Application of Perioperative Pain Management in the Perioperative Nursing of Labia Minora Plasty and its Effect on the Rehabilitation of Patients.

Objective: The objective of this study is to investigate effective pain management strategies for women undergoing labiaplasty surgery. By focusing on pain relief, patient rehabilitation, and satisfaction improvement, we aim to enhance the overall patient experience and outcomes of this common gynecological plastic surgery. Methods: A total of 126 individuals diagnosed with labia minora hypertrophy and who underwent plastic surgery on their labia minora within the period of July 2020 to July 2023 were chosen as the participants for this study. They were divided into an observation group and a comparison group, each consisting of 63 cases, based on the different nursing methods. The comparison group was treated with routine perioperative nursing after labia minora surgery, and the observation group was treated with perioperative pain nursing management based on the comparison group. Postoperative pain score, comfort score, incision healing time, first urination time, night Pittsburgh Sleep Quality Index (PSQI) score, complications, and satisfaction were compared between the two groups. All data were established in an Excel database, and statistical analysis was performed using SPSS26.0. Statistical methods used include descriptive analysis, t tests, and Chi-square tests. Results: The mean incision healing time of the observation group was 3.90±0.61 days, and that of the control group was 3.62±0.64 days. The mean incision healing time of the observation group was significantly different from that of the control group (P < .05). VRS scores and PSQI scores were significantly lower in both groups 1 week aftercare compared with 1 day before care, indicating improvements in pain and sleep quality. The improvement degree of VRS score and PSQI score in the observation group was significantly different (P < .05). The number of incision infections, hematoma, flap necrosis, skin scar, delayed healing, and total complication rate were 3 in the observation group and 11 in the comparison group, indicating that the complication rate in the observation group was significantly lower than that in the comparison group. The comparison difference was statistically significant (P < .05). Through the Chi-square test, the nursing satisfaction and perineal aesthetic effect satisfaction of the observation group were significantly higher than those of the comparison group, and the difference was statistically significant (P < .05). Conclusions: The implementation of perioperative pain nursing management has been shown to effectively alleviate pain in patients diagnosed with labia minora hypertrophy. This approach not only enhances treatment comfort but also significantly reduces the occurrence of postoperative complications. Additionally, it accelerates the healing process of incisions, improves the quality of incision healing, and enhances patient satisfaction with both the aesthetic outcome of the perineal area and the quality of nursing care provided.

Association of antenatal corticosteroids with mortality and morbidities in very preterm infants born to women with hypertensive disorders of pregnancy: a multicenter prospective cohort study.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) is the most common cause of indicated preterm delivery, but the impact of prenatal steroid exposure on the outcomes of preterm infants born to HDP mothers, who may be at risk for intrauterine hypoxia-ischemia, remains uncertain. The study objective is to evaluate the mortality and morbidities in HDP for very preterm infants (VPIs) exposed to different course of ANS. METHODS: This is a prospective cohort study comprising infants with < 32 weeks gestation born to women with HDP only from 1 Jan. 2019 to 31 Dec. 2021 within 40 participating neonatal intensive care units (NICUs) in Sino-northern network. ANS courses included completed, partial, repeated, and no ANS. Univariate and multivariable analyses were performed on administration of ANS and short-term outcomes before discharge. RESULTS: Among 1917 VPIs born to women with HDP only, 987(51.4%) received a complete course of ANS within 48 h to 7 days before birth, 560(29.2%) received partial ANS within 24 h before delivery, 100(5.2%) received repeat ANS and 270 (14.1%) did not receive any ANS. Compared to infants who received complete ANS, infants unexposed to ANS was associated with higher odds of death (AOR 1.85; 95%CI 1.10, 3.14), Severe Neurological Injury (SNI) or death (AOR 1.68; 95%CI 1.29,3.80) and NEC or death (AOR 1.78; 95%CI 1.55, 2.89), the repeated ANS group exhibits a significant negative correlation with the duration of oxygen therapy days (correlation coefficient - 18.3; 95%CI-39.2, -2.1). However, there were no significant differences observed between the full course and partial course groups in terms of outcomes. We can draw similar conclusions in the non-SGA group, while the differences are not significant in the SGA group. From KM curve, it showed that the repeated group had the highest survival rate, but the statistical analysis did not indicate a significant difference. CONCLUSIONS: Even partial courses of ANS administered within 24 h before delivery proved to be protective against death and other morbidities. The differences mentioned above are more pronounced in the non-SGA group. Repeat courses demonstrate a trend toward protection, but this still needs to be confirmed by larger samples.

