Estrogen receptor alpha (ERα) is expressed by 70% of breast cancers (BCs). Any deregulation in ERα signaling is crucial for the initiation and progression of BC. Because of development of resistance to anti-estrogenic compounds, repurposing existing drugs is an apt strategy to avoid a long drug-discovery process. Substantial epidemiologic evidence suggests that Aspirin use reduces the risk of different cancers including BC, while its role as an adjuvant or a possible antineoplastic agent in cancer treatment is being investigated. In this study, we attempted to explore possibilities of ERα inhibition by Aspirin which may act through competitive binding to the ligand binding domain (LBD) of ERα. A list of 48 ERα-LBD crystal structures bound with agonists, antagonists, and selective ER modulators (SERMs) was thoroughly analysed to determine interaction patterns specific to each ligand category. Exhaustive docking and 500 ns molecular dynamics (MD) studies were performed on three ERα - Aspirin complexes generated using agonist, antagonist, and SERM-bound crystal structures. Besides, three ERα crystal structures bound to agonist, antagonist, and SERM respectively were also subjected to MD simulations. Aspirin showed good affinity to LBD of ERα. Comparative analyses of binding patterns, conformational changes and molecular interaction profiles from the docking results and MD trajectories suggests that Aspirin was most stable in complex generated using SERM bound crystal structure of ERα and showed interactions with Gly-521, Ala-350, Leu-525 and Thr-347 like SERMs. In addition, in-vitro assays, qPCR, and immunofluorescent assay demonstrated the decline in the expression of ERα in MCF-7 upon treatment with Aspirin. These preliminary bioinformatical and in-vitro findings may form the basis to consider Aspirin as a potential candidate for targeting ERα, especially in tamoxifen-resistant cancers.Communicated by Ramaswamy H. Sarma.

OBJECTIVE: This study aimed to determine the effect of ovarian stimulation regimens on the top-quality blastocyst development rate and perinatal outcomes with the freeze-all strategy.
METHODS: A retrospective comparative cohort analysis of 149 in vitro fertilization (IVF) cycles using the freeze-all strategy was conducted. The IVF cycles were stimulated with either a gonadotropin-releasing hormone antagonist or clomiphene citrate along with gonadotropin based on the patient\'s serum anti-Müllerian hormone level. Oocyte retrieval, fertilization, and embryo culture were performed following standard procedures. All good-quality blastocysts were cryopreserved and used for frozen-thawed embryo transfer (FET) in subsequent cycles. The fertilization, blastulation, and top-quality blastocyst development rates were calculated. The perinatal outcomes of FET cycles, gestational period, and birth weight were assessed.
RESULTS: The main outcome of this study was the top-quality blastocyst development rate, and the secondary outcomes were perinatal parameters (e.g., gestational period and birth weight) between the stimulation regimens. Despite the higher number of usable-quality embryos in the antagonist group, the blastocyst development rate remained comparable (p=0.105). Similarly, perinatal outcomes were comparable in subsequent FET cycles (p=0.538).
CONCLUSIONS: These findings suggest that the choice between antagonist and clomiphene citrate with gonadotropin as stimulation in controlled ovarian stimulation regimens may not affect the top-quality blastocyst development rate. The IVF outcomes (e.g., clinical pregnancy, miscarriage, and live birth rates) remained unaffected in subsequent FET cycles. Unlike fresh embryo transfer, the birth weight and gestational length were not associated with prior controlled ovarian stimulation regimens when the freeze-all strategy was used.

BACKGROUND: Only a small number of studies have reported the use of progesterone vaginal gel in combination with dydrogesterone as part of the antagonist protocol for fresh embryo transfer. Therefore, this study aimed to compare the effects of two types of luteal support on pregnancy outcomes following the antagonist protocol for fresh embryo transfer.
METHODS: We performed a retrospective analysis of clinical data from infertile patients who underwent fresh embryo transfer via the antagonist protocol (2785 cycles) between February and July 2019 and between February and July 2021 at the Peking University Third Hospital Reproductive Medicine Centre. According to the luteal support received, the cycle groups were divided into the progesterone vaginal gel group (single medication or VP group; 1170 cycles) and the progesterone vaginal gel plus dydrogesterone group (combination medication or DYD + VP group; 1615 cycles). After propensity score matching, the clinical pregnancy, ongoing pregnancy, early miscarriage, and ectopic pregnancy rates were compared between the two groups.
RESULTS: In total, 1057 pairs of cycles were successfully matched via propensity scores. The clinical and ongoing pregnancy rates in the combination medication group were significantly higher than those in the single medication group (P < 0.05), whereas no significant differences were noted in the early miscarriage and ectopic pregnancy rates between the two groups (both P > 0.05).
CONCLUSIONS: Combined luteal support after the antagonist protocol is preferred for patients undergoing fresh cycle embryo transfer.

