Tunable narrow-linewidth laser at 2†µm wavelength for gravitational wave detector research.

We present and characterize a narrow-linewidth external-cavity diode laser at 2 µm, and show that it represents a low-cost, high-performance alternative to fiber lasers for research into 2 µm photonic technologies for next-generation gravitational-wave detectors. A linewidth of 20 kHz for a 10 ms integration time was measured without any active stabilization, with frequency noise of ∼ 15 Hz/Hz between 3 kHz and 100 kHz. This performance is suitable for the generation of quantum squeezed light, and we measure intensity noise comparable to that of master oscillators used in current gravitational wave interferometers. The laser wavelength is tunable over a 120 nm range, and both the frequency and intensity can be modulated at up to 10 MHz by modulating the diode current. These features also make it suitable for other emerging applications in the 2 µm wavelength region including gas sensing, optical communications and LIDAR.

Squeezed vacuum phase control at 2 µm.

We demonstrate phase control for vacuum-squeezed light at a 2 µm wavelength, which is a necessary technology for proposed future gravitational wave observatories. The control scheme allowed examination of noise behavior at frequencies below 1 kHz and indicated that squeezing below this frequency was limited by dark noise and scattered light. We directly measure 3.9±0.2 dB of squeezing from 2 kHz to 80 kHz and 14.2±0.3 dB of antisqueezing relative to the shot noise level. The observed maximum level of squeezing is currently limited by photodetector quantum efficiency and laser instabilities at this new wavelength for squeezed light. Accounting for all losses, we conclude the generation of 11.3 dB of squeezing at the optical parametric oscillator.

Quantum-Enhanced Advanced LIGO Detectors in the Era of Gravitational-Wave Astronomy.

The Laser Interferometer Gravitational Wave Observatory (LIGO) has been directly detecting gravitational waves from compact binary mergers since 2015. We report on the first use of squeezed vacuum states in the direct measurement of gravitational waves with the Advanced LIGO H1 and L1 detectors. This achievement is the culmination of decades of research to implement squeezed states in gravitational-wave detectors. During the ongoing O3 observation run, squeezed states are improving the sensitivity of the LIGO interferometers to signals above 50 Hz by up to 3 dB, thereby increasing the expected detection rate by 40% (H1) and 50% (L1).

Towards a global cancer knowledge network: dissecting the current international cancer genomic sequencing landscape.

BACKGROUND: While next generation sequencing has enhanced our understanding of the biological basis of malignancy, current knowledge on global practices for sequencing cancer samples is limited. To address this deficiency, we developed a survey to provide a snapshot of current sequencing activities globally, identify barriers to data sharing and use this information to develop sustainable solutions for the cancer research community. METHODS: A multi-item survey was conducted assessing demographics, clinical data collection, genomic platforms, privacy/ethics concerns, funding sources and data sharing barriers for sequencing initiatives globally. Additionally, respondents were asked as to provide the primary intent of their initiative (clinical diagnostic, research or combination). RESULTS: Of 107 initiatives invited to participate, 59 responded (response rate = 55%). Whole exome sequencing (P = 0.03) and whole genome sequencing (P = 0.01) were utilized less frequently in clinical diagnostic than in research initiatives. Procedures to identify cancer-specific variants were heterogeneous, with bioinformatics pipelines employing different mutation calling/variant annotation algorithms. Measurement of treatment efficacy varied amongst initiatives, with time on treatment (57%) and RECIST (53%) being the most common; however, other parameters were also employed. Whilst 72% of initiatives indicated data sharing, its scope varied, with a number of restrictions in place (e.g. transfer of raw data). The largest perceived barriers to data harmonization were the lack of financial support (P < 0.01) and bioinformatics concerns (e.g. lack of interoperability) (P = 0.02). Capturing clinical data was more likely to be perceived as a barrier to data sharing by larger initiatives than by smaller initiatives (P = 0.01). CONCLUSIONS: These results identify the main barriers, as perceived by the cancer sequencing community, to effective sharing of cancer genomic and clinical data. They highlight the need for greater harmonization of technical, ethical and data capture processes in cancer sample sequencing worldwide, in order to support effective and responsible data sharing for the benefit of patients.

