Suppression of Ah Receptor (AhR) increases the aggressiveness of TNBC cells and 11-Cl-BBQ-activated AhR inhibits their growth.

Triple-negative breast cancer (TNBC) represents around 15% of the 2.26 million breast cancers diagnosed worldwide annually and has the worst outcome. Despite recent therapeutic advances, there remains a lack of targeted therapies for this breast cancer subtype. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with biological roles in regulating development, xenobiotic metabolism, cell cycle progression and cell death. AhR activation by select ligands can promote tumor suppression in multiple cancer types. AhR can negatively regulate the activity of different oncogenic signaling pathways and can directly upregulate tumor suppressor genes such as p27Kip1. To determine the role of AhR in TNBC, we generated AhR-deficient cancer cells and investigated the impact of AhR loss on TNBC cell growth phenotypes. We found that AhR-deficient MDA-MB-468 TNBC cells have increased proliferation and formed significantly more colonies compared to AhR expressing cells. These cells without AhR expression grew aggressively in vivo. To determine the molecular targets driving this phenotype, we performed transcriptomic profiling in AhR expressing and AhR knockout MDA-MB-468 cells and identified tyrosine receptor kinases, as well as other genes involved in proliferation, survival and clonogenicity that are repressed by AhR. In order to determine therapeutic targeting of AhR in TNBC, we investigated the anti-cancer effects of the novel AhR ligand 11-chloro-7H-benzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (11-Cl-BBQ), which belongs to a class of high affinity, rapidly metabolized AhR ligands called benzimidazoisoquinolines (BBQs). 11-Cl-BBQ induced AhR-dependent cancer cell-selective growth inhibition and strongly inhibited colony formation in TNBC cells.

Induction of Aryl Hydrocarbon Receptor-Mediated Cancer Cell-Selective Apoptosis in Triple-Negative Breast Cancer Cells by a High-Affinity Benzimidazoisoquinoline.

Triple-negative breast cancer (TNBC) remains a disease with a paucity of targeted treatment opportunities. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is involved in a wide range of physiological processes, including the sensing of xenobiotics, immune function, development, and differentiation. Different small-molecule AhR ligands drive strikingly varied cellular and organismal responses. In certain cancers, AhR activation by select small molecules induces cell cycle arrest or apoptosis via activation of tumor-suppressive transcriptional programs. AhR is expressed in triple-negative breast cancers, presenting a tractable therapeutic opportunity. Here, we identify a novel ligand of the aryl hydrocarbon receptor that potently and selectively induces cell death in triple-negative breast cancer cells and TNBC stem cells via the AhR. Importantly, we found that this compound, Analog 523, exhibits minimal cytotoxicity against multiple normal human primary cells. Analog 523 represents a high-affinity AhR ligand with potential for future clinical translation as an anticancer agent.

Systematic integration of protein-affecting mutations, gene fusions, and copy number alterations into a comprehensive somatic mutational profile.

Somatic mutations occur as random genetic changes in genes through protein-affecting mutations (PAMs), gene fusions, or copy number alterations (CNAs). Mutations of different types can have a similar phenotypic effect (i.e., allelic heterogeneity) and should be integrated into a unified gene mutation profile. We developed OncoMerge to fill this niche of integrating somatic mutations to capture allelic heterogeneity, assign a function to mutations, and overcome known obstacles in cancer genetics. Application of OncoMerge to TCGA Pan-Cancer Atlas increased detection of somatically mutated genes and improved the prediction of the somatic mutation role as either activating or loss of function. Using integrated somatic mutation matrices increased the power to infer gene regulatory networks and uncovered the enrichment of switch-like feedback motifs and delay-inducing feedforward loops. These studies demonstrate that OncoMerge efficiently integrates PAMs, fusions, and CNAs and strengthens downstream analyses linking somatic mutations to cancer phenotypes.

The Impact of Victim Blaming and Locus of Control on Mental Health Outcomes Among Female Sexual Assault Survivors.

