Publications by authors named "Elena Martinez"

176 Publications

Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast.

J Clin Oncol 2021 Oct 21:JCO2100640. Epub 2021 Oct 21.

UWM Joseph J. Zilber School of Public Health, Milwaukee, WI.

Purpose: To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast.

Materials And Methods: The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (, , , , , , , , , , , and ) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC).

Results: The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, and PVs were associated with high risks of ILC (odds ratio [OR] > 4) and , , and PVs were associated with moderate (OR = 2-4) risks. PVs and p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, PVs were > 10-fold enriched, whereas PVs in were substantially reduced in ILC.

Conclusion: The study establishes that PVs in , , , , and are associated with an increased risk of ILC, whereas PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but should be specifically discussed because of low prevalence and gastric cancer risk.
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http://dx.doi.org/10.1200/JCO.21.00640DOI Listing
October 2021

Host characteristics associated with serologic inflammatory biomarkers in women.

Cytokine 2021 Oct 16;149:155726. Epub 2021 Oct 16.

University of California San Francisco, CA, USA.

Background: There is growing evidence that exposure to low-grade inflammation may be associated with adverse health outcomes.

Methods: We conducted a cross-sectional study within the California Teachers Study prospective cohort, among female participants who had completed a questionnaire that asked about their health behaviors (e.g., diabetes, physical activity, body mass index, medication use) and who had donated blood within a year of their questionnaire. 822 women with stored serum were evaluated for 16 immune biomarkers. In addition, four immune pathways were constructed: Th1, pro-inflammatory/macrophage activation, B-cell activation, and T-cell activation. Odds ratios (ORs) and 95% confidence intervals (CI) for the association between host characteristics and immune biomarkers were assessed using logistic regression models.

Result: Compared to women of a normal BMI, obese women (>30 kg/m) were positively associated with sTNFR2, CD27, IL6, CXCL13, sIL-2Rα, and IL6Ra levels above the median, with odds ratios ranging from 1.5 to 6.0. The pro-inflammatory/macrophage activation pathway was positively associated with diabetes (OR = 2.12, 95% CI = 1.14-3.95), fueled by individual associations between diabetes and sTNF-R2, TNFα and sCD27. Physical activity was inversely associated with sTNF-R2, TNFα, CXCL13, IL6, IL10, and IFN-γ levels, particularly for the highest category of activity (5.88+ hours/week) (ORs = 0.32-0.69). In pathway-based analyses, the Th1 pathway which includes decreased levels of IL4 and IL10 was positively associated with elevated physical activity (OR = 1.5). In contrast, the pro-inflammatory, B- and T-cell activation pathways were positively associated with higher BMI (OR ranging from 1.6 to 3) and inversely associated with increasing levels of physical activity.

Conclusions: Several host characteristics were associated with circulating levels of immune biomarkers, including markers of inflammation. Further understanding of associations between immune marker profiles with human disease are warranted.
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http://dx.doi.org/10.1016/j.cyto.2021.155726DOI Listing
October 2021

The Role of Food and Beverage Companies in Transforming Food Systems: Building Resilience at Multiple Scales.

Curr Dev Nutr 2021 Sep 24;5(9):nzab110. Epub 2021 Aug 24.

Friedman School of Nutrition Science and Policy, Division of Agriculture, Food, and Environment, Tufts University, Boston, MA, USA.

Food and beverage companies are increasingly aware of the risks posed by climate change and many are interested in addressing them by building resilience along their supply chains. Financial incentives for environmental, social, and governance criteria further motivate mitigation action by firms. To achieve sustainable outcomes, human and ecological systems must be managed for resilience. The scientific community and food and beverage firms must collaborate in the development of measurable and verifiable indicators that support adaptation and mitigation action along food supply chains. This article identifies 3 areas in which a synergistic progress would set a resilient trajectory toward sustainability: ) incentives for sustainable intensification, ) expanded reporting standards, and ) pre-competitive collaborations. Incremental, clear, and measurable steps can be taken to adapt food supply chains to the pressing challenges imposed by climate change, mitigate further emissions, and bring producers and consumers along in the journey towards planetary health.
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http://dx.doi.org/10.1093/cdn/nzab110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452525PMC
September 2021

A Case of Trauma-Induced Eumycetoma in a Renal Transplant Recipient.

Trop Med Infect Dis 2021 Aug 3;6(3). Epub 2021 Aug 3.

Infectious Diseases Department, St Vincent's Hospital, Melbourne, VIC 3065, Australia.

Mycetoma is a chronic, granulomatous, subcutaneous infection caused by several species of fungi and soil-inhabiting bacteria, and is divided into eumycetoma and actinomycetoma, respectively. Endemicity is described with worldwide distribution within the "mycetoma belt"; however, the global burden is ill-defined. Mycetoma is rare in Australia, with only a few published case reports. Over time, the breadth of eumycetoma pathogens has expanded with local epidemiology accounting for variations in regional prevalence. Direct inoculation of pathogens typically heralds the triad of subcutaneous mass, sinus formation and discharging grains. We describe a case of eumycetoma in a 48-year-old male Filipino renal transplant recipient who presented with a painless slow-growing elbow lesion. Ultrasonography revealed two ovoid masses and surgical excision ensued. Histopathology revealed necrotising granulomata with numerous chestnut-brown thick-walled cells, septate hyphae, and occasional grains. On suspicion of localised chromoblastomycosis, the isolate was sent to a reference laboratory which identified the fungus as , an organism not hitherto associated with human infection. Amongst the solid organ transplant cohort, similar atypical presentations have been described. Clinicians need to consider eumycetoma where an epidemiological link with the tropics exists, especially in atypical presentations in transplant recipients, including absent preceding trauma.
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http://dx.doi.org/10.3390/tropicalmed6030144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396353PMC
August 2021

Risk of Late-Onset Breast Cancer in Genetically Predisposed Women.