Dynamic Screening of Thyroid Function for the Timely Diagnosis of Congenital Hypothyroidism in Very Preterm Infants: A Prospective Multicenter Cohort Study.

Background: Preterm infants presented a high prevalence of congenital hypothyroidism (CH), while the optimal screening pattern is still under debate. This study aimed at evaluating the characteristics of thyroid function by conducting weekly screening during the first month of life in very preterm infants (VPIs) to achieve timely diagnosis and treatment of CH. Methods: A prospective cohort study was carried out on VPIs born with gestational age (GA) <32 weeks (w) and admitted to the participating institutes from January 1, 2019 to December 31, 2022. Serial serum thyroid hormone levels were measured weekly within the first month after birth, and at 36 w of corrected age, or before discharge. Datasets for serial thyroid hormone levels and general information were obtained. Results: A total of 5992 VPIs were enrolled in this study, of which 456 (7.6%) [95% confidence interval (CI), 6.9-8.3%] were diagnosed with CH. The incidence of CH increased with lower GA, moving from 4.8% [CI, 3.4-6.1%] at GA 31 w to 16.9% [CI, 8.3-25.4%] at GA <26 w. Among the CH subjects, 57.7% [CI, 53.1-62.2%] were identified after the first screening and classified as delayed thyrotropin elevation (dTSH). With the decrease of GA, the proportion of dTSH also increased, moving from 38.1% [CI, 27.5-48.7%] at GA 31 w to 82.6% [CI, 65.8-99.4%] at GA <26 w. Through conducting weekly screening of thyroid function, it was remarkable that only 42.3% [CI, 37.8-46.9%] of CH subjects were diagnosed during the first screening. The cumulative rate of CH identified by rescreening performed at the second, third, and fourth week was 76.1% [CI, 72.2-80.0%], 90.6% [CI, 87.9-93.3%], and 98.9% [CI, 97.9-99.9%], respectively. Conclusion: The incidence of CH and dTSH both increase with lower GA in VPIs. Dynamic screening of thyroid function by weeks within the first month of life is crucial for the timely diagnosis and treatment of CH in VPIs, and it might effectively reduce the implications of missed diagnosis and delayed treatment. Clinical Trials Registration: ChiCTR1900025234 and ChiCTR2000037918 (Registration number).

Determining resuscitation threshold for extremely preterm infants based on the survival rates without severe neurological injury.

Background: Published guidelines on decision-making and resuscitation of extremely preterm infants primarily focus on high-income countries. For rapidly industrializing ones like China, there is a lack of population-based data for informing prenatal management and practice guidelines. Methods: The Sino-northern Neonatal Network conducted a prospective multi-centre cohort study between 1 January 2018 and 31 December 2021. Infants with a gestational age (GA) between 22 (postnatal age in days = 0) and 28 (postnatal age in days = 6) admitted to 40 tertiary NICUs in northern China were included and evaluated for death or severe neurological injury before discharge. Results: For all extremely preterm infants (n = 5838), the proportion of admission to the neonatal was 4.1% at 22-24 weeks, 27.2% at 25-26 weeks, and 75.2% at 27 and 28 weeks. Among 2228 infants admitted to the NICU, 216 (11.1%) were still elected for withdrawal of care (WIC) due to non-medical factors. Survival rates without severe neurological injury were 6.7% for infants at 22-23 weeks, 28.0% at 24 weeks, 56.7% at 24 weeks, 61.7% at 25 weeks, 79.9% at 26 weeks, and 84.5% at 27 and 28 weeks. Compared with traditional criterion at 28 weeks, the relative risk for death or severe neurological injury were 1.53 (95% confidence interval (CI) = 1.26-1.86) at 27 weeks, 2.32 (95% CI = 1.73-3.11) at 26 weeks, 3.62 (95% CI = 2.43-5.40) at 25 weeks, and 8.91 (95% CI = 4.69-16.96) at 24 weeks. The NICUs with higher proportion of WIC also had a higher rate of death or severe neurological injury after maximal intensive care (MIC). Conclusions: Compared to the traditional threshold of 28 weeks, more infants received MIC after 25 weeks, leading to significant increases in survival rates without severe neurological injury. Therefore, the resuscitation threshold should be gradually adjusted from 28 to 25 weeks based on reliable capacity. Registration: China Clinical Trials Registry. ID: ChiCTR1900025234.

