Nature of the open state in long polynucleotide double helices: possibility of soliton excitations.

The existence of transiently open states in DNA and synthetic polynucleotide double helices has been demonstrated by hydrogen exchange measurements; base pairs reversibly separate and reclose, exposing nucleotide protons to exchange with solvent protons. Recently it has been possible to define the equilibrium, kinetic, and activation parameters of the major open state that determines base pair hydrogen exchange. However, there is no direct information at the moment about the conformation of the open form. Here we consider the possibility that the low energy and slow opening and closing rates observed reflect a deformation involving several adjacent base pairs. Assuming a mobile open unit capable of diffusing along the double helix, we find that available data are consistent with structures of 10 or so adjacent open pairs. It is further suggested that these structures correspond to thermally induced soliton excitations of the double helix, which retain coherence by sharing the energy of a twist deformation among several base pairs. Solitons are nonlinear excitations that can travel as coherent solitary waves, and have been recognized as an important mechanism for mediating conformational changes in polymers and condensed systems generally. Comparison of the double helix with simple mechanical analogs suggests that soliton excitations may well exist within DNA chains, and the present analysis shows that the hydrogen exchange open state is consistent with these.     

Breast cancer incidence and early diagnosis in a family history risk and prevention clinic: 33-year experience in 14,311 women

Breast Cancer Research and Treatment - Women at increased familial breast cancer risk have been offered screening starting at an earlier age and increased frequency than national Screening...     

Food questionnaire for assessment of infant gluten consumption

BACKGROUND: In light of the possibly preventive role of timing and amount of gluten in celiac disease, it would be helpful to have a questionnaire to assess the gluten intake in infants. AIMS: Development and validation of a food questionnaire to assess gluten consumption in healthy infants aged 0-12 months (FQ-gluten). METHODS: A food frequency questionnaire, previously developed for the Generation R study, was adapted for the assessment of gluten intake. The results of a 2-day food record (FR) were compared with the results of this FQ-gluten. RESULTS: Eighty-seven parents filled in the FR and the FQ-gluten. The number of children who consume gluten and who are breast-fed is higher, reported in the FQ-gluten. The amount of gluten is comparable from the age of 3 up to 10 months, but at 11 and 12 months a higher gluten intake is reported using the FR, probably due to a larger variety of food products not detectable by the FQ-gluten. However, there is a high agreement in the food groups (Cohens' kappa=0.6-0.8). CONCLUSIONS: This new, short, standardized, validated and easy to use FQ-gluten may be a useful instrument to assess gluten intake in infants, both at the individual and at the population level. The use of this method by investigators in other countries provides the opportunity for a better comparison of the results of gluten consumption in (co-operative) studies throughout different countries.     

Survival and Racial Differences of Non-Small Cell Lung Cancer in the United States Military

BACKGROUND

Lung cancer is the leading cause of cancer-related death in the United States (US) Military and worldwide, with non-small cell lung cancer (NSCLC) accounting for 87 % of cases.

OBJECTIVES

Using a US military cohort who receives equal and open access to healthcare, we sought to examine demographic, clinical features and outcomes with NSCLC.

DESIGN AND PARTICIPANTS

We conducted a retrospective cohort analysis of 4,751 patients, aged ≥ 18 years and diagnosed with a first primary NSCLC between 1 January 2003 and 31 December 2013 in the US Department of Defense (DoD) cancer registry.

MAIN MEASURES

Differences by patient and disease characteristics were compared using Chi-square and t-test. Kaplan Meier curves and Cox proportional hazards regression assessed overall survival.

RESULTS

The mean age at diagnosis was 66 years, 64 % were male, 72 % were Caucasian, 41 % were diagnosed at early stage, 77 % received treatment and 82 % had a history of tobacco use. Mean age at diagnosis was highest among Caucasians (67 years) and lowest among African Americans (AA; 62 years). Asian/Pacific Islanders (PI) were more likely to be female (p < 0.0001), have adenocarcinoma histology (p = 0.0003) and less likely to have a history of tobacco use (p < 0.0001) compared to other racial/ethnic groups. In multivariable survival analysis, older age, male gender, increasing stage, not receiving treatment, and tobacco history were associated with higher mortality risk. Untreated patients exhibited a 39 % higher mortality risk compared to treated patients (HR = 1.39; 95%CI = 1.23–1.57). Compared to Caucasian patients, Asian/PIs demonstrated a 20 % lower risk of death (HR = 0.80; 95%CI = 0.66–0.96). There was no difference in mortality risk between AAs and Hispanics compared to Caucasians.

