Fertility-Sparing Approaches in Atypical Endometrial Hyperplasia and Endometrial Cancer Patients: Current Evidence and Future Directions

Endometrial cancer (EC) is the fourth most common cancer in women in developed countries. Although it is usually diagnosed in postmenopausal women, its incidence has increased in young women, as well in recent decades, with an estimated rate of 4% in those under 40 years of age. Factors involved in this increase, particularly in resource-rich countries, include delayed childbearing and the rise in obesity. The new molecular classification of EC should help to personalize treatment, through appropriate candidate selection. With the currently available evidence, the use of oral progestin either alone or in combination with other drugs such as metformin, levonorgestrel-releasing intrauterine devices and hysteroscopic resection, seems to be feasible and safe in women with early-stage EC limited to the endometrium. However, there is a lack of high-quality evidence of the efficacy and safety of conservative management in EC. Randomized clinical trials in younger women and obese patients are currently underway.     

Enhanced recombinant protein synthesis in batch and fed‐batch Escherichia coli fermentation based on removal of inhibitory acetate by electrodialysis

BACKGROUND: The formation of acetate as a metabolic by‐product in Escherichia coli fermentation is well known to have detrimental effects on cell growth and productivity. Various bioprocess and genetic approaches have previously been made to limit acetate accumulation, however, they tend to be conservative, limiting overall process productivity, or lead to other problems such as a decrease in maximum specific growth rate and decreased product yield on carbon. RESULTS: In this work, the utility of electrodialysis is examined as a potentially generic approach for in situ acetate removal and its impact on recombinant protein production. Using the induced synthesis of recombinant green fluorescent protein (GFP) in E. coli Tg1 (pGLO) as an example, it is shown that in situ removal of acetate to below inhibitory levels (～1 g L^?1) provides significant improvements in cell growth rate as well as specific biomass and recombinant protein yields. Experiments were performed in a 7.5 L stirred‐tank bioreactor using an external single cell‐pair electrodialysis module with an effective ion exchange membrane area of 0.01 m 2 . For this system increases in specific recombinant protein yield of up to 4‐fold have been observed dependent upon the time of induction, the mode of operation and the level to which acetate concentration is reduced in the fermentation broth. CONCLUSIONS: The implementation of ED can significantly increase the level of recombinant protein synthesis in batch and fed‐batch fermentation. The approach is considered to be generic, readily implemented and has wide application for the production of recombinant enzymes and proteins. Copyright © 2009 Society of Chemical Industry     

Electrocoagulation pretreatment of seawater prior to ultrafiltration: Pilot-scale applications for military water purification systems

The objectives were to investigate the performance of a pilot-scale electrocoagulation (EC) reactor and to determine the feasibility of using in-line EC as a pretreatment to ultrafiltration (UF) of seawater. Work was conducted at Port Hueneme, CA, using components of a U.S. military water purification system. Ferric chloride in-line coagulation was also tested. Both the EC and ferric chloride pretreatments improved UF membrane performance compared to UF without in-line coagulation. EC resulted in slightly greater increases in transmembrane pressure (TMP) than observed following ferric chloride pretreatment during sub-critical flux UF. Substantial accumulation of precipitates developed on the EC electrodes during the testing period. X-ray diffraction identified magnetite, maghemite, lepidocrocite, and akaganeite phases. Accumulation of these precipitates was due in part to conservative hydraulic design of the EC unit. It is recommended that EC units should be designed with short hydraulic retention times and higher electrode current density in order to increase upflow (scour) velocity and thus inhibit accumulation on the electrodes. Progressively longer cycling times for polarity reversal are also recommended. This research indicates that EC offers the potential for a feasible and effective pretreatment strategy for mobile water production facilities.     

