TAM Group Research Articles

Do aromatase inhibitors and tamoxifen impact the number of oocytes retrieved in oocyte or embryo banking cycles?

Research QuestionDoes the number of oocytes retrieved differ in oocyte/embryo banking cycles using tamoxifen versus aromatase inhibitors versus no adjuvant medications? DesignObservational cohort study of patients 18-43 years old undergoing oocyte or embryo banking cycles between 2016 and 2018 recorded in the Society for Assisted Reproductive Technology Clinic Outcome Reporting System. ResultsAutologous fresh banking cycles from 2016-2018 (n=42,854) were analyzed in three different groups: oocyte and embryo banking cycles using aromatase inhibitors (AI, n= 2096), tamoxifen (TAM, n=58), and no adjuvant medication (NAM, n=40,700). The average age at cycle initiation was 35 and the majority of patients were nulligravid (77%) and nulliparous (92%). The number of oocytes retrieved and cryopreserved in all banking cycles was higher in the NAM group compared to the AI group (oocytes retrieved: 14.2 vs 12.6, p<.05, oocytes cryopreserved: 11.4 vs 10.3, p<.05); however, no difference in oocyte yield was observed between the AI and NAM groups in gonadotoxic treatment cycles. There was no significant difference in the number of oocytes retrieved or cryopreserved between the TAM and NAM group in all banking cycles. In the generalized linear model, the adjusted mean difference of oocytes retrieved was significantly less in the AI vs NAM group (-1.25, 95% CI: -1.7, -0.80), p <.05) in all oocyte and embryo banking cycles combined. ConclusionBanking cycles utilizing AI may compromise oocyte yield when used for non-gonadotoxic indications. Our data supports the continued use of AI for gonadotoxic treatment cycles as IVF cycle outcomes and live birth rates are comparable to those for cycles with NAM.

Therapeutic efficiency of Tamoxifen/Orlistat nanocrystals against solid ehrlich carcinoma via targeting TXNIP/HIF1-α/MMP-9/P27 and BAX/Bcl2/P53 signaling pathways

BackgroundOrlistat (Orli) is an anti-obesity medication that has been approved by the US Food and Drug Administration. It has relatively limited oral bioavailability with promising inhibitory effects on cell proliferation as well as reducing the growth of tumors. AimsThis investigation was done to evaluate the potential protective effect of Tamoxifen/Orlistat nanocrystals alone or in combination against Solid Ehrlich Carcinoma (SEC) and to clarify the possible underlying influences. Materials and methodsThe liquid antisolvent precipitation technique (bottom-up technology) was utilized to manufacture Orlistat Nanocrystals. To explore potential causes for the anti-tumor action, female Swiss Albino mice bearing SEC were randomly assigned into five equal groups (n = 6). Group 1: Tumor control group, group 2: Tam group: tamoxifen (0.01 g/kg, IP), group 3: Free-Orli group: orlistat (0.24 g/kg, IP), group 4: Nano-Orli: orlistat nanocrystals (0.24 g/kg, IP), group 5: Tam–Nano-Orli: Both doses of Tam and Nano-Orli. All treatments were administered for 16 days. Key findingsThe untreated mice showed development in the tumor volume and weight. As well as histopathology results from these mice revealed many tumor large cells as well as solid sheets of malignant cells. Also, untreated mice showed raised VEGF and TGF-1beta content. Moreover, results of gene expression in the SEC-bearing mice noted upregulation in HIF-1α, MMP-9, Bcl-2, and P27 gene expression and downregulation of TXNIP, BAX, and P53 gene expression. On the other hand, administrated TAM, Free-Orli, Nano-Orli, and a combination of Tam-Nano-Orli distinctly suppressed the tumor effects on estimated parameters with special reference to Tam-Nano-Orli. SignificanceThe developed Tamoxifen/Orlistat nanocrystals combination could be considered a promising approach to augment antitumor effects.

A commercial seaweed extract increases growth performance, immune responses, and related gene expressions in whiteleg shrimp (Litopenaeus vannamei)

Seaweed liquid extracts are an attractive source of phytochemicals with high potential applicability in the aquafeed-additive industry. A commercial seaweed liquid extract (True Algae Max, TAM®), which has a marine seaweed odor, also dislplays significant levels of polysaccharides, phytochemicals, phenolic, and flavonoid compounds showing antioxidant activities and DPPH inhibition. This study investigates the impact of diets supplemented with TAM® as a functional additive on the growth, nutrient utilization, immune responses, and immune-related gene expressions of whiteleg shrimp (Litopenaeus vannamei). A total of 750 postlarvae (PL, with an average initial weight of 0.053±0.001 g) were divided into five experimental groups, comprising three replicates per dietary treatment. For an eight-week experimental period, all groups were fed identical diets except for the variation in TAM® inclusion levels. The basal diet (control diet) had no inclusion level of TAM® (TAM0%). Groups 2–5 each contain TAM® inclusion at levels of 1% (10 mL gk−1 diet TAM1%), 2% (20 mL gk−1 diet TAM2%), 3% (30 mL gk−1 diet TAM3%), and 4% (40 mL gk−1 diet TAM4%), respectively. The results concluded that TAM® has great potential as a feed additive for whiteleg shrimp, compared to the control group. The group TAM2% significantly achieved final weight (4.337 g), weight gain (4.287 g) specific growth rate (3.423% / day), feed conversion ratio (1.970), feed efficiency ratio (0.507), and protein efficiency ratio (1.407), compared to the control group (3.900 g, 3.850 g, 3.347%/day, 2.183, 0.458, and 1.270, respectively). Whole-body composition of protein and lipid contents were significantly improved by all TAM group including TAM2% (51.18% and 4.49%, respectively), compared to the control group (49.38% and 4.15%, respectively). As well as, shrimp in group TAM2% achieved the highest values of lysozyme (3.92 µg mL−1), superoxide dismutase (SOD, 11.92 IU mL−1), catalase (CAT, 13.04 IU g−1), lipase (31.24 IU L−1), and amylase (31.24 IU L−1), compared to the control group (3.19 µg mL−1, 8.80 IU mL−1, 10.84 IU g−1, 17.35 IU L−1, 21.65 IU L−1, respectively). For gene expressions experiment, four immune-related were performed in this study; Peroxiredoxin (Prx), Prophenoloxidase (PPO1), P53-like protein isoform delta (p53), and Hemocyanin subunit L5 (L5H). The results showed that shrimp in group TAM2% achieved the highest significant P53 gene transcription compared to the control group or the other TAM groups. Compared to other groups, the TAM1% group considerably increased PPO1 gene transcription, while TAM3% displayed the greatest Prx gene transcription. On the other hand, compared to control group, all TAM groups significantly improved L5H gene transcription. In conclusion, the current study revealed that TAM® diet supplementation (20 mL of TAM® per kg diet) represents a promising, eco-friendly, and sustainable feed additive in the shrimp aquadiet industry.