Longer duration of initial invasive mechanical ventilation is still a crucial risk factor for moderate-to-severe bronchopulmonary dysplasia in very preterm infants: a multicentrer prospective study.

OBJECTIVES: We aimed to evaluate the risk factors for moderate-to-severe bronchopulmonary dysplasia (BPD) and focus on discussing its relationship with the duration of initial invasive mechanical ventilation (IMV) in very preterm neonates less than 32 weeks of gestational age (GA). METHODS: We performed a prospective cohort study involving infants born at 23-31 weeks of GA who were admitted to 47 different neonatal intensive care unit (NICU) hospitals in China from January 2018 to December 2021. Patient data were obtained from the Sina-northern Neonatal Network (SNN) Database. RESULTS: We identified 6538 very preterm infants, of whom 49.5% (3236/6538) received initial IMV support, and 12.6% (823/6538) were diagnosed with moderate-to-severe BPD symptoms. The median duration of initial IMV in the moderate-to-severe BPD group was 26 (17-41) days, while in the no or mild BPD group, it was 6 (3-10) days. The incidence rate of moderate-to-severe BPD and the median duration of initial IMV were quite different across different GAs. Multivariable logistic regression analysis showed that the onset of moderate-to-severe BPD was significantly associated with the duration of initial IMV [adjusted odds ratio (AOR): 1.97; 95% confidence interval (CI): 1.10-2.67], late-onset neonatal sepsis (LONS), and patent ductus arteriosus (PDA). CONCLUSION: In this multicenter cohort study, the duration of initial IMV was still relatively long in very premature infants, and the longer duration of initial IMV accounts for the increased risk of moderate-to-severe BPD.

Clinicopathological Features of Breast Cancer in Relation to Exposure of Cycling Reproductive Hormones: A Multicenter Retrospective Study of 14,731 Patients Diagnosed with Invasive Breast Cancer.

BACKGROUND Reproductive period for women, begins at menarche and ends at menopause, which represented the total time period of exposure to cycling reproductive hormones. The potential associations between clinicopathological features and the exposure of cycling reproductive hormones has not been extensively studied. The retrospective study enrolled 14,731 patients diagnosed with invasive breast cancer was designed to evaluate factors associated with the reproductive period on breast cancer type and patient outcomes. MATERIAL AND METHODS 14, 731 female breast cancer (BC) patients from Western China Clinical Cooperation Group (WCCCG) between January 1, 2008 to December 31, 2017 were identified. Unconditional logistic regression was performed to assess the associations between clinicopathological features and menarche age, menopause age, and reproductive years. The differences in risk factors between lower and higher number of reproductive years (<35 and ³35 yrs) were examined with the chi-square test. RESULTS First, patients with late menarche age were more likely to present with tumors of higher histological grade and larger sizes. Second, the findings suggested a higher likelihood of smaller tumor sizes in postmenopausal patients with a greater length of reproductive years. Conversely, higher histological grade was associated with this group of patients, compared to their counterparts with shorter reproductive years. Third, in luminal breast cancer, patients with a greater length of reproductive years were more probably present larger tumor. CONCLUSIONS Our findings indicated that several clinicopathologic factors including tumor size and histological grade were associated with the length of reproductive years in patients diagnosed with breast cancer.