J Clin Oncol 2021 Jul 22:JCO2100531. Epub 2021 Jul 22.

Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose: The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years.

Methods: A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs.

Results: The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in , , and were found in 3.42% of women diagnosed with estrogen receptor (ER)-negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in , , , and were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in , , and .

Conclusion: This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with and PVs and perhaps with and PVs should be considered for magnetic resonance imaging screening.
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http://dx.doi.org/10.1200/JCO.21.00531DOI Listing
July 2021

Improved Copper-Epoxy Adhesion by Laser Micro- and Nano-Structuring of Copper Surface for Thermal Applications.

Polymers (Basel) 2021 May 24;13(11). Epub 2021 May 24.

Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, 50018 Zaragoza, Spain.

The objective of this work is the enhancement of metal-to-metal bonding to provide high thermal conductivity together with electrical insulation, to be used as heat sinks at room and cryogenic temperatures. High thermal conductive metal (copper) and epoxy resin (Stycast 2850FT) were used in this study, with the latter also providing the required electrical insulation. The copper surface was irradiated with laser to induce micro- and nano-patterned structures that result in an improvement of the adhesion between the epoxy and the copper. Thus, copper-to-copper bonding strength was characterized by means of mechanical tensile shear tests. The effect of the laser processing on the thermal conductivity properties of the Cu/epoxy/Cu joint at different temperatures, from 10 to 300 K, is also reported. Using adequate laser parameters, it is possible to obtain high bonding strength values limited by cohesive epoxy fracture, together with good thermal conductivity at ambient and cryogenic temperatures.
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http://dx.doi.org/10.3390/polym13111721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197336PMC
May 2021

Elaboration of Gluten-Free Cookies with Defatted Seed Flours: Effects on Technological, Nutritional, and Consumer Aspects.

Foods 2021 May 27;10(6). Epub 2021 May 27.

E.T.S.I. Agrónomos y de Montes (UCLM), Campus Universitario s/n, 02071 Albacete, Spain.

Cookies, which form the largest category of bakery snacks, are considered a good vehicle to introduce nutrients into the diet. In this study, to increase the nutritional value of traditional commercial cookies, wheat flour was substituted with defatted flours made from flax, sesame, chia, and poppy, which are byproducts of the oil extraction industry. The differences in the technological properties, nutritional composition, and consumer acceptance of the reformulated cookies were evaluated. The results show that the wheat cookies used as the control showed a more elastic behavior than the cookies elaborated with defatted seed flours, which showed a greater tendency to crumble. The use of defatted seed flours yielded cookies with a higher content of protein and fiber, and a lower content in carbohydrates than the wheat cookies. Consumer evaluations for the sesame and flax cookies were similar to those for the traditional wheat cookies, with positive assessments on all of the parameters evaluated. On the other hand, the cookies elaborated using chia and poppy flours received the least positive evaluations from consumers. Thus, the use of some defatted seed flours, mainly flax and sesame, is proposed as an interesting alternative to produce health-promoting cookies in order to cover the current demand for gluten-free products.
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http://dx.doi.org/10.3390/foods10061213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228105PMC
May 2021

Do tradeoffs among dimensions of women's empowerment and nutrition outcomes exist? Evidence from six countries in Africa and Asia.

Food Policy 2021 Apr;100:102001

International Food Policy Research Institute, Washington, DC, USA.

Although women's empowerment and gender equality are often linked with better maternal and child nutrition outcomes, recent systematic reviews find inconclusive evidence. This paper applies a comparable methodology to data on the Women's Empowerment in Agriculture Index (WEAI), an internationally-validated measure based on interviews of women and men within the same household, from six countries in Africa and Asia to identify which dimensions of women's empowerment are related to household-, woman-, and child-level dietary and nutrition outcomes. We examine relationships between women's empowerment and household-level dietary diversity; women's dietary diversity and BMI; and child-related outcomes, controlling for woman, child, and household characteristics. We also test for differential associations of women's empowerment with nutrition outcomes for boys and girls. We find few significant associations between the aggregate empowerment scores and nutritional outcomes. The women's empowerment score is positively associated only with child HAZ, while lower intrahousehold inequality is associated with a higher likelihood of exclusive breastfeeding and higher HAZ but with lower BMI. However, analysis of the subdomain indicators finds more significant associations, suggesting that tradeoffs exist among different dimensions of empowerment. Women's empowerment accounts for a small share of the variance in nutritional outcomes, with household wealth and country-level factors accounting for the largest share of the variation in household and women's dietary diversity. In contrast, most of the variation in child outcomes comes from child age. Improving nutritional outcomes requires addressing the underlying determinants of poor nutrition in addition to empowering women and improving gender equality.
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http://dx.doi.org/10.1016/j.foodpol.2020.102001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097635PMC
April 2021

Thyroid Hormone Deiodinases: Dynamic Switches in Developmental Transitions.

Endocrinology 2021 08;162(8)

National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Endocrinology and Receptor Biology, National Institutes of Health, Bethesda, Maryland 20892, USA.

