Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s.

We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (BAP1) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies).

A multiplex immunoassay for the non-invasive detection of bladder cancer.

BACKGROUND: Urine based assays that can non-invasively detect bladder cancer (BCa) have the potential to reduce unnecessary and invasive procedures. The purpose of this study was to develop a multiplex immunoassay that can accurately and simultaneously monitor ten diagnostic urinary protein biomarkers for application as a non-invasive test for BCa detection. METHODS: A custom electrochemiluminescent multiplex assay was constructed (Meso Scale Diagnostics, LLC, Rockville, MD, USA) to detect the following urinary proteins; IL8, MMP9, MMP10, ANG, APOE, SDC1, A1AT, PAI1, CA9 and VEGFA. Voided urine samples from two cohorts were collected prior to cystoscopy and samples were analyzed blinded to the clinical status of the participants. Means (±SD) and receiver operating characteristic (ROC) curve analysis were used to compare assay performance and to assess the diagnostic accuracy of the diagnostic signature. RESULTS: Comparative diagnostic performance analyses revealed an AUROC value of 0.9258 for the multiplex assay and 0.9467 for the combination of the single-target ELISA assays (p = 0.625), so there was no loss of diagnostic utility for the MSD multiplex assay. Analysis of the independent 200-sample cohort using the multiplex assay achieved an overall diagnostic sensitivity of 0.85, specificity of 0.81, positive predictive value 0.82 and negative predictive value 0.84. CONCLUSIONS: It is technically feasible to simultaneously monitor complex urinary diagnostic signatures in a single assay without loss of performance. The described protein-based assay has the potential to be developed for the non-invasive detection of BCa.

History, pelvic examination findings and mobility of ovaries as a sonographic marker to detect pelvic adhesions with fixed ovaries.

AIM: To compare the performance of history and examination findings combined with transvaginal ultrasound (TVS) 'soft marker' evaluation of ovarian mobility for the prediction of fixed ovaries secondary to endometriosis at laparoscopy. METHODS: This was a prospective observational study performed at the University Gynecology unit, National Hospital of Colombo Sri Lanka. Women who were scheduled for laparoscopic assessment of their pelvis to investigate subfertility or chronic pelvic pain were enrolled. All women underwent history evaluation for dysmenorrhea and dyspareunia, vaginal examination and detailed presurgical TVS. TVS was used to assess 'soft marker' of ovarian mobility. 'Fixed' ovaries on ultrasound were defined as one or other of the ovaries being fixed or adherent to the internal iliac artery or pelvic sidewall laterally or to the uterus medially. These findings were compared with 'fixed' ovaries confirmed at laparoscopy. RESULTS: A total of 106 patients were analyzed. Mean age was 33.3 years (standard deviation, 5.1). Sensitivity, specificity, positive and negative predictive values of each of the screening methods against laparoscopy in detecting endometriosis were as follows: dyspareunia, 45.9%, 76.8%, 51.5% and 72.6%; dysmenorrhea, 75.7%, 69.6%, 57.1% and 84.2%; positive vaginal examination, 73%, 88.4%, 77.1% and 85.9%; fixed ovaries with TVS, 78.4%, 94.2%, 87.9% and 89%; and a combination of history, examination findings and detection of fixed ovaries in TVS, 91.9%, 60.9%, 55.7% and 93.3%, respectively. CONCLUSION: A combination of clinical and TVS-based 'soft marker' of ovarian mobility provides a valid method for identifying fixed ovaries secondary to endometriosis.

BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs.