To elucidate individual differences in sexual assault survivor outcomes, we examined locus of control as a moderator of the relationship between victim blaming and both posttraumatic stress disorder (PTSD) symptoms and unhealthy alcohol use. The sample consisted of 82 female sexual assault survivors who had disclosed their victimization to at least one person. The results of this survey demonstrated that locus of control did not moderate the relationship between victim blaming and PTSD, or the relationship between victim blaming and unhealthy alcohol use. The findings further supported the direct relationship between victim blaming and a range of negative mental health outcomes among survivors.

Microbial community succession of submerged bones in an aquatic habitat.

After death, microbes (including bacteria and fungi) colonize carrion from a variety of sources during the decomposition process. The predictable succession of microbes could be useful for forensics, such as postmortem submersion interval estimation (PMSI) for aquatic deaths. However, gaps exist in our understanding of microbial succession on submerged bone, particularly regarding longer-term decomposition (>1 year), fungal composition, and differences between internal and external microbial communities. To further explore this potential forensic tool, we described the postmortem microbial communities (bacteria and fungi) on and within submerged bones using targeted amplicon sequencing. We hypothesized predictable successional patterns of microbial colonization would be detected on the surface and within submerged bones, which would eventually converge to a similar microbial community. To best replicate forensic contexts, we sampled bones from replicate swine (Sus scrofa domesticus) carcasses submerged in a freshwater pond, every three months for nearly two years. Microbial bone (internal vs. external) community structure (taxa abundance and diversity) of bones differed for both bacteria and fungi, but internal and external communities did not converge to a similar structure. PMSI estimation models built with random forest regression of postmortem microbiomes were highly accurate (>80% variation explained in PMSI) and showed promise for forensic purposes. Overall, we provide further evidence that internal and external bone microbial communities submerged in an aquatic habitat are distinct and each community undergoes predictable succession, demonstrating potential utility in forensics for modeling PMSI in unattended deaths and/or cold cases.

Calidad de vida, pérdida ponderal y evolución de las comorbilidades: estudio comparativo de gastrectomía vertical vs. bypass gástrico. Resultados preliminares / Quality of life, weight loss and evolution of comorbidities: comparative study of sleeve vs bypass. Preliminary results

Resumen Objetivo: Comparar los resultados obtenidos en calidad de vida, pérdida ponderal y resolución de comorbilidades al año, en pacientes con obesidad mórbida intervenidos de Gastrectomía vertical laparoscópica (GVL) o bypass gástrico en Y de Roux laparoscópico (BGYRL) en nuestro centro. Materiales y Método: Estudio observacional de una base de datos prospectiva. Las variables del estudio fueron IMC pre y posoperatorio, porcentaje de exceso de IMC perdido (PEIMCP), puntuación obtenida en los cuestionarios Gastrointestinal Quality of Life Index (GIQLI) y Bariatric Analysis and Reporting Outcomes System (BAROS) y la resolución de las comorbilidades. Resultados: De 60 pacientes: 37 fueron intervenidos de GVL y 23 de BGYRL. El IMC posoperatorio al año fue 29,9 ± 4 kg/m2 en BGYRL y 31,3 ± 5 kg/m2 en GVL. El PEIMCP fue de 74,5 ± 19,2% (BGYRL) y de 67,5 ± 23,1% (GVL). Con BAROS, se obtuvieron resultados buenos o superiores en el 87% (BGYRL) y en 83,8% (GVL). Con GIQLI se obtuvo una puntuación media de 108,3 ± 19 (BGYRL) y 109,8 ± 18,3 (GVL). No se observaron diferencias estadísticamente significativas entre ambos grupos en ninguna de las variables previas. En cuanto a la evolución de las comorbilidades, 50% de BGYRL y 53,8% de GVL presentaron resolución de todas las comorbilidades. Conclusiones: Ambas técnicas son eficaces en cuanto al PEIMCP, a la calidad de vida y al control de comorbilidades al año de la intervención. El BGYRL presenta mejores resultados en PEIMCP y BAROS, y la GVL presenta mejor puntación global y especifica de síntomas digestivos con GIQLI, sin ser diferencias estadísticamente significativas.