Antioxidant food additives were routinely used for increasing the keeping quality of packaged food items. Butylated Hydroxyanisole (BHA) is one of the most widely used synthetic phenolic antioxidants of such kind. Although quantity of antioxidants in packaged eatables and admissible daily intake (ADI) per person per day are limited by laws, the urbanisation and changes in lifestyle has cross these limits. Although studies on BHA has been carried out, there exists a great deal of uncertainty about the exact molecular mechanism of interaction of BHA with various receptors in the body. Since earlier reports suggested BHA plausibly interferes with reproductive system development, we opted docking of critical receptors of endogenous hormones controlling growth and development of reproductive system with BHA. Nuclear receptors of estrogen (ER), androgen (AR) and progesterone (PR) were selected for this purpose. This manuscript describes the comparison of binding pattern of BHA towards AR, ER and PR along with their agonists and antagonist. Lamarckian Genetic Algorithm of AutoDock 4.0 was used for analysing the mode of binding of ligands with the receptors. It is evident form the docking studies that, BHA exhibited similar binding pattern` with antagonists of AR and agonists of ER. But the interaction of BHA with PR was not compatible with either agonists or antagonists. The docking patterns produced could reliably demonstrate the interactions of BHA with selected receptors and also predict its possible agonistic and antagonistic action.

Fluorescence as a parameter for analysis of intracellular binding and localization of neurotransmitters also named biomediators (acetylcholine and biogenic amines such as catecholamines, serotonin, histamine) as well as their receptors in plant cells has been estimated basing on several world publications and own experiments of the author. The subjects of the consideration were 1. application of reagents forming fluorescent products (for catecholamines - glyoxylic acid, for histamine - formaldehyde or ortho-phthalic aldehyde) to show the presence and binding of the compounds in cells, 2. binding of their fluorescent agonists and antagonists with cell, 3. effects of the compounds, their agonists and antagonists on autofluorescence, 4. action of external factors on the accumulation of the compounds in cells. How neurotransmitters can bind to certain cellular compartments has been shown on intact individual cells (vegetative microspores, pollens, secretory cells) and isolated organelles. The staining with reagents on biogenic amines leads to the appearance blue or blue-green emission on the surface and excretions of intact cells as well in some DNA-containing organelles within cells. The difference between autofluorescence and histochemically induced fluorescence may reflect the occurrence and amount of biogenic amines in the cells studied. Ozone and salinity as external factors can regulate the emission of intact cells related to biogenic amines. After the treatment of isolated cellular organelles with glyoxylic acid blue emission with maximum 460-475 nm was seen in nuclei and chloroplasts (in control variants in this spectral region the noticeable emission was absent) and very expressive fluorescence (more than twenty times as compared to control) in the vacuoles. After exposure to ortho-phthalic aldehyde blue emission was more noticeable in nuclei and chloroplasts. Fluorescent agonists (muscarine, 6,7-diOHATN, BODIPY-dopamine or BODIPY-5HT) or antagonists (d-tubocurarine for acetylcholine, yohimbine for dopamine and norepinephrine, inmecarb for serotonin) of neurotransmitters that bound with animal receptors fluorescent in blue (460-480 nm) or blue-green (490-530 nm) and usually are bound with the plasmatic membrane of intact cells or with membrane of the isolated organelles studied. In some model cells autofluorescence (belonging to chlorophyll or not, for example secondary metabolites) may be stimulated by exogenous biogenic amines or their agonists and, on the contrary, be inhibited by certain antagonists. The fluorescence data may be applied for the testing in ecological monitoring, medicine and pharmacology.

