Experimental quantum key distribution certified by Bell's theorem.

Cryptographic key exchange protocols traditionally rely on computational conjectures such as the hardness of prime factorization1 to provide security against eavesdropping attacks. Remarkably, quantum key distribution protocols such as the Bennett-Brassard scheme2 provide information-theoretic security against such attacks, a much stronger form of security unreachable by classical means. However, quantum protocols realized so far are subject to a new class of attacks exploiting a mismatch between the quantum states or measurements implemented and their theoretical modelling, as demonstrated in numerous experiments3-6. Here we present the experimental realization of a complete quantum key distribution protocol immune to these vulnerabilities, following Ekert's pioneering proposal7 to use entanglement to bound an adversary's information from Bell's theorem8. By combining theoretical developments with an improved optical fibre link generating entanglement between two trapped-ion qubits, we obtain 95,628 key bits with device-independent security9-12 from 1.5 million Bell pairs created during eight hours of run time. We take steps to ensure that information on the measurement results is inaccessible to an eavesdropper. These measurements are performed without space-like separation. Our result shows that provably secure cryptography under general assumptions is possible with real-world devices, and paves the way for further quantum information applications based on the device-independence principle.

Emergence of spatio-temporal variations in chemotherapeutic drug efficacy: in-vitro and in-Silico 3D tumour spheroid studies.

BACKGROUND: The mechanisms of action and efficacy of cisplatin and paclitaxel at cell population level are well studied and documented, however the localized spatio-temporal effects of the drugs are less well understood. We explore the emergence of spatially preferential drug efficacy resulting from variations in mechanisms of cell-drug interactions. METHODS: 3D spheroids of HeLa-C3 cells were treated with drugs, cisplatin and paclitaxel. This was followed by sectioning and staining of the spheroids to track the spatio-temporal apoptotic effects of the drugs. A mechanistic drug-cell interaction model was developed and simulated to analyse the localized efficacy of these drugs. RESULTS: The outcomes of drug actions on a local cell population was dependant on the interactions between cell repair probability, intracellular drug concentration and cell's mitosis phase. In spheroids treated with cisplatin, drug induced apoptosis is found to be scattered throughout the volume of the spheroids. In contrast, effect of paclitaxel is found to be preferentially localized along the periphery of the spheroids. Combinatorial treatments of cisplatin and paclitaxel result in varying levels of cell apoptosis based on the scheduling strategy. CONCLUSIONS: The preferential action of paclitaxel can be attributed to the cell characteristics of the peripheral population. The model simulations and experimental data show that treatments initiated with paclitaxel are more efficacious due to the cascading of spatial effects of the drugs.

Noisy Preprocessing Facilitates a Photonic Realization of Device-Independent Quantum Key Distribution.

Device-independent quantum key distribution provides security even when the equipment used to communicate over the quantum channel is largely uncharacterized. An experimental demonstration of device-independent quantum key distribution is however challenging. A central obstacle in photonic implementations is that the global detection efficiency, i.e., the probability that the signals sent over the quantum channel are successfully received, must be above a certain threshold. We here propose a method to significantly relax this threshold, while maintaining provable device-independent security. This is achieved with a protocol that adds artificial noise, which cannot be known or controlled by an adversary, to the initial measurement data (the raw key). Focusing on a realistic photonic setup using a source based on spontaneous parametric down conversion, we give explicit bounds on the minimal required global detection efficiency.

Breast-conserving surgery versus mastectomy in young women with breast cancer in Asian settings.

Background: Mastectomy rates among women with early breast cancer in Asia have traditionally been high. This study assessed trends in the surgical management of young women with early-stage breast cancer in Asian settings. Survival in women treated with breast-conserving surgery (BCS; lumpectomy with adjuvant radiotherapy) and those undergoing mastectomy was compared. Methods: Young women (aged less than 50 years) newly diagnosed with stage I or II (T1-2 N0-1 M0) breast cancer in four hospitals in Malaysia, Singapore and Hong Kong in 1990-2012 were included. Overall survival (OS) was compared for patients treated by BCS and those who had a mastectomy. Propensity score analysis was used to account for differences in demographic, tumour and treatment characteristics between the groups. Results: Some 63·5 per cent of 3536 women underwent mastectomy. Over a 15-year period, only a modest increase in rates of BCS was observed. Although BCS was significantly associated with favourable prognostic features, OS was not significantly different for BCS and mastectomy; the 5-year OS rate was 94·9 (95 per cent c.i. 93·5 to 96·3) and 92·9 (91·7 to 94·1) per cent respectively. Inferences remained unchanged following propensity score analysis (hazard ratio for BCS versus mastectomy: 0·81, 95 per cent c.i. 0·64 to 1·03). Conclusion: The prevalence of young women with breast cancer treated by mastectomy remains high in Asian countries. Patients treated with BCS appear to survive as well as those undergoing mastectomy.