BACKGROUND: BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene located on chromosome 3p21. Germline BAP1 mutations have been recently associated with an increased risk of malignant mesothelioma, atypical melanocytic tumors and other neoplasms. To answer the question if different germline BAP1 mutations may predispose to a single syndrome with a wide phenotypic range or to distinct syndromes, we investigated the presence of melanocytic tumors in two unrelated families (L and W) with germline BAP1 mutations and increased risk of malignant mesothelioma. METHODS: Suspicious cutaneous lesions were clinically and pathologically characterized and compared to those present in other families carrying BAP1 mutations. We then conducted a meta-analysis of all the studies reporting BAP1-mutated families to survey cancer risk related to the germline BAP1 mutation (means were compared using t-test and proportions were compared with Pearson χ2 test or two-tailed Fisher's exact test). RESULTS: Melanocytic tumors: of the five members of the L family studied, four (80%) carried a germline BAP1 mutation (p.Gln684*) and also presented one or more atypical melanocytic tumors; of the seven members of W family studied, all carried a germline BAP1 mutation (p.Pro147fs*48) and four of them (57%) presented one or more atypical melanocytic tumors, that we propose to call "melanocytic BAP1-mutated atypical intradermal tumors" (MBAITs). Meta-analysis: 118 individuals from seven unrelated families were selected and divided into a BAP1-mutated cohort and a BAP1-non-mutated cohort. Malignant mesothelioma, uveal melanoma, cutaneous melanoma, and MBAITs prevalence was significantly higher in the BAP1-mutated cohort (p ≤ 0.001). CONCLUSIONS: Germline BAP1 mutations are associated with a novel cancer syndrome characterized by malignant mesothelioma, uveal melanoma, cutaneous melanoma and MBAITs, and possibly by other cancers. MBAITs provide physicians with a marker to identify individuals who may carry germline BAP1 mutations and thus are at high risk of developing associated cancers.

The Werner's Syndrome RecQ helicase/exonuclease at the nexus of cancer and aging.

Werner's Syndrome (WS) or adult-onset progeria is an autosomal recessive disorder of accelerated aging caused by mutations of the DNA RecQ helicase/exonuclease (WRN). WRN is an ATP-dependent helicase with 3' to 5' DNA exonuclease activity that regulates the replicative potential of dividing cells, and WRN loss-of-function mutations promote cellular senescence and neoplastic transformation. These molecular findings translate clinically into adult-onset progeria manifested by premature hair graying, dermal atrophy, cardiovascular disease, and cancer predilection along with a markedly reduced life expectancy. Recently, a patient with WS who developed pancreatic adenocarcinoma was identified in Honolulu suggesting a significant prevalence of loss-of-function WRN mutations in Hawaii's Japanese-American population. Based upon the indigenous Japanese WRN loss-of-function mutation heterozygote rate of 6 per 1,000, we speculate the possibility of approximately 1,200 heterozygotes in Hawaii. Our ongoing studies aim to evaluate Hawaii's true allelic prevalence of WRN loss-of-function mutations in the Japanese-American population, and the role of WRN silencing in sporadic cancers. In summary, WRN plays a nexus-like role in the complex interplay of cellular events that regulate aging, and analysis of WRN polymorphisms in Hawaii's population will generate novel insights to advance care for age-related pathologies.

Serum micro-RNA Identifies Early Stage Colorectal Cancer in a Multi-Ethnic Population.

OBJECTIVE: Certain microRNAs (miR) have been previously described to be dysregulated in cancers and can be detected in blood samples. Studies examining the utility of miRs for colon cancer screening have primarily been performed in ethnically homogeneous groups of patients, thus the performance of miRs in multiethnic populations is unknown. METHODS: Four miRs were selected that were shown to be aberrantly expressed in the blood or stool of patients with colorectal cancer (CRC) of various ethnicities. In this study, the ability of these miRs to discern early stage CRC was determined in a previously untested multiethnic population of 73 CRC cases and 18 controls. RESULTS: The ratios of non-vesicular to extracellular vesicular levels of miR's -21, -29a, and -92a were statistically and quantitatively related to CRC stage compared to controls. CONCLUSION: Serum levels of miR-21, miR-29a and miR-92a were able to significantly detect early stage CRC in a multiethnic and previously untested population.
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Acetonitrile based single step slot-die compatible perovskite ink for flexible photovoltaics.

The demonstration of photovoltaic devices with high power conversion efficiencies using low cost perovskite materials hints at the possibility of dramatically lowering the cost of solar energy. Key to further exploiting the potential of these materials is developing rapid processing techniques that can be used to deliver lower cost high throughput manufacture. This work details the development of low viscosity rapid drying perovskite formulations designed to give high quality solar films when slot-die coated on flexible roll-to-roll compatible substrates. A single step slot-die compatible perovskite ink based on an acetonitrile/methylamine solvent system utilizing a chloride additive is developed, resulting in large area perovskite films from slot-die coating under ambient conditions. The drying conditions for the perovskite film are optimized and fast (<10 min), low temperature (<120 °C) drying of slot-die coated films on flexible substrates are demonstrated and result in high performance devices.

