Effects of matcha tea extract on cell viability and estrogen receptor-ß expression on MCF-7 breast cancer cells.

PURPOSE: In the following work, we investigated the effect of matcha green tea extract (MTE) on MCF-7 breast cancer cell viability and estrogen receptor-beta expression (ERß). METHODS: MCF-7 cells were stimulated with MTE at concentrations of 5 and 10 µg/ml. Cell viability was assessed using a water-soluble tetrazolium assay (WST-1 assay) after an incubation time of 72 h. ERß was quantified at gene level by real-time polymerase chain reaction (PCR). A western blot (WB) was carried out for the qualitative assessment of the expression behavior of on a protein level. RESULTS: The WST-1 test showed a significant inhibition of viability in MFC-7 cells after 72 h at 10 µg/ml. The WB demonstrated a significant quantitative decrease of ERß at protein level with MTE concentrations of 10 µg/ml. In contrast, the PCR did not result in significant downregulation of ERß. CONCLUSION: MTE decreases the cell viability of MCF-7 cells and furthermore leads to a decrease of ERß at protein level.

Cytoplasmic Localization of Thyroid Hormone Receptor (TR) Alpha and Nuclear Expression of Its Isoform TRα2 Determine Survival in Breast Cancer in Opposite Ways.

The aim of this retrospective study was to assess the respective prognostic values of cytoplasmic and nuclear TRα, TRα1, and TRα2 expression in breast cancer (BC) tissue samples and correlate the results with clinico-pathological parameters. In 249 BC patients, the expression patterns of general TRα and the α1 and α2 isoforms were evaluated via immuno-histochemistry. Prognosis-determining aspects were calculated via univariate, as well as multivariate, analysis. Univariate Cox-regression analysis revealed no association between nuclear TRα expression and overall survival (OS) (p = 0.126), whereas cytoplasmic TRα expression was significantly correlated with a poor outcome for both OS (p = 0.034) and ten-year survival (p = 0.009). Strengthening these results, cytoplasmic TRα was found to be an independent marker of OS (p = 0.010) when adjusted to fit clinico-pathological parameters. Analyses of the TRα-subgroups revealed that TRα1 had no prognostic relevance, whereas nuclear TRα2 expression was positively associated with OS (p = 0.014), ten-year survival (p = 0.029), and DFS (p = 0.043). Additionally, nuclear TRα2 expression was found to be an independent positive prognosticator (p = 0.030) when adjusted to fit clinico-pathological parameters. Overall, our results support the hypothesis that subcellular localization of TRα and its isoforms plays an important role in the carcinogenesis and prognosis of breast cancer. Cytoplasmic TRα expression correlates with more aggressive disease progression, whereas nuclear TRα2 expression appears to be a protective factor. These data may help us to prioritize high-risk BC subgroups for possible targeted tumor therapy.

Prostaglandin E2 receptor EP1 expression in vulvar cancer.

PURPOSE: In recent years, incidence of vulvar cancer has been on the rise, whereas therapeutic options are still restricted. Therefore, new prognosticators and therapeutic targets are essential. Chronic inflammation plays an important role in carcinogenesis and COX-2, and its product prostaglandin E2 and its receptors EP1-4 are known to be important mediators in cancer initiation and progression. METHODS: EP1 expression in vulvar cancer specimens (n = 129) was investigated via immunohistochemistry and evaluated using the well-established immunoreactive score (IRS). Subsequently, the values were correlated with clinicopathological parameters. RESULTS: Our analysis did not reveal EP1 expression as a negative prognostic factor in overall and disease-free survival. However, in the subgroup of patients with lymph-node metastasis, overall survival was significantly shorter in tumors with high EP1 expression. Moreover, EP1 expression correlated positively with good differentiation of the tumor, but not with p16 status or COX-2 expression. CONCLUSIONS: This study shed first light on EP1 expression in vulvar carcinoma. EP1 expression correlated significantly with the grading of the tumor, suggesting that it influences cell differentiation. Further research on EP1 signaling may lead to a deeper understanding of the molecular mechanisms of carcinogenesis.