Thyroid hormones exert pleiotropic, essential actions in mammalian, including human, development. These actions depend on provision of thyroid hormones in the circulation but also to a remarkable extent on deiodinase enzymes in target tissues that amplify or deplete the local concentration of the primary active form of the hormone T3 (3,5,3'-triiodothyronine), the high affinity ligand for thyroid hormone receptors. Genetic analyses in mice have revealed key roles for activating (DIO2) and inactivating (DIO3) deiodinases in cell differentiation fates and tissue maturation, ultimately promoting neonatal viability, growth, fertility, brain development, and behavior, as well as metabolic, endocrine, and sensory functions. An emerging paradigm is how the opposing activities of DIO2 and DIO3 are coordinated, providing a dynamic switch that controls the developmental timing of a tissue response, often during neonatal and maturational transitions. A second paradigm is how cell to cell communication within a tissue determines the response to T3. Deiodinases in specific cell types, often strategically located near to blood vessels that convey thyroid hormones into the tissue, can regulate neighboring cell types, suggesting a paracrine-like layer of control of T3 action. We discuss deiodinases as switches for developmental transitions and their potential to influence tissue dysfunction in human thyroid disorders.
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http://dx.doi.org/10.1210/endocr/bqab091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248586PMC
August 2021

Bioengineered3D model of myotonic dystrophy type 1 human skeletal muscle.

Biofabrication 2021 04 26;13(3). Epub 2021 Apr 26.

Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), c/Baldiri Reixac 10-12, E08028 Barcelona, Spain.

Myotonic dystrophy type 1 (DM1) is the most common hereditary myopathy in the adult population. The disease is characterized by progressive skeletal muscle degeneration that produces severe disability. At present, there is still no effective treatment for DM1 patients, but the breakthroughs in understanding the molecular pathogenic mechanisms in DM1 have allowed the testing of new therapeutic strategies. Animal models andtwo-dimensional cell cultures have been essential for these advances. However, serious concerns exist regarding how faithfully these models reproduce the biological complexity of the disease. Biofabrication tools can be applied to engineer human three-dimensional (3D) culture systems that complement current preclinical research models. Here, we describe the development of the first3D model of DM1 human skeletal muscle. Transdifferentiated myoblasts from patient-derived fibroblasts were encapsulated in micromolded gelatin methacryloyl-carboxymethyl cellulose methacrylate hydrogels through photomold patterning on functionalized glass coverslips. These hydrogels present a microstructured topography that promotes myoblasts alignment and differentiation resulting in highly aligned myotubes from both healthy and DM1 cells in a long-lasting cell culture. The DM1 3D microtissues recapitulate the molecular alterations detected in patient biopsies. Importantly, fusion index analyses demonstrate that 3D micropatterning significantly improved DM1 cell differentiation into multinucleated myotubes compared to standard cell cultures. Moreover, the characterization of the 3D cultures of DM1 myotubes detects phenotypes as the reduced thickness of myotubes that can be used for drug testing. Finally, we evaluated the therapeutic effect of antagomiR-23b administration on bioengineered DM1 skeletal muscle microtissues. AntagomiR-23b treatment rescues both molecular DM1 hallmarks and structural phenotype, restoring myotube diameter to healthy control sizes. Overall, these new microtissues represent an improvement over conventional cell culture models and can be used as biomimetic platforms to establish preclinical studies for myotonic dystrophy.
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http://dx.doi.org/10.1088/1758-5090/abf6aeDOI Listing
April 2021

Value of routine whole genome sequencing for Mycobacterium tuberculosis drug resistance detection.

Int J Infect Dis 2021 Mar 19. Epub 2021 Mar 19.

Centre for Infectious Diseases and Microbiology-Public Health, Westmead Hospital, Western Sydney Local Health District, Sydney, New South Wales, Australia; NSW Mycobacterium Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research, NSW Health Pathology - Western, Sydney, New South Wales, Australia; Marie Bashir Institute for Infectious Diseases and Biosecurity and Centre for Research Excellence in Tuberculosis (TB-CRE), The University of Sydney, Sydney, New South Wales, Australia.

Routine whole genome sequencing (WGS) of pathogens is becoming more feasible as sequencing costs decrease and access to benchtop sequencing equipment and bioinformatics pipelines increases. This study examined the added value gained from implementing routine WGS of all Mycobacterium tuberculosis isolates in New South Wales, Australia. Drug resistance markers inferred from WGS data were compared to commercial genotypic drug susceptibility testing (DST) assays and conventional phenotypic DST in all isolates sequenced between 2016 and 2019. Of the 1107 clinical M. tuberculosis isolates sequenced, 29 (2.6%) were multi-drug resistant (MDR); most belonged to Beijing (336; 30.4%) or East-African Indian (332; 30%) lineages. Compared with conventional phenotypic DST, WGS identified an additional 1% of isolates which were likely drug resistant, explained by mutations previously associated with treatment failure and mixed bacterial populations. However, WGS provided a 20% increase in drug resistance detection in comparison with commercial genotypic assays by identifying mutations outside of the classic resistance determining regions in rpoB, inhA, katG, pncA and embB genes. Gains in drug resistance detection were significant (p = 0.0137, paired t-test), but varied substantially for different phylogenetic lineages. In low incidence settings, routine WGS of M. tuberculosis provides better guidance for person-centered management of drug resistant tuberculosis than commercial genotypic assays.
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http://dx.doi.org/10.1016/j.ijid.2021.03.033DOI Listing
March 2021

Whole genome sequencing based differentiation between re-infection and relapse in Indian patients with tuberculosis recurrence, with and without HIV co-infection.

Int J Infect Dis 2021 Mar 16. Epub 2021 Mar 16.

Centre for Infectious Diseases and Microbiology - Public Health, Westmead Hospital, Sydney, New South Wales, Australia; Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, New South Wales, Australia; Sydney Medical School, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia.

Introduction: Differentiation between relapse and reinfection in cases with tuberculosis (TB) recurrence has important implications for public health, especially in patients with human immunodeficiency virus (HIV) co-infection. We compared Mycobacterial Interspersed Repeat Unit (MIRU) typing and spoligotyping with whole genome sequencing (WGS) to differentiate between relapse and reinfection in patients (HIV-positive and HIV-negative) with TB recurrence. We also assessed the value of WGS to track acquired drug resistance in those with relapse after successful treatment.