Impaired cholesterol esterification in the plasma in patients with breast cancer

An important factor which determines the movement of cholesterol in and out of the cells is the free cholesterol (FC)/esterified cholesterol (EC) ratio in the plasma. Although this ratio has been shown to be increased in several types of malignancies in humans as well as experimental animals, it is not known whether such an abnormality is found in breast cancer patients. Furthermore, the reasons for such an increase in cancer patients are unknown. We studied the plasma lipid composition and the activity of lecithin-cholesterol acyltransferase (LCAT), the enzyme responsible for the formation of most of EC in human plasma, in 12 women with breast cancer and 9 agematched control women. The plasma EC concentration was found to be significantly decreased in cancer patients, whereas the FC concentration was unchanged, leading to increased FC/EC ratios (P<0.05). The concentration of phosphatidylcholine, the acyl donor in the LCAT reaction, was decreased significantly, whereas all other phospholipids were unaffected. The cholesterol-esterifying activity of LCAT was significantly lower in cancer patients, whether assayed with endogenous substrates (P<0.05), or with an exogenous substrate (P<0.01). However, another function of the enzyme, namely the lysolecithin acyltransferase activity, was increased (P<0.02), indicating that the enzyme concentration in plasma may not be decreased. These results show that the increase in the FC/EC ratio in cancer patients is due to an impaired esterification of cholesterol by plasma LCAT, probably due to an alteration in the composition of substrate lipoproteins, or the presence of an inhibitory factor.     

Limitations of the LDF/equimolar counterdiffusion assumption for mass transport within porous adsorbent pellets

Mass transfer resistance plays an important role in the performance of a periodic adsorption process under rapid cycling conditions. In this study, we examine the limitations of the Fick plus equimolar counterdiffusion (F+EC) and linear driving force (LDF) model for simulating the enrichment of oxygen from air in comparison to the dusty gas model (DGM) under rapid pressure swing adsorption (RPSA) conditions. A conservative, finite volume approach to the solution of the governing differential equations is developed and validated for an adsorbent pellet. Two variations on the RPSA boundary conditions at the pellet surface are investigated. The first considers the square-wave change in concentration from adsorption to desorption investigated with the RPSA-LDF model of Nakao and Suzuki (J. Chem. Eng. Jpn. 16(1983)114). The second considers the partial pressure variation as predicted from an adsorption simulator, representative of the true conditions experienced over a two-step RPSA cycle. From both cases, the impact of bulk gas motion within the pores (DGM) resulted in deviations exceeding 30% on the predicted working capacity of the sieve. This identifies the equimolar counterdiffusion assumption as a significant limitation for predicting performance with macro-mesoporous adsorbents. Along with bulk flow, an additional 10-50% deviation resulted from the RPSA-LDF model incorrectly predicting working capacity (in relation to the F+EC) for the case where boundary conditions do not follow a step change. To propose additional cycle-time-corrected correlations and/or intrapellet concentration profiles when approaching the RPSA limit appears futile given the range of operating conditions expected over a true cycle. The level of radial discretisation within the pellet also appears to be more sensitive for the F+EC as opposed to the DGM approach. These trends were observed for dimensionless cycle times exceeding the traditionally excepted critical value of 0.1, highlighting the importance of a DGM approach in describing mass transfer when approaching the RPSA limit.     

An elucidation of symmetric supercapacitor with crustacean-based polymer blend electrolyte

Searching for alternative materials that have biodegradable properties is one of the efforts to increase knowledge and green technology that contributes to the reduction of waste produced from electronics. A biodegradable biopolymer electrolyte system based on polyvinyl alcohol-chitosan blend is prepared using an easy and affordable method called solution cast technique. Lithium acetate (LiOAc) and ethylene carbonate (EC) are incorporated as charge carrier and plasticizing agent. The plasticization effect of EC concentrations on physical structure has been investigated and reported. The real and imaginary parts of dielectric permittivity confirmed that the highest dielectric constant and loss values are recorded at low-frequencies regions. A disruption in the crystalline region of the film can be observed with the existence of LiOAc and EC. The inclusion of EC promotes the ions dissociation thus enhanced the amorphous region of the electrolytes which is beneficial for ionic conduction. Linear sweep voltammetry analysis revealed that the highest conducting electrolyte is electrochemically stable up to 1.82 V. No redox peaks are shown in the cyclic voltammetry of the fabricated supercapacitor. The supercapacitor showed a great performance with average specific capacitance of 130 F g⁻¹.     

