roberts Robin W. 
Published: January 2012

ABSTRACT
The history of Alaska is a colonial history (Pomeroy 1947; Haycox 2002). The purpose of this paper is to examine how the corporate form of organization and corporate accounting were used by the United States (U.S.) government to rationalize decisions, exercise control, and exploit Alaskan resources to benefit corporate America and the existing U.S. states. The Alaska Native Claims Settlement Act of 1971 (ANCSA) established Alaska Native Corporations (ANCs), whose stock was distributed to qualifying Alaska Natives in exchange for their agreement to extinguish all aboriginal land claims. Guided by prior work in accounting and postmodern colonialism, our analysis uncovers ways in which ANCSA, though lauded by the U.S. government as an innovative and generous settlement, perpetuated a historical pattern of indigenous exploitation by western economic interests, and employed corporate accounting policies and techniques to further the interests of the U.S. government and large corporations at the expense of Native Alaskans.
Efficacy and Safety of Exenatide Once Weekly Versus Metformin, Pioglitazone, and Sitagliptin Used as Monotherapy in Drug-Naive Patients With Type 2 Diabetes (DURATION-4)
Authors: Russell-Jones David , Cuddihy Robert M. , Hanefeld Markolf , Kumar Ajay , González Jose G. , Chan Melanie , Wolka Anne M. , Boardman Marilyn K. ,   on behalf of the DURATION-4 Study Group
Published: December 2011

OBJECTIVE
To test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally treated (diet and exercise) drug-naive patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS
Patients were randomized to subcutaneous (SC) EQW 2.0 mg + oral placebo (n = 248), MET 2,000 mg/day + SC placebo (n = 246), PIO 45 mg/day + SC placebo (n = 163), or SITA 100 mg/day + SC placebo (n = 163) for 26 weeks. MET and PIO therapies were increased to maximum-tolerated dosages. Injections with EQW or placebo were administered weekly, while oral medication or placebo was administered daily.

RESULTS
Baseline characteristics were as follows: 59% men, 67% Caucasian, mean age 54 years, HbA1c 8.5%, fasting serum glucose 9.9 mmol/L, body weight 87.0 kg, and diabetes duration 2.7 years. HbA1c reductions (%) at 26 weeks (least-squares means) with EQW versus MET, PIO, and SITA were −1.53 vs. −1.48 (P = 0.620), −1.63 (P = 0.328), and −1.15 (P &lt; 0.001), respectively. Weight changes (kg) were −2.0 vs. −2.0 (P = 0.892), +1.5 (P &lt; 0.001), and −0.8 (P &lt; 0.001), respectively. Common adverse events were as follows: EQW, nausea (11.3%) and diarrhea (10.9%); MET, diarrhea (12.6%) and headache (12.2%); PIO, nasopharyngitis (8.6%) and headache (8.0%); and SIT, nasopharyngitis (9.8%) and headache (9.2%). Minor (confirmed) hypoglycemia was rarely reported. No major hypoglycemia occurred.

CONCLUSIONS
EQW was noninferior to MET but not PIO and superior to SITA with regard to HbA1c reduction at 26 weeks. Of the agents studied, EQW and MET provided similar improvements in glycemic control along with the benefit of weight reduction and no increased risk of hypoglycemia.
Insulin Secretion and Its Determinants in the Progression of Impaired Glucose Tolerance to Type 2 Diabetes in Impaired Glucose-Tolerant Individuals
Authors: de Mello Vanessa D.F. , Lindström Jaana , Eriksson Johan , Ilanne-Parikka Pirjo , Keinänen-Kiukaanniemi Sirkka , Sundvall Jouko , Laakso Markku , Tuomilehto Jaakko , Uusitupa Matti 
Published: December 2011

OBJECTIVE
We investigated the effect of early-phase insulin secretion on the incidence of type 2 diabetes in individuals with impaired glucose tolerance (IGT) participating in the Finnish Diabetes Prevention Study (DPS). We examined how a lifestyle intervention affected early-phase insulin secretion (ratio of total insulin area under the curve [AUC] and total glucose AUC [AIGR] from 0 to 30 min) during a 4-year follow-up intervention trial and whether AIGR0–30 response was modified by insulin sensitivity (IS) and obesity.

RESEARCH DESIGN AND METHODS
A total of 443 participants with IGT originally randomized to a lifestyle intervention or control group were studied. IS and AIGR0–30 were estimated from an oral tolerance glucose test administered annually during the 4-year follow-up trial and were related to the risk of diabetes onset over a 6-year follow-up.

RESULTS
Lifestyle intervention resulted in higher IS (P = 0.02) and lower unadjusted AIGR0–30 (P = 0.08) during the 4-year follow-up. A higher IS and a lower BMI during the follow-up were associated with a lower unadjusted AIGR0–30 during the follow-up, independently of study group (P &lt; 0.001). A greater increase in IS on the median cutoff point of a 0.69 increase was associated with higher IS-adjusted AIGR0–30 during the follow-up (P = 0.002). In multivariate models, IS and IS-adjusted AIGR0–30 were both inversely associated with diabetes incidence (P &lt; 0.001). Participants who progressed to type 2 diabetes were more obese and had lower IS and Matsuda IS index-AIGR0–30 than nonprogressors.

CONCLUSIONS
Our results indicate that the reduction in the risk of developing type 2 diabetes after lifestyle intervention is related to the improvement of IS along with weight loss. Improved IS may also have beneficial effects on preservation of β-cell function.