RAD21 cohesin overexpression is a prognostic and predictive marker exacerbating poor prognosis in KRAS mutant colorectal carcinomas.

BACKGROUND: RAD21 is a component of the cohesion complex and is integral to chromosome segregation and error-free DNA repair. RAD21 is functionally important in tumour progression but its role in colorectal carcinoma (CRC) is unclear. We therefore assessed its clinicopathological and prognostic significance in CRC, as well as its effect on chemosensitivity. METHODS: A retrospective observation study examined RAD21 expression in 652 CRCs using a tissue microarray approach. Correlation with clinicopathological factors including gender, tumour grade, mucinous subtype, TNM stage, disease-specific survival (DSS), BRAF and KRAS mutation status, tumour p53 immunostaining, tumour microsatellite instability and tumour CpG island methylator phenotype was performed. Colorectal cancer cell clones with stable RAD21 knockdown were generated and tested for cellular sensitivity to conventional chemotherapeutic drugs. RESULTS: RAD21 expression was significantly correlated with male gender (56.7% vs 43.3%, P=0.02), well-differentiated histology (14.4% vs 4.0%, P=0.0001), higher T-stage (36.1% vs 27.0%, P=0.01), presence of metastasis (18.8% vs 12.6%, P=0.03), and shorter DSS (hazard ratio (HR) 1.4, 95% CI 1.1 to 1.9, P=0.01) in both univariate and multivariate analysis. RAD21 expression was associated with shorter DSS in patients with KRAS mutant tumours (HR:2.6, 95% CI:1.4-4.3, P=0.001) and in patients receiving adjuvant chemoradiotherapy (HR:1.9, 95% CI:1.2-3.0, P=0.008). Colorectal cancer cells with RAD21 knockdown exhibited enhanced sensitivity to 5-fluorouracil, either alone or in combination with oxaliplatin. CONCLUSIONS: RAD21 expression in CRC is associated with aggressive disease especially in KRAS mutant tumours and resistance to chemoradiotherapy. RAD21 may be an important novel therapeutic target.

The non-canonical Wnt ligand, Wnt5a, is upregulated and associated with epithelial to mesenchymal transition in epithelial ovarian cancer.

OBJECTIVE: Aberrant Wnt signalling has previously been associated with gynaecological cancers, and the aim of this study was to investigate the expression of Wnt5a in epithelial ovarian cancer, and clarify its role in activating or inhibiting ß-catenin dependent and independent Wnt signalling pathways. METHOD: Wnt5a expression was investigated in a large cohort of epithelial ovarian cancer patient samples using immunohistochemistry and correlated with clinicopathological variables. Wnt5a function was investigated in vitro in ovarian cell lines. RESULTS: Wnt5a expression was found to be upregulated in all major subtypes (serous, endometrioid, clear cell and mucinous) of epithelial ovarian cancer compared to borderline tumours and benign controls. Treatment of ovarian surface epithelial cells with recombinant Wnt5a decreased cell adhesion and was associated with increased epithelial to mesenchymal transition (EMT). In addition, downstream targets of ß-catenin dependent Wnt signalling were inhibited, and ß-catenin independent targets increased following Wnt5a upregulation. Knockdown of Wnt5a in ovarian cancer cells was associated with a mesenchymal to epithelial transition (MET), but had no significant effect on cell migration or proliferation. CONCLUSION: This study adds to the increasing evidence that Wnt signalling may play an important role in ovarian cancer development. Utilising an unparalleled large cohort of 623 patients, Wnt5a protein expression was shown to be significantly higher in ovarian cancer patients when compared to benign and borderline ovarian tumours and healthy control patients. In addition, we have utilised in vitro models to show for the first time in ovarian cancer that Wnt5a driven non-canonical pathways can alter epithelial to mesenchymal transition (EMT).

Polarization selection rules for inter-Landau-level transitions in epitaxial graphene revealed by the infrared optical Hall effect.