Method: Forty-one paired M. tuberculosis isolates collected from 20 HIV-positive and 21 HIV-negative patients were subjected to WGS in addition to spoligotyping and MIRU typing. Phylogenetic and Single Nucleotide Substitution (SNP) clustering analyses were performed to determine whether recurrences were due to relapse or re-infection.

Results: Comparison of M. tuberculosis genomes indicated that 95% of TB recurrences in the HIV-negative cohort were due to relapse, while the majority of TB recurrences (75%) in the HIV-positive cohort was due to reinfection (P = 0.0001). New drug resistance mutations were acquired in 5/24 cases (20.8%) that experienced relapse.

Conclusions: WGS provided increased resolution, but differentiation between relapse and reinfection was broadly consistent with MIRU and spoligotyping. The high contribution of reinfection among HIV infected patients experiencing TB recurrence warrants further study to explore risk factors for TB exposure.
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http://dx.doi.org/10.1016/j.ijid.2021.03.020DOI Listing
March 2021

Engineering Tissue Barrier Models on Hydrogel Microfluidic Platforms.

ACS Appl Mater Interfaces 2021 Mar 19;13(12):13920-13933. Epub 2021 Mar 19.

Biomimetic Systems for Cell Engineering, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain.

Tissue barriers play a crucial role in human physiology by establishing tissue compartmentalization and regulating organ homeostasis. At the interface between the extracellular matrix (ECM) and flowing fluids, epithelial and endothelial barriers are responsible for solute and gas exchange. In the past decade, microfluidic technologies and organ-on-chip devices became popular as in vitro models able to recapitulate these biological barriers. However, in conventional microfluidic devices, cell barriers are primarily grown on hard polymeric membranes within polydimethylsiloxane (PDMS) channels that do not mimic the cell-ECM interactions nor allow the incorporation of other cellular compartments such as stromal tissue or vascular structures. To develop models that accurately account for the different cellular and acellular compartments of tissue barriers, researchers have integrated hydrogels into microfluidic setups for tissue barrier-on-chips, either as cell substrates inside the chip, or as self-contained devices. These biomaterials provide the soft mechanical properties of tissue barriers and allow the embedding of stromal cells. Combining hydrogels with microfluidics technology provides unique opportunities to better recreate in vitro the tissue barrier models including the cellular components and the functionality of the in vivo tissues. Such platforms have the potential of greatly improving the predictive capacities of the in vitro systems in applications such as drug development, or disease modeling. Nevertheless, their development is not without challenges in their microfabrication. In this review, we will discuss the recent advances driving the fabrication of hydrogel microfluidic platforms and their applications in multiple tissue barrier models.
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http://dx.doi.org/10.1021/acsami.0c21573DOI Listing
March 2021

Self-organized Mouse Small Intestinal Epithelial Monolayer Protocol.

Bio Protoc 2020 Feb 5;10(3):e3514. Epub 2020 Feb 5.

Biomimetic Systems for Cell Engineering Laboratory, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

Developing protocols to obtain intestinal epithelial monolayers that recapitulate physiology to overcome the limitations of the organoids' closed geometry has become of great interest during the last few years. Most of the developed culture models showed physiological-relevant cell composition but did not prove self-renewing capacities. Here, we show a simple method to obtain mouse small intestine-derived epithelial monolayers organized into proliferative crypt-like domains, containing stem cells, and differentiated villus-like regions, closely resembling the cell composition and distribution. In addition, we adapted our model to a tissue culture format compatible with functional studies and prove close to physiological barrier properties of our epithelial monolayers. Thus, we have set-up a protocol to generate physiologically relevant intestinal epithelial monolayers to be employed in assays where independent access to both luminal and basolateral compartments is needed, such as drug absorption, intracellular trafficking and microbiome-epithelium interaction assays.
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http://dx.doi.org/10.21769/BioProtoc.3514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842693PMC
February 2020

Surface Superconductivity Changes of Niobium Sheets by Femtosecond Laser-Induced Periodic Nanostructures.

Nanomaterials (Basel) 2020 Dec 16;10(12). Epub 2020 Dec 16.

Bundesanstalt für Materialforschung und -prüfung (BAM), Unter den Eichen 87, 12205 Berlin, Germany.

Irradiation with ultra-short (femtosecond) laser beams enables the generation of sub-wavelength laser-induced periodic surface structures (LIPSS) over large areas with controlled spatial periodicity, orientation, and depths affecting only a material layer on the sub-micrometer scale. This study reports on how fs-laser irradiation of commercially available Nb foil samples affects their superconducting behavior. DC magnetization and AC susceptibility measurements at cryogenic temperatures and with magnetic fields of different amplitude and orientation are thus analyzed and reported. This study pays special attention to the surface superconducting layer that persists above the upper critical magnetic field strength , and disappears at a higher nucleation field strength . Characteristic changes were distinguished between the surface properties of the laser-irradiated samples, as compared to the corresponding reference samples (non-irradiated). Clear correlations have been observed between the surface nanostructures and the nucleation field , which depends on the relative orientation of the magnetic field and the surface patterns developed by the laser irradiation.
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http://dx.doi.org/10.3390/nano10122525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765670PMC
December 2020

Editorial: When the Shape Does Matter: Three-Dimensional Models of Epithelial Barriers.

Front Bioeng Biotechnol 2020 1;8:617361. Epub 2020 Dec 1.

Biomimetic Systems for Cell Engineering, Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology, Barcelona, Spain.

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http://dx.doi.org/10.3389/fbioe.2020.617361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736602PMC
December 2020

Priority and emerging organic microcontaminants in three Mediterranean river basins: Occurrence, spatial distribution, and identification of river basin specific pollutants.