CONCLUSION

The lack of significant outcome disparity between AAs and Caucasians and the earlier stage at diagnosis than usually seen in civilian populations suggest that equal access to healthcare may play a role in early detection and survival.KEY WORDS: military, lung cancer, survival outcomes     

Immune profile of pediatric renal transplant recipients following alemtuzumab induction

The incidence of developing circulating anti-human leukocyte antigen antibodies and the kinetics of T cell depletion and recovery among pediatric renal transplant recipients who receive alemtuzumab induction therapy are unknown. In a collaborative endeavor to minimize maintenance immunosuppression in pediatric renal transplant recipients, we enrolled 35 participants from four centers and treated them with alemtuzumab induction therapy and a steroid-free, calcineurin-inhibitor–withdrawal maintenance regimen. At 3 months after transplant, there was greater depletion of CD4⁺ than CD8⁺ T cells within the total, naive, memory, and effector memory subsets, although depletion of the central memory subset was similar for CD4⁺ and CD8⁺ cells. Although CD8⁺ T cells recovered faster than CD4⁺ subsets overall, they failed to return to pretransplant levels by 24 months after transplant. There was no evidence for greater recovery of either CD4⁺ or CD8⁺ memory cells than naïve cells. Alemtuzumab relatively spared CD4⁺CD25⁺FoxP3⁺ regulatory T cells, resulting in a rise in their numbers relative to total CD4⁺ cells and a ratio that remained at least at pretransplant levels throughout the study period. Seven participants (20%) developed anti-human leukocyte antigen antibodies without adversely affecting allograft function or histology on 2-year biopsies. Long-term follow-up is underway to assess the potential benefits of this regimen in children.The effects of alemtuzumab on T cell subsets have been extensively studied in adults since its introduction in the 1990s. It has been associated with profound depletion of total T cells and differential recovery among T cell subsets, with early and near-complete recovery of CD8⁺ T cells, but late, partial recovery of CD4⁺ T cells.^1–3 CD4⁺ memory T cells were relatively spared compared with other CD4⁺ subsets; some investigators reported preferential sparing of central memory (T_CM) cells, whereas others observed preferential sparing of the effector memory (T_EM) subset. Emergence of the T_EM subset, whether identified peripherally or in the allograft, has been associated with acute rejection, raising concerns about the tolerogenic potential of alemtuzumab.^1–4 Although the use of alemtuzumab was not associated with an increase in either FoxP3 expression or regulatory T cell counts in vitro, both transient and sustained expansion of regulatory T cells were observed when alemtuzumab was used in association with sirolimus in vivo.^2,5,6 Notwithstanding this, however, the combination of alemtuzumab and sirolimus in protocols free of calcineurin inhibitor (CNI) was associated with rates of acute rejection exceeding 20%, with a humoral rejection rate as high as 62.5%.^7,8 In the absence of long-term CNI treatment, alemtuzumab-treated adults may therefore have a propensity to develop alloantibodies and antibody-mediated rejection.^9,10In contrast, there is a paucity of data regarding the use of alemtuzumab in pediatric solid organ transplantation.¹¹ From a clinical perspective, two small series investigating the outcomes of selected high-risk recipients of renal, liver, and intestinal transplants treated with alemtuzumab yielded conflicting results, whereas a recent series of 42 renal transplant recipients of living donor grafts reported few cases of acute rejection and excellent graft function up to 4 years after transplant.^12–14 From a mechanistic perspective, only one study reported T cell counts in a single pediatric patient, demonstrating profound and prolonged depletion of CD3⁺, CD4⁺, CD8⁺, and CD20⁺ cells, with counts only reaching 50% of their baseline levels 12 months after transplant.¹²In this study, we investigated the longitudinal immune profiles of pediatric renal transplant recipients treated with alemtuzumab induction therapy, followed by a CNI-withdrawal regimen. Specific aims were to characterize the depletion and recovery patterns of various T cell subsets and to screen for anti-human leukocyte antigen (anti-HLA) antibody development.