Reduced fertility in an adenomyosis mouse model is associated with an altered immune profile in the uterus during the implantation period.

Does a reduction in fertility and/or systemic immune cell change occur during the early implantation period in a mouse model of adenomyosis? A reduction in fertility was observed in mice with adenomyosis, coinciding with local and systemic immune changes observed during the implantation period. Adenomyosis is a pathology responsible for impaired fertility in humans, with a still unclear pathophysiology. One hypothesis is that changes in immune cells observed in adenomyosis-affected uteri may alter fertility, notably the physiological immune environment necessary for successful implantation and a healthy pregnancy. Randomly selected CD-1 female neonatal pups were orally dosed by administration of tamoxifen to induce adenomyosis (TAM group), while others received solvent only (control group). From 6 weeks of life, CD-1 mice of both groups were mated to study impaired fertility and related local and/or systemic immune cell changes during the early implantation period. To evaluate fertility and pregnancy outcomes, ultrasound imaging was performed at E (embryonic day) 7.5 and E11.5 to count the number of gestational sacs and the number of resorptions in eight mice of the TAM group and 16 mice of the control group. The mice were sacrificed at E18.5, and morphometric, functional (quantitative reverse transcription PCR; RT-qPCR), and histological analyses were performed on the placentas. To identify local and/or systemic immune changes during the early implantation period, 8 mice of the TAM group and 12 mice of the control group were sacrificed at E4.5. Uterine horns and spleens were collected for flow cytometry and RT-qPCR analyses to study the immune cell populations. To investigate the profile of the cytokines secreted during the early implantation period at the systemic level, supernatants from stimulated spleen cells were analyzed by multiplex immunoassay analysis. By ultrasound imaging, we observed a lower number of implantation sites (P < 0.005) and a higher number of resorptions (P < 0.001) in the TAM group, leading to smaller litters (average number of fetuses per litter: 1.00 [0.00; 5.25] in the TAM group versus 12.00 [9.50; 13.75] in the control group (P < 0.001). Histological and morphometric analyses of the placentas at E18.5 showed a higher junctional/labyrinthine area ratio in the TAM group (P = 0.005). The expression levels of genes that play a role in vascularization and placental growth (Vegf (P < 0.001), Plgf (P < 0.005), Pecam (P < 0.0001), and Igf2 (P = 0.002)) were reduced in the TAM group. In the TAM group, the percentages of macrophages, natural killer (NK) cells, and dendritic cells (DC) were significantly decreased in the uterus around the implantation period. However, the number of M1 macrophages was increased. Both macrophages and DC had an increased activation profile (higher expression of MCHII, P = 0.012; CD80, P = 0.015; CCR7, P = 0.043 for macrophages, and higher expression of CD206, P = 0.018; CXCR4, P = 0.010; CCR7, P = 0.006, MCHII, P = 0.010; and CD80, P = 0.012 for DC). In spleen, an increase in the activation of macrophages (CCR7, P = 0.002; MCHII, P = 0.001; and CD80, P = 0.034) and DC was observed in the TAM group (CCR7, P = 0.001; MCHII, P = 0.001; Ly6C, P = 0.015). In the uteri and the spleen, we observed increased percentages of CD4+ T lymphocytes (P = 0.0237 and P = 0.0136, respectively) in the TAM group and, in the uteri, an increased number of regulatory T cells (P = 0.036) compared with the controls. Not applicable. This study is limited by the use of an animal model and the lack of intervention. These data support involvement of innate and adaptive immune cells in the implantation failure and the increased rate of resorption observed in the mouse model of adenomyosis. This substantiates the need for additional research in this domain, with the goal of addressing fertility challenges in women affected by this condition. None.

Short-term outcomes of robot-assisted versus thoracoscopic-assisted Mckeown esophagectomy.

Thoracoscopic-assisted and robot-assisted Mckeown esophagectomy are currently two common surgical methods, but there is no clear statement on the advantages and disadvantages of the two. This study conducted a single-centre retrospective analysis of esophageal cancer patients diagnosed and treated at Lanzhou University Second Hospital from 1 February 2020 to 31 July 2022. According to the inclusion and exclusion criteria, 126 patients were finally included in the RAM group and 169 patients in the TAM group. There was no significant difference between the RAM and TAM groups in the number of lymph node dissections, operative time, the length of stay in the intensive care unit after surgery, the incidence of hoarseness, postoperative pulmonary complications, surgery-related complications, use of opioids after surgery, the length of postoperative hospital stay, and 30-day mortality. RAM is a minimally invasive alternative to TAM and has similar short-term oncological efficacy.