Sci Total Environ 2021 Feb 17;754:142344. Epub 2020 Sep 17.

Dept. of Environmental Chemistry, IDAEA-CSIC, c/Jordi Girona 18-26, 08034 Barcelona, Spain; Catalan Institute for Water Research (ICRA), Emili Grahit, 101, Edifici H(2)O, Parc Científic i Tecnològic de la Universitat de Girona, 17003 Girona, Spain.

There is a worldwide growing use of chemicals by our developed, industrialized, and technological society. More than 100,000 chemical substances are thus commonly used both by industry and households. Depending on the amount produced, physical-chemical properties, and mode of use, many of them may reach the environment and, notably, the aquatic receiving systems. This may result in undesirable and harmful side-effects on both the human and the ecosystem's health. Mediterranean rivers are largely different from Northern and Central European rivers in terms of hydrological regime, climate conditions (e.g. air temperature, solar irradiation, precipitation), and socio-economics (e.g. land use, tourism, crop types, etc.), with all these factors leading to differences in the relative importance of the environmental stressors, in the classes and levels of the pollutants found and their environmental fate. Furthermore, water scarcity might be critical in affecting water pollution because of the lowered dilution capacity of chemicals. This work provides raw chemical data from different families of microcontaminants identified in three selected Mediterranean rivers (the Sava, Evrotas, and Adige) collected during two sampling campaigns conducted in 2014 and 2015 in three different matrices, namely, water, sediments, and biota (fish). More than 200 organic micropollutants were analyzed, including relevant groups like pharmaceuticals, personal care products, perfluorinated compounds, pesticides, pyrethroid insecticides, flame retardants, and persistent organic pollutants. Data obtained were summarized with some basic statistics for all compound families and matrices analyzed. Observed occurrence and spatial patterns were interpreted both in terms of compound physical-chemical properties and local environmental pressures. Finally, their spatial distribution was examined and their ecotoxicological risk in the water phase was assessed. This allowed locating, at each basin, the most polluted sites ("hot spots") and identifying the respective river basin specific pollutants (RBSPs), prioritizing them in terms of the potential ecotoxicological risk posed to the aquatic ecosystems.
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http://dx.doi.org/10.1016/j.scitotenv.2020.142344DOI Listing
February 2021

Complete microbial genomes for public health in Australia and the Southwest Pacific.

Microb Genom 2020 12 12;6(12). Epub 2020 Nov 12.

Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3001, Australia.

Complete genomes of microbial pathogens are essential for the phylogenomic analyses that increasingly underpin core public health laboratory activities. Here, we announce a BioProject (PRJNA556438) dedicated to sharing complete genomes chosen to represent a range of pathogenic bacteria with regional importance to Australia and the Southwest Pacific; enriching the catalogue of globally available complete genomes for public health while providing valuable strains to regional public health microbiology laboratories. In this first step, we present 26 complete high-quality bacterial genomes. Additionally, we describe here a framework for reconstructing complete microbial genomes and highlight some of the challenges and considerations for accurate and reproducible genome reconstruction.
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http://dx.doi.org/10.1099/mgen.0.000471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116684PMC
December 2020

Body size and weight change over adulthood and risk of breast cancer by menopausal and hormone receptor status: a pooled analysis of 20 prospective cohort studies.

Eur J Epidemiol 2021 Jan 30;36(1):37-55. Epub 2020 Oct 30.

Epidemiology and Prevention Group, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan.

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC.
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http://dx.doi.org/10.1007/s10654-020-00688-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847460PMC
January 2021

Contaminants of emerging concern in the Basque coast (N Spain): Occurrence and risk assessment for a better monitoring and management decisions.

Sci Total Environ 2021 Apr 5;765:142765. Epub 2020 Oct 5.

AZTI, Marine Research, Basque Research and Technology Alliance (BRTA), Herrera Kaia, Portualdea z/g, 20110, Pasaia, Spain.

The study of the presence in the aquatic environment of certain substances considered as contaminants of emerging concern (CEC) is a preliminary step to the analysis of the possible harmful effects on aquatic ecosystems and the establishment of the corresponding environmental quality standards. In order to monitor the occurrence of CECs in the aquatic environment, the European Commission established in 2015 and 2018 two watch-list of substances for Union-wide monitoring in the field of water policy (Decision (EU) 2015/495 and Decision (EU) 2018/840). In the coast of the Basque Country, southeast of the Bay of Biscay, 19 of these watch list substances were monitored quarterly from May 2017 to March 2019. Water samples were collected at the effluent of three wastewater treatment plants and five control points associated with receiving waters (transitional and coastal water bodies). The most frequently quantified substances were azithromycin (91%), imidacloprid (82%), clarithromycin (80%), diclofenac (78%) and erythromycin (73%), with frequencies of quantification higher in wastewaters (83-100%) than in receiving waters (70-85%). In general, concentrations in wastewater were also higher than in receiving waters, indicating a dilution effect in the environment. In receiving waters, six out of the nineteen substances monitored exceeded their respective Predicted No-Effect Concentrations: azithromycin (34%), imidacloprid (9%), 17β-estradiol (E2) (9%), clarithromycin (7%), ciprofloxacin (7%), and diclofenac (5%); and therefore, their levels could pose an environmental risk.
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http://dx.doi.org/10.1016/j.scitotenv.2020.142765DOI Listing
April 2021

Development of an Improved 3D Intestinal Model to Perform Permeability Studies of Paracellular Compounds.

Front Bioeng Biotechnol 2020 17;8:524018. Epub 2020 Sep 17.

Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.