Limitations to the diagnostic information obtained from soil analyses

The limitations of various methods of soil analysis are discussed. The total analysis of an element gives a simple figure which is, however, useless for diagnositic purposes since nutrient availability differs in various soil fractions. Since the transfer coefficient applied to soil pollutants is based on total soil analysis, it also has no diagnostic value. The use of soil extractants is empirical and is only as good as the calibration curve. It should, therefore, only be applied to those soils for which a good calibration curve has been shown to exist. The scientific approach of Schofield in proposing nutrient potentials is basically correct, but it fails to fully characterize the nutrient availability in soils. Difficulties are of a fundamental nature or are soil or plant related.A possible means of improvement may be a soil classification which is geared towards soil fertility. Soils which react similarly to nutrients should be combined in classification units. For these units, detailed information on the reaction behavior must be obtained. A few simple analyses might suffice to show how a specific field fits into this reaction pattern. Based on the thorough knowledge of the soil (especially its reaction pattern) it is then possible to quantitatively predict for a specific crop plant the changes that occur when nutrients are removed by uptake or added by fertilization.     

Tensile modulus modeling of carbon black/polycarbonate,carbon nanotube/polycarbonate,and exfoliated graphite nanoplatelet/polycarbonate composites

Conductive fillers are often added to thermoplastic polymers to increase the resulting composite's electrical conductivity (EC) which would enable them to be used in electrostatic dissipative and semiconductive applications. The resulting composite also exhibits increased tensile modulus. The filler aspect ratio plays an important role in modeling composite EC, and tensile modulus. It is difficult to measure the filler aspect ratio after the manufacturing process (often extrusion followed by injection molding) in the composite, especially when nanomaterials are used. The EC percolation threshold is a function of the filler aspect ratio; hence, knowledge of this percolation threshold provides a means to extract the filler aspect ratio. In this study, the percolation threshold of the composite was determined from EC measurements and modeling, which in turn was used to determine the filler aspect ratio for tensile modulus modeling. Per the authors' knowledge, this approach has not been previously reported in the open literature. The fillers; carbon black (CB: 2–10 wt %), multiwalled carbon nanotubes (CNT: 0.5–8 wt %), or exfoliated graphite nanoplatelets (GNP: 2–12 wt %); were added to polycarbonate (PC) and the resulting composites were tested for EC and tensile modulus. With the filler aspect ratio determined from EC values for CNT/PC and GNP/PC composites, the three‐dimensional randomly oriented fiber Halpin‐Tsai model accurately estimates the tensile modulus for the CNT/PC composites and the Nielsen model predicts the tensile modulus well for the CB/PC and GNP/PC composites. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Vibrational Biospectroscopy: An Alternative Approach to Endometrial Cancer Diagnosis and Screening

Endometrial cancer (EC) is the sixth most common cancer and the fourth leading cause of death among women worldwide. Early detection and treatment are associated with a favourable prognosis and reduction in mortality. Unlike other common cancers, however, screening strategies lack the required sensitivity, specificity and accuracy to be successfully implemented in clinical practice and current diagnostic approaches are invasive, costly and time consuming. Such limitations highlight the unmet need to develop diagnostic and screening alternatives for EC, which should be accurate, rapid, minimally invasive and cost-effective. Vibrational spectroscopic techniques, Mid-Infrared Absorption Spectroscopy and Raman, exploit the atomic vibrational absorption induced by interaction of light and a biological sample, to generate a unique spectral response: a “biochemical fingerprint”. These are non-destructive techniques and, combined with multivariate statistical analysis, have been shown over the last decade to provide discrimination between cancerous and healthy samples, demonstrating a promising role in both cancer screening and diagnosis. The aim of this review is to collate available evidence, in order to provide insight into the present status of the application of vibrational biospectroscopy in endometrial cancer diagnosis and screening, and to assess future prospects.     