Prognostic Relevance of Nuclear Receptors in Relation to Peritumoral Inflammation and Tumor Infiltration by Lymphocytes in Breast Cancer.

The prognostic impact of tumor-infiltrating lymphocytes (TILs) is intensively investigated in breast cancer (BC). It is already known that triple-negative breast cancer (TNBC), the most aggressive type of BC, has the highest percentage of TILs. In addition, there is an influence of steroid hormone receptor expression (type I nuclear receptors) on TIL subpopulations in breast cancer tissue. The link between type II nuclear receptors and the level of TILs is unclear. Therefore, the aim of this study was to quantify TILs in a panel of 264 sporadic breast cancers and investigate the correlation of TIL levels with type I and II nuclear receptors expression. TIL levels were significantly increased in the subgroup of TNBC. By contrast, they decreased in estrogen (ER)- or progesterone receptor (PR)-positive cases. Moreover, TIL levels were correlated with type II nuclear receptors, including PPARγ, with a significant inverse correlation of the nuclear form (r = −0.727, p < 0.001) and a weak positive correlation of the cytoplasmic form (r = 0.202, p < 0.002). Surprisingly, BC cases with a TIL Salgado score of >15% showed a significantly decreased overall survival. In addition, peritumoral inflammation was also quantified in BC tissue samples. In our cohort, although the level of peritumoral inflammation was not correlated with OS, it determined the prognostic value of ER, PR, and PPARγ in BC. Altogether, the present study provides a differentiated overview of the relations between nuclear receptor expression, TIL levels, peritumoral inflammation, and prognosis in BC.

CCL22-Polarized TAMs to M2a Macrophages in Cervical Cancer In Vitro Model.

Macrophages are dynamic cells susceptible to the local microenvironment which includes tumor-associated macrophages (TAMs) in cancers. TAMs are a collection of heterogeneous macrophages, including M1 and M2 subtypes, shaped by various activation modes and labeled with various markers in different tumors. CCL22+-infiltrating cells are thought to be significantly associated with the prognosis of cervical cancer patients. Moreover, CCL22 is an established marker of M2a macrophages. Although the phenotypic identification of M1 and M2 macrophages is well established in mice and human macrophages cultured in a medium with fetal calf serum (FCS), fewer studies have focused on M2 subtypes. In addition, the question of whether CCL22 affects polarization of M2a macrophages remains unanswered. This study constructed a co-culture system to shape TAMs in vitro. We found that CCL22 was mainly secreted by TAMs but not cervical cancer cell lines. Human peripheral blood monocytes were differentiated into uncommitted macrophages (M0) and then polarized to M1, M2a, M2b, and M2c macrophages using LPS plus IFNr, IL-4, LPS plus IL1ß, and IL-10, respectively. Using flowcytometry, we found CD80++ was the marker of M1 and M2b, CD206++ was the marker of M2a, and CD163++ was the marker of M2c, compared with M0 macrophages. By regulating CCL22, we found that the mean fluorescence intensity (MFI) of CD206 in TAMs was significantly affected compared to the control group. Therefore, CCL22 could polarize TAMs of cervical cancer toward M2a macrophages. In conclusion, our study revealed that CCL22 could be a therapeutic target for cervical cancer, which might be because of its role in regulating macrophage polarization.

Cytoplasmic Colocalization of RXRα and PPARγ as an Independent Negative Prognosticator for Breast Cancer Patients.