Oxidative stress induced cardiomyocytes injury by Tamoxifen and abrogates by zinc supplement in adult female rabbits

Tamoxifen (TAM) is used in breast cancer chemotherapy since its approval by the Food and Drug Administration in 1977. However, TAM therapy is accompanied with cardiomyocytes apoptosis. Oxidative stress and inflammation are the major implicated mechanisms contributing to TAM apoptosis. In this study, we explored whether zinc (Zn) supplementation could prevent TAM-induced cardiomyocytes injury in adult female rabbits. Rabbits were received zinc orally (0.3 mg/ kg body weight / day for 42 days) in zinc group, Tamoxifen group were received orally (0.25 mg/ kg body weight for 42 days), and combination (Zn+Tam) group were received equal dose from zinc and tamoxifen. To study the effect of the tamoxifen (selective estrogen receptor modulator) on the cardiac muscle. Results showed of histopathological study of heart taken from zinc treated group not showed any important abnormalities in histological appearance, tamoxifen group in heart tissue showed a massive necrotic tissue and a huge inflammatory cell infiltration to damaged area and combination group lesion showed active inflammatory process which included blood vessels congestion, edema formation, inflammatory cell aggregation especially macrophage and Myocyte vacuolization. As a consequence, the finding of the research Tam induction over production of reactive oxygen species (ROS) within cardiac cell and the imbalance between the ROS generating system and the antioxidant system can lead to a potentially harmful to tissues and cells.

P-372 The role of the immune system in the physiopathology of infertility in case of adenomyosis: a mouse model study

Abstract Study question Are there any fertility disorders and related local and/or systemic immune changes during the early implantation period in a mouse model of adenomyosis? Summary answer An increase in fertility disorders was observed in adenomyosis mice and coincide with local and systemic immune changes observed during the period of implantation. What is known already Adenomyosis is as a common pathology that could be responsible for fertility alteration. Immune changes in uterus are implicated in adenomyosis physiopathology. One hypothesis is that the physiological immune environment necessary for a successful implantation can be altered in adenomyosis, leading to fertility disorders. Study design, size, duration Randomly selected CD-1 female neonatal pups were orally dosed with oral administration of tamoxifen in order to induce adenomyosis (TAM group), while other received solvent only (control group). At 3 months, CD-1 mice (F1) of both group were put into mating. 36 pregnant mice were included in the TAM group and 30 in the control group. Participants/materials, setting, methods Ultrasounds were performed during pregnancy at E(E=embryonic day)7.5 and E12.5 to evaluate fertility outcomes in mice of the TAM and control group. Mice were sacrificed at E18.5 and histological,morphometric and functional analysis were performed on the placentas. In order to identify local and/or systemic immune changes in the uterus, mice of both group were sacrificed at E4.5 of pregnancy, during the implantation period. Uterine horns and spleen were collected for flow cytometry and RT-qPCR analyzes. Main results and the role of chance We observed a significantly lower number of implantation sites and a significantly higher number of resorption (3.88±2.36 versus 1.00±0.82(p &amp;lt; 0.001)) in TAM compared to control group. Analysis of placentas showed a significantly higher junctional/labyrinthic area ratio (0.60±0.09 versus 0.30±0.05(p = 0.0052)) and a significantly lower expression of Vascular Endothelial Growth-Factor(GF), Platelet endothelial cell adhesion molecule, Insulin-like GF2 and Placental GF in the TAM group compared to the control group, indicating an altered placental vascularization compared to controls. To characterize the immune change during the early implantation period, we analyzed some immune cells populations in the uteri and the spleen: In the TAM group, the number of macrophages(F4/80), Natural Killers(NK) cells(NKP46+/NKG2D+) and dendritic cells (DC)(CD11b+) were significantly decreased compared to control uteri. However, the number of M1 macrophages(Ly6c+hight) and their activation were significantly increased. DC activation was also increased in TAM group. In the spleen, a significant increase in the activation macrophages and DC was observed in adenomyosis group compared to control. In the uteri, the number of LT4(CD4+) cells and number of LTreg cells(CD25+/FOXP3+) were significantly increased in the TAM group compared to control group. In the spleen, a significant increase in LT4 cells count was observed in TAM compared to control group. Limitations, reasons for caution This study is limited by the use of an animal model and the lack of intervention. Wider implications of the findings This study provides evidence that adenomyotic lesions in mice induced fertility disorders and immune modifications at a local and at a systemic level during the early implantation period. These data support the involvement of innate and adaptive immune cells in implantation failure observed in the mouse model of adenomyosis. Trial registration number not applicable

Efficacy and tolerability of the hexanic extract of Serenoa repens compared to tamsulosin in moderate-severe LUTS-BPH patients

In a subset analysis of data from a 6-month, multicenter, non-interventional study, we compared change in symptoms and quality of life (QoL), and treatment tolerability, in men with moderate to severe lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) receiving tamsulosin (TAM, 0.4 mg/day) or the hexanic extract of Serenoa repens (HESr, 320 mg/day) as monotherapy. Symptoms and QoL were assessed using the IPSS and BII questionnaires, respectively. Patients in the treatment groups were matched using two statistical approaches (iterative and propensity score matching). Within the iterative matching approach, data was available from a total of 737 patients (353 TAM, 384 HESr). After 6 months, IPSS scores improved by a mean (SD) of 5.0 (4.3) points in the TAM group and 4.5 (4.7) points in the HESr group (p = 0.117, not significant). Improvements in QoL were equivalent in the two groups. TAM patients reported significantly more adverse effects than HESr patients (14.7% vs 2.1%; p < 0.001), particularly ejaculation dysfunction and orthostatic hypotension. These results show that HESr is a valid treatment option for men with moderate/severe LUTS/BPH; improvements in urinary symptoms and QoL were similar to those observed for tamsulosin, but with considerably fewer adverse effects.