Fibronectin Molecular Status in Plasma of Women with Endometriosis and Fertility Disorders

The diagnosis of endometriosis and fertility disorders is difficult; therefore, it is necessary to look for reliable biomarkers. Analysis of the molecular status of fibronectin as a key player in repair and wound healing processes, as well as in coagulation and fibrinolysis pathways, is justified. ELISA and SDS-agarose immunoblotting were applied to determine the fibronectin concentration and presence and occurrence of soluble FN-fibrin complexes in the blood plasma of women with endometriosis (n = 38), fertility disorders (n = 28) and the healthy group (n = 25). The concentration of fibronectin in the blood plasma of women with endometriosis (292.61 ± 96.17 mg/L) and fertility disorders (287.53 ± 122.68 mg/L) was significantly higher than in the normal group (226.55 ± 91.98 mg/L). The presence of FN-fibrin complexes of 750, 1000, 1300, 1600 and 1900 kDa in the plasma of women with endometriosis and fertility disorders was shown. The presence of FN-fibrin complexes with a molecular mass of more than 1300 kDa in women with endometriosis and infertility and the complete absence of these complexes in healthy women may indicate an increased and chronic activation of coagulation mechanisms in these patients. The presence of complexes of high molecular mass may be one of the biomarkers of fertility disorders in women.     

以PAM,CMC和EC代替PVA作醋酸乙烯酯乳液聚合保护胶体的研究

本文尝试用聚丙烯酰胺、羧甲基纤维素及乙基纤维素代替聚乙烯醇作醋酸乙烯乳液聚合的保护胶体。实验结果显示,聚丙烯酰胺、乙基纤维素可以作为醋酸乙烯乳液聚合的保护胶体。本文对所得乳液的物化性质尚未进行详细研究。     

Synthetic Procedures Yielding Targeted Nitro and Nitroso Derivatives of the Propellant Stabilisers Diphenylamine,N‐Methyl‐4‐nitroaniline,and N,N′‐Diethyl‐N,N′‐diphenylurea

Synthetic methodologies have been developed which yield a variety of diphenylamine (DPA) and 1,3‐diethyl‐l,3‐diphenylurea (ethylcentralite or EC) propellant stabiliser degradation derivatives in high yield. The N‐alkyl nitroanilines (N‐methyl‐2,4,6‐trinitroaniline; N‐methyl‐2,4‐dinitroaniline; N‐ethyl‐2,4,6‐trinitroaniline; N‐ethyl‐2,4‐dinitroaniline; N‐ethyl‐4‐nitroaniline; N‐ethyl‐2‐nitroaniline) have been obtained either by reaction of the parent aniline with the required alkyl halide under mild conditions or via Ullmann type chemistry. A robust and high yielding approach for the synthesis of di, tri and tetranitrodiphenylamines (2,2′,4,4′‐tetranitrodiphenylamine; 2,4,4′‐trinitrodiphenylamine; 2,2′,4‐trinitrodiphenylamine; 2,4,6‐trinitrodiphenyl‐amine; 2,4‐dinitrodiphenylamine) is reported which involves passing the nitroanilines and chloronitrobenzenes down a base activated alumina column. The N‐nitroso‐N‐alkyl compounds (N‐nitroso‐N‐ethyl‐4‐nitroaniline; N‐nitroso‐N‐ethyl‐2‐nitroaniline; N‐nitroso‐N‐Methyl‐4‐nitroaniline; N‐ethyl‐N‐nitrosoaniline; N‐nitroso‐2‐nitrodiphenylamine) have been synthesised using nitrosyl acetate in acetic acid as the N‐nitrosating agent.     

Synthesis of latices with hydrophobic cores and poly(vinyl acetate) shells. 2. Use of poly(vinyl acetate) seeds

A strategy is explored for synthesizing latex particles with polystyrene cores and poly(vinyl acetate) shells. The seed particles are poly(vinyl acetate), which theory indicates should be immune to secondary particle formation when a second-stage seeded emulsion polymerization with styrene is carried out. The objective is to form a single hydrophobic core by inversion of the second and first stages. While this morphology is favoured thermodynamically, conditions need to be optimized so that it is kinetically achievable: many attempts to implement this using straightforward synthetic procedures result in either no core (acorn morphology) or multiple polystyrene cores. A series of experiments enables this goal to be implemented by ensuring sufficiently fast diffusion of the first-stage hydrophilic polymer (using chain-transfer agent to reduce the molecular weight and, more importantly, the degree of branching of the parent poly(vinyl acetate) seed polymer), an initiator which minimized grafting between the first- and second-stage polymers, and modifying the seed poly(vinyl acetate) to increase its hydrophilicity.     