Retinoid X receptor α (RXRα) is a nuclear receptor (NR) which functions as the primary heterodimeric partner of other NRs including the peroxisome proliferator-activated receptor γ (PPARγ). We previously reported that, in breast cancers (BC), the subcellular localization of these two receptors was strongly associated with patient prognosis. In the present work, we investigated the prognosis value of the combined cytoplasmic expression of RXRα and PPARγ using a retrospective cohort of 250 BC samples. Patients with tumors expressing both NRs in tumor cell cytoplasm exhibited a significant shorter overall (OS) and disease-free survival (DFS). This was also observed for patients with stage 1 tumors. Cox univariate analysis indicated that patients with tumors coexpressing RXRα and PPARγ in the cytoplasm of tumor cells have a decreased 5 y OS rate. Cytoplasmic co-expression of the two NRs significantly correlated with HER2 positivity and with NCAD and CD133, two markers of tumor aggressiveness. Finally, in Cox multivariate analysis, the co-expression of RXRα and PPARγ in the cytoplasm appeared as an independent OS prognosticator. Altogether, this study demonstrates that the cytoplasmic co-expression of RXRα and PPARγ could be of relevance for clinicians by identifying high-risk BC patients, especially amongst those with early and node-negative disease.

Effects of matcha tea extract on cell viability and peroxisome proliferator-activated receptor γ expression on T47D breast cancer cells.

PURPOSE: In the following work, we investigated the nuclear peroxisome proliferator-activated receptor gamma (PPARγ)-dependent proliferation behavior of breast cancer cells after stimulation with matcha green tea extract (MTE). METHODS: T47D cells were stimulated with MTE at concentrations of 5, 10 and 50 µg/ml. Cell viability was assessed using a WST-1 assay after an incubation time of 72 h. PPARγ expression was quantified at the gene level by real-time polymerase chain reaction (PCR). A western blot (WB) was carried out for the qualitative assessment of the expression behavior of on a protein level. RESULTS: The WST-1 test showed a significant inhibition of viability in T47D cells after 72 h at 5, 10 and 50 µg/ml. The PCR showed an overexpression of PPARγ in T47D cells in all concentrations. At the concentration of 50 µg/ml the expression was significantly increased (p < 0.05). The WB demonstrated a significant quantitative increase of PPARγ at protein level with MTE concentrations of 10 and 50 µg/ml. In addition, there was a negative correlation between the overexpression of PPAR γ and the inhibition of proliferation. CONCLUSION: MTE decreases the cell viability of T47D cells and furthermore leads to an overexpression of PPARγ on protein and mRNA level.

Dynamics of urinary and respiratory shedding of Severe acute respiratory syndrome virus 2 (SARS-CoV-2) RNA excludes urine as a relevant source of viral transmission.

PURPOSE: To investigate the expression of the receptor protein ACE-2 alongside the urinary tract, urinary shedding and urinary stability of SARS-CoV-2 RNA. METHODS: Immunohistochemical staining was performed on tissue from urological surgery of 10 patients. Further, patients treated for coronavirus disease (COVID-19) at specialized care-units of a university hospital were assessed for detection of SARS-CoV-2 RNA in urinary samples via PCR, disease severity (WHO score), inflammatory response of patients. Finally, the stability of SARS-CoV-2 RNA in urine was analyzed. RESULTS: High ACE-2 expression (3/3) was observed in the tubules of the kidney and prostate glands, moderate expression in urothelial cells of the bladder (0-2/3) and no expression in kidney glomeruli, muscularis of the bladder and stroma of the prostate (0/3). SARS-CoV-2 RNA was detected in 5/199 urine samples from 64 patients. Viral RNA was detected in the first urinary sample of sequential samples. Viral RNA load from other specimen as nasopharyngeal swabs (NPS) or endotracheal aspirates revealed higher levels than from urine. Detection of SARS-CoV-2 RNA in urine was not associated with impaired WHO score (median 5, range 3-8 vs median 4, range 1-8, p = 0.314), peak white blood cell count (median 24.1 × 1000/ml, range 5.19-48.1 versus median 11.9 × 1000/ml, range 2.9-60.3, p = 0.307), peak CRP (median 20.7 mg/dl, 4.2-40.2 versus median 11.9 mg/dl, range 0.1-51.9, p = 0.316) or peak IL-6 levels (median: 1442 ng/ml, range 26.7-3918 versus median 140 ng/ml, range 3.0-11,041, p = 0.099). SARS-CoV-2 RNA was stable under different storage conditions and after freeze-thaw cycles. CONCLUSIONS: SARS-CoV-2 RNA in the urine of COVID-19 patients occurs infrequently. The viral RNA load and dynamics of SARS-CoV-2 RNA shedding suggest no relevant route of transmission through the urinary tract.

