Ultra-low threshold CW Triply Resonant OPO in the near infrared using Periodically Poled Lithium Niobate

We have operated a CW triply resonant OPO using a PPLN crystal pumped by a Nd:YAG laser at 1.06 micron and generating signal and idler modes in the 2-2.3 micron range. The OPO was operated stably in single mode operation over large periods of time with a pump threshold as low as 500 microwatts.Comment: 7 pages, 5 figures, submitted to JEOS

A 750 mW, continuous-wave, solid-state laser source at 313 nm for cooling and manipulating trapped 9Be+ ions

We present a solid-state laser system that generates 750 mW of continuous-wave single-frequency output at 313 nm. Sum-frequency generation with fiber lasers at 1550 nm and 1051 nm produces up to 2 W at 626 nm. This visible light is then converted to UV by cavity-enhanced second-harmonic generation. The laser output can be tuned over a 495 GHz range, which includes the 9Be+ laser cooling and repumping transitions. This is the first report of a narrow-linewidth laser system with sufficient power to perform fault-tolerant quantum-gate operations with trapped 9Be+ ions by use of stimulated Raman transitions.Comment: 9 pages, 4 figure

Revision of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis Classification Schema for Melanocytic Lesions: A Consensus Statement

IMPORTANCE A standardized pathology classification system for melanocytic lesions is needed to aid both pathologists and clinicians in cataloging currently existing diverse terminologies and in the diagnosis and treatment of patients. The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) has been developed for this purpose. OBJECTIVE To revise the MPATH-Dx version 1.0 classification tool, using feedback from dermatopathologists participating in the National Institutes of Health-funded Reducing Errors in Melanocytic Interpretations (REMI) Study and from members of the International Melanoma Pathology Study Group (IMPSG). EVIDENCE REVIEW Practicing dermatopathologists recruited from 40 US states participated in the 2-year REMI study and provided feedback on the MPATH-Dx version 1.0 tool. Independently, member dermatopathologists participating in an IMPSG workshop dedicated to the MPATH-Dx schema provided additional input for refining the MPATH-Dx tool. A reference panel of 3 dermatopathologists, the original authors of the MPATH-Dx version 1.0 tool, integrated all feedback into an updated and refined MPATH-Dx version 2.0. FINDINGS The new MPATH-Dx version 2.0 schema simplifies the original 5-class hierarchy into 4 classes to improve diagnostic concordance and to provide more explicit guidance in the treatment of patients. This new version also has clearly defined histopathological criteria for classification of classes I and II lesions; has specific provisions for the most frequently encountered low-cumulative sun damage pathway of melanoma progression, as well as other, less common World Health Organization pathways to melanoma; provides guidance for classifying intermediate class II tumors vs melanoma; and recognizes a subset of pT1a melanomas with very low risk and possible eventual reclassification as neoplasms lacking criteria for melanoma. CONCLUSIONS AND RELEVANCE The implementation of the newly revised MPATH-Dx version 2.0 schema into clinical practice is anticipated to provide a robust tool and adjunct for standardized diagnostic reporting of melanocytic lesions and management of patients to the benefit of both health care practitioners and patients

InterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma

We are conducting a multicenter study to identify classifiers predictive of disease-specific survival in patients with primary melanomas. Here we delineate the unique aspects, challenges, and best practices for optimizing a study of generally small-sized pigmented tumor samples including primary melanomas of at least 1.05mm from AJTCC TNM stage IIA-IIID patients. We also evaluated tissue-derived predictors of extracted nucleic acids’ quality and success in downstream testing. This ongoing study will target 1,000 melanomas within the international InterMEL consortium.Medicin

Therapy-induced tumour secretomes promote resistance and tumour progression.

Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafenib is driven by downregulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and the PI(3)K/AKT/mTOR intracellular signalling pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant human melanoma, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy

The effect of bovine colostrum supplementation on intestinal injury and circulating intestinal bacterial DNA following exercise in the heat

Purpose Exercise-induced changes in intestinal permeability are exacerbated in the heat. The aim of this study was to determine the effect of 14 days of bovine colostrum (Col) supplementation on intestinal cell damage (plasma intestinal fatty acid-binding protein, I-FABP) and bacterial translocation (plasma bacterial DNA) following exercise in the heat. Methods In a double-blind, placebo-controlled, crossover design, 12 males completed two experimental arms (14 days of 20 g/day supplementation with Col or placebo, Plac) consisting of 60 min treadmill running at 70% maximal aerobic capacity (30 ??C, 60% relative humidity). Blood samples were collected pre-exercise (Pre-Ex), post-exercise (Post-Ex) and 1 h post-exercise (1 h Post-Ex) to determine plasma I-FABP concentration, and bacterial DNA (for an abundant gut species, Bacteroides). Results Two-way repeated measures ANOVA revealed an arm ?~ time interaction for I-FABP (P = 0.005, with greater Post- Ex increase in Plac than Col, P = 0.01: Plac 407 ?} 194% of Pre-Ex vs Col, 311 ?} 134%) and 1 h Post-Ex (P = 0.036: Plac 265 ?} 80% of Pre-Ex vs Col, 229 ?} 56%). There was no interaction (P = 0.904) but there was a main effect of arm (P = 0.046) for plasma Bacteroides/total bacterial DNA, with lower overall levels evident in Col. Conclusion This is the first investigation to demonstrate that Col can be effective at reducing intestinal injury following exercise in the heat, but exercise responses (temporal pattern) of bacterial DNA were not influenced by Col (although overall levels may be lower).publishersversionPeer reviewe

Somatic p16INK4a loss accelerates melanomagenesis

Loss of p16INK4a–RB and ARF–p53 tumor suppressor pathways, as well as activation of RAS–RAF signaling, is seen in a majority of human melanomas. Although heterozygous germline mutations of p16INK4a are associated with familial melanoma, most melanomas result from somatic genetic events: often p16INK4a loss and N-RAS or B-RAF mutational activation, with a minority possessing alternative genetic alterations such as activating mutations in K-RAS and/or p53 inactivation. To generate a murine model of melanoma featuring some of these somatic genetic events, we engineered a novel conditional p16INK4a-null allele and combined this allele with a melanocyte-specific, inducible CRE recombinase strain, a conditional p53-null allele and a loxP-stop-loxP activatable oncogenic K-Ras allele. We found potent synergy between melanocyte-specific activation of K-Ras and loss of p16INK4a and/or p53 in melanomagenesis. Mice harboring melanocyte-specific activated K-Ras and loss of p16INK4a and/or p53 developed invasive, unpigmented and nonmetastatic melanomas with short latency and high penetrance. In addition, the capacity of these somatic genetic events to rapidly induce melanomas in adult mice suggests that melanocytes remain susceptible to transformation throughout adulthood

Integrative Genome Comparison of Primary and Metastatic Melanomas

A cardinal feature of malignant melanoma is its metastatic propensity. An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients. In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression. In addition to uncovering three genomic subclasses of metastastic melanomas, we delineated 39 focal and recurrent regions of amplification and deletions, many of which encompassed resident genes that have not been implicated in cancer or metastasis. To identify progression-associated metastasis gene candidates, we applied a statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic regions of interest that were significantly altered in metastatic relative to primary melanomas, encompassing 30 resident genes with statistically significant expression deregulation. Functional assays on a subset of these candidates, including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their pro-invasion activities in human melanoma cells. Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases. Together, these functional validation results and correlative analysis of human tissues support the thesis that integrated genomic and pathological analyses of staged melanomas provide a productive entry point for discovery of melanoma metastases genes