The small intestine is the primary site of drug absorption following oral administration, making paramount the proper monitoring of the absorption process. tools to predict intestinal absorption are particularly important in preclinical drug development since they are less laborious and cost-intensive and raise less ethical considerations compared to studies. The Caco-2 model is considered the gold standard of intestinal models regarding the prediction of absorption of orally delivered compounds. However, this model presents several drawbacks, such as the expression of tighter tight junctions, not being suitable to perform permeability of paracellular compounds. Besides, cells are representative of only one intestinal cell type, without considering the role of non-absorptive cells on the absorption pathway of drugs. In the present study, we developed a new three-dimensional (3D) intestinal model that aims to bridge the gap between tools and animal studies. Our 3D model comprises a collagen layer with human intestinal fibroblasts (HIFs) embedded, mimicking the intestinal lamina propria and providing 3D support for the epithelium, composed of Caco-2 cells and mucus-producing HT29-MTX cells, creating a model that can better resemble, both in terms of composition and regarding the outcomes of drug permeability when testing paracellular compounds, the human small intestine. The optimization of the collagen layer with HIFs was performed, testing different collagen concentrations and HIF seeding densities in order to avoid collagen contraction before day 14, maintaining HIF metabolically active inside the collagen disks during time in culture. HIF morphology and extracellular matrix (ECM) deposition were assessed, confirming that fibroblasts presented a normal and healthy elongated shape and secreted fibronectin and laminin, remodeling the collagen matrix. Regarding the epithelial layer, transepithelial electrical resistance (TEER) values decreased when cells were in the 3D configuration, comparing with the 2D analogs (Caco-2 and coculture of Caco-2+HT29-MTX models), becoming more similar with values. The permeability assay with fluorescein isothiocyanate (FITC)-Dextran 4 kDa showed that absorption in the 3D models is significantly higher than that in the 2D models, confirming the importance of using a more biorelevant model when testing the paracellular permeability of compounds.
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http://dx.doi.org/10.3389/fbioe.2020.524018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527803PMC
September 2020

Primary Maxillary Reconstruction With Fibula Flap and Dental Implants: A Comparative Study Between Virtual Surgical Planning and Standard Surgery in Class IIC Defects.

J Oral Maxillofac Surg 2021 01 8;79(1):237-248. Epub 2020 Aug 8.

Professor and Head, Maxillofacial Surgery Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Purpose: Oncological patients who undergo bilateral subtotal maxillectomies develop functional and esthetic sequelae that require immediate reconstruction. The purpose of this study is to evaluate the primary reconstruction of maxillary defects with fibula flap and dental implants assisted by virtual surgical planning (VSP) and to assess the postoperative outcomes compared with standard surgery.

Material And Methods: A retrospective study was designed between January 2016 and April 2020 with 12 oncologic patients who underwent subtotal bilateral maxillectomy. Six consecutive patients were treated by standard surgical procedure (SS) at the beginning of the study. In 2018, the VSP was implemented, and 6 consecutive patients were treated using this technique. All patients were rehabilitated with Ticare implants and implant prostheses. Anatomic position of the bone, bone apposition, change of vertical distance, and horizontal shift, the operative and ischemia time, the esthetic results, and the functional rehabilitation were evaluated and compared.

Results: The position of the bone in anatomical position was 100% in the VSP group vs 66% in the SS group. The bone apposition was 100% in the VSP group vs 83.3%. The change of vertical distance and the horizontal shift were lower in the VSP group (P < .05). The ischemia time and operative time were shorter in the VSP group (P < .05). A good esthetic result was achieved in 83.3% in the VSP group vs 33.3% in the SS group; 81 dental implants and 1 zygomatic implant were placed. The success rate was 95% in the VSP group and 92.6% in the SS group. All patients were rehabilitated with implant prosthesis.

Conclusions: VSP improves the accuracy of midface reconstruction (class IIC defect) with a better anatomical position of the bone, a higher rate of bone contact, and a lower change in vertical distance compared with standard surgery. It significantly improves the esthetic result, reduces ischemia time, and operation time.
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http://dx.doi.org/10.1016/j.joms.2020.08.003DOI Listing
January 2021

Risk of COVID-19 among front-line health-care workers and the general community: a prospective cohort study.

Lancet Public Health 2020 09 31;5(9):e475-e483. Epub 2020 Jul 31.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Background: Data for front-line health-care workers and risk of COVID-19 are limited. We sought to assess risk of COVID-19 among front-line health-care workers compared with the general community and the effect of personal protective equipment (PPE) on risk.

Methods: We did a prospective, observational cohort study in the UK and the USA of the general community, including front-line health-care workers, using self-reported data from the COVID Symptom Study smartphone application (app) from March 24 (UK) and March 29 (USA) to April 23, 2020. Participants were voluntary users of the app and at first use provided information on demographic factors (including age, sex, race or ethnic background, height and weight, and occupation) and medical history, and subsequently reported any COVID-19 symptoms. We used Cox proportional hazards modelling to estimate multivariate-adjusted hazard ratios (HRs) of our primary outcome, which was a positive COVID-19 test. The COVID Symptom Study app is registered with ClinicalTrials.gov, NCT04331509.

Findings: Among 2 035 395 community individuals and 99 795 front-line health-care workers, we recorded 5545 incident reports of a positive COVID-19 test over 34 435 272 person-days. Compared with the general community, front-line health-care workers were at increased risk for reporting a positive COVID-19 test (adjusted HR 11·61, 95% CI 10·93-12·33). To account for differences in testing frequency between front-line health-care workers and the general community and possible selection bias, an inverse probability-weighted model was used to adjust for the likelihood of receiving a COVID-19 test (adjusted HR 3·40, 95% CI 3·37-3·43). Secondary and post-hoc analyses suggested adequacy of PPE, clinical setting, and ethnic background were also important factors.