Cytoplasmic Localization of RXRα Determines Outcome in Breast Cancer.

The aim of this retrospective study was to assess the prognostic value of cytoplasmic versus nuclear RXRα expression in breast cancer (BC) tissue samples and to correlate the results with clinicopathological parameters. In 319 BC patients, the expression of RXRα was evaluated via immunohistochemistry. Prognosis-determining aspects were calculated through uni- and multivariate analyses. Correlation analysis revealed a trend association with nuclear RXRα expression regarding an improved overall survival (OS) (p = 0.078), whereas cytoplasmic RXRα expression was significantly correlated with a poor outcomes in terms of both OS (p = 0.038) and disease-free survival (DFS) (p = 0.037). Strengthening these results, cytoplasmic RXRα was found to be an independent marker for DFS (p = 0.023), when adjusted to clinicopathological parameters, whereas nuclear RXRα expression was positively associated with lower TNM-staging, i.e., pT (p = 0.01), pN (p = 0.029) and pM (p = 0.001). Additionally, cytoplasmic RXRα expression was positively associated with a higher histopathological tumor grading (p = 0.02). Cytoplasmic RXRα was also found to be a negative prognosticator for Her-2neu-negative and triple-negative patients. Altogether, these findings support the hypothesis that the subcellular localization of RXRα plays an important role in carcinogenesis and the prognosis of BC. The expression of cytoplasmic RXRα is correlated with a more aggressive course of the disease, whereas nuclear RXRα expression appears to be a protective factor. These data may help to identify high-risk BC subgroups in order to find possible specific options in targeted tumor therapy.

Identification of a Novel Tumor Microenvironment Prognostic Signature for Advanced-Stage Serous Ovarian Cancer.

(1) Background: The tumor microenvironment is involved in the growth and proliferation of malignant tumors and in the process of resistance towards systemic and targeted therapies. A correlation between the gene expression profile of the tumor microenvironment and the prognosis of ovarian cancer patients is already known. (2) Methods: Based on data from The Cancer Genome Atlas (379 RNA sequencing samples), we constructed a prognostic 11-gene signature (SNRPA1, CCL19, CXCL11, CDC5L, APCDD1, LPAR2, PI3, PLEKHF1, CCDC80, CPXM1 and CTAG2) for Fédération Internationale de Gynécologie et d'Obstétrique stage III and IV serous ovarian cancer through lasso regression. (3) Results: The established risk score was able to predict the 1-, 3- and 5-year prognoses more accurately than previously known models. (4) Conclusions: We were able to confirm the predictive power of this model when we applied it to cervical and urothelial cancer, supporting its pan-cancer usability. We found that immune checkpoint genes correlate negatively with a higher risk score. Based on this information, we used our risk score to predict the biological response of cancer samples to an anti-programmed death ligand 1 immunotherapy, which could be useful for future clinical studies on immunotherapy in ovarian cancer.

Listening to Music during Outpatient Cystoscopy Reduces Pain and Anxiety and Increases Satisfaction: Results from a Prospective Randomized Study.

