Latin American Study of Hereditary Breast and Ovarian Cancer LACAM: A Genomic Epidemiology Approach.

Purpose: Hereditary Breast and Ovarian Cancer (HBOC) syndrome is responsible for ~5-10% of all diagnosed breast and ovarian cancers. Breast cancer is the most common malignancy and the leading cause of cancer-related mortality among women in Latin America (LA). The main objective of this study was to develop a comprehensive understanding of the genomic epidemiology of HBOC throughout the establishment of The Latin American consortium for HBOC-LACAM, consisting of specialists from 5 countries in LA and the description of the genomic results from the first phase of the study. Methods: We have recruited 403 individuals that fulfilled the criteria for HBOC from 11 health institutions of Argentina, Colombia, Guatemala, Mexico and Peru. A pilot cohort of 222 individuals was analyzed by NGS gene panels. One hundred forty-three genes were selected on the basis of their putative role in susceptibility to different hereditary cancers. Libraries were sequenced in MiSeq (Illumina, Inc.) and PGM (Ion Torrent-Thermo Fisher Scientific) platforms. Results: The overall prevalence of pathogenic variants was 17% (38/222); the distribution spanned 14 genes and varied by country. The highest relative prevalence of pathogenic variants was found in patients from Argentina (25%, 14/57), followed by Mexico (18%, 12/68), Guatemala (16%, 3/19), and Colombia (13%, 10/78). Pathogenic variants were found in BRCA1 (20%) and BRCA2 (29%) genes. Pathogenic variants were found in other 12 genes, including high and moderate risk genes such as MSH2, MSH6, MUTYH, and PALB2. Additional pathogenic variants were found in HBOC unrelated genes such as DCLRE1C, WRN, PDE11A, and PDGFB. Conclusion: In this first phase of the project, we recruited 403 individuals and evaluated the germline genetic alterations in an initial cohort of 222 patients among 4 countries. Our data show for the first time in LA the distribution of pathogenic variants in a broad set of cancer susceptibility genes in HBOC. Even though we used extended gene panels, there was still a high proportion of patients without any detectable pathogenic variant, which emphasizes the larger, unexplored genetic nature of the disease in these populations.

Experimental Demonstration of Temperature Sensing with Packaged Glass Bottle Microresonators.

Whispering gallery mode (WGM) glass bottle microresonators are potential highly sensitive structures for a variety of physical and bio-chemical sensing applications. In this paper, we experimentally demonstrate the practical use of glass bottle resonators as temperature sensors. The basic parameters, such as WGM resonance wavelengths, free spectral ranges, and Q factors, have been investigated by coupling light from a tapered fiber to the bottle structure. We show the spectral characteristics of the WGMs by choosing different bottle dimensions and taper diameters. For practical measurements, a robust 3D-printed package that includes the bottle resonator and the tapered fiber has been proposed. The packaged bottle has a central diameter Dc = 207 µm and a length L = 300 µm. Temperature sensing experiments were also performed. A linear response of the WGM shifts as a function of the temperature is confirmed. The fitted experimental data indicate a temperature sensitivity of 10.5 pm/K at λ ~ 1550 nm, resulting in a limit of detection of 0.06 K. These values can be compared with values reported for other WGM resonators. Additionally, bottle resonators are made with simple splicing methods and their assembly method can be easily defined due to large coupling tolerances.

Bioactive lipid profiling reveals drug target engagement of a soluble epoxide hydrolase inhibitor in a murine model of tobacco smoke exposure.

