Spatially resolved common-path high-order harmonic interferometry

In this letter we report on interference between high harmonic emission from two longitudinally separated sources driven by the same laser pulse. Compared with previous implementations of in-line interferometry we demonstrate that by analysing the spatially-resolved harmonic signal as a function of longitudinal separation quantum trajectory-dependent interference can be identified. The inline geometry demonstrated here offers a high degree of stability, since both harmonic sources are generated from the same driving pulse, as opposed to pulse replicas, which has typically been the case in other interferometric schemes. The inherent synchronization and high timing stability afforded by this approach offers a new route for the measurement and timing of ultrafast processes

Gaussian-Schell analysis of the transverse spatial properties of high-harmonic beams

High harmonic generation (HHG) is a compact source of coherent, ultrafast soft x-ray radiation. HHG is increasingly being used as a source to image biological and physical systems. However, many imaging techniques such as coherent diffractive imaging, and ptychography require coherent illumination. Characterization the spatial coherence of HHG sources is vital if these sources are to kind widespread applications. Here a new method for characterizing coherent radiation is used to investigate the near- and far- field spatial properties of high harmonic radiation generated in a gas cell. The intensity distribution, wavefront curvature, and complex coherence factor are measured for a range of harmonic orders, and the Gaussian-Schell model is used to determine the properties of the harmonic beam in the plane of generation. Our results show the measured spatial properties of the harmonic beam are consistent with the finite spatial coherence of the driving laser beam as well as variations of the atomic dipole phase. These findings are used to suggest new approaches for controlling and optimizing the spatial properties of light for imaging applications

Association between the Cytotoxic T-Lymphocyte Antigen 4 +49G > A polymorphism and cancer risk: a meta-analysis

<p>Abstract</p> <p>Background</p> <p>As a key gene in the immunosurveillance of cell malignancy, Cytotoxic T-lymphocyte antigen 4 (CTLA-4 is an important negative regulator of T cell activation and proliferation. The CTLA-4 +49G > A polymorphism is one of the most commonly studied polymorphisms in this gene due to its association with cancer risks, but previous results have been conflicting.</p> <p>Methods</p> <p>We preformed a meta-analysis using 22 eligible case-control studies (including 32 datasets) with a total of 11,273 patients and 13,179 controls to summarize the existing data on the association between the <it>CTLA-4 </it>+49G > A polymorphism and cancer risk.</p> <p>Results</p> <p>Compared with the common <it>CTLA-4 </it>+49G > A GG genotype, the carriers of variant genotypes (<it>CTLA-4 </it>+49 GC/CC) had a 1.24-fold elevated risk of cancer (95% CI = 1.18-1.32, <it>P </it>< 0.05) under the dominant genetic model, as estimated using a fixed effect model. The effect of the <it>CTLA-4 </it>+49G > A polymorphism was further evaluated using stratification analysis. In four breast cancer studies, patients with the variant genotypes had a significantly increased risk of breast cancer (OR = 1.31, 95% CI = 1.17-1.48, <it>P </it>< 0.00001). A similar result was found in three skin cancer studies (OR = 1.30, 95% CI = 1.10-1.52, <it>P </it>= 0.001). In 26 solid tumor studies, subjects with the variant genotypes had a significantly higher risk of developing solid tumors (OR = 1.25, 95% CI = 1.18-1.33, <it>P </it>< 0.00001) compared with the 6 non-solid tumor studies (OR = 1.08, 95% CI = 0.79-1.48, <it>P </it>= 0.62). Patients with variant genotypes had significantly increased risk of non-epithelial tumors and epithelial tumors, with ORs of 1.23 (95% CI = 1.14-1.32, <it>P </it>< 0.00001) and 1.29 (95% CI = 1.17-1.41, <it>P </it>< 0.00001), respectively. It was also demonstrated that the increased risk of cancer associated with <it>CTLA-4 </it>+49G > A variant genotypes was more pronounced in Caucasians (OR = 1.29, 95% CI = 1.13-1.47, <it>P </it>= 0.0002), Asians (OR = 1.23, 95% CI = 1.16-1.32, <it>P </it>< 0.00001) and Chinese (OR = 1.23, 95% CI = 1.15-1.31, <it>P </it>< 0.00001).</p> <p>Conclusion</p> <p>Our meta-analysis suggests that the <it>CTLA-4 </it>+49G > A polymorphism genotypes (GA + AA) might be associated with an increased risk of cancer, especially in Caucasians and Chinese.</p