Crowd medical services in the English Football League: remodelling the team for the 21st century using a realist approach.

OBJECTIVES: To evaluate the new model of providing care based on demand. This included reconfiguration of the workforce to manage workforce supply challenges and meet demand without compromising the quality of care. DESIGN: Currently the Sports Ground Safety Authority recommends the provision of crowd medical cover at English Football League stadia. The guidance on provision of services has focused on extreme circumstances such as the Hillsborough disaster in 1989, while the majority of demand on present-day services is from patients with minor injuries, exacerbations of injuries and pre-existing conditions. A new model of care was introduced in the 2009/2010 season to better meet demand. A realist approach was taken. Data on each episode of care were collected over 14 consecutive football league seasons at Millwall FC divided into two periods, preimplementation of changes and postimplementation of changes. Data on workforce retention and volunteer satisfaction were also collected. SETTING: The data were obtained from one professional football league team (Millwall FC) located in London, UK. PRIMARY AND SECONDARY OUTCOMES: The primary outcome was to examine the demand for crowd medical services. The secondary outcome was to remodel the service to meet these demands. RESULTS: In total, 981 episodes of care were recorded over the evaluation period of 14 years. The groups presenting, demographic and type of presentation did not change over the evaluation. First aiders were involved in 87.7% of episodes of care, nurses in 44.4% and doctors 17.8%. There was a downward trend in referrals to hospital. Workforce feedback was positive. CONCLUSIONS: The new workforce model has met increased service demands while reducing the number of referrals to acute care. It involves the first aid workforce in more complex care and key decision-making and provides a flexible registered healthcare professional team to optimise the skill mix of the team.

Improved Manufacturing Performance of Screen Printed Carbon Electrodes through Material Formulation.

Printed carbon graphite materials are the primary common component in the majority of screen printed sensors. Screen printing allows a scalable manufacturing solution, accelerating the means by which novel sensing materials can make the transition from laboratory material to commercial product. A common bottleneck in any thick film printing process is the controlled drying of the carbon paste material. A study has been undertaken which examines the interaction between material solvent, printed film conductivity and process consistency. The study illustrates that it is possible to reduce the solvent boiling point to significantly increase process productivity while maintaining process consistency. The lower boiling point solvent also has a beneficial effect on the conductivity of the film, reducing the sheet resistance. It is proposed that this is a result of greater film stressing increasing charge percolation through greater inter particle contact. Simulations of material performance and drying illustrate that a multi layered printing provides a more time efficient manufacturing method. The findings have implications for the volume manufacturing of the carbon sensor electrodes but also have implications for other applications where conductive carbon is used, such as electrical circuits and photovoltaic devices.

Werner syndrome through the lens of tissue and tumour genomics.

Werner syndrome (WS) is the canonical adult human progeroid ('premature aging') syndrome. Patients with this autosomal recessive Mendelian disorder display constitutional genomic instability and an elevated risk of important age-associated diseases including cancer. Remarkably few analyses of WS patient tissue and tumors have been performed to provide insight into WS disease pathogenesis or the high risk of neoplasia. We used autopsy tissue from four mutation-typed WS patients to characterize pathologic and genomic features of WS, and to determine genomic features of three neoplasms arising in two of these patients. The results of these analyses provide new information on WS pathology and genomics; provide a first genomic characterization of neoplasms arising in WS; and provide new histopathologic and genomic data to test several popular models of WS disease pathogenesis.

Proteomic evaluation of archival cytologic material using SELDI affinity mass spectrometry: potential for diagnostic applications.

Proteomic studies of cells via surface-enhanced laser desorption/ionization spectrometry (SELDI) analysis have enabled rapid, reproducible protein profiling directly from crude samples. We applied this technique to archival cytology material to determine whether distinct, reproducible protein fingerprints could be identifiedfor potential diagnostic purposes in blinded specimens. Rapid Romanowsky-stained cytocentrifuged specimens from fine-needle aspirates of metastatic malignant melanoma (with both known cutaneous primary and unknown primary sites), clear cell sarcoma, and renal cell carcinoma and reactive effusions were examined using the SELDI technology. A unique characteristic fingerprint was identified for each disease entity. Fifteen "blinded" unknown samples then were analyzed. When the protein profilefingerprints were plotted against the known fingerprints for the aforementioned diagnoses, the appropriate match or diagnosis was obtained in 13 (87%) of 15 cases. These preliminary findings suggest a substantial potential for SELDI applications to specific pathologic diagnoses.