Immune cells and Notch1 signaling appear to drive the epithelial to mesenchymal transition in the development of adenomyosis in mice.

The epithelial to mesenchymal transition (EMT) has been implicated in the development of adenomyosis, along with dysregulated immune responses. Inflammation potentially induces Notch signaling, which could promote this EMT. The objective of this study was to investigate the involvement of immune cells and Notch1-mediated EMT in the development of adenomyosis. Adenomyosis was induced in 18 CD-1 mice by neonatal oral administration of tamoxifen (TAM group), while 18 neonates received vehicle only (Control group). Their uteri were sampled at 30, 60 or 90 days of age. Immune cell markers (Cd45, Ly6c1, Cd86, Arginine1, Cd19, Cd4, Cd8), Notch1 and its target genes (Hey1, Hey2, Hes1, Hes5) and biomarkers of EMT (E-Cadherin, Vimentin, Tgfb, Snail1, Slug, Snail3) were analyzed by quantitative RT-PCR and immunohistochemistry. Activated-Notch1 protein was measured by western blot. Aberrant expression of immune cell markers was observed in the uteri of mice as they developed adenomyosis. The expression of inflammatory cell markers, notably M1 macrophages and natural killer cells, was increased from Day 30 in the TAM group compared to controls, followed by an increase in the Cd4 marker (T cells) at Day 60. Conversely, expression of the Cd19 marker (B cells) was significantly reduced at all of the stages studied. Notch1 signaling was also highly activated compared to controls at Day 30 and Day 60. Concomitantly, the levels of several markers for EMT were also higher. Therefore, the activation of Notch1 coincides with aberrant expression of immune and EMT markers in the early development of adenomyosis.

Effects of Tamoxifen vs. Toremifene on fatty liver development and lipid profiles in breast Cancer

BackgroundTamoxifen (TAM) and Toremifene (TOR), two kinds of selective estrogen receptor modulators (SERMs), have equal efficacy in breast cancer patients. However, TAM has been proved to affect serum lipid profiles and cause fatty liver disease. The study aimed to compare the effects of TAM and TOR on fatty liver development and lipid profiles.MethodsThis study performed a retrospective analysis of 308 SERMs-treated early breast cancer patients who were matched 1:1 based on propensity scores. The follow-up period was 3 years. The primary outcomes were fatty liver detected by ultrasonography or computed tomography (CT), variation in fibrosis indexes, and serum lipid profiles change.ResultsThe cumulative incidence rate of new-onset fatty liver was higher in the TAM group than in the TOR group (113.2 vs. 67.2 per 1000 person-years, p < 0.001), and more severe fatty livers occurred in the TAM group (25.5 vs. 7.5 per 1000 person-years, p = 0.003). According to the Kaplan-Meier curves, TAM significantly increased the risk of new-onset fatty liver (25.97% vs. 17.53%, p = 0.0243) and the severe fatty liver (5.84% vs. 1.95%, p = 0.0429). TOR decreased the risk of new-onset fatty liver by 45% (hazard ratio = 0.55, p = 0.020) and showed lower fibrotic burden, independent of obesity, lipid, and liver enzyme levels. TOR increased triglycerides less than TAM, and TOR increased high-density lipoprotein cholesterol, while TAM did the opposite. No significant differences in total cholesterol and low-density lipoprotein cholesterol are observed between the two groups.ConclusionsTAM treatment is significantly associated with more severe fatty liver disease and liver fibrosis, while TOR is associated with an overall improvement in lipid profiles, which supports continuous monitoring of liver imaging and serum lipid levels during SERM treatment.

Outcomes and complications of naftopidil versus tamsulosin for elderly men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: A systematic review and meta-analysis.

We conducted a systematic review and meta-analysis to assess the outcomes and complications of naftopidil in treating elderly men with lower urinary tract symptoms secondary to benign prostatic hyperplasia and compared them with those administered with tamsulosin. A literature review was performed to identify the available randomised controlled trials concerning the comparison between naftopidil and tamsulosin for men with LUTS/BPH. We searched the following databases: the Cochrane Library Database, PubMed, Embase and Web of Science. Eleven publications involving 1,114 men (557 in the naf group and 557 in the tam group) were pooled in our analysis. We found no significant differences in the total IPSS, IPSS storage score, IPSS voiding score, quality of life index, peak urinary flow rate, average flow rate and post-void residual volumes. We assessed cardiovascular and sexual adverse events, acute urinary retention, surgical intervention, withdrawals due to any reason and withdrawals due to adverse events. The incidence of adverse events was similar among patients in naf and tam groups. In conclusion, naftopidil shared comparable efficacy and similar incidence of adverse events with tamsulosin and appears to be a promising agent for and alternative to tam. However, more prospective trials with high quality and long-term treatment duration are needed to verify this observation.