Aim: The purpose of our study was to compare the postoperative quality of life, weight loss and improvement of co-morbidities in laparoscopic Roux-en-Y gastric bypass (LRYGB) and Laparoscopic sleeve gastrectomy (LSG) patients one year after surgery. Materials and Method: Match pair analysis of the prospectively collected database of the 23 gastric bypass and 37 gastric sleeve patients operated on in our hospital was performed. Weight loss, quality of life and improvement of co-morbidities were measured at one year after surgery. The quality of life parameters were measured with two standard questionnaires: Gastrointestinal Quality of Life Index (GIQLI) and Bariatric Analysis and Reporting Outcomes System (BAROS). Results: After one year of follow-up the mean BMI was 29.9 ± 4 kg/m2 in LRYGB and 31.3 ± 5 kg/m2 in LSG. The percent excess BMI Loss (%EBMIL) was 74.5 ± 19.2% (LRYGB) and 67.5 ± 23.1% (LSG). A success score in BAROS was obtained in 87% (LRYGB) and 83.8% (LSG). The mean GIQLI score was 108.3 ± 19 (LRYGB) and 109.8 ± 18.3 (LSG). These results did not differ significantly. Remission of co-morbidities was similar in the BGYRL and LSG groups (50 vs 53.8%). Conclusions: Both types of surgery are effective in quality of life, co-morbidities and weight loss after one year of follow-up. The LRYGB produced better results in %EBMIL and BAROS, and the LSG produced better results in GIQLI (overall and digestive symptoms). These results did not differ significantly.

Healthy Aging Biomarkers: The INSPIRE's Contribution.

The find solutions for optimizing healthy aging and increase health span is one of the main challenges for our society. A novel healthcare model based on integration and a shift on research and care towards the maintenance of optimal functional levels are now seen as priorities by the WHO. To address this issue, an integrative global strategy mixing longitudinal and experimental cohorts with an innovative transverse understanding of physiological functioning is missing. While the current approach to the biology of aging is mainly focused on parenchymal cells, we propose that age-related loss of function is largely determined by three elements which constitute the general ground supporting the different specific parenchyma: i.e. the stroma, the immune system and metabolism. Such strategy that is implemented in INSPIRE projects can strongly help to find a composite biomarker capable of predicting changes in capacity across the life course with thresholds signalling frailty and care dependence.

Grasping Embodiment: Haptic Feedback for Artificial Limbs.

Upper-limb prostheses are subject to high rates of abandonment. Prosthesis abandonment is related to a reduced sense of embodiment, the sense of self-location, agency, and ownership that humans feel in relation to their bodies and body parts. If a prosthesis does not evoke a sense of embodiment, users are less likely to view them as useful and integrated with their bodies. Currently, visual feedback is the only option for most prosthesis users to account for their augmented activities. However, for activities of daily living, such as grasping actions, haptic feedback is critically important and may improve sense of embodiment. Therefore, we are investigating how converting natural haptic feedback from the prosthetic fingertips into vibrotactile feedback administered to another location on the body may allow participants to experience haptic feedback and if and how this experience affects embodiment. While we found no differences between our experimental manipulations of feedback type, we found evidence that embodiment was not negatively impacted when switching from natural feedback to proximal vibrotactile feedback. Proximal vibrotactile feedback should be further studied and considered when designing prostheses.

Towards a Large-Scale Assessment of the Relationship between Biological and Chronological Aging: The INSPIRE Mouse Cohort.