Blue dye is sufficient for sentinel lymph node biopsy in breast cancer.

BACKGROUND: Most previous studies have reported superior results when blue dye and radiocolloids were used together for sentinel lymph node (SLN) biopsy in early breast cancer. Blue dye was reported to perform poorly when used alone, although more recent studies have found otherwise. This study reviewed the authors' practice of performing SLN biopsy with blue dye alone. METHODS: This was a retrospective review of patients who underwent SLN biopsy using blue dye alone from 2001 to 2005, when SLN biopsy was performed selectively and always followed by axillary lymph node dissection (ALND), and from 2006 to 2010, when SLN biopsy was offered to all suitable patients and ALND done only when the SLN was not identified or positive for metastasis. RESULTS: Between 2001 and 2005, 170 patients underwent SLN biopsy with blue dye alone. The overall SLN non-identification rate was 8·4 per cent. The overall false-negative rate was 34 per cent, but decreased with each subsequent year to 13 per cent in 2005. From 2006 to 2010, 610 patients underwent SLN biopsy with blue dye alone. The SLN was not identified in 12 patients (2·0 per cent) and no significant contributing factor was identified. A median of 2 (range 1-11) SLNs were identified. A non-SLN was found to be positive for metastasis in two patients with negative SLNs. Axillary nodal recurrence developed in one patient; none developed internal mammary nodal recurrence. Anaphylaxis occurred in one patient. CONCLUSION: Blue dye performed well as a single modality for SLN biopsy. Non-identification, axillary nodal recurrence and serious allergic reactions were uncommon.

ALDH1 expression is enriched in breast cancers arising in young women but does not predict outcome.

BACKGROUND: Tumours arising in younger women appear to be biologically more aggressive and tend to have a poorer outcome. Being relatively resistant to conventional treatments, breast cancer stem cells (CSCs) have been postulated as a possible cause of disease recurrence after treatment. In this study, we used ALDH1 as a CSC marker and determined whether ALDH1 expression correlated with clinical outcome in young women with breast cancer. METHODS: The expression of ALDH1 was evaluated through immunohistochemistry on microarrayed cores obtained from 141 consecutive patients up to 35 years of age. RESULTS: The expression of ALDH1 was observed in 25% (35 of 141) of tumours, in a median of 5% of cells. Younger women were 14 times more likely to have ALDH1-positive tumours (P<0.01, OR 14.4, 95% CI 4.34-48.09). The ALDH1 correlated independently with ER negativity (P=0.01, OR 0.33, 95% CI 0.15-0.77). There was no correlation with disease recurrence or breast cancer-related deaths. CONCLUSION: In younger women, ALDH1 was more highly expressed, and it correlated with ER negativity. It, however, did not predict survival in this study.

The changing trend of diverticular disease in a developing nation.

AIM: Left-sided diverticular disease (LDD) is associated with reduced dietary intake, whereas right-sided diverticular disease (RDD) is more common amongst Oriental populations. We aimed to determine whether the prevalence, site and distribution of diverticular disease in our Oriental population has changed over the past two decades. METHOD: A total of 1663 barium enema studies performed between January 2001 and August 2002 were reviewed retrospectively. The site of disease was correlated with age, gender and ethnicity of the patient. RESULTS: Forty-five per cent of patients in the study population had diverticular disease. Older patients were more likely to have LDD, whereas the Chinese ethnic group was more likely to have RDD. Right-sided diverticular disease peaks at in the sixth decade, while for LDD this occurred in the seventh and eighth decades. Right-sided diverticular disease was more common in all age groups overall. When compared with two barium enema studies carried out in Singapore two decades earlier, there was a statistically significant increase in the incidence of RDD and LDD. CONCLUSION: There is a positive association of RDD and LDD with Chinese race and increasing age. There is an increasing incidence of both LDD and RDD compared with two decades previously.

Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer.

BACKGROUND: Delta-like ligand 4 (Dll4) is a Notch ligand that is upregulated by hypoxia and vascular endothelial growth factor-A (VEGF-A) and is reported to have a role in tumor angiogenesis. Evidence from xenograft studies suggests that inhibiting Dll4-Notch signalling may overcome resistance to anti-VEGF therapy. The aim of this study was to characterise the expression of Dll4 in colon cancer and to assess whether it is associated with markers of hypoxia and prognosis. METHOD: In all, 177 colon cancers were represented in tissue microarrays. Immunohistochemistry was performed using validated antibodies against Dll4, VEGF, hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, prolyl hydroxylase (PHD)1, PHD2, PHD3 and carbonic anhydrase 9 (CA9). RESULTS: The expression of Dll4 was observed preferentially in the endothelium of 71% (125 out of 175) of colon cancers, but not in the endothelium adjacent to normal mucosa (none out of 107, P<0.0001). The expression of VEGF was significantly associated with HIF-2alpha (P<0.0001) and Dll4 (P=0.010). Only HIF-2alpha had a significant multivariate prognostic effect (hazard ratio 1.61, 95% confidence interval 1.01-2.57). Delta-like ligand 4 was also expressed by neoplastic cells, particularly neoplastic goblet cells. CONCLUSION: Endothelial expression of Dll4 is not a prognostic factor, but is significantly associated with VEGF. Assessing endothelial Dll4 expression may be critical in predicting response to anti-VEGF therapies.