Interpretation: In the UK and the USA, risk of reporting a positive test for COVID-19 was increased among front-line health-care workers. Health-care systems should ensure adequate availability of PPE and develop additional strategies to protect health-care workers from COVID-19, particularly those from Black, Asian, and minority ethnic backgrounds. Additional follow-up of these observational findings is needed.

Funding: Zoe Global, Wellcome Trust, Engineering and Physical Sciences Research Council, National Institutes of Health Research, UK Research and Innovation, Alzheimer's Society, National Institutes of Health, National Institute for Occupational Safety and Health, and Massachusetts Consortium on Pathogen Readiness.
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http://dx.doi.org/10.1016/S2468-2667(20)30164-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491202PMC
September 2020

AlO:Yb integrated microdisk laser label-free biosensor.

Opt Lett 2019 Dec;44(24):5937-5940

Whispering gallery mode resonator lasers hold the promise of an ultralow intrinsic limit of detection. However, the widespread use of these devices for biosensing applications has been hindered by the complexity and lack of robustness of the proposed configurations. In this work, we demonstrate biosensing with an integrated microdisk laser. doped with was utilized because of its low optical losses as well as its emission in the range 1020-1050 nm, outside the absorption band of water. Single-mode laser emission was obtained at a wavelength of 1024 nm with a linewidth of 250 kHz while the microdisk cavity was submerged in water. A limit of detection of 300 pM (3.6 ng/ml) of the protein rhS100A4 in urine was experimentally demonstrated, showing the potential of the proposed devices for biosensing.
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http://dx.doi.org/10.1364/OL.44.005937DOI Listing
December 2019

Impact of COVID-19 outbreak on ischemic stroke admissions and in-hospital mortality in North-West Spain.

Int J Stroke 2020 10 26;15(7):755-762. Epub 2020 Jun 26.

Department of Neurology, Hospital Clínico Lozano Blesa, Zaragoza, Spain.

Background And Purpose: Spain has been one of the countries heavily stricken by COVID-19. But this epidemic has not affected all regions equally. We analyzed the impact of the COVID-19 pandemic on hospital stroke admissions and in-hospital mortality in tertiary referral hospitals from North-West Spain.

Methods: Spanish multicenter retrospective observational study based on data from tertiary hospitals of the NORDICTUS network. We recorded the number of patients admitted for ischemic stroke between 30 December 2019 and 3 May 2020, the number of IVT and EVT procedures, and in-hospital mortality.

Results: In the study period, 2737 patients were admitted with ischemic stroke. There was a decrease in the weekly mean admitted patients during the pandemic (124 vs. 173, p<0.001). In-hospital mortality of stroke patients increased significantly (9.9% vs. 6.5%, p = 0.003), but there were no differences in the proportion of IVT (17.3% vs. 16.1%, p = 0.405) or EVT (22% vs. 23%, p = 0.504).

Conclusion: We found a decrease in the number of ischemic stroke admissions and an increase in in-hospital mortality during the COVID-19 epidemic in this large study from North-West Spain. There were regional changes within the network, not fully explained by the severity of the pandemic in different regions.
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http://dx.doi.org/10.1177/1747493020938301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322514PMC
October 2020

Imaging the Cell Morphological Response to 3D Topography and Curvature in Engineered Intestinal Tissues.

Front Bioeng Biotechnol 2020 7;8:294. Epub 2020 Apr 7.

Biomimetic Systems for Cell Engineering, Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology, Barcelona, Spain.

While conventional cell culture methodologies have relied on flat, two-dimensional cell monolayers, three-dimensional engineered tissues are becoming increasingly popular. Often, engineered tissues can mimic the complex architecture of native tissues, leading to advancements in reproducing physiological functional properties. In particular, engineered intestinal tissues often use hydrogels to mimic villi structures. These finger-like protrusions of a few hundred microns in height have a well-defined topography and curvature. Here, we examined the cell morphological response to these villus-like microstructures at single-cell resolution using a novel embedding method that allows for the histological processing of these delicate hydrogel structures. We demonstrated that by using photopolymerisable poly(ethylene) glycol as an embedding medium, the villus-like microstructures were successfully preserved after sectioning with vibratome or cryotome. Moreover, high-resolution imaging of these sections revealed that cell morphology, nuclei orientation, and the expression of epithelial polarization markers were spatially encoded along the vertical axis of the villus-like microstructures and that this cell morphological response was dramatically affected by the substrate curvature. These findings, which are in good agreement with the data reported for experiments on the native tissue, are likely to be the origin of more physiologically relevant barrier properties of engineered intestinal tissues when compared with standard monolayer cultures. By showcasing this example, we anticipate that the novel histological embedding procedure will have a positive impact on the study of epithelial cell behavior on three-dimensional substrates in both physiological and pathological situations.
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http://dx.doi.org/10.3389/fbioe.2020.00294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154059PMC
April 2020

The Implication of Spatial Statistics in Human Mesenchymal Stem Cell Response to Nanotubular Architectures.

Int J Nanomedicine 2020 30;15:2151-2169. Epub 2020 Mar 30.

Faculty of Engineering, Department of Mechanical Engineering, University of Ottawa, Ottawa, ON, Canada.

Introduction: In recent years there has been ample interest in nanoscale modifications of synthetic biomaterials to understand fundamental aspects of cell-surface interactions towards improved biological outcomes. In this study, we aimed at closing in on the effects of nanotubular TiO surfaces with variable nanotopography on the response on human mesenchymal stem cells (hMSCs). Although the influence of TiO nanotubes on the cellular response, and in particular on hMSC activity, has already been addressed in the past, previous studies overlooked critical morphological, structural and physical aspects that go beyond the simple nanotube diameter, such as spatial statistics.