We report on the polarization selection rules of inter-Landau-level transitions using reflection-type optical Hall effect measurements from 600 to 4000 cm(-1) on epitaxial graphene grown by thermal decomposition of silicon carbide. We observe symmetric and antisymmetric signatures in our data due to polarization preserving and polarization mixing inter-Landau-level transitions, respectively. From field-dependent measurements, we identify that transitions in coupled graphene monolayers are governed by polarization mixing selection rules, whereas transitions in decoupled graphene monolayers are governed by polarization preserving selection rules. The selection rules may find explanation by different coupling mechanisms of inter-Landau-level transitions with free charge carrier magneto-optic plasma oscillations.

Bilayer graphene grown on 4H-SiC (0001) step-free mesas.

We demonstrate the first successful growth of large-area (200 × 200 µm(2)) bilayer, Bernal stacked, epitaxial graphene (EG) on atomically flat, 4H-SiC (0001) step-free mesas (SFMs) . The use of SFMs for the growth of graphene resulted in the complete elimination of surface step-bunching typically found after EG growth on conventional nominally on-axis SiC (0001) substrates. As a result heights of EG surface features are reduced by at least a factor of 50 from the heights found on conventional substrates. Evaluation of the EG across the SFM using the Raman 2D mode indicates Bernal stacking with low and uniform compressive lattice strain of only 0.05%. The uniformity of this strain is significantly improved, which is about 13-fold decrease of strain found for EG grown on conventional nominally on-axis substrates. The magnitude of the strain approaches values for stress-free exfoliated graphene flakes. Hall transport measurements on large area bilayer samples taken as a function of temperature from 4.3 to 300 K revealed an n-type carrier mobility that increased from 1170 to 1730 cm(2) V(-1) s(-1), and a corresponding sheet carrier density that decreased from 5.0 × 10(12) cm(-2) to 3.26 × 10(12) cm(-2). The transport is believed to occur predominantly through the top EG layer with the bottom layer screening the top layer from the substrate. These results demonstrate that EG synthesized on large area, perfectly flat on-axis mesa surfaces can be used to produce Bernal-stacked bilayer EG having excellent uniformity and reduced strain and provides the perfect opportunity for significant advancement of epitaxial graphene electronics technology.

Implementing a web-based oncology protocol system in Australia: evaluation of the first 3 years of operation.

BACKGROUND: EviQ is a web-based oncology protocol system launched across Australia in 2005 (http://www.eviq.org.au). We evaluated eviQ use at the point-of-care and determined the factors impacting on its uptake and routine use in the first three years of operation. METHODS: We conducted a suite of qualitative and quantitative studies with over 200 Australian oncology physicians, nurses and pharmacists working at treatment centres in diverse geographical locations. RESULTS: EviQ was part of routine care at many hospitals; however, the way in which it was used at the point-of-care varies according to clinician roles and hospital location. We identified a range of factors impacting on eviQ uptake and routine use. Infrastructure, such as availability of point-of-care computers, and formal policies endorsing eviQ are fundamental to increasing uptake. Furthermore, the level of clinical and computer experience of end-users, the attitudes and behaviour of clinicians, endorsement and promotion strategies, and level and type of eviQ education all need to be considered and managed to ensure that the system is being used to its full potential. CONCLUSION: Our findings show that the dissemination of web-based treatment protocols does not guarantee widespread use. Organisational, environmental and clinician-specific factors play a role in uptake and utilisation. The deployment of sufficient computer infrastructure, implementation of targeted training programmes and hospital policies and investment in marketing approaches are fundamental to uptake and continued use. This study highlights the value of ongoing monitoring and evaluation to ensure systems like eviQ achieve their primary purpose - reducing treatment variation and improving quality of care.

Positive spillover effects of prescribing requirements: increased cardiac testing in patients treated with trastuzumab for HER2+ metastatic breast cancer.