Effects of Nickel,Chlorpyrifos and Their Mixture on the Dictyostelium discoideum Proteome

Mixtures of chemicals can have additive, synergistic or antagonistic interactions. We investigated the effects of the exposure to nickel, the organophosphate insecticide chlorpyrifos at effect concentrations (EC) of 25% and 50% and their binary mixture (Ec25 + EC25) on Dictyostelium discoideum amoebae based on lysosomal membrane stability (LMS). We treated D. discoideum with these compounds under controlled laboratory conditions and evaluated the changes in protein levels using a two-dimensional gel electrophoresis (2DE) proteomic approach. Nickel treatment at EC25 induced changes in 14 protein spots, 12 of which were down-regulated. Treatment with nickel at EC50 resulted in changes in 15 spots, 10 of which were down-regulated. Treatment with chlorpyrifos at EC25 induced changes in six spots, all of which were down-regulated; treatment with chlorpyrifos at EC50 induced changes in 13 spots, five of which were down-regulated. The mixture corresponding to EC25 of each compound induced changes in 19 spots, 13 of which were down-regulated. The data together reveal that a different protein expression signature exists for each treatment, and that only a few proteins are modulated in multiple different treatments. For a simple binary mixture, the proteomic response does not allow for the identification of each toxicant. The protein spots that showed significant differences were identified by mass spectrometry, which revealed modulations of proteins involved in metal detoxification, stress adaptation, the oxidative stress response and other cellular processes.     

GnRH Analogues as a Co-Treatment to Therapy in Women of Reproductive Age with Cancer and Fertility Preservation

In this review, we analyzed existing literature regarding the use of Gonadotropin-releasing Hormone (GnRH) analogues (agonists, antagonists) as a co-treatment to chemotherapy and radiotherapy. There is a growing interest in their application as a prophylaxis to gonadotoxicity caused by chemotherapy and/or radiotherapy due to their ovarian suppressive effects, making them a potential option to treat infertility caused by such chemotherapy and/or radiotherapy. They could be used in conjunction with other fertility preservation options to synergistically maximize their effects. GnRH analogues may be a valuable prophylactic agent against chemotherapeutic infertility by inhibiting rapid cellular turnover on growing follicles that contain types of cells unintentionally targeted during anti-cancer treatments. These could create a prepubertal-like effect in adult women, limiting the gonadotoxicity to the lower levels that young girls have. The use of GnRH agonists was found to be effective in hematological and breast cancer treatment whereas for ovarian endometrial and cervical cancers the evidence is still limited. Studies on GnRH antagonists, as well as the combination of both agonists and antagonists, were limited. GnRH antagonists have a similar protective effect to that of agonists as they preserve or at least alleviate the follicle degradation during chemo-radiation treatment. Their use may be preferred in cases where treatment is imminent (as their effects are almost immediate) and whenever the GnRH agonist-induced flare-up effect may be contra-indicated. The combination treatment of agonists and antagonists has primarily been studied in animal models so far, especially rats. Factors that may play a role in determining their efficacy as a chemoprotective agent that limits gonadal damage, include the type and stage of cancer, the use of alkylating agents, age of patient and prior ovarian reserve. The data for the use of GnRH antagonist alone or in combination with GnRH agonist is still very limited. Moreover, studies evaluating the impact of this treatment on the ovarian reserve as measured by Anti-Müllerian Hormone (AMH) levels are still sparse. Further studies with strict criteria regarding ovarian reserve and fertility outcomes are needed to confirm or reject their role as a gonadal protecting agent during chemo-radiation treatments.     