Cost-effective violence prevention through targeted family interventions.

Efforts in violence prevention can focus on individual youth, their families, their schools, or the communities in which they live. Among the small number of program models that have been proven effective in repeated replications, those that focus on improving family management and child care have been found to be the most cost-effective. The four model programs include Nurse Home Visitation, Functional Family Therapy, Multi-systemic Therapy, and Multidimensional Foster Care. All of these programs involve detailed protocols, extensive staff training and supervision, and quality-assurance procedures. The factors limiting their wider adoption include staff resistance to their structured approach, cost-sharing issues between local and state levels of government, and the political power of existing programs.

Implementing and sustaining evidence-based practice in juvenile justice: a case study of a rural state.

US juvenile justice is at the forefront of experimentation with the evidence-based paradigm, whereby the best available research is utilized to help inform more rational and effective practice. Increasingly, state governments are playing a major role in this endeavor. Maine is one of these states and is the focus of this article. Using a case-study design, we set out to develop a fuller understanding of the events and processes that have contributed to the development, implementation, and sustainment of evidence-based practice in juvenile justice in the state. Four major themes emerged. First, Maine has benefited from strong and lasting leadership within its corrections department. These leaders paved the way for the implementation and sustainment of programs, including finding innovative ways to use existing resources. Second, the adoption of the Risk-Need-Responsivity model was important in laying the groundwork for the use of evidence-based programming. Third, collaborations within and among state agencies and public and private groups were essential. Finally, buy-in and support from multiple stakeholders was and continues to be essential to Maine's work. Ongoing problems remain with respect to ensuring agencies prioritize fidelity to the model and locating increasingly scarce funding. Implications for other states are discussed.

A transparent conductive adhesive laminate electrode for high-efficiency organic-inorganic lead halide perovskite solar cells.

A self-adhesive laminate solar-cell electrode is presented based on a metal grid embedded in a polymer film (x-y conduction) and set in contact with the active layer using a pressure-sensitive adhesive containing a very low quantity (1.8%) of organic conductor, which self-organizes to provide z conduction to the grid. This ITO-free material performs in an identical fashion to evaporated gold in high-efficiency perovskite solar cells.

Field histology: Point-of-care microscopic technique.

CONTEXT: Standard histology services in geographically remote areas are often not available or have long turn-around time, resulting in delayed diagnosis or inappropriate treatment due to incomplete diagnostic data. The use of rapid tissue processing and a portable microtome technique may offer timely, point-of-care histologic diagnosis to patients in a low resources setting, such as medical missions. OBJECTIVE: To present an alternative to the conventional histologic processing that will permit point-of-care histopathology service. DESIGN: A total of 21 tissue samples from a variety of sites were collected and subjected to a protocol of rapid manual tissue processing, lightweight portable field microtome sectioning, and hematoxylin-eosin staining. The histologic preparations were evaluated for diagnostic quality. The scoring of the preparations was based on completeness and uniformity of the sections, integrity of architectural features, cytologic detail, staining quality, and overall adequacy for diagnosis. RESULTS: Diagnostic quality microscopic slides were obtained from each of the 21 samples that included lesions of the skin, uterus, colon, and breast. The average preparation time, including routine hematoxylin-eosin staining, was 1.5 hours. CONCLUSIONS: We validated a point-of-care field histology technique that will be useful in settings of low resources, such as medical missions. Actual field testing of the procedure with special staining for fungi and acid-fast bacilli is the next step in the validation of the methodology.

Prevention and intervention programs for juvenile offenders.

