Does the environment affect menopause? A review of the effects of endocrine disrupting chemicals on menopause.

Endocrine disrupting chemicals are widely distributed in our environment. Humans are exposed to these compounds not only through their occupations, but also through dietary consumption and exposure to contaminated water, personal care products and textiles. Chemicals that are persistent in the body and in our environment include dioxins and polychlorinated biphenyls. Non-persistent chemicals including bisphenol A, phthalates and parabens are equally as important because they are ubiquitous in our environment. Heavy metals, including lead and cadmium, can also have endocrine disrupting properties. Although difficult to study due to their variety of sources of exposures and mechanisms of action, these chemicals have been associated with early menopause, increased frequency of vasomotor symptoms, altered steroid hormone levels and markers of diminished ovarian reserve. Understanding the impacts of these exposures is important given the potential for epigenetic modification, which can alter gene function and result in multi-generational effects. This review summarizes findings in humans and animals or cell-based models from the past decade of research. Continued research is needed to assess the effects of mixtures of chemicals, chronic exposures and new compounds that are continuously being developed as replacements for toxic chemicals that are being phased out.

Intratumoral delivery of tavokinogene telseplasmid yields systemic immune responses in metastatic melanoma patients.

BACKGROUND: Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT01502293). PATIENTS AND METHODS: Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre- and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). RESULTS: The objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance. CONCLUSIONS: Intratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/distal lesions, adaptive immune resistance limited the response.

Simulation of TTT Curves for Additively Manufactured Inconel 625.

The ability to use common computational thermodynamic and kinetic tools to study the microstructure evolution in Inconel 625 (IN625) manufactured using the additive manufacturing (AM) technique of laser powder-bed fusion is evaluated. Solidification simulations indicate that laser melting and re-melting during printing produce highly segregated interdendritic regions. Precipitation simulations for different degrees of segregation show that the larger the segregation, i.e., the richer the interdendritic regions are in Nb and Mo, the faster the δ-phase (Ni3Nb) precipitation. This is in accordance with the accelerated d precipitation observed experimentally during post-build heat treatments of AM IN625 compared to wrought IN625. The δ-phase may be undesirable since it can lead to detrimental effects on the mechanical properties. The results are presented in the form of a TTT diagram and agreement between the simulated diagram and the experimental TTT diagram demonstrate how these computational tools can be used to guide and optimize post-build treatments of AM materials.

Topographic Measurement of Individual Laser Tracks in Alloy 625 Bare Plates.

Additive manufacturing (AM) combines all of the complexities of materials processing and manufacturing into a single process. The digital revolution made this combination possible, but the commercial viability of these technologies for critical parts may depend on digital process simulations to guide process development, product design, and part qualification. For laser powder bed fusion (LPBF), one must be able to model the behavior of a melt pool produced by a laser moving at a constant velocity over a smooth bare metal surface before taking on the additional complexities of this process. To provide data on this behavior for model evaluations, samples of a single-phase nickel-based alloy were polished smooth and exposed to a laser beam at 3 different power and speed settings in the National Institute of Standards and Technology (NIST) Additive Manufacturing Metrology Testbed (AMMT) and a commercial AM machine. The solidified track remaining in the metal surface after the passing of the laser is a physical record of the position of the air-liquid-solid interface of the melt pool trailing behind the laser. The surface topography of these tracks was measured and quantified using confocal laser scanning microscopy (CLSM) for use as benchmarks in AM model development and validation. These measurements are part of the Additive Manufacturing Benchmark Test Series (AM-Bench).

Grafts for Peyronie's disease: a comprehensive review.

The difficulty implicit in combining all the characteristics that an ideal patch to treat Peyronie's disease with a lengthening procedure should have, together with the challenges of comparing results from different series, means that the ideal patch has yet to be determined. Our objective with this review was to determine whether any given patch type is preferable to the others based on the evaluation of the results of published studies. A systematic search of the literature was conducted from PubMed until December 2016. Articles reporting basic research, animal research, reviews or meta-analyses and studies in children were eliminated. Series with patients undergoing some kind of other surgical intervention were only included if results were reported separately. Case reports and series of five patients were excluded. Five variables were selected to evaluate the results: number of patients, follow-up period, straightening rate, shortening rate and post-operative ED rate. For this purpose, 69 papers were included for review, and the outcomes of the use of autologous dermis, tunica vaginalis, dura mater, fascia, saphenous vein, tunica albuginea, buccal mucosa, porcine intestinal submucosa, pericardium, TachoSil® and synthetic materials were presented and analysed separately. The different series published are extremely variable and heterogeneous in terms of the number of patients included, patient selection, follow-up periods, and in the measurement and interpretation of the outcomes analysed. Given these facts, it is not possible to draw any definitive conclusion, homogeneous, prospective studies using validated tools are required to determine which the ideal graft is.

The Influence of Annealing Temperature and Time on the Formation of δ-Phase in Additively-Manufactured Inconel 625.

This research evaluated the kinetics of δ-phase growth in laser powder bed additively-manufactured (AM) Inconel 625 during post-build stress-relief heat treatments. The temperatures ranged between 650°C and 1050°C, and the times from 0.25 to 168 hours. The presence of δ-phase was verified for each temperature/time combination through multiple techniques. A conventional time-temperature-transformation diagram was constructed from the time-temperature data. Comparison to the growth in wrought IN625 with a similar nominal composition revealed that δ-phase formation occurred at least two orders of magnitude faster in the AM IN625. The results of this study also revealed that the segregated microstructure in the as-built condition has a strong influence on the kinetics of δ-phase formation in AM IN625 as compared to a homogenized material. Since control of the δ-phase growth is essential for reliable prediction of the performance of IN625 components in service, avoiding heat treatments that promote the formation of δ-phase in AM components that are not homogenized is highly recommended. This will be particularly true at elevated temperatures where the microstructural stability and the consistency of mechanical properties are more likely to be affected by the presence of δ-phase.

The Influence of Post-Build Microstructure on the Electrochemical Behavior of Additively Manufactured 17-4 PH Stainless Steel.

The additive manufacturing (AM) build process produces a segregated microstructure with significant variations in composition and phases that are uncommon in traditional wrought materials. As such, the relationship between the post-build microstructure and the corrosion resistance is not well understood. Stainless steel alloy 17-4PH is an industrially-relevant alloy for applications requiring high-strength and good corrosion resistance. A series of potentiodynamic scans conducted in a deaerated 0.5 mol/L NaCl solution evaluated the influence of these microstructural differences on the pitting behavior of SS17-4. The pitting potentials were found to be higher in the samples of additively-processed material than in samples of the alloy in wrought form. This indicates that the additively-processed material is more resistant to localized corrosion and pitting in this environment than the wrought alloy. The results also suggest that after homogenization, the additively-produced SS17-4 could be more resistant to pitting than wrought SS17-4 in an actual service environment.