Aging is the major risk factor for the development of chronic diseases. After decades of research focused on extending lifespan, current efforts seek primarily to promote healthy aging. Recent advances suggest that biological processes linked to aging are more reliable than chronological age to account for an individual's functional status, i.e. frail or robust. It is becoming increasingly apparent that biological aging may be detectable as a progressive loss of resilience much earlier than the appearance of clinical signs of frailty. In this context, the INSPIRE program was built to identify the mechanisms of accelerated aging and the early biological signs predicting frailty and pathological aging. To address this issue, we designed a cohort of outbred Swiss mice (1576 male and female mice) in which we will continuously monitor spontaneous and voluntary physical activity from 6 to 24 months of age under either normal or high fat/high sucrose diet. At different age points (6, 12, 18, 24 months), multiorgan functional phenotyping will be carried out to identify early signs of organ dysfunction and generate a large biological fluids/feces/organs biobank (100,000 samples). A comprehensive correlation between functional and biological phenotypes will be assessed to determine: 1) the early signs of biological aging and their relationship with chronological age; 2) the role of dietary and exercise interventions on accelerating or decelerating the rate of biological aging; and 3) novel targets for the promotion of healthy aging. All the functional and omics data, as well as the biobank generated in the framework of the INSPIRE cohort will be available to the aging scientific community. The present article describes the scientific background and the strategies employed for the design of the INSPIRE Mouse cohort.

Formation of Environmentally Persistent Free Radicals (EPFRs) on the Phenol-Dosed α-Fe2O3(0001) Surface.

Environmentally persistent free radicals (EPFRs) are a class of toxic air pollutants that are found to form by the chemisorption of substituted aromatic molecules on the surface of metal oxides. In this study, we employ X-ray photoelectron spectroscopy (XPS) and ultraviolet photoelectron spectroscopy (UPS) to perform a temperature-dependent study of phenol adsorption on α-Fe2O3(0001) to probe the radical formation mechanism by monitoring changes in the electronic structure of both the adsorbed phenol and metal oxide substrate. Upon dosing at room temperature, new phenol-derived electronic states have been clearly observed in the UPS spectrum at saturation coverage. However, upon dosing at high temperature (>200 °C), both photoemission techniques have shown distinctive features that strongly suggest electron transfer from adsorbed phenol to Fe2O3 surface atoms and consequent formation of a surface radical. Consistent with the experiment, DFT calculations show that phenoxyl adsorption on the iron oxide surface at RT leads to a minor charge transfer to the adsorbed molecule. The experimental findings at high temperatures agree well with the EPFRs' proposed formation mechanism and can guide future experimental and computational studies.

Age-Related Frailty: A Clinical Model for Geroscience?

In their everyday practice, geriatricians are confronted with the fact that older age and multimorbidity are associated to frailty. Indeed, if we take the example of a very old person with no diseases that progressively becomes frail with no other explanation, there is a natural temptation to link frailty to aging. On the other hand, when an old person with a medical history of diabetes, arthritis and congestive heart failure becomes frail there appears an obvious relationship between frailty and comorbidity. The unsolved question is: Considering that frailty is multifactorial and in the majority of cases comorbidity and aging are acting synergistically, can we disentangle the main contributor to the origin of frailty: disease or aging? We believe that it is important to be able to differentiate age-related frailty from frailty related to comorbidity. In fact, with the emergence of geroscience, the physiopathology, diagnosis, prognosis and treatment will probably have to be different in the future.

Dysbiosis in the Dead: Human Postmortem Microbiome Beta-Dispersion as an Indicator of Manner and Cause of Death.