The structural and dynamical properties of PPARγ receptor in a complex with either partial or full agonists have been intensively studied but little is known about the receptor antagonistic conformation. A composition of microsecond accelerated molecular dynamics (aMD) simulation show that like partial agonists a non-covalent PPARγ full antagonist can bind in different modes of similar population size and free energies of binding. Four different and periodically exchanging ligand conformations are detected and described. The studied antagonist interacts with different receptor substructures and affects both the co-activator and the Cdk5 phosphorylation sites and, presumably, the natural complex with the DNA. However, no significant changes in the conformational states of the activation helix 12, and in particular an antagonist orientation, have been recorded. Finally, our results show also that the aMD approach can be successfully used in recovering the possible binding modes, considering fully the receptor flexibility, and is not dependent on the starting conformation.

Preclinical and clinical studies have indicated that somatostatin receptor (sst)-expressing tumors demonstrate higher uptake of radiolabeled sst antagonists than of sst agonists. In 4 consecutive patients with advanced neuroendocrine tumors, we evaluated whether treatment with (177)Lu-labeled sst antagonists is feasible.
METHODS: After injection of approximately 1 GBq of (177)Lu-DOTA-[Cpa-c(DCys-Aph(Hor)-DAph(Cbm)-Lys-Thr-Cys)-DTyr-NH2] ((177)Lu-DOTA-JR11) and (177)Lu-DOTATATE, 3-dimensional voxel dosimetry analysis based on SPECT/CT was performed. A higher tumor-to-organ dose ratio for (177)Lu-DOTA-JR11 than for (177)Lu-DOTATATE was the prerequisite for treatment with (177)Lu-DOTA-JR11.
RESULTS: Reversible minor adverse effects of (177)Lu-DOTA-JR11 were observed. (177)Lu-DOTA-JR11 showed a 1.7-10.6 times higher tumor dose than (177)Lu-DOTATATE. At the same time, the tumor-to-kidney and tumor-to-bone marrow dose ratio was 1.1-7.2 times higher. All 4 patients were treated with (177)Lu-DOTA-JR11, resulting in partial remission in 2 patients, stable disease in 1 patient, and mixed response in the other patient.
CONCLUSIONS: Treatment of neuroendocrine tumors with radiolabeled sst antagonists is clinically feasible and may have a significant impact on peptide receptor radionuclide therapy.

BACKGROUND: Biologic therapies represent a significant advance in the treatment of psoriasis. However, no studies have examined the patient characteristics predictive of biologic treatment of psoriasis. The purpose of this study was to ascertain the frequency and predictors of treatment of psoriasis with biologics in three European countries, ie, France, Spain, and the UK.
METHODS: This was a cross-sectional analysis of physician-recorded demographic and clinical data on patients receiving either conventional or biologic treatments for psoriasis. Data were drawn from the Adelphi 2007 Psoriasis Disease Specific Program (DSP®), a multinational, real-world survey of patients with psoriasis consulting practicing dermatologists. The numbers of patients treated with biologic and nonbiologic agents were recorded. Data were subjected to bivariate analysis according to treatment regimen (biologic versus nonbiologic). Predictors of treatment with biologics were identified by logistic regression analysis.
RESULTS: A total of 2,509 psoriasis patients were included in this study (1,374 from France, 561 from Spain, and 574 from the UK). Biologic use was most prevalent in Spain (19.4% of patients), followed by the UK (9.1%), and France (8.4%). In the logistic regression analysis, psoriatic arthritis was a statistically significant predictor of increased biologic use in France (odds ratio [OR] 5.38, 95% confidence interval [CI] 3.32-8.77), Spain (OR 2.71, 95% CI 1.16-6.33), and the UK (OR 8.70, 95% CI 3.65-20.83). Physician-assessed moderate-to-severe disease was also a statistically significant predictor of increased biologic use in France (OR 5.08, 95% CI 2.01-12.82), Spain (OR 11.11, 95% CI 4.33-28.57), and the UK (OR 8.55, 95% CI 1.11-66.67).
CONCLUSIONS: In this study, an average of about one tenth of psoriasis patients enrolled in Spain, France, and the UK were treated with biologics in 2007. Physician-assessed moderate-to-severe disease and presence of psoriatic arthritis were significantly associated with biologic use in all three countries.