BACKGROUND: Cardiotoxicity is a concern in patients on trastuzumab therapy, and cardiac function assessment is a recommended practice. In 2006, trastuzumab was publically subsidised for human epidermal growth factor receptor-2 early stage breast cancer with a requirement for cardiac testing prior to and during treatment. AIM: To investigate the spillover effects of this requirement on testing rates in metastatic patients treated with trastuzumab where no monitoring requirements are applied. METHODS: We examined cardiac testing (echocardiography or multiple-gated acquisition scan) in 3779 women with metastatic breast cancer receiving trastuzumab between December 2001 and February 2010 and used interrupted time-series analyses to estimate changes in testing rates. The main outcome measures were the proportion of eligible patients, by quarter, receiving a cardiac function test pretreatment and during trastuzumab therapy. RESULTS: Only 21% of women had a cardiac function test pretreatment, and 47% were tested at some point during the first year of trastuzumab therapy. The introduction of mandatory cardiac testing for early breast cancer was associated with an immediate 8% increase (95% confidence interval, 2-14%) in pretreatment cardiac testing and an immediate 7% increase (95% confidence interval, 4-10%) in testing during therapy in metastatic patients. Testing rates during therapy increased steadily from early 2005, coinciding with the release of interim results from several trastuzumab trials reporting cardiac-safety outcomes. CONCLUSION: The introduction of mandatory cardiac testing for early stage disease spilled over to the metastatic setting. While deviation from guidelines may be warranted in some cases, this study suggests underutilisation of cardiac testing among patients treated with trastuzumab in the metastatic setting.

Governance approval for multisite, non-interventional research: what can Harmonisation of Multi-Centre Ethical Review learn from the New South Wales experience?

BACKGROUND: In 2007, New South Wales Health mandated the separation of ethical and scientific review from research governance at all New South Wales public health sites based on their distinction in the National Health and Medical Research Council National Statement. This separation allowed for single-site ethical review of multicentre studies. AIMS: To investigate the time taken for governance approval of multicentre studies through the site-specific approval (SSA) process. METHODS: A retrospective audit of the SSA process for five non-interventional studies proposed by a university cancer research unit. RESULTS: The median total governance approval time for all submissions (n= 28) was 12 weeks (range 2.5-64); median time from starting the SSA to submission was 8 weeks (range 1-48) and median time for governance approval was 5 weeks (range 0.3-40). Approval times were shorter for public compared to private institutions. Reasons for delays in finalising submissions for approval were the absence of institutional governance officers, lack of clarity regarding signatories, the need to identify a principal investigator employed by the institution, and lack of recognition of ethical approval by private institutions. The need to develop legal agreements between the university and hospital was the main reason for lengthy delays in obtaining approval. CONCLUSIONS: The advantages of a harmonised single ethical review process were undermined by the coexistence of a fragmented, complex and lengthy governance approval process. This experience has implications for the success of the national Harmonisation of Multi-Centre Ethical Review (HoMER) model. A harmonised and fully supported national approach to research governance should be developed contemporaneously with HoMER.

The quality of web-based oncology guidelines and protocols: how do international sites stack up?

BACKGROUND: The Internet is a popular medium for disseminating information relevant to oncology practitioners. Despite the widespread use of web-based guidelines and protocols, the quality of these resources has not been evaluated. This study addresses this gap. METHODS: The Appraisal of Guidelines for Research and Evaluation (AGREE-II) instrument was used to assess the quality of breast and sarcoma guidelines and protocols according to six independent domains. The oncology resources were selected from eight websites developed for healthcare settings in North America, the United Kingdom, Europe, and Australia. RESULTS: Mean quality scores across domains were highly variable for both guidelines (29-73%) and protocols (31-71%). Guidelines scored highly in terms of articulating their Scope and Purpose (72.6 ± 11.2%) but poorly with respect to Applicability in clinical practice (29.0 ± 17.3%). Protocols scored highly on Clarity of Presentation (70.6 ± 17.6%) but poorly in terms of the processes used to synthesise underlying evidence, develop, and update recommendations (30.8 ± 20.0%). CONCLUSION: Our evaluation provides a quick reference tool for clinicians about the strengths and limitations of oncology resources across several major websites. Further, it supports resource developers in terms of where to direct efforts to enhance guideline and protocol development processes or the communication of these processes to end-users.