Methods: To bridge this gap, we implemented an extensive characterization of nanotubular surfaces generated by anodization of titanium with a focus on spatial structural variables including eccentricity, nearest neighbour distance (NND) and Voronoi entropy, and associated them to the hMSC response. In addition, we assessed the biological potential of a two-tiered honeycomb nanoarchitecture, which allowed the detection of combinatory effects that this hierarchical structure has on stem cells with respect to conventional nanotubular designs. We have combined experimental techniques, ranging from Scanning Electron (SEM) and Atomic Force (AFM) microscopy to Raman spectroscopy, with computational simulations to characterize and model nanotubular surfaces. We evaluated the cell response at 6 hrs, 1 and 2 days by fluorescence microscopy, as well as bone mineral deposition by Raman spectroscopy, demonstrating substrate-induced differential biological cueing at both the short- and long-term.

Results: Our work demonstrates that the nanotube diameter is not sufficient to comprehensively characterize nanotubular surfaces and equally important parameters, such as eccentricity and wall thickness, ought to be included since they all contribute to the overall spatial disorder which, in turn, dictates the overall bioactive potential. We have also demonstrated that nanotubular surfaces affect the quality of bone mineral deposited by differentiated stem cells. Lastly, we closed in on the integrated effects exerted by the superimposition of two dissimilar nanotubular arrays in the honeycomb architecture.

Discussion: This work delineates a novel approach for the characterization of TiO nanotubes which supports the incorporation of critical spatial structural aspects that have been overlooked in previous research. This is a crucial aspect to interpret cellular behaviour on nanotubular substrates. Consequently, we anticipate that this strategy will contribute to the unification of studies focused on the use of such powerful nanostructured surfaces not only for biomedical applications but also in other technology fields, such as catalysis.
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http://dx.doi.org/10.2147/IJN.S238280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125340PMC
June 2020

Modeling Variation in the Reproductive Lifespan of Female Adolescent and Young Adult Cancer Survivors Using AMH.

J Clin Endocrinol Metab 2020 08;105(8)

Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health and Moores Cancer Center, University of California, San Diego, La Jolla, California.

Context: Many female survivors of adolescent and young adult cancers (AYA survivors) have shortened reproductive lifespans. However, the timing and duration of ovarian function after cancer treatment are largely unknown.

Objective: To model the trajectory of ovarian function over two decades following cancer treatment and evaluate how trajectories vary by treatment gonadotoxicity and age.

Design: In a prospective cohort, AYA survivors aged 18-39 at variable times since cancer treatment completion provided dried blood spots (DBS) every 6 months for up to 18 months. Anti-Müllerian hormone (AMH) levels were measured using the Ansh DBS AMH enzyme-linked immunosorbent assay. The mean AMH trajectory was modeled for the entire cohort and separately by treatment gonadotoxicity and age using functional principal components analysis.

Results: 763 participants, mean (standard deviation) enrollment age 33.3 (4.7) and age at cancer diagnosis 25.9 (5.7) years, contributed 1905 DBS samples. The most common cancers were breast (26.9%), lymphoma (24.8%), and thyroid (18.0%). AMH trajectories differed among survivors by treatment gonadotoxicity (low, moderate, or high) (P < 0.001). Following low or moderately gonadotoxic treatments, AMH levels increased over 2-3 years and plateaued over 10-15 years before declining. In contrast, following highly gonadotoxic treatment, AMH levels were lower overall and declined shortly after peak at 2-3 years. Younger age at treatment was associated with higher trajectories, but a protective effect of younger age was not observed in survivors exposed to highly gonadotoxic treatments (Pinteraction < 0.001).

Conclusions: In this large AYA survivor cohort, timing and duration of ovarian function strongly depended on treatment gonadotoxicity and age at treatment. The findings provide novel, more precise information to guide reproductive decision-making.
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http://dx.doi.org/10.1210/clinem/dgaa172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329316PMC
August 2020

Microfabrication of poly(acrylamide) hydrogels with independently controlled topography and stiffness.

Biofabrication 2020 03 4;12(2):025023. Epub 2020 Mar 4.

Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), c/Baldiri Reixac 10-12, E-08028, Barcelona, Spain.

The stiffness and topography of a cell's extracellular matrix (ECM) are physical cues that play a key role in regulating processes that determine cellular fate and function. While substrate stiffness can dictate cell differentiation lineage, migration, and self-organization, topographical features can change the cell's differentiation profile or migration ability. Although both physical cues are present and intrinsic to the native tissues in vivo, in vitro studies have been hampered by the lack of technological set-ups that would be compatible with cell culture and characterization. In vitro studies therefore either focused on screening stiffness effects in cells cultured on flat substrates or on determining topography effects in cells cultured onto hard materials. Here, we present a reliable, microfabrication method to obtain well defined topographical structures of micrometer size (5-10 μm) on soft polyacrylamide hydrogels with tunable mechanical stiffness (3-145 kPa) that closely mimic the in vivo situation. Topographically microstructured polyacrylamide hydrogels are polymerized by capillary force lithography using flexible materials as molds. The topographical microstructures are resistant to swelling, can be conformally functionalized by ECM proteins and sustain the growth of cell lines (fibroblasts and myoblasts) and primary cells (mouse intestinal epithelial cells). Our method can independently control stiffness and topography, which allows to individually assess the contribution of each physical cue to cell response or to explore potential synergistic effects. We anticipate that our fabrication method will be of great utility in tissue engineering and biophysics, especially for applications where the use of complex in vivo-like environments is of paramount importance.
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http://dx.doi.org/10.1088/1758-5090/ab7552DOI Listing
March 2020
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