Autoantibodies to muscarinic acetylcholine receptors found in patients with primary biliary cirrhosis

<p>Abstract</p> <p>Background</p> <p>Autoantibodies to the human muscarinic acetylcholine receptor of the M3 type (hmAchR M3) have been suggested to play an etiopathogenic role in Sjögren's syndrome. Primary biliary cirrhosis (PBC) often is associated with this syndrome. Therefore, we studied the co-presence of hmAchR M3 autoantibodies in patients with PBC.</p> <p>Methods</p> <p>Frequency of hmAchR M3 autoantibodies was assessed by Western blotting analysis as well as by an ELISA using a 25-mer peptide of the 2^ndextracellular loop of hmAchR M3. Co-localization of hmAchR M3/PBC-specific autoantibodies was studied by confocal laser scanning microscopy. Finally, sera from patients with PBC as well as from healthy controls were tested.</p> <p>Results</p> <p>Western blotting analysis as well as results from ELISA testing revealed a significantly enhanced IgG reactivity in PBC patients in contrast to healthy controls. Co-localization of autoantibodies with the hmAchR M3 receptor-specific autoantibodies was observed in 10 out of 12 PBC-patients but none of the 5 healthy controls. Antibodies of the IgM type were not found to be affected.</p> <p>Conclusions</p> <p>For the first time, our data demonstrate the presence of autoantibodies to the hmAchR M3 in PBC patients. These findings might contribute to the understanding of the pathogenesis of this disease. Further studies have to focus on the functionality of hmAchR M3 autoantibodies in PBC patients.</p

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis and cirrhosis of the liver and may need liver transplantation in the late stage of disease. PBC primarily affects women (female preponderance 9–10:1) with a prevalence of up to 1 in 1,000 women over 40 years of age. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The diagnosis is based on sustained elevation of serum markers of cholestasis, i.e., alkaline phosphatase and gamma-glutamyl transferase, and the presence of serum antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex. Histologically, PBC is characterized by florid bile duct lesions with damage to biliary epithelial cells, an often dense portal inflammatory infiltrate and progressive loss of small intrahepatic bile ducts. Although the insight into pathogenetic aspects of PBC has grown enormously during the recent decade and numerous genetic, environmental, and infectious factors have been disclosed which may contribute to the development of PBC, the precise pathogenesis remains enigmatic. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at adequate doses of 13–15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. The mode of action of UDCA is still under discussion, but stimulation of impaired hepatocellular and cholangiocellular secretion, detoxification of bile, and antiapoptotic effects may represent key mechanisms. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarizes current knowledge on the clinical, diagnostic, pathogenetic, and therapeutic aspects of PBC