The efficacy of HER2-targeted agents in metastatic breast cancer: a meta-analysis.

BACKGROUND: The addition of HER2-targeted agents to standard treatment has been shown to improve outcomes for HER2 positive metastatic breast cancer patients. We undertook a meta-analysis to evaluate the efficacy of HER2-targeted therapy in addition to standard treatment in metastatic breast cancer patients. PATIENTS AND METHODS: Eligible trials were randomised controlled trials (RCTs) comparing the addition of HER2 therapy to standard treatment (hormone or chemotherapy) reporting overall survival (OS), time to progression (TTP), progression-free survival (PFS) and/or response rates. RESULTS: Eight trials comprising 1848 patients were eligible for inclusion. HER2-targeted agents were trastuzumab and lapatinib and therapeutic partners were taxanes (4 RCTs), anthracyclines (1), capecitabine (2), anastrozole (1) and letrozole (1). The addition of HER2-targeted agents improved OS [hazard ratios (HR) 0.78; 95% confidence interval (CI) 0.67-0.91], TTP (HR 0.56; 95% CI 0.48-0.64), PFS (HR 0.63; 95% CI 0.53-0.74) and overall response rate (relative risk 1.67; 95% CI 1.46-1.90). CONCLUSIONS: Our meta-analysis confirms the benefit of adding HER2-targeted therapy to standard treatment in HER2 positive metastatic breast cancer. Compared with OS, TTP, PFS and ORR overestimate treatment benefit. Trials in our meta-analysis differed in terms of partner drug or HER2 agents, yet delivered comparable outcomes.

Second primary colorectal cancers (SPCRCs): experiences from a large Australian Cancer Registry.

BACKGROUND: We examined the rate of second primary colorectal cancer (SPCRC) in a cohort of 29 471 patients first diagnosed with colorectal cancer (CRC) from 1987 to 1996, in New South Wales (NSW), Australia. METHODS: The 5-year age group, date and site of first and subsequent CRC diagnoses as well as death dates were obtained from the NSW Central Cancer Registry. The time to SPCRC and standardised incidence ratios (SIRs) were generated. RESULTS: Six hundred and sixty patients (2.1%) developed SPCRCs and the cumulative incidence at 18 years was 5.5%, 95% confidence interval (CI) 4.9% to 6.3%. The risk of SPCRC was increased in patients with a CRC history compared with the general population (SIR = 1.5, 95% CI 1.4-1.6) and inversely related to age at first diagnosis (30-49 years, SIR = 5.1, 95% CI 3.6-7.1 versus >/=80 years, SIR = 1.1, 95% CI 0.9-1.4). The excess absolute risk of SPCRC was greater for females aged 50-69 years at first diagnosis than for males in the same age group. SPCRC was also increased in individuals with right-sided first primaries (SIR = 2.0, 95% CI 1.6-2.4). CONCLUSIONS: The SPCRC rate was increased during the first 5 years after first diagnosis but remained increased for up to 10 years in females, in patients with right-sided cancers and in patients <60 years at first diagnosis. These findings support active surveillance up to 10 years in these risk groups.

Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome characterised by a predisposition to early onset colorectal, endometrial and other cancers. The tumours typically exhibit microsatellite instability due to defective mismatch repair. HNPCC is classically caused by heterozygous loss-of-function mutations within the mismatch repair genes MLH1, MSH2, MSH6 and PMS2, but no pathogenic mutations are identified in a third of cases. In recent years, constitutional epimutations of the MLH1 gene, characterised by soma-wide allele specific promoter methylation and transcriptional silencing, have been identified in a handful of mutation negative HNPCC cases. In contrast to genetic mutations, MLH1 epimutations are reversible between generations and thus display non-Mendelian inheritance. This review focuses on the aetiological role of constitutional MLH1 epimutations in the development of HNPCC related cancers. The molecular characteristics, clinical ramifications and potential mechanism underlying this defect are discussed. Recommendations for the selection of cases warranting screening for MLH1 epimutations are proffered.