The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy.

Basal-like tumours account for 15% of invasive breast carcinomas and are associated with a poorer prognosis and resistance to therapy. We hypothesised that this aggressive phenotype is because of an intrinsically elevated hypoxic response. Microarrayed tumours from 188 patients were stained for hypoxia-inducible factor (HIF)-1alpha, prolyl hydroxylase (PHD)1, PHD2, PHD3 and factor inhibiting HIF (FIH)-1, and carbonic anhydrase (CA) IX stained in 456 breast tumours. Tumour subtypes were correlated with standard clincopathological parameters as well as hypoxic markers. Out of 456 tumours 62 (14%) tumours were basal-like. These tumours were positively correlated with high tumour grade (P<0.001) and were associated with a significantly worse disease-free survival compared with luminal tumours (P<0.001). Fifty percent of basal-like tumours expressed HIF-1alpha, and more than half expressed at least one of the PHD enzymes and FIH-1. Basal-like tumours were nine times more likely to be associated with CAIX expression (P<0.001) in a multivariate analysis. Carbonic anhydrase IX expression was positively correlated with tumour size (P=0.005), tumour grade (P<0.001) and oestrogen receptor (ER) negativity (P<0.001). Patients with any CAIX-positive breast tumour phenotype and in the basal tumour group had a significantly worse prognosis than CAIX-negative tumours when treated with chemotherapy (P<0.001 and P=0.03, respectively). The association between basal phenotype and CAIX suggests that the more aggressive behaviour of these tumours is partly due to an enhanced hypoxic response. Further, the association with chemoresistance in CAIX-positive breast tumours and basal-like tumours in particular raises the possibility that targeted therapy against HIF pathway or downstream genes such as CAs may be an approach to investigate for these patients.

Traumatic abdominal wall herniation.

Most reported cases of traumatic abdominal wall herniation result from seatbelt or handlebar injuries. The diagnosis is often made on physical examination or abdominal computed tomography (CT). We report a 59-year-old man with traumatic herniation through the rectus muscle following low-velocity blunt abdominal trauma. This patient was initially thought to have a rectus sheath haematoma and initial CT showed a soft tissue haematoma over the left lower anterior abdominal wall but no herniation. The traumatic herniation was diagnosed four days later, and confirmed on CT. Intraoperatively, a segment of the sigmoid colon was found to have herniated through the rectus defect and was gangrenous with impending perforation. A left hemicolectomy followed by primary repair of the defect was done. This case highlights the need for a high index of suspicion for traumatic herniation in patients who sustain low-velocity blunt abdominal wall trauma even when initial CT scans are negative.

The angiogenic factor thymidine phosphorylase up-regulates the cell adhesion molecule P-selectin in human vascular endothelial cells and is associated with P-selectin expression in breast cancers.

Thymidine phosphorylase (TP) is an angiogenic enzyme, catalysing the reversible phosphorylation of thymidine to thymine and 2-deoxyribose. TP is up-regulated in neoplasia, being associated with advanced tumour stage, microvessel density and prognosis in several tumour types. Although TP is a non-mitogenic migratory factor for endothelium, the mechanism by which TP mediates these effects is still unclear. We compared the gene expression profile of endothelial cells grown in vitro in the presence or absence of TP by cDNA microarray analysis. To determine the time-course of TP angiogenic induction, endothelial cells were stimulated with TP (10 ng/ml) for 5 and 18 h. Gene expression levels of Tie2, angiopoietin (Ang)1 and Ang2, measured by RNase protection assay (RPA), showed maximal alteration at 18 h. cDNA from human umbilical vein endothelial cells (HUVEC) grown for 18 h in the presence or absence of TP (10 ng/ml) was hybridized to a human cDNA cytokine array representing 375 angiogenic genes. Significantly altered expression occurred in 89 human angiogenic genes (72 genes were up-regulated and 17 down-regulated). Changes in five genes relevant to vascular remodelling biology (Tie2, nNos, P-selectin, ephrin-B1 and TP) were validated in triplicate experiments by real-time RT-PCR. But only P-selectin gene expression remained significant. Correlation between P-selectin and TP was assessed by immunohistochemistry on 161 human breast cancers, using human tissue microarray. Tumour cell TP correlated with tumour cell P-selectin but not with endothelial cell P-selectin. These data show that TP stimulates changes in mRNA expression maximally after 18 h culture in vitro. It confirms a role for TP in vascular remodelling involving several classes of genes, including the cell adhesion molecule, P-selectin. Although confirmation of the role of TP-mediated cell adhesion molecule (CAM) induction is required; however, this pathway may provide an attractive therapeutic target, since it is likely to affect several important tumour processes, including angiogenesis and metastasis.