Efficacy and Safety of Adding Immune Checkpoint Inhibitors to Neoadjuvant Chemotherapy Against Triple-Negative Breast Cancer: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have shown promising anti-tumor activity in multiple malignances including breast cancer. However, the responses can vary. This meta-analysis was conducted to evaluate the efficacy and safety profile of adding ICIs to neoadjuvant chemotherapy against triple-negative breast cancer (TNBC) and assess correlation of PD-L1 tumor status with responses. METHODS: Eligible studies were retrieved from the PubMed, Embase, and Web of Science databases. Randomized controlled trials (RCTs) that investigated ICI-containing versus ICI-free neoadjuvant therapy were included in this study. Meta-analyses were performed using Review Manager Version 5.2 software. RESULTS: This study included four RCTs containing 1795 patients with early TNBC. Compared with ICI-free neoadjuvant therapy, ICI-containing neoadjuvant therapy significantly increased the pathological complete response (pCR) rates in TNBC (odds ratio [OR] = 2.14, 95% confidence interval [CI]: 1.37-3.35, P < 0.001). In subgroup analysis, the addition of ICI to neoadjuvant chemotherapy was significantly associated with increased pCR rate in both PD-L1-positive TNBC (OR = 1.79, 95% CI: 1.33-2.41, P < 0.001) and PD-L1-negative TNBC (OR = 1.84, 95% CI: 1.14-2.99, P = 0.01). Patients with TNBC receiving ICI-containing neoadjuvant therapy had a better event-free survival (hazard ratio = 0.66, 95% CI: 0.48-0.89, P = 0.007) than those who receiving ICI-free neoadjuvant therapy. A significantly higher risk of adverse events including adrenal insufficiency, increased aspartate aminotransferase, dry skin, hepatitis, hyperthyroidism, hypothyroidism, infusion related reaction, pyrexia, and stomatitis was associated with ICI-containing neoadjuvant therapy. CONCLUSION: ICI-containing neoadjuvant therapy significantly increased the pCR rate in TNBC patients, independently of PD-L1 status. The addition of ICI to neoadjuvant chemotherapy may be considered an option for TNBC patients.

Clinical study of the feasibility, complications, and cosmetic outcomes of immediate autologous fat grafting during breast-conserving surgery for early-stage breast cancer in China.

BACKGROUND: The resection of tumors in small breasts or in areas such as the upper and inner parts of the breast may have disabling cosmetic results. Tumor resection reduces the volume of the breast and may result in asymmetry or distortion of the nipple-areola complex. Autologous fat transfer/grafting has been shown to be a reliable technique for improving these poor cosmetic results. This study aimed to evaluate the feasibility, complications, and cosmetic outcomes of immediate autologous fat grafting during breast-conserving surgery (BCS) in Chinese patients with early-stage breast cancer. METHODS: This retrospective study included 58 patients with early breast cancer treated by the same surgical team from October 2016 to May 2017. The patients were divided into two groups: BCS with lipofilling (experiment group, n=30) and BCS without lipofilling (control group, n=28). All patients received the recommended breast cancer treatment with complementary radiotherapy. The follow-up period after the completion of radiotherapy ranged from 36-44 months. The resected and grafted volumes, complications, esthetic results, patient satisfaction, and recurrence rate within 3 years were compared between the groups. RESULTS: The average resected and grafted volumes in the lipofilled group were 47 and 74 mL, respectively, with only one seroma and no other complications. Regarding physician evaluation, BCS with lipofilling resulted in better cosmetic outcomes than BCS without lipofilling (33% versus 15%, respectively). Poor responses occurred in only 7% of patients with lipofilling, compared with 15% without lipofilling. Regarding patient self-evaluation, Breast-Q scores including patient satisfaction with their breasts and psychosocial well-being, were significantly higher in patients who received lipofilling compared with non-lipofilled patients. Regional recurrence occurred in one patient (case 21) (3.7%) in the lipofilling group and systemic recurrence occurred in one patient (case 12) (3.8%) in the control group. CONCLUSIONS: Immediate autologous fat grafting is a promising, effective, and convenient technique for partial breast reconstruction after BCS, with potentially higher levels of patient and physician satisfaction compared with traditional BCS. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-ONN-17010514. Registered 24 January 2017.

Tumor suppressor DRD2 facilitates M1 macrophages and restricts NF-κB signaling to trigger pyroptosis in breast cancer.