Over the past decade researchers have identified intervention strategies and program models that reduce delinquency and promote pro-social development. Preventing delinquency, says Peter Greenwood, not only saves young lives from being wasted, but also prevents the onset of adult criminal careers and thus reduces the burden of crime on its victims and on society. It costs states billions of dollars a year to arrest, prosecute, incarcerate, and treat juvenile offenders. Investing in successful delinquency-prevention programs can save taxpayers seven to ten dollars for every dollar invested, primarily in the form of reduced spending on prisons. According to Greenwood, researchers have identified a dozen "proven" delinquency-prevention programs. Another twenty to thirty "promising" programs are still being tested. In his article, Greenwood reviews the methods used to identify the best programs, explains how program success is measured, provides an overview of programs that work, and offers guidance on how jurisdictions can shift toward more evidence-based practices The most successful programs are those that prevent youth from engaging in delinquent behaviors in the first place. Greenwood specifically cites home-visiting programs that target pregnant teens and their at-risk infants and preschool education for at-risk children that includes home visits or work with parents. Successful school-based programs can prevent drug use, delinquency, anti-social behavior, and early school drop-out. Greenwood also discusses community-based programs that can divert first-time offenders from further encounters with the justice system. The most successful community programs emphasize family interactions and provide skills to the adults who supervise and train the child. Progress in implementing effective programs, says Greenwood, is slow. Although more than ten years of solid evidence is now available on evidence-based programs, only about 5 percent of youth who should be eligible participate in these programs. A few states such as Florida, Pennsylvania, and Washington have begun implementing evidence-based programs. The challenge is to push these reforms into the mainstream of juvenile justice.

An analysis of use of crowd medical services at an English football league club.

AIM: Although crowd medical services in English league football are common, there is little data examining the use of such services. The aim of this study was to provide detailed data by examining the usage of the Crowd Medical Service at a First Division Football Club (Millwall FC) over six Football League seasons. This usage has implications in terms of resources, provision of level of service and training needs of staff. METHODS: A prospective data collection form was designed and used to capture all episodes of care over the length of six football league seasons, each approximately 9 months in duration which resulted in a census of activity. This included episodes that did not normally require detailed documentation for statutory purposes, such as informal advice. RESULTS: There were 445 episodes of care recorded over 146 home games. Over six years presentation was consistent. This gives a mean of 3.14 episodes per game (2.7-4.1). There is little research in this area and so it is difficult to compare uptake with other clubs. The episodes of care were broadly grouped into medical (67.0%) or injury (33.0%). Most of those presenting did so with non-emergent (pre-existing) medical problems or minor injuries. Staff (for example Stewards) made up 44% of consultations. One hundred and eight people had a primary and secondary reason for presenting. Such episodes are more time consuming and in turn have an impact on resources. Some stated they had presented because of ease of access to the service, they found access to their General Practitioner (GP) difficult or were not registered with a GP at all. CONCLUSION: The principal focus of a crowd medical service is to manage a major incident and medically emergent spectators. The majority of presentations were minor injuries and pre-existing medical conditions. In addition staff make up a significant proportion of the users. Some re-focussing of guidance is therefore necessary if these results are typical of English League Football. In turn this reflects a need for more education in the management of minor injuries and chronic disease management and recognition in training and service provision.

Aggregation of nanosized colloidal silica in the presence of various alkali cations investigated by the electrospray technique.

The slow aggregation process of a concentrated silica dispersion (Bindzil 40/220) in the presence of alkali chlorides (LiCl, NaCl, KCl, RbCl, and CsCl) was investigated by means of mobility measurements. At intervals during the aggregation, particles and aggregates were transferred from the liquid phase to the gas phase via electrospray (ES) and subsequently size selected and counted using a scanning mobility particle sizer (SMPS). This method enables the acquisition of particle and aggregate size distributions with a time resolution of minutes. To our knowledge, this is the first time that the method has been applied to study the process of colloidal aggregation. The obtained results indicate that, independent of the type of counterion, a sufficient dilution of the formed gel will cause the particles to redisperse. Hence, the silica particles are, at least initially, reversibly aggregated. The reversibility of the aggregation indicates additional non-DLVO repulsive steric interactions that are likely due to the presence of a gel layer at the surface. The size of the disintegrating aggregates was monitored as a function of the time after dilution. It was found that the most stable aggregates were formed by the ions that adsorb most strongly on the particle surface. This attractive effect was ascribed to an ion-ion correlation interaction.