Demographic, social and lifestyle risk factors for cancer registry-notified cancer of unknown primary site (CUP).

BACKGROUND: Little is known about the risk factors for cancer of unknown primary site (CUP). We examined the demographic, social and lifestyle risk factors for CUP in a prospective cohort of 266,724 people aged 45 years and over in New South Wales, Australia. METHODS: Baseline questionnaire data were linked to cancer registration, hospitalisation, emergency department admission, and mortality data. We compared individuals with incident cancer registry-notified CUP (n = 327) to two sets of controls randomly selected (3:1) using incidence density sampling with replacement: (i) incident cancer registry-notified metastatic cancer of known primary site (n = 977) and (ii) general cohort population (n = 981). We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In a fully adjusted model incorporating self-rated overall health and comorbidity, people diagnosed with CUP were more likely to be older (OR 1.05, 95% CI 1.04-1.07 per year) and more likely to have low educational attainment (OR 1.77, 95% CI 1.24-2.53) than those diagnosed with metastatic cancer of known primary. Similarly, compared to general cohort population controls, people diagnosed with CUP were older (OR 1.10, 95% CI 1.08-1.12 per year), of low educational attainment (OR 1.69, 95% CI 1.08-2.64), and current (OR 3.42, 95% CI 1.81-6.47) or former (OR 1.95, 95% CI 1.33-2.86) smokers. CONCLUSION: The consistent association with educational attainment suggests low health literacy may play a role in CUP diagnosis. These findings highlight the need to develop strategies to achieve earlier identification of diagnostically challenging malignancies in people with low health literacy.

Health-related predictors of cancer registry-notified cancer of unknown primary site (CUP).

BACKGROUND: The relationship between comorbid disease and health service use and risk of cancer of unknown primary site (CUP) is uncertain. METHODS: A prospective cohort of 266,724 people aged 45 years and over in New South Wales, Australia. Baseline questionnaire data were linked to cancer registration, health service records 4-27 months prior to diagnosis, and mortality data. We compared individuals with incident registry-notified CUP (n = 327; 90% C80) to two sets of randomly selected controls (3:1): (i) incident metastatic cancer of known primary site (n = 977) and (ii) general cohort population (n = 981). We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In fully adjusted models incorporating sociodemographic and lifestyle factors, people with cancer registry-notified CUP were more likely to have fair compared with excellent self-rated overall health (OR 1.78, 95% CI 1.01-3.14) and less likely to self-report anxiety (OR 0.48, 95% CI 0.24-0.97) than those registered with metastatic cancer of known primary. Compared to general cohort population controls, people registered with CUP were more likely to have poor rather than excellent self-rated overall health (OR 6.22, 95% CI 1.35-28.6), less likely to self-report anxiety (OR 0.28, 95% CI 0.12-0.63), and more likely to have a history of diabetes (OR 1.89, 95% CI 1.15-3.10) or cancer (OR 1.62, 95% CI 1.03-2.57). Neither tertiary nor community-based health service use independently predicted CUP risk. CONCLUSION: Low self-rated health may be a flag for undiagnosed cancer, and an investigation of its clinical utility in primary care appears warranted.

Reduced nuclear DNA methylation and mitochondrial transcript changes in adenomas do not associate with mtDNA methylation.