The postmortem microbiome plays an important functional role in host decomposition after death. Postmortem microbiome community successional patterns are specific to body site, with a significant shift in composition 48 h after death. While the postmortem microbiome has important forensic applications for postmortem interval estimation, it also has the potential to aid in manner of death (MOD) and cause of death (COD) determination as a reflection of antemortem health status. To further explore this association, we tested beta-dispersion, or the variability of microbiomes within the context of the "Anna Karenina Principle" (AKP). The foundational principle of AKP is that stressors affect microbiomes in unpredictable ways, which increases community beta-dispersion. We hypothesized that cases with identified M/CODs would have differential community beta-dispersion that reflected antemortem conditions, specifically that cardiovascular disease and/or natural deaths would have higher beta-dispersion compared to other deaths (e.g., accidents, drug-related deaths). Using a published microbiome data set of 188 postmortem cases (five body sites per case) collected during routine autopsy in Wayne County (Detroit), MI, we modeled beta-dispersion to test for M/COD associations a priori. Logistic regression models of beta-dispersion and case demographic data were used to classify M/COD. We demonstrated that beta-dispersion, along with case demographic data, could distinguish among M/COD - especially cardiovascular disease and drug related deaths, which were correctly classified in 79% of cases. Binary logistic regression models had higher correct classifications than multinomial logistic regression models, but changing the defined microbial community (e.g., full vs. non-core communities) used to calculate beta-dispersion overall did not improve model classification or M/COD. Furthermore, we tested our analytic approach on a case study that predicted suicides from other deaths, as well as distinguishing MOD (e.g., homicides vs. suicides) within COD (e.g., gunshot wound). We propose an analytical workflow that combines postmortem microbiome indicator taxa, beta-dispersion, and case demographic data for predicting MOD and COD classifications. Overall, we provide further evidence the postmortem microbiome is linked to the host's antemortem health condition(s), while also demonstrating the potential utility of including beta-dispersion (a non-taxon dependent approach) coupled with case demographic data for death determination.

Cold Case Experiment Demonstrates the Potential Utility of Aquatic Microbial Community Assembly in Estimating a Postmortem Submersion Interval.

Microbial community assembly (MCA) of both human and nonhuman animal carcasses provides indicators useful for estimating the postmortem interval (PMI) in terrestrial settings. However, there are fewer studies estimating postmortem submersion intervals (PMSIs) in aquatic habitats. No aquatic studies to date assessed MCA in the context of a death investigation, with all previous studies focusing on important basic ecological questions. Within the context of a cold case investigation, we performed an experiment using replicate adult swine carcasses to describe postmortem MCA variability within a nonflowing aquatic habitat. Using high-throughput sequencing of carcass postmortem microbiomes, we described MCA variability and identified key taxa associated with decomposition in an aquatic habitat similar to the cold case body recovery site. We also modeled key taxa for estimating PMSIs, modeling within ±3 days (mean square error) postmortem using random forest regression. Our findings show significant changes in microbial communities as decomposition progressed, and several taxa were identified as important indicator taxa which may be useful for future estimates of PMSI. While descriptive, this study provides initial findings quantifying MCA variability within a nonflowing aquatic habitat. Within the context of the cold case investigation, we discuss how postmortem microbial samples collected at the time of body recovery could have been an important piece of evidence for understanding the PMSI of recovered remains. Additional experimental studies are needed to explicitly test and identify mechanisms associated with postmortem MCA variability in other habitats and under different temperature (e.g., seasons) conditions.

Double-balloon enteroscopy: Experience with an innovative endoscopic technique at the Hospital Universitario de la Fundación Santa Fe de Bogotá. / Enteroscopia de doble balón: experiencia de una técnica endoscópica innovadora en el Hospital Universitario de la Fundación Santa Fe de Bogotá.

INTRODUCTION AND AIMS: Double-balloon enteroscopy is a recently introduced endoscopic method that enables complete visualization of the small bowel, as well as biopsy sampling and therapeutic interventions in that part of the intestine. The aim of the present study was to describe the experience acquired at our hospital to determine the characteristics of the patients that underwent the procedure. MATERIALS AND METHODS: A descriptive, cross-sectional study was conducted on all patients above 18 years of age admitted to the Hospital Universitario de la Fundación Santa Fe de Bogotá for double-balloon enteroscopy, within the time frame of January 2013 to December 2017. RESULTS: The study sample included 93 procedures in 73 patients. Mean patient age was 57.91 years, with a similar number of men and women. There were no severe complications. The most frequent indication for the enteroscopy was gastrointestinal bleeding (overt or occult), presenting in 49.46% of the patients, followed by chronic diarrhea (16.13%). Video capsule endoscopy was the previous study most frequently performed (53.76%). Anterograde double-balloon enteroscopy was carried out in 49 patients and 44 patients underwent the retrograde procedure. A total of 86.02% of the enteroscopies were diagnostic procedures and 13.98% were therapeutic. Normal enteroscopy was the most frequent finding (59.68%), followed by the presence of ulcers (15.05%). CONCLUSIONS: Our results were similar to those reported worldwide, with respect to indications, insertion route, and insertion depth, and there were no severe complications.

