Constraints on Non-Newtonian Gravity from Recent Casimir Force Measurements

Corrections to Newton's gravitational law inspired by extra dimensional physics and by the exchange of light and massless elementary particles between the atoms of two macrobodies are considered. These corrections can be described by the potentials of Yukawa-type and by the power-type potentials with different powers. The strongest up to date constraints on the corrections to Newton's gravitational law are reviewed following from the E\"{o}tvos- and Cavendish-type experiments and from the measurements of the Casimir and van der Waals force. We show that the recent measurements of the Casimir force gave the possibility to strengthen the previously known constraints on the constants of hypothetical interactions up to several thousand times in a wide interaction range. Further strengthening is expected in near future that makes Casimir force measurements a prospective test for the predictions of fundamental physical theories.Comment: 20 pages, crckbked.cls is used, to be published in: Proceedings of the 18th Course of the School on Cosmology and Gravitation: The Gravitational Constant. Generalized Gravitational Theories and Experiments (30 April- 10 May 2003, Erice). Ed. by G. T. Gillies, V. N. Melnikov and V. de Sabbata, 20pp. (Kluwer, in print, 2003

Functional polymorphisms in the BRCA1 promoter influence transcription and are associated with decreased risk for breast cancer in Chinese women

Background: The BRCA1 gene is an important breast-cancer susceptibility gene. Promoter polymorphisms can alter the binding affinity of transcription factors, changing transcriptional activity and may affect susceptibility to disease. Methods and Results: Using direct sequencing of the BRCA1 promoter region, we identified four polymorphisms c.-2804T→C (rs799908:T→C), c.-2265C→T (rs11655505:C→T), c.-2004A→G (rs799906:A→G) and c.-1896(ACA) 1→(ACA) 2 (rs8176071:(ACA) 1→(ACA) 2) present in Hong Kong Chinese. Each polymorphism was studied independently and in combination by functional assays. Although all four variants significantly altered promoter activity, the c.-2265T allele had stronger binding than the C allele, and the most common mutant haplotype, which contains the c.-2265T allele, increased promoter activity by 70%. Risk association first tested in Hong Kong Chinese women with breast cancer and age-matched controls and replicated in a large population-based study of Shanghai Chinese, together totalling >3000 participants, showed that carriers of the c.-2265T allele had a reduced risk for breast cancer (combined odd ratio (OR) = 0.80, 95% Cl 0.69 to 0.93; p = 0.003) which was more evident among women aged ≥45 years at first diagnosis of breast cancer and without a family history of breast cancer (combined OR = 0.75, 95% Cl 0.61 to 0.91; p = 0.004). The most common haplotype containing the c.-2265T allele also showed significant risk association for women aged ≥45 years without a family history of breast cancer (OR = 0.64, 95% Cl 0.46 to 0.89; p = 0.008). Conclusion: This comprehensive study of BRCA1 promoter polymorphisms found four variants that altered promoter activity and with the most significant contribution from c.-2265C→T, which could affect susceptibility to breast cancer in the Chinese population. Its significance in other populations remains to be investigated.published_or_final_versio

Matched sizes of activating and inhibitory receptor/ligand pairs are required for optimal signal integration by human Natural Killer cells

It has been suggested that receptor-ligand complexes segregate or co-localise within immune synapses according to their size, and this is important for receptor signaling. Here, we set out to test the importance of receptor-ligand complex dimensions for immune surveillance of target cells by human Natural Killer (NK) cells. NK cell activation is regulated by integrating signals from activating receptors, such as NKG2D, and inhibitory receptors, such as KIR2DL1. Elongating the NKG2D ligand MICA reduced its ability to trigger NK cell activation. Conversely, elongation of KIR2DL1 ligand HLA-C reduced its ability to inhibit NK cells. Whereas normal-sized HLA-C was most effective at inhibiting activation by normal-length MICA, only elongated HLA-C could inhibit activation by elongated MICA. Moreover, HLA-C and MICA that were matched in size co-localised, whereas HLA-C and MICA that were different in size were segregated. These results demonstrate that receptor-ligand dimensions are important in NK cell recognition, and suggest that optimal integration of activating and inhibitory receptor signals requires the receptor-ligand complexes to have similar dimensions

Expression of CDX2 and Hepatocyte Antigen in Benign and Malignant Lesions of Gallbladder and Its Correlation with Histopathologic Type and Clinical Outcome

Recent studies have shown that both CDX2 and Hepatocyte antigen (Hep) are detected in different types of cancer and associated with clinical prognosis. However, fever studies have examined gallbladder cancer specimens, and little is known about the clinicopathological significance of both CDX2 and Hep expression in gallbladder adenocarcinomas. In present study, we examined the expression frequencies of CDX2 and Hepatocyte antigen (Hep), and explored their clinicopathologic significances in gallbladder adenocarcinoma. Immunohistochemistry was used to detect and compare the frequencies of CDX2 and Hep expression in 108 samples of gallbladder adenocarcinoma, 46 peri-tumor tissues and 35 chronic cholecystitis. The expression frequencies for CDX2 and Hep were 49/108 (45.4%) and 45/108 (41.7%) in gallbladder carcinoma; 13/46 (28.3%) and 11/46 (23.9) in peri-tumor tissues; 5/35 (14.3%) and 2/35 (5.7%) in chronic cholecystitis. The positive staining of CDX2 or Hep in gallbladder adenocarcinoma was significantly higher than that in peritumoral tissues (both, P < 0.05), and chronic cholecystits (both, P < 0.01). The expression of CDX2 or Hep was negatively correlated to grade of differentiation, tumor size and lymph node metastasis (P < 0.01 or P < 0.05). Elevated expression frequency of CDX2 or Hep was associated with increased overall survival (P = 0.003 or P = 0.002). Multivariate Cox regression analysis showed that CDX2 (P = 0.014) or Hep (P = 0.026) expression was an independent prognostic predictor in gallbladder adenocarcinoma. CDX2 and Hep might function as important biological markers in the development and prognosis of gallbladder adenocarcinoma

Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway

Eradicating tumor dormancy that develops following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR-mutant non-small cell lung cancer, is an attractive therapeutic strategy but the mechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state characterized by high YAP/TEAD activity. YAP/TEAD engage the epithelial-to-mesenchymal transition transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced apoptosis. Pharmacological co-inhibition of YAP and TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR/MEK inhibition-induced apoptosis. Enhancing the initial efficacy of targeted therapies could ultimately lead to prolonged treatment responses in cancer patients