BACKGROUND: This study investigates the effect of classical music, music of patients' own choice, or no music on pain reduction during elective cystoscopy. OBJECTIVES: The aim of the study was to describe the effect of listening to classical music, music of patients' own choice, or no music on patient's pain and satisfaction rates when carrying out an elective cystoscopy and the effect on the assessment capability of the performing urologist. DESIGN, SETTING, AND PARTICIPANTS: This randomized trial included 127 patients undergoing elective cystoscopy at the Urological Department of the University Clinic of Munich between June 2019 and March 2020. Outcome Measurements and Statistical Analysis: Patients were assigned randomly to 3 groups: group I: listening to standardized classical music (n = 35), group II: listening to music according to the patients' choice (n = 34), and control group III: no music (n = 44). Prior to cystoscopy, anxiety levels were assessed by the Beck Anxiety Inventory (BAI). The Visual Analog Scale (VAS, range 1-100) was used for a self-assessment of pain, discomfort, and satisfaction. Statistical analysis was done with Spearman's rank correlation and t-tests. RESULTS AND LIMITATIONS: The median age was 63 (range 27-91) years. The duration of cystoscopy was 5.7 (1-30) min. Patients had undergone a median of 2.3 cystoscopies in the past. Between giving informed consent and cystoscopy, patients had to wait for a median of 64 (0-260) min. The median VAS pain score was significantly lower in group I at 1.7 and group II at 2.3 versus 5.2 in the control group III (p < 0.001). The control group III had significantly worse pain and patient satisfaction rates compared with groups I and II. Group I had a significant lower VAS pain score than groups II and III (p < 0.001). Classical music also increased the assessment capability of the preforming urologist. CONCLUSIONS: Listening to music during elective cystoscopy significantly reduces pain and distress and leads to higher patient and surgeon satisfaction. We recommend listening to classical music or music chosen by the patients during outpatient flexible/rigid cystoscopy in daily clinical routine. Patient Summary: In this study, we found that patients who listened to classical music or music of their own choice while undergoing a cystoscopy showed significant reduction of pain and distress.

Age at surgery is not a prognostic factor for the AdVance-XP male sling efficacy: A post-hoc analysis of a prospective 7-year multicentric study.

OBJECTIVE: To evaluate the factor age at the surgery on long-term postoperative outcomes in patients with postprostatectomy incontinence (PPI) after AdVance XP transobturator male sling implantation. METHODS: A total of 115 male patients with PPI, who had undergone AdVance XP sling implantation, were included. Patients had PPI with endoscopically confirmed good sphincteric-contractility and a positive coaptive response. Kruskal-Wallis test with Dunn post-hoc tests were used to analyze the postoperative outcome differences between the patient groups aged less than 66, 66-75, and over greater than 75 years. Outcome measures were the 24 h pad test, the number of daily pads used, the International Consultation on Incontinence Questionnaire short form (ICIQ-SF), International Quality of Life Score (IQOL), Patient Global Impression of Improvement (PGI-I), International Index of Erectile Function-5 (IIEF-5), International Prostate Symptom Score (IPSS), and Visual Analog Scale scores. Observation time points were 3, 6, 12, 24, 36, 48, 60, and 84 months after surgery. RESULTS: Between the age groups, there was no difference in the success rate of the procedure (defined as 0 pads/24 h and less than 5 g in the 24-h pad test) at any point in time. Subjective parameters measures using the ICIQ-SF, PGI-I, IQOL, and IPSS scores showed no differences between the two cohorts. Only erectile function (IIEF-5 score) was lower in older patients in comparison to the cohort aged less than 66 years (p < 0.05 at 3, 6, 12, 24, 36, and 48 months). CONCLUSIONS: The present study complements the European multicentre AdVance XP follow-up study. Here, we show that age at surgery does not affect the objective success, subjective success, or the complication rate. Thus, we do not recommend factoring in chronological age into surgical selection criteria for the AdVance XP implantation.

Nuclear receptor corepressor (NCoR) is a positive prognosticator for cervical cancer.

PURPOSE: Enzymes with epigenetic functions play an essential part in development of cancer. However, the significance of epigenetic changes in cervical carcinoma as a prognostic factor has not been fully investigated. Nuclear receptor corepressor (NCoR) presents itself as a potentially important element for epigenetic modification and as a potential prognostic aspect in cervical cancer. METHODS: By immunohistochemical staining of 250 tumor samples, the expression strength of NCoR was measured and evaluated by immunoreactive score (IRS) in the nucleus and cytoplasm. RESULTS: A low expression of NCoR in our patients was a disadvantage in overall survival. Expression of NCoR was negatively correlated with viral oncoprotein E6, acetylated histone H3 acetyl K9 and FIGO status, and positively correlated to p53. CONCLUSIONS: Our study has identified epigenetic modification of tumor cells thus seems to be of relevance in cervical cancer as well for diagnosis, as a marker or as a potential therapeutic target in patients with advanced cervical carcinoma.

EP4 as a Negative Prognostic Factor in Patients with Vulvar Cancer.

New prognostic factors and targeted therapies are urgently needed to improve therapeutic outcomes in vulvar cancer patients and to reduce therapy related morbidity. Previous studies demonstrated the important role of prostaglandin receptors in inflammation and carcinogenesis in a variety of tumor entities. In this study, we aimed to investigate the expression of EP4 in vulvar cancer tissue and its association with clinicopathological data and its prognostic relevance on survival. Immunohistochemistry was performed on tumor specimens of 157 patients with vulvar cancer treated in the Department of Obstetrics and Gynecology, Ludwig-Maximilian-University of Munich, Germany, between 1990 and 2008. The expression of EP4 was analyzed using the well-established semiquantitative immunoreactivity score (IRS) and EP4 expression levels were correlated with clinicopathological data and patients' survival. To specify the tumor-associated immune cells, immunofluorescence double staining was performed on tissue samples. In vitro experiments including 5-Bromo-2'-Deoxyuridine (BrdU) proliferation assay and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromid (MTT) viability assay were conducted in order to examine the effect of EP4 antagonist L-161,982 on vulvar carcinoma cells. EP4 expression was a common finding in in the analyzed vulvar cancer tissue. EP4 expression correlated significantly with tumor size and FIGO classification and differed significantly between keratinizing vulvar carcinoma and nonkeratinizing carcinoma. Survival analysis showed a significant correlation of high EP4 expression with poorer overall survival (p = 0.001) and a trending correlation between high EP4 expression and shorter disease-free survival (p = 0.069). Cox regression revealed EP4 as an independent prognostic factor for overall survival when other factors were taken into account. We could show in vitro that EP4 antagonism attenuates both viability and proliferation of vulvar cancer cells. In order to evaluate EP4 as a prognostic marker and possible target for endocrinological therapy, more research is needed on the influence of EP4 in the tumor environment and its impact in vulvar carcinoma.

Immunogenomic Identification for Predicting the Prognosis of Cervical Cancer Patients.

Cervical cancer is primarily caused by the infection of high-risk human papillomavirus (hrHPV). Moreover, tumor immune microenvironment plays a significant role in the tumorigenesis of cervical cancer. Therefore, it is necessary to comprehensively identify predictive biomarkers from immunogenomics associated with cervical cancer prognosis. The Cancer Genome Atlas (TCGA) public database has stored abundant sequencing or microarray data, and clinical data, offering a feasible and reliable approach for this study. In the present study, gene profile and clinical data were downloaded from TCGA, and the Immunology Database and Analysis Portal (ImmPort) database. Wilcoxon-test was used to compare the difference in gene expression. Univariate analysis was adopted to identify immune-related genes (IRGs) and transcription factors (TFs) correlated with survival. A prognostic prediction model was established by multivariate cox analysis. The regulatory network was constructed and visualized by correlation analysis and Cytoscape, respectively. Gene functional enrichment analysis was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). A total of 204 differentially expressed IRGs were identified, and 22 of them were significantly associated with the survival of cervical cancer. These 22 IRGs were actively involved in the JAK-STAT pathway. A prognostic model based on 10 IRGs (APOD, TFRC, GRN, CSK, HDAC1, NFATC4, BMP6, IL17RD, IL3RA, and LEPR) performed moderately and steadily in squamous cell carcinoma (SCC) patients with FIGO stage I, regardless of the age and grade. Taken together, a risk score model consisting of 10 novel genes capable of predicting survival in SCC patients was identified. Moreover, the regulatory network of IRGs associated with survival (SIRGs) and their TFs provided potential molecular targets.

Five-Year Results of a Prospective Multicenter Trial: AdVance XP for Postprostatectomy-Incontinence in Patients with Favorable Prognostic Factors.

OBJECTIVE: The aim of this study was to assess the security, value, and efficacy of the second-generation AdVance male sling XP (Boston Scientific®), after implementation in 2010 with advantageous modifications in the sling structure and needle shape, in a prospective multicenter long-term follow-up study. METHODS: In total, 115 patients were included. Exclusion criteria were earlier incontinence (UI) surgery, nocturnal UI, former radiotherapy, or night-time incontinence. We also excluded patients with a functional urethra <1 cm in a preoperatively performed repositioning test. A consistent 24-h pad test, International Quality of Life (IQOL) score, visual analog pain scale (VAS), International Consultation-Incontinence Questionnaire (ICIQ-UI SF), International Index of Erectile Function (IIEF-5), International Prostate Symptom Score (IPSS), and Patient Global Impression of Improvement (PGI-I) scores were requested postoperatively. RESULTS: The 24-month follow-up (114 patients) revealed 64.0% cured and 28.8% improved patients. Mean urine loss was reduced significantly to 19.0 g (p < 0.001). A mean PGI score of 1.5 and a mean VAS score of 0.2 were obtained. The 60-month follow-up (59 patients) revealed 57.6% cured and 25.4% improved patients. Mean urine loss was reduced significantly to 18.3 g (p < 0.001). A mean PGI score of 1.6 and a mean VAS score of 0.2 were obtained. CONCLUSIONS: The AdVance XP displays excellent continence results and secure effectiveness over a 5-year period. Moreover, these data are demonstrating low complication rates and improved quality of life in the long-term use of AdVance XP.

The Prognostic Impact of Retinoid X Receptor and Thyroid Hormone Receptor alpha in Unifocal vs. Multifocal/Multicentric Breast Cancer.

The aim of this study was to assess the prognostic value of the steroid hormone receptor expression, counting the retinoid X receptor (RXR) and thyroid hormone receptors (THRs), on the two different breast cancer (BC) entities: multifocal/multicentric versus unifocal. The overall and disease-free survival were considered as the prognosis determining aspects and analyzed by uni- and multi-variate analysis. Furthermore, histopathological grading and TNM staging (T = tumor size, N = lymph node involvement, M = distant metastasis) were examined in relation to RXR and THRs expression. A retrospective statistical analysis was carried out on survival-related events in a series of 319 sporadic BC patients treated at the Department of Gynecology and Obstetrics at the Ludwig-Maximillian's University in Munich between 2000 and 2002. The expression of RXR and THRs, including its two major isoforms THRα1 and THRα2, was analyzed by immunohistochemistry and showed to have a significant correlation for both BC entities in regard to survival analysis. Patients with multifocal/multicentric BC were exposed to a significantly worse disease-free survival (DFS) when expressing RXR. Patients with unifocal BC showed a significantly worse DFS when expressing THRα1. In contrast, a statistically significant positive association between THRα2 expression and enhanced DFS in multifocal/multicentric BC was shown. Especially the RXR expression in multifocal/multicentric BC was found to play a remarkably contradictory role for BC prognosis. The findings imply the need for a critical review of possible molecular therapies targeting steroid hormone receptors in BC treatment. Our results strengthen the need to further investigate the behavior of the nuclear receptor family, especially in relation to BC focality.

Interleukin 15 and Eotaxin correlate with the outcome of breast cancer patients vice versa independent of CTC status.