Molecularly Imprinted Polymer and Computational Study of (E)-4-(2- cyano-3-(dimethylamino)acryloyl)benzoic Acid from Poly(ethylene terephthalate) Plastic Waste

Background: Molecularly imprinted polymers (MIPs) are utilized in the separation of a pure compound from complex matrices. A stable template-monomer complex generates MIPs with the highest affinity and selectivity for the template. In this investigation, degradation of Poly(ethylene terephthalate) PET afforded the (E)-4-(2-cyano-3-(dimethylamino) acryloyl) benzoic acid (4) (TAM) which used TAM as template which interacts with Methacrylic Acid (MAA) monomer, in the presence of CH3CN as progen. The TAM-MMA complex interactions are dependent on stable hydrogen bonding interaction between the carboxylic acid group of TAM and the hydroxyl group of MMA with minimal interference of porogen CH3CN. The DFT/B3LYP/6-31+G model chemistry was used to optimize their structures and frequency calculations. The binding energies between TAM with different monomers showed the most stable molar ratio of 1:4 which was confirmed through experimental analysis. Methods: The present work describes the synthesis of (E)-4-(2-cyano-3-(dimethylamino) acryloyl) benzoic acid (4) (TAM) from PET waste and formation of molecularly imprinted polymer from TAM with the methacrylic acid monomer. The optimization of molecular imprinted was stimulated via DFT/B3LYP/6-31G (d). The imprinted polymer film was characterized via thermal analysis, pore size, FT-IR and scanning electron microscopy. Results: The most stable molecularly imprinted polymers (MIPs) showed binding energy of TAM(MMA4)=-2063.456 KJ/mol with a small value of mesopores (10-100 Å). Also, the sorption capability of TAM-MIPs showed 6.57 mg/g using STP-MIP-9VC. Moreover, the average pore size ranged between 0.2-1 nm with the BET surface about 300 m2/g. Conclusion: The proposed TAM exhibited a high degree of selectivity for MMA in comparison with other different monomers through hydrogen bond interaction, which was thermally stable, good reproducibility and excellent regeneration capacity and elucidated in the computational study and analytical analysis.

THE IMPACT OF IONIZED WATER SUPPLEMENTED WITH GLUTATION AND VITAMIN C DURING ACUTE HYPERTHERMIC EXPOSURE ON THE CONCENTRATION OF TOTAL PROTEINS IN THE BLOOD SERUM AT WHITE LABORATORY RATS

Alkaline water is in the focus of scientific interest over the last decade, due to its ability to alkalize the organism as well as its antioxidant effect. The aim of our research is to determine the impact of ionized water by adding enzymatic and non-enzymatic antioxidants, glutathione and vitamin C, during hyperthermic stress, on the concentration of total proteins. The experiment performed on a white laboratory Wistar rats, a female sex, weighing 180-220 g, young rats, divided into three groups of 15 individuals. Oxidative stress was caused by acute hyperthermic exposure at 41˚C. The first group is the control group (KPM), the second group is treated with ionized water (TAM), and the third group with ionized water with added glutathione and vitamin C (TAD). The duration of treatment lasted 21 days. Acute hyperthermic exposure caused a significant difference in total protein concentration between the 7th and 14th day taken as the starting points and the 21st day of treatment, respectively, on the day of hyperthermic exposure of rats. Such a significant difference was observed in the KPM and the TAM group (p &lt;0.001), whereas the TAD group is an exception where no statistically significant difference was observed in the same period (p&gt; 0.05). Animals treated with ionized water on day 14 showed a significantly higher total protein concentration (p &lt;0.01) compared to the group receiving only natural water, which is consistent with the finding obtained by comparison between the KPM and TAD group at 21st day where the difference is also statistically significant (p &lt;0.05). The acute application of the treatment with ionized water, without or in combination with other antioxidants, in the absence of hyperthermic stress does not lead to a significant alteration in protein concentration. The hyperthermic exposure intensifies the production of oxygen radicals and the potential for oxidative modification of proteins and molecules with a protein structure. Individual action of ionized water as well as synergism with the added antioxidants caused a high protective effect on oxidative damage. Because of this, the effect of oxidative cleavage is less pronounced in rats treated with ionized water and antioxidants because they have a stronger antioxidant defense that prevents oxidative modification of proteins and all biomolecules in the body.

Saikosaponin A Inhibits Breast Cancer by Regulating Th1/Th2 Balance.

Saikosaponin A (SSa) is isolated from the dried root of Radix Bupleuri, an herb widely used in traditional Chinese medicine, exerting antitumor activities. The T helper cell type 1(Th1)/Th2 balance is associated with antitumor immunity in breast cancer. The present study aimed to investigate the effects of SSa on Th1/Th2 balance in breast cancer and to explore the underlying mechanisms. Breast cancer in rats was induced by intragastrical administration of 7,12-dimethyl-benz[a] anthracene once (100 mg/kg). At d91, the rats suffering from tumors were randomly divided into three groups and treated with vehicle solution (control group), tamoxifen (TAM group), and SSa (SSa group) daily for 56 days, respectively. The tumor volume reduction ratio and tumor cell proliferation were detected to assess the antitumor effect of SSa. The positive staining numbers of CD8+ and CD4+ T cells infiltrated in breast tumors were measured by immunohistochemistry to evaluate the antitumor immunity of SSa. Cytokine levels in serum secreted by Th1 cells [interferon gamma (IFN-γ), interleukin (IL)-12] and Th2 cells (IL-4, IL-10) were detected to evaluate Th1/Th2 balance. The related molecules of IL-12/signal transducers and activators of transcription 4 (STAT4) pathway were detected by immunohistochemistry staining, RT-PCR, and Western blot to explore the mechanisms of SSa. The results showed that, compared with the control group, SSa significantly inhibited tumor growth and tumor cell proliferation. SSa enhanced antitumor immunity, which was demonstrated as increased CD8+ T cells and CD4+ T cells infiltrated in tumors. SSa shifted Th1/Th2 balance toward Th1, which was confirmed as increased serum IFN-γ and IL-12 levels, while decreased serum IL-4 and IL-10 levels. SSa increased IL-12, IL-12 receptor, and phosphorylated STAT4 expressions to promote Th1 differentiation. In conclusion, the present work suggested that SSa could inhibit breast cancer growth by shifting Th1/Th2 balance toward Th1. The underlying mechanism may involve activation of the IL-12/STAT4 pathway that induced Th1 differentiation.