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival

Prostate Cancer Induced by Loss of Apc Is Restrained by TGFβ Signaling

Recent work with mouse models of prostate cancer (CaP) has shown that inactivation of TGFβ signaling in prostate epithelium can cooperate with deletion of the Pten tumor suppressor to drive locally aggressive cancer and metastatic disease. Here, we show that inactivating the TGFβ pathway by deleting the gene encoding the TGFβ type II receptor (Tgfbr2) in combination with a deletion of the Apc tumor suppressor gene specifically in mouse prostate epithelium, results in the rapid onset of invasive CaP. Micro-metastases were observed in the lymph nodes and lungs of a proportion of the double mutant mice, whereas no metastases were observed in Apc single mutant mice. Prostate-specific Apc;Tgfbr2 mutants had a lower frequency of metastasis and survived significantly longer than Pten;Tgfbr2 double mutants. However, all Apc;Tgfbr2 mutants developed invasive cancer by 30 weeks of age, whereas invasive cancer was rarely observed in Apc single mutant animals, even by one year of age. Further comparison of the Pten and Apc models of CaP revealed additional differences, including adenosquamous carcinoma in the Apc;Tgfbr2 mutants that was not seen in the Pten model, and a lack of robust induction of the TGFβ pathway in Apc null prostate. In addition to causing high-grade prostate intra-epithelial neoplasia (HGPIN), deletion of either Pten or Apc induced senescence in affected prostate ducts, and this restraint was overcome by loss of Tgfbr2. In summary, this work demonstrates that TGFβ signaling restrains the progression of CaP induced by different tumor suppressor mutations, suggesting that TGFβ signaling exerts a general tumor suppressive effect in prostate.This work was supported by a Program Project Grant from the National Cancer Institute (2P01CA104106 to B. Paschal and D. Wotton), and by a pilot grant from the UVA Cancer Center (funded from the CCSG P30 CA44579, the James and Rebecca CraigFoundation, and UVA Women's Oncology fund) to D. Wotton. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Sharon Birdsall for technical assistance, Anindya Dutta and Dan Gioeli for helpful discussions, and Chun-Song Yang for advice and reagent

Worldwide trends in population-based survival for children, adolescents, and young adults diagnosed with leukaemia, by subtype, during 2000–14 (CONCORD-3) : analysis of individual data from 258 cancer registries in 61 countries

Background Leukaemias comprise a heterogenous group of haematological malignancies. In CONCORD-3, we analysed data for children (aged 0–14 years) and adults (aged 15–99 years) diagnosed with a haematological malignancy during 2000–14 in 61 countries. Here, we aimed to examine worldwide trends in survival from leukaemia, by age and morphology, in young patients (aged 0–24 years). Methods We analysed data from 258 population-based cancer registries in 61 countries participating in CONCORD-3 that submitted data on patients diagnosed with leukaemia. We grouped patients by age as children (0–14 years), adolescents (15–19 years), and young adults (20–24 years). We categorised leukaemia subtypes according to the International Classification of Childhood Cancer (ICCC-3), updated with International Classification of Diseases for Oncology, third edition (ICD-O-3) codes. We estimated 5-year net survival by age and morphology, with 95% CIs, using the non-parametric Pohar-Perme estimator. To control for background mortality, we used life tables by country or region, single year of age, single calendar year and sex, and, where possible, by race or ethnicity. All-age survival estimates were standardised to the marginal distribution of young people with leukaemia included in the analysis. Findings 164563 young people were included in this analysis: 121328 (73·7%) children, 22963 (14·0%) adolescents, and 20272 (12·3%) young adults. In 2010–14, the most common subtypes were lymphoid leukaemia (28205 [68·2%] patients) and acute myeloid leukaemia (7863 [19·0%] patients). Age-standardised 5-year net survival in children, adolescents, and young adults for all leukaemias combined during 2010–14 varied widely, ranging from 46% in Mexico to more than 85% in Canada, Cyprus, Belgium, Denmark, Finland, and Australia. Individuals with lymphoid leukaemia had better age-standardised survival (from 43% in Ecuador to ≥80% in parts of Europe, North America, Oceania, and Asia) than those with acute myeloid leukaemia (from 32% in Peru to ≥70% in most high-income countries in Europe, North America, and Oceania). Throughout 2000–14, survival from all leukaemias combined remained consistently higher for children than adolescents and young adults, and minimal improvement was seen for adolescents and young adults in most countries. Interpretation This study offers the first worldwide picture of population-based survival from leukaemia in children, adolescents, and young adults. Adolescents and young adults diagnosed with leukaemia continue to have lower survival than children. Trends in survival from leukaemia for adolescents and young adults are important indicators of the quality of cancer management in this age group.peer-reviewe