BACKGROUND: Altered mitochondrial function and large-scale changes to DNA methylation patterns in the nuclear genome are both hallmarks of colorectal cancer (CRC). Mitochondria have multiple copies of a 16 kb circular genome that contains genes that are vital for their function. While DNA methylation is known to alter the nuclear genome in CRC, it is not clear whether it could have a similar influence in mtDNA; indeed, currently, the issue of whether mitochondrial genome (mtDNA) methylation occurs is controversial. Thus our goal here was to determine whether the methylation state of mtDNA is linked to mitochondrial gene transcription in colorectal adenomas, and to assess its suitability as a biomarker in CRC. METHODS: To investigate the relationship between DNA methylation and mitochondrial transcripts in adenomas, we performed RNA-sequencing and Whole Genome Bisulphite Sequencing (WGBS) of mtDNA-enriched DNA from normal mucosa and paired adenoma patient samples. RESULTS: Transcriptional profiling indicated that adenomas had reduced mitochondrial proton transport versus normal mucosa, consistent with altered mitochondrial function. The expression of 3 tRNAs that are transcribed from mtDNA were also decreased in adenoma. Overall methylation of CG dinucleotides in the nuclear genome was reduced in adenomas (68%) compared to normal mucosa (75%, P < 0.01). Methylation in mtDNA was low (1%) in both normal and adenoma tissue but we observed clusters of higher methylation at the ribosomal RNA genes. Levels of methylation within these regions did not differ between normal and adenoma tissue. CONCLUSIONS: We provide evidence that low-level methylation of specific sites does exist in the mitochondrial genome but that it is not associated with mitochondrial gene transcription changes in adenomas. Furthermore, as no large scale changes to mtDNA methylation were observed it is unlikely to be a suitable biomarker for early-stage CRC.

A robust single-beam optical trap for a gram-scale mechanical oscillator.

Precise optical control of microscopic particles has been mastered over the past three decades, with atoms, molecules and nano-particles now routinely trapped and cooled with extraordinary precision, enabling rapid progress in the study of quantum phenomena. Achieving the same level of control over macroscopic objects is expected to bring further advances in precision measurement, quantum information processing and fundamental tests of quantum mechanics. However, cavity optomechanical systems dominated by radiation pressure - so-called 'optical springs' - are inherently unstable due to the delayed dynamical response of the cavity. Here we demonstrate a fully stable, single-beam optical trap for a gram-scale mechanical oscillator. The interaction of radiation pressure with thermo-optic feedback generates damping that exceeds the mechanical loss by four orders of magnitude. The stability of the resultant spring is robust to changes in laser power and detuning, and allows purely passive self-locking of the cavity. Our results open up a new way of trapping and cooling macroscopic objects for optomechanical experiments.

Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polyps and serrated adenomas.

BACKGROUND: Microsatellite instability (MSI) is seen in 10%-15% of sporadic colorectal cancers mostly in the right colon, but the precursors of cancers with MSI remain unknown. We examined whether sporadic cancers with MSI arise from pre-existing benign proliferative lesions (such as hyperplastic polyps or serrated adenomas [together denoted as "serrated polyps"]). METHODS: The frequency of benign epithelial lesions (serrated polyps and conventional adenomas) was determined by histologic review of resection specimens from individuals (n = 29) with sporadic colorectal cancer with MSI and from a matched control group (n = 29) with cancer showing microsatellite stability (MSS). MSI status, expression of mismatch repair enzyme (product of the human mut-L homologue 1 [hMLH1] gene), and hMLH1 gene promoter methylation in the benign lesions were determined. Data were analyzed by the chi-square test, by Wilcoxon's rank-sum test, and by conditional logistic regression as appropriate, and a two-sided probability less than.05 was considered to be statistically significant. RESULTS: Individuals with cancers showing MSI were more likely to harbor at least one serrated polyp than individuals with cancers showing MSS (odds ratio = 4.0; 95% confidence interval = 1.1 to 14.2; P =.03), but the frequency of conventional adenomas was the same in both groups (P =.52, Mann-Whitney test). Loss of hMLH1 protein expression was seen in lesions from 10 of 13 patients with MSI, but no loss was seen in lesions from four patients with MSS (P =.02, Fisher's exact test). Loss of hMLH1 protein expression was associated with MSI in assessable lesions. The hMLH1 promoter was methylated in all assessable serrated polyps from patients with cancers showing MSI but in none of the lesions from patients with MSS cancers. CONCLUSIONS: Some right-sided hyperplastic polyps may give rise to sporadic colorectal carcinomas with MSI. Methylation of the hMLH1 gene promoter within neoplastic cell subpopulations may be a critical step in the progression to carcinoma. The frequency with which benign lesions progress to cancer with MSI is unknown.