Attenuating pregnane X receptor (PXR) activation: a molecular modelling approach.

Recent studies have demonstrated that the pregnane X receptor (PXR) is a key regulator of cytochromes P450 3A (e.g. CYP3A4 in human) gene expression. As a result, activation of PXR may lead to CYP3A4 protein over-expression. Because induction of CYP3A4 could result in clinically important drug drug interactions, there has been a great interest in reducing the possibility of PXR activation by drug candidates in drug-discovery programmes. In order to provide structural insight for attenuating drug candidate-mediated PXR activation, we used a docking approach to study the structure activity relationship for PXR activators. Based on our docking models, it is proposed that introducing polar groups to the end of an activator should reduce its human PXR (hPXR) activity via destabilizing interactions in the hydrophobic areas of the PXR ligand-binding pocket. A number of analogues that incorporate these structural features then were designed and synthesized, and they exhibited significantly lower hPXR activation in a transactivation assay and decreased CYP3A4 induction in a human hepatocytes-based assay. In addition, an example in which attenuating hPXR activation was achieved by sterically destabilizing the helices 11 and 12 of the receptor is presented.

Locally advanced and metastatic breast cancer in a tertiary hospital.

INTRODUCTION: The breast cancer incidence among Singapore women has risen through the years and is now the highest in Asia. Despite efforts to promote a greater awareness of breast cancer among the public, a significant number of patients still present with locally advanced or metastatic breast cancer. Our study aims to evaluate the clinical and pathological characteristics between patients presenting with locally advanced (LABC) and metastatic breast cancer (MBC) and those presenting with early breast cancer (EBC), to identify factors that predict for advanced disease. MATERIALS AND METHODS: We reviewed 622 patients who were newly diagnosed with invasive breast cancer in our department over a 4-year period from January 2000 to December 2003. Patient and tumour characteristics including age, parity, family history, tumour size and histology, grade and hormonal receptor status were analysed. Comparisons were made between those with EBC and those with LABC and MBC, as well as between Malay women and women of other ethnic groups. RESULTS: One hundred and thirty-four patients (21.5%) presented with either LABC or MBC. Adjusted analysis found that these patients were older and more likely to be nulliparous than those with EBC. Older patients tend to have larger tumours, but otherwise, age and parity did not correlate with tumour histology, grade or hormonal status. It was noted that Malay women, who were more likely to present with LABC or MBC, were more likely to have oestrogen receptor- and progesterone receptor-negative tumours. CONCLUSIONS: Older women and those who were nulliparous were found more likely to present with LABC and MBC. However, age and parity did not appear to be related to tumour histology, grade and hormonal status. Given that tumour size and stage have the greatest impact on overall survival, efforts to raise public awareness of the benefits of early detection and treatment should be continued, and possibly directed towards these groups of women who appear to be at an increased risk of presenting late.

First clinical evaluation of ganstigmine in patients with probable Alzheimer's disease.

The objective of this study was to evaluate the safety, tolerability, maximum tolerated dose, pharmacokinetics, and pharmacodynamics of five fixed doses of ganstigmine (CHF 2819) in patients with probable Alzheimer's disease (AD). This randomized, double-blind, placebo-controlled trial evaluated five dose levels (5, 7.5, 10, 12.5, and 15 mg) administered orally once daily for 7 days. Adverse events and continuous telemetry were collected on successive panels of six patients (five active, one placebo). Acetylcholinesterase, butyrylcholinesterase, and plasma drug levels were measured. A total of 29 patients were randomized and 18 completed the study. A total of seven patients, including five of five in the 12.5-mg panel, discontinued because of adverse events. Four patients were withdrawn administratively from the first panel while an episode of atrial fibrillation (the only serious adverse event) was investigated. This panel was then repeated. Mild, transient headache or nausea were the most commonly reported adverse events. Multiple moderate adverse events in the 12.5-mg panel (including nausea, vomiting, and anorexia) led to the decision not to proceed with a 15-mg panel. Ten milligrams was determined to be the maximum tolerated dose. Ganstigmine exhibited nonlinear pharmacokinetics, was absorbed rapidly, and reached peak concentrations within 1 hour. Acetylcholinesterase inhibition was dose dependent and lasted as long as 24 hours. Ganstigmine, a novel cholinesterase inhibitor, was well tolerated within a dosing range of 5 to 10 mg. Once-daily dosing is supported by data on acetylcholinesterase inhibition.