The inflammatory process underlying chronic obstructive pulmonary disease (COPD) may be caused by tobacco smoke (TS) exposure. Previous studies show that epoxyeicosatrienoic acids (EETs) possess promising anti-inflammatory properties, therefore stabilization of EETs and other fatty acid epoxides through inhibition of soluble epoxide hydrolase (sEH) was investigated in mouse models of acute and sub-chronic inflammation caused by TS exposure. During the entire TS exposure, the potent sEH inhibitor 1-(1-methylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS) was given via drinking water. To assess drug target engagement of TUPS, a tandem mass spectrometry method was used for bioactive lipid profiling of a broad range of fatty acid metabolites, including EETs, and their corresponding diols (DHETs) derived from arachidonic acid, as well as epoxides and diols derived from other fatty acids. Several, but not all, plasma epoxide/diol ratios increased in mice treated with sEH inhibitor, compared to non-treated mice suggesting a wider role for sEH involving more fatty acid precursors besides arachidonic acid. This study supports qualitative use of epoxide/diol ratios explored by bioactive lipid profiling to indicate drug target engagement in mouse models of TS exposure relevant to COPD, which may have ramifications for future therapeutic interventions of sEH.

A highly sensitive refractometric sensor based on cascaded SiN microring resonators.

We investigate a highly sensitive optical sensor based on two cascaded microring resonators exploiting the Vernier effect. The architecture consists of two microrings with a slight difference in their free spectral ranges. This allows the generation of the Vernier effect for achieving ultra-high sensitivities. The sensor chip was fabricated using a silicon nitride platform and characterized with isopropanol/ethanol mixtures. A sensitivity of 0.95 nm/% was found for isopropanol concentrations in ethanol ranging from 0% to 10%. Furthermore, a collection of measurements was carried out using aqueous sodium chloride (NaCl) in solutions of different concentrations, confirming a high sensitivity of 10.3 nm/% and a bulk refractive index sensitivity of 6,317 nm/RIU. A limit of detection of 3.16 × 10(-6) RIU was determined. These preliminary results show the potential features of cascaded silicon nitride microring resonators for real-time and free-label monitoring of biomolecules for a broad range of applications.

Investigation of cascaded SiN microring resonators at 1.3 µm and 1.5 µm.

An optical device operating at wavelengths around 1.3 µm and 1.5 µm is demonstrated experimentally. It is based on cascaded microring resonators (CMRRs) and the Vernier effect (VE). The architecture consists of two microring resonators (MRRs) connected via a common waveguide; two waveguides were added for the interrogation of CMRRs. The free spectral ranges of both MRRs are slightly different in order to activate the VE, which is known to enhance the sensitivity in optical sensors. CMRRs were fabricated on a silicon nitride (SiN) platform. Two types of buffer layers-benzocyclobutene (BCB) polymer and thermal silicon oxide (SiOx)-were tested. A study of CMRRs was carried out with three structures of different structural parameters. The experimental results show good agreement with the theoretical analysis. This approach is promising for the fabrication of highly sensitive optical sensors in wide operating wavelength range.

Interrogation of whispering-gallery modes resonances in cylindrical microcavities by backreflection detection.

The excitation of whispering-gallery-mode resonances of cylindrical microcavities, using narrow fiber tapers, produces simultaneously the excitation of spiral modes. The power coupled to the spiral modes leads to a significant broadening of the dips observed in the spectrum of light transmitted through the taper. We demonstrate that whispering-gallery modes resonances of cylindrical microcavities can also be interrogated by measuring the reflection spectrum. Unlike the dips observed in transmission, the peaks in the reflection spectrum are symmetric and narrower than the corresponding transmission dips.

Refractometric sensor based on whispering-gallery modes of thin capillarie.

Whispering-gallery modes resonances of submicron wall thickness capillaries exhibit very large wavelength shifts as a function of the refractive index of the medium that fills the inside. The sensitivity to refractive index changes is larger than in other optical microcavities as microspheres, microdisks and microrings. The outer surface where total internal reflection takes place remains always in air, enabling the measure of refractive index values higher than the refractive index of the capillary material. The fabrication of capillaries with submicron wall thickness has required the development of a specific technique. A refractometer with a response higher than 390 nm per refractive index unit is demonstrated. These sensors are readily compatible with microfluidic systems.