Evaluating Bioinformatic Pipeline Performance for Forensic Microbiome Analysis*,†,‡.

Microbial communities have potential evidential utility for forensic applications. However, bioinformatic analysis of high-throughput sequencing data varies widely among laboratories. These differences can potentially affect microbial community composition and downstream analyses. To illustrate the importance of standardizing methodology, we compared analyses of postmortem microbiome samples using several bioinformatic pipelines, varying minimum library size or minimum number of sequences per sample, and sample size. Using the same input sequence data, we found that three open-source bioinformatic pipelines, MG-RAST, mothur, and QIIME2, had significant differences in relative abundance, alpha-diversity, and beta-diversity, despite the same input data. Increasing minimum library size and sample size increased the number of low-abundant and infrequent taxa detected. Our results show that bioinformatic pipeline and parameter choice affect results in important ways. Given the growing potential application of forensic microbiology to the criminal justice system, continued research on standardizing computational methodology will be important for downstream applications.

Juniperanol: First total synthesis and evaluation in Type 2 Diabetes disease.

The first total synthesis of juniperanol, the tricyclic sesquiterpenoid enantiomer of α-cedrol is described. The synthesis relies on stereoselective gold-catalyzed Ohloff-type propargylic ester rearrangement performed on a 10 g scale, and a carbocationic cascade in the presence of acetyl methanesulfonate. The ability of juniperanol to interfere in glucose processes in different cell types is described.

Suspended LRSPP for the development of highly integrated active plasmonic devices.

We present a novel long-range surface plasmon polariton (LRSPP) device consisting of a suspended dielectric matrix in which an electrically active, millimeter-long metallic waveguide is embedded. We show that, by opening an air gap under the lower cladding, the influence of the substrate is suppressed and the symmetry of the thermo-optical distribution around the LRSPP waveguide is preserved over extended ranges of applied electrical current with minimal optical losses. Experimental results show that, compared to a standard nonsuspended structure, our device allows either the induction of a phase change that is three times larger, for a fixed electrical power, or, equivalently, a scaling down of the device to one-tenth of its original length, for a fixed phase change.

Flow morphometry to assess the red blood cell storage lesion.

We present a novel automated system for morphology analysis of red blood cells (RBC) under flow. RBC concentrates collected by blood banks for transfusions are stored for periods of up to several weeks, during which time a number of changes occur, collectively termed the storage lesion. Typically the extent of hemolysis is the defining criterion to determine the acceptability of the RBCs for transfusions. Morphological changes are related with biochemical alteration during the storage of RBCs. The typical blood smear procedure for determining such changes is a labor-intensive and potentially biased manual process. The advantage of the flow morphometry system presented here is that it provides fully automated morphological classification of RBCs with large sample numbers in a short time. Our system uses a commercially available flow cell and flow conditions that prevent adhesion of RBCs, thus eliminating the need for blocking agents such as albumin that affect the distribution of cell shapes. Our morphometry results are validated by comparison with standard biochemical assays (hemolysis, ATP) for blood from 17 donors stored under blood bank conditions for 13 weeks. We show that the percentage of spherocytes present can be used to estimate the status of RBC concentrates. © 2017 International Society for Advancement of Cytometry.

Dynamics of soliton cascades in fiber amplifiers.

We study numerically the formation of cascading solitons when femtosecond optical pulses are launched into a fiber amplifier with less energy than required to form a soliton of equal duration. As the pulse is amplified, cascaded fundamental solitons are created at different distances, without soliton fission, as each fundamental soliton moves outside the gain bandwidth through the Raman-induced spectral shifts. As a result, each input pulse creates multiple, temporally separated, ultrashort pulses of different wavelengths at the amplifier output. The number of pulses depends not only on the total gain of the amplifier but also on the width of the input pulse.