BACKGROUND: Circulating tumor cells (CTC) in the peripheral blood in women with breast cancer has been found to be an indicator of prognosis before the start of systemic treatment. The aim of this study is the assessment of specific cytokine profiles as markers for CTC involvement that could act as independent prognostic markers in terms of survival outcome for breast cancer patients. METHODS: Patients selected for this study were defined as women with breast cancer of the SUCCESS study. A total of 200 patients' sera were included in this study, 100 patients being positive for circulating tumor cells (CTC) and 100 patients being CTC negative. The matching criteria were histo-pathological grading, lymph node metastasis, hormone receptor status, TNM classification, and patient survival. Commercial ELISA with a multi cytokine/chemokine array was used to screen the sera for Interleukin 15 (IL-15) and eotaxin. RESULTS: Statistically significant concentrations were exposed for IL-15 levels regardless of the CTC-Status, lymph node involvement, or hormone receptor status. Significantly enhanced serum IL-15 concentrations were observed in those patients with worse overall survival (OS) and disease-free survival (DFS). Elevated serum concentrations of IL-15 significantly correlate with patients diagnosed with Grade 3 tumor and worse OS. In contrast, patients with a Grade 3 tumor with a favourable OS and DFS demonstrated significantly decreased IL-15 values. The CTC negative patient subgroup with a favourable OS and DFS, showed statistically significant elevated eotaxin values. CONCLUSION: These findings suggest a potential functional interaction of increased IL-15 concentrations in the peripheral blood of patients with a worse OS and DFS, regardless of prognostic factors at primary diagnosis. The increased levels of the chemokine eotaxin in CTC negative patients and a favourable OS and DFS, on the other hand, suggest that the overexpression inhibits CTCs entering the peripheral blood, thus emphasizing a significant inhibition of circulation specific metastasis. To sum up, IL-15 could be used as an independent prognostic marker in terms of survival outcome for breast cancer patients and used as an early indicator to highlight high-risk patients and consequently the adjustment of cancer therapy strategies.

Development and Validation of a Novel 11-Gene Prognostic Model for Serous Ovarian Carcinomas Based on Lipid Metabolism Expression Profile.

(1) Background: Biomarkers might play a significant role in predicting the clinical outcomes of patients with ovarian cancer. By analyzing lipid metabolism genes, future perspectives may be uncovered; (2) Methods: RNA-seq data for serous ovarian cancer were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. The non-negative matrix factorization package in programming language R was used to classify molecular subtypes of lipid metabolism genes and the limma package in R was performed for functional enrichment analysis. Through lasso regression, we constructed a multi-gene prognosis model; (3) Results: Two molecular subtypes were obtained and an 11-gene signature was constructed (PI3, RGS, ADORA3, CH25H, CCDC80, PTGER3, MATK, KLRB1, CCL19, CXCL9 and CXCL10). Our prognostic model shows a good independent prognostic ability in ovarian cancer. In a nomogram, the predictive efficiency was notably superior to that of traditional clinical features. Related to known models in ovarian cancer with a comparable amount of genes, ours has the highest concordance index; (4) Conclusions: We propose an 11-gene signature prognosis prediction model based on lipid metabolism genes in serous ovarian cancer.

L-Dopa-Decarboxylase (DDC) Is a Positive Prognosticator for Breast Cancer Patients and Epinephrine Regulates Breast Cancer Cell (MCF7 and T47D) Growth In Vitro According to Their Different Expression of Gi- Protein- Coupled Receptors.

A coherence between thyroid dysfunction and breast cancer incidence exists. Thyroid hormone metabolites bind to TAAR1 (trace amine-associated receptor 1) and through that modulate the serotonergic and dopaminergic system. Catecholamines themselves are synthesized by the L-dopa decarboxylase (DDC). The aim of our study was to analyze the influence of catecholamines on the DDC expression in primary breast cancer patients and the role of DDC concerning overall survival (OS). DDC expression was analyzed by immunohistochemistry. The effect of epinephrine on the expression of DDC and the Gi- protein was analyzed on the protein level via Western blot. A viability assay was performed to test the metabolic cell viability. The overexpression of DDC in the primary tumor was associated with longer OS (p = 0.03). Stimulation with epinephrine induced the downregulation of DDC (p = 0.038) and significantly increased viability in T47D cells (p = 0.028). In contrast, epinephrine induced an upregulation of DDC and decreased the proliferation of MCF7 cells (p = 0.028). Epinephrine led to an upregulation of Gi protein expression in MCF7 cells (p = 0.008). DDC is a positive prognostic factor for OS in breast cancer patients, and it is regulated through epinephrine differently in MCF7 and T47D. DDC may represent a novel target for the treatment of breast cancer, especially concerning its interaction with epinephrine.