Rationale: Breast cancer (BrCa) is the most common cancer worldwide, and the 5-year relative survival rate has declined in patients diagnosed at stage IV. Advanced BrCa is considered as incurable, which still lack effective treatment strategies. Identifying and characterizing new tumor suppression genes is important to establish effective prognostic biomarkers or therapeutic targets for late-stage BrCa. Methods: RNA-seq was applied in BrCa tissues and normal breast tissues. Through analyzing differentially expressed genes, DRD2 was selected for further analysis. And expression and promoter methylation status of DRD2 were also determined. DRD2 functions were analyzed by various cell biology assays in vitro. Subcutaneous tumor model was used to explore DRD2 effects in vivo. A co-cultivated system was constructed to investigate interactions of DRD2 and macrophages in vitro. WB, IHC, IF, TUNEL, qRT-PCR, Co-IP, Antibody Array, and Mass Spectrum analysis were further applied to determine the detailed mechanism. Results: In BrCa, DRD2 was found to be downregulated due to promoter methylation. Higher expression of DRD2 positively correlated with longer survival times especially in HER2-positive patients. DRD2 also promoted BrCa cells sensitivity to Paclitaxel. Ectopic expression of DRD2 significantly inhibited BrCa tumorigenesis. DRD2 also induced apoptosis as well as necroptosis in vitro and in vivo. DRD2 restricted NF-κB signaling pathway activation through interacting with ß-arrestin2, DDX5 and eEF1A2. Interestingly, DRD2 also regulated microenvironment as it facilitated M1 polarization of macrophages, and triggered GSDME-executed pyroptosis. Conclusion: Collectively, this study novelly manifests the role of DRD2 in suppressing BrCa tumorigenesis, predicting prognosis and treatment response. And this study further reveals the critical role of DRD2 in educating M1 macrophages, restricting NF-κB signaling pathway and triggering different processes of programmed cell death in BrCa. Taking together, those findings represent a predictive and therapeutic target for BrCa.

Clinicopathological Characteristics and Breast Cancer-Specific Survival of Patients With Single Hormone Receptor-Positive Breast Cancer.

Importance: Steroid hormone receptors, including estrogen receptor (ER) and progesterone receptor (PR), are crucial biomarkers in breast cancer (BC). However, limited data are available regarding single hormone receptor-positive (ER-positive/PR-negative and ER-negative/PR-positive) subtypes, rendering treatment decision and survival forecast difficult in patients with these BC subtypes. Objective: To investigate the clinicopathological characteristics and BC-specific survival (BCSS) of patients with single hormone receptor-positive BC. Design, Setting, and Participants: In this cohort study, data on patients diagnosed with BC between 1990 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results database (N = 1 158 032). Patients lacking information on ER status, PR status, or BCSS were excluded (n = 334 633). Comparisons were performed between single hormone receptor-positive BC and double hormone receptor-positive/double hormone receptor-negative BC. The dates of analysis were September 1, 2018, to June 31, 2019. Main Outcomes and Measures: The BCSS of patients with single hormone receptor-positive BC. Results: This cohort study included 823 399 patients with BC (818 002 women and 5397 men). The median (range) age at diagnosis was 60 (8-108) years, and the median (range) follow-up duration was 71 (0-311) months. The percentages of ER-positive/PR-positive, ER-positive/PR-negative, ER-negative/PR-positive, and ER-negative/PR-negative cases were 67.2%, 12.2%, 1.6%, and 19.0%, respectively. Single hormone receptor-positive subtypes showed distinct clinical characteristics compared with double hormone receptor-positive/double hormone receptor-negative subtypes. Multivariable Cox proportional hazards regression analysis showed that patients with ER-positive/PR-negative (hazard ratio [HR], 1.36; 95% CI, 1.34-1.38) and ER-negative/PR-positive (HR, 1.61; 95% CI, 1.55-1.67) tumors had worse BCSS than patients with the ER-positive/PR-positive subtype. In contrast, patients with ER-positive/PR-negative (HR, 1.27; 95% CI, 1.24-1.29) and ER-negative/PR-positive (HR, 1.07; 95% CI, 1.03-1.11) tumors had better BCSS than patients with the ER-negative/PR-negative subtype. The BCSS was statistically significantly worse in patients with ER-negative/PR-positive tumors than in patients with ER-positive/PR-negative tumors (HR, 1.18; 95% CI, 1.14-1.23). Conclusions and Relevance: In this cohort study, statistically significant distinctions between survival rates of patients with single hormone receptor-positive BC vs double hormone receptor-positive/double hormone receptor-negative BC were observed. Different strategies may be required for patients with single hormone receptor-positive tumors to ensure optimal treatment and maximum benefits from therapies.

Efficacy and safety of neoadjuvant chemotherapy regimens for triple-negative breast cancer: a network meta-analysis.

Different neoadjuvant chemotherapies are available for triple-negative breast cancer (TNBC). Here, we performed a network meta-analysis to evaluate the pathological complete response (pCR) benefit and safety of treatment regimens. Pairwise and Bayesian network meta-analyses were performed to compare direct and indirect evidence, respectively. Twenty-three studies involving 12 regimens namely standard chemotherapeutic agents, bevacizumab