Switching to anastrozole plus goserelin vs continued tamoxifen for adjuvant therapy of premenopausal early-stage breast cancer: preliminary results from a randomized trial.

PurposeTo assess the efficacy, safety, and quality-of-life impact of switching adjuvant treatment in hormone receptor-positive primary breast cancer patients who are still premenopausal after 2–3 years of tamoxifen therapy to anastrozole plus goserelin as compared with continuing tamoxifen over a total period of 5 years.Patients and methodsHormone receptor-positive, premenopausal, lymph node-positive, or tumor size ≥4 cm breast cancer patients who had received tamoxifen for 2–3 years were randomly assigned to continue tamoxifen treatment (TAM group) or switch to adjuvant anastrozole plus goserelin (ADD group) and continue treatment for another 2–3 years (total treatment duration 5 years). Endpoints evaluated were adverse events (AEs), changes in bone mineral density, quality of life, and disease-free survival-related events.ResultsA total of 62 patients (33 in the ADD group and 29 in the TAM group) were evaluated. Grade 3–4 drug-related AEs occurred in five patients (15.2%) in the ADD group vs none in the TAM group. In the ADD group, arthralgias were the most common AEs (5/33 patients; 15.2%), and three patients in this group were discontinued because of AEs. Treatment was temporarily suspended due to AEs in three patients (9.1%) in the ADD group and one patient (3.4%) in the TAM group. Compared with continuing TAM therapy, switching to anastrozole plus goserelin did not result in any worsening of bone mineral density or quality of life. During a median follow-up of 34 months, five patients (15.2%) in the ADD group had disease-free survival events vs four patients (13.8%) in the TAM group.ConclusionFor early-stage breast cancer patients who remain premenopausal following 2–3 years of adjuvant tamoxifen therapy, switching to anastrozole plus goserelin therapy was safe with tolerable adverse effects. However, it did not show superior efficacy compared to remaining on tamoxifen treatment.Trial RegistrationClinicalTrials.gov (identifier NCT01352091).

Abstract P4-15-06: Low dose tamoxifen lowers recurrences after mastectomy for in situ neoplasia. Ten-year results of a monoinstitutional study

Abstract There is no agreement upon the need of a preventive treatment after breast mastectomy for in situ neoplasia. Low-dose tamoxifen (5 mg/day) has comparable antiproliferative effect than the standard dose of 20 mg/day in biomarker trials and has been shown to halve ipsilateral recurrence in a large cohort of postmenopausal ER positive DCIS treated with breast conserving surgery (Guerrieri-Gonzaga et al., Int J Cancer 2016). Here we investigated the effect of low dose tamoxifen in patients treated with mastectomy for an in situ neoplasia and followed-up in a single Institution for a median of 10 years. Our cohort consists of 404 consecutive premenopausal (n=281) or postmenopausal (n=123) women who underwent unilateral mastectomy at the European Institute of Oncology (IEO), with or without nipple preservation, between 1996 and 2011. Patients had a diagnosis of pure LCIS (n=12) or ER positive (ER&amp;gt;1%) DCIS (n=363) or both (n=29) and were treated with tamoxifen 5 mg/day (n=162) or no treatment (n=242) upon medical judgment, patient preference and/or clinical trial assignment. The main subject and tumor characteristics are reported in table 1. Patient and tumor characteristics No tam (n=242)Low dose tam (n=162)P-valueMedian age, years (IQR)46 (41, 54)47 (42, 51)0.65Premenopausal status (n, %)160 (66)121 (75)0.07Median BMI (kg/m2, IQR)22 (20, 25)22 (20, 24)0.7Breast cancer family history (%)29320.44Histology (LCIS, DCIS, both; %)4/92/42/86/120.01Grading (G1,G2,G3;%)11/59/2918/61/200.04Median ER (%, IQR)90 (70, 95)90 (80, 95)0.005Median PgR (%, IQR)40 (5, 80)68 (25, 90)0.0002Median Ki67 (%, IQR)15 (10, 23)14 (10, 20)0.03Radiotherapy (n, %)95 (39)76 (47)0.13 After a median follow-up of 10 years (range 4-21 years) and a median low dose tamoxifen treatment of 4.9 years (IQR 2.7, 5.0), a total of 85 events were observed (28 in situ, 40 invasive breast cancers, 3 metastatic diseases, 12 other primary cancers, 2 deaths). A total of 36 ipsilateral breast events (23 versus 13 in the no tam versus tam group, respectively), 32 contralateral breast events (22 versus 10 in the no tam versus tam, respectively) and 17 other events (11 versus 6 in the no tam versus tam, respectively) occurred. Overall, eleven deaths (3%) occurred and no endometrial cancers were observed. A time-dependent competing risk model was applied for tamoxifen use and we have shown that low-dose tamoxifen was associated with a 48% reduction on all breast events (adjusted HR=0.52, 95% CI: 0.31–0.88, p=0.01), adjusting for radiotherapy and age. Although limited by the observational nature of the study, we show for the first time that treatment with low dose tamoxifen is effective and safe in women who underwent mastectomy for non-invasive breast neoplasms and should be taken into consideration as a risk reduction strategy for premenopausal and postmenopausal women with breast intraepithelial neoplasia. Citation Format: Guerrieri-Gonzaga A, Gandini S, Serrano D, Lazzeroni M, Pruneri G, Varricchio C, Cazzaniga M, Leonardi MC, Galimberti V, Viale G, De Censi A, Bonanni B. Low dose tamoxifen lowers recurrences after mastectomy for in situ neoplasia. Ten-year results of a monoinstitutional study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-15-06.

Abstract PD2-04: FOXA1 induces a pro-metastatic secretome through ER-dependent and independent transcriptional reprogramming in endocrine-resistant breast cancer

Abstract Background: Metastasis in ER-positive (+) breast cancer (BC) occurring years to decades after initial diagnosis presents a daunting challenge for clinical care and preclinical research due to limited known key players and experimental models. FOXA1 is a pioneer factor for ER-chromatin binding and function, and is highly expressed in ER+ BC metastases, yet the underlying mechanism is unclear. Tumor-secreted proteins play a crucial role in the reciprocal interplay between cancer cells and host microenvironmental factors at both primary and secondary sites. We hypothesized that high FOXA1 provokes an ER-dependent transcriptional program that includes a unique pro-tumorigenic secretome essential for promoting ER+ BC metastasis. Methods: A lentiviral doxycycline (Dox)-inducible FOXA1 overexpression vector and a dual luciferase/GFP (LG) tracking vector were integrated to construct a stable MCF7-LG/FOXA1 cell model. Ovariectomized nude mice bearing MCF7-LG/FOXA1 xenografts in the presence of exogenous estrogen (E2) were randomized to ± Dox, each with continued E2, E2 deprivation (ED), or tamoxifen (Tam). Survival surgery removing the therapy-naïve (E2 arm) and relapsed (ED/Tam arms) tumors was performed when tumors reached ∼1000 mm3. All mice then received ED/Tam 'adjuvant' therapy, with longitudinal luminescence imaging to monitor local/distant recurrences. Mice were or will be euthanized at the ethical end-point. Integrative bioinformatics was performed using RNA-seq and FOXA1/ER ChIP-seq data from our preclinical models to identify secretome targets for functional intervention. Times to tumor regression (TTR) and progression (TTP) were defined by when the tumor reached half or twice the volume at randomization. Results: Median (m) TTR was achieved in ED (31/34 days, -/+Dox, P = 0.184) but not in Tam groups — Tam delayed tumor growth but failed to prevent progression in all mice with mTTP of 94/93 days (-/+Dox, P = 0.517). Despite no difference in mTTP at Tam-/+Dox, a quarter of +Dox tumors (3/12) had volume doubled by day 11. No metastases were observed by imaging in any of the mice before surgery ('neoadjuvant' setting). Local relapse and lymph-node/lung metastases were detected after surgery ('adjuvant' setting). At day 90 in the adjuvant Tam group with previously relapsed tumors, +Dox mice succumbed to metastasis more often than -Dox mice (7/8 vs. 3/10, P = 0.023). Compared to the adjuvant Tam+Dox mice with previous therapy-naïve tumors, the Tam+Dox with previously relapsed tumors showed higher distant metastasis rate (7/8 vs. 5/14, P = 0.026). Analysis of the ED setting is pending due to late recurrence. Data integration and functional study revealed a set of cytokines, growth factors, and extracellular matrix components (including IL-8, CTGF, and LOX), regulated by FOXA1 often in conjunction with ER, that are highly involved in FOXA1-induced metastasis. Global secretome profiling by mass spectrometry and target validation are ongoing. Conclusions: FOXA1 overexpression increases metastatic potential in ER+ BC. We established a pertinent metastatic xenograft mouse model to characterize a pro-metastatic secretome with diagnostic and therapeutic potential for treating metastatic ER+ BC. Citation Format: Fu X, Pereira R, Zhao D, Jung SY, Jeselsohn R, Creighton CJ, Shea M, Nardone A, Angelis CD, Tsimelzon A, Wang T, Gutierrez C, Huang S, Edwards DP, Rimawi MF, Hilsenbeck SG, Brown M, Chen K, Osborne CK, Schiff R. FOXA1 induces a pro-metastatic secretome through ER-dependent and independent transcriptional reprogramming in endocrine-resistant breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD2-04.

Abstract S6-04: Patient-reported outcome (PRO) results, NRG Oncology/NSABP B-35: A clinical trial of anastrozole (A) vs tamoxifen (tam) in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy

Abstract Background The clinical results of NSABP B-35, phase III trial comparing 1 mg/day A to 20 mg/day tam, each given for 5 years, were reported at ASCO 2015. B-35 demonstrated a statistically significant benefit in breast cancer free interval for women assigned to A, primarily in women &amp;lt;60 years. A secondary endpoint of B-35 was quality of life (QOL) and symptom (SX) outcomes in the two treatment groups. The primary hypotheses of the PRO study were that there would be no differences in QOL between the two treatments, and that patients receiving A would report higher rates of hot flashes compared to patients receiving tam. Other SX comparisons were secondary endpoints. Methods QOL and SX were assessed at baseline (prior to randomization), and every 6 months thereafter for 5 years of treatment and in the following 12 months. QOL was measured with the SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS). SX were measured with selected scales from the BCPT symptom-checklist, and other standardized instruments. Stratification was by age (&amp;lt;60 v ≥60) as in the main trial. Study hypotheses and endpoints were examined by comparing PROs in the two treatment arms using a mixed model for repeated measures analysis with adjustment for the baseline scores, time point and age category, using an intention-to-treat principle and including only patients who completed the baseline and at least one follow-up questionnaire. Patients with protocol events were censored. Only data through 60 months are reported here. The accrual goal for the sub-study was 1,150 consecutive patients. Results Between January 6, 2003 and June 15, 2006, a total of 3,104 patients were entered and randomly assigned to NSABP Protocol B-35. Accrual to the PRO study of B-35 closed on December 28, 2004, at which time 1,275 patients were entered, with 1,193 patients included in this analysis. There were no medical or demographic differences between patients assigned to A or tam in the PRO sub-study, and they reflected the characteristics of the parent trial. Adherence to data collection across the 60 months was 87%. There were no significant differences in QOL outcomes by treatment for the PCS (p=0.16) or the MCS (p=0.38). SX subscales: hot flash scale was greater in tam group and this difference varied over time (p=0.001); musculoskeletal pain was significantly greater in A group for time points 6-24 months (all p&amp;lt;.001); vaginal problems were greater in A group (p=0.03). Hot flash and vaginal problems were significantly worse in women &amp;lt;60 years. Additional SX outcomes (depression, fatigue, sexual function) will be reported at presentation. Conclusion In this large, double-blind, placebo-controlled trial comparing A to tam in patients with DCIS, there was no significant difference in QOL between the two treatments. However, there were important treatment differences in SX outcomes, which should be considered as part of treatment decision-making discussions, along with the clinical breast cancer outcome results. Support: CA-180868, 180822, 189867, 196067, 114732; AstraZeneca Pharmaceuticals LP. Citation Format: Ganz PA, Cecchini RS, Julian TB, Margolese RG, Costantino JP, Vallow LA, Albain KS, Whitworth PW, Cianfrocca ME, Brufsky A, Gross HM, Soori GS, Hopkins JO, Fehrenbacher L, Sturtz K, Wozniak TF, Seay TE, Mamounas EP, Wolmark N. Patient-reported outcome (PRO) results, NRG Oncology/NSABP B-35: A clinical trial of anastrozole (A) vs tamoxifen (tam) in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S6-04.

Comparative Evaluation of Antimicrobial Effect of Three Endodontic Sealers with and Without Antibiotics - An In-vitro Study.

Root canal sealers with good sealing ability and antimicrobial activity are desired to entomb the surviving microorganisms. Aim of the present study is to evaluate the antimicrobial effect of different sealers mixed with antibiotics. Sixty extracted premolars were taken and were cut coronally & apically such that 7mm of tooth specimen was prepared. They were sterilized by autoclaving, inoculated with E.faecalis and incubated for three weeks. The specimens were divided into six groups of 10 each. Group 1 - ZnOE, Group 2 - ZnOE +TAM, Group 3 - Apexit Plus, Group 4 - Apexit Plus +TAM, Group 5 - AH Plus, Group 6 - AH Plus + TAM. Bacterial growth in the each specimen was calculated before & after sealer application and noted as initial & final colony count. Antimicrobial effect of each sealer was measured by calculating the Percentage Reduction in Colony Count (%RCC). One way analysis of variance and post hoc tests were used for statistical analysis. ZnOE + TAM group showed maximum antibacterial effect among the sealers tested and AH Plus sealer showed least antimicrobial effect. When the sealers were mixed with triple antibiotic mixture the antimicrobial effect was increased significantly.

Primary results, NRG Oncology/NSABP B-35: A clinical trial of anastrozole (A) versus tamoxifen (tam) in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy.

LBA500 Background: The primary endpoint of NSABP B-35, a phase III trial comparing 1 mg/day anastrozole to 20 mg/day tamoxifen, each given for 5 years, was breast cancer-free interval (BCFI), defined as the time from randomization to any breast cancer (BC) event including local, regional, or distant recurrence or contralateral disease, invasive or DCIS. Methods: Postmenopausal women with ER-receptor or PgR-receptor positive (by IHC analysis) DCIS and no invasive BC who had undergone a lumpectomy with clear resection margins were randomly assigned to receive either 20 mg/day tam or 1 mg/day A (blinded) for 5 years. Stratification was by age (&lt;60 v ≥60). Results: From 1/6/2003 to 6/15/2006, 3,104 pts were entered and randomized (1552 in groups tam and A each). As of 2/28/15, follow-up information was available on 3,083 pts for OS and on 3,077 pts for all other disease-free endpoints, with mean time of follow-up of 8.6 years. There were 198 BCFI events, 114 in the tam group and 84 in the A group (HR, 0.73; p=0.03). 10-year point estimates for BCFI were 89.2% for tam and 93.5% for A. A significant time-by-treatment interaction (p=0.02) indicated that the effect was not evident until later in the study. There was a significant interaction between treatment and age group (p=0.04); benefit of A is only in women &lt;60 years old. As to secondary endpoints, there were 495 DFS events, 260 in the tam group and 235 in the A group (HR, 0.89; p=0.21). 10-year point estimates for DFS were 77.9% for tam and 82.7% for A. There were 186 deaths, 88 in the tam group and 98 in the A group (HR, 1.11; p=0.48). 10-year point estimates for OS were 92.1% for tam, 92.5% for A. There were 8 deaths due to breast cancer in the tam group and 5 in the A group. There were 63 cases of invasive breast cancer in the tam group and 39 in the A group (HR, 0.61; p=0.02). There was a non-significant trend for a reduction in breast second primary cancers with A (HR, 0.68; p=0.07). Conclusions: Anastrozole provided a significant improvement compared to tamoxifen for BCFI, which was seen later in the study, primarily in women &lt;60 years. Support: CA12027, 37377, 69651, 69974; 180868, 180822, 189867 196067, 114732; AstraZeneca Pharmaceuticals LP. Clinical trial information: NCT00053898.