Biomolecular and Genetic Prognostic Factors That Can Facilitate Fertility-Sparing Treatment (FST) Decision Making in Early Stage Endometrial Cancer (ES-EC): A Systematic Review

Endometrial cancer occurs in up to 29% of women before 40 years of age. Seventy percent of these patients are nulliparous at the time. Decision making regarding fertility preservation in early stage endometrial cancer (ES-EC) is, therefore, a big challenge since the decision between the risk of cancer progression and a chance to parenthood needs to be made. Sixty-two percent of women with complete remission of ES-EC after fertility-sparing treatment (FST) report to have a pregnancy wish which, if not for FST, they would not be able to fulfil. The aim of this review was to identify and summarise the currently established biomolecular and genetic prognostic factors that can facilitate decision making for FST in ES-EC. A comprehensive search strategy was carried out across four databases; Cochrane, Embase, MEDLINE, and PubMed; they were searched between March 1946 and 22nd December 2022. Thirty-four studies were included in this study which was conducted in line with the PRISMA criteria checklist. The final 34 articles encompassed 9165 patients. The studies were assessed using the Critical Appraisal Skills Program (CASP). PTEN and POLE alterations we found to be good prognostic factors of ES-EC, favouring FST. MSI, CTNNB1, and K-RAS alterations were found to be fair prognostic factors of ES-EC, favouring FST but carrying a risk of recurrence. PIK3CA, HER2, ARID1A, P53, L1CAM, and FGFR2 were found to be poor prognostic factors of ES-EC and therefore do not favour FST. Clinical trials with bigger cohorts are needed to further validate the fair genetic prognostic factors. Using the aforementioned good and poor genetic prognostic factors, we can make more confident decisions on FST in ES-EC.     

Fabrication of porous microspheres and network arrays of Zn–Al hydrotalcite-like compounds on Al substrate via facile hydrothermal method

The porous microspheres and network arrays of Zn–Al hydrotalcite-like compounds were synthesized on Al substrate using sodium oxalate via a facile one-step hydrothermal approach at low temperature (70 °C). The Zn–Al hydrotalcite-like microspheres assembled by numerous interlaced curved nanoplates with thickness of about 50 nm were generated when the concentration of sodium oxalate is 0.21 M. The XRD pattern indicates that the product was of good quality in terms of phase purity and crystallinity. The morphology of Zn–Al hydrotalcite-like compounds and the thickness of nanoplates varied with the concentration of sodium oxalate, which should be attributed to the different nucleation density and growth rate. When the concentration of Zn²⁺ and sodium oxalate was proportionally reduced the low nucleation density and growth caused the formation of porous network arrays. The reaction temperature directly affected the diffusion rates of ions and thus the density of the nucleation and growth is responsible for the morphology change when the reaction temperature is varied. Additionally, the Zn–Al hydrotalcite-like microspheres transformed into porous network arrays when the sodium oxalate was substituted by the equivalent sodium acetate, which should be attributed to the low alkalinity of sodium acetate. The density and thickness of nanoplates composed of the porous network arrays can be effectively tailored by adjusting the concentration of sodium acetate. On the basis of experimental results, the growth mechanism was proposed and discussed.     

Genomic Validation of Endometrial Cancer Patient-Derived Xenograft Models as a Preclinical Tool

Endometrial cancer (EC) is the second most frequent gynecological cancer worldwide. Although improvements in EC classification have enabled an accurate establishment of disease prognosis, women with a high-risk or recurrent EC face a dramatic situation due to limited further treatment options. Therefore, new strategies that closely mimic the disease are required to maximize drug development success. Patient-derived xenografts (PDXs) are widely recognized as a physiologically relevant preclinical model. Hence, we propose to molecularly and histologically validate EC PDX models. To reveal the molecular landscape of PDXs generated from 13 EC patients, we performed histological characterization and whole-exome sequencing analysis of tumor samples. We assessed the similarity between PDXs and their corresponding patient’s tumor and, additionally, to an extended cohort of EC patients obtained from The Cancer Genome Atlas (TCGA). Finally, we performed functional enrichment analysis to reveal differences in molecular pathway activation in PDX models. We demonstrated that the PDX models had a well-defined and differentiated molecular profile that matched the genomic profile described by the TCGA for each EC subtype. Thus, we validated EC PDX’s potential to reliably recapitulate the majority of histologic and molecular EC features. This work highlights the importance of a thorough characterization of preclinical models for the improvement of the success rate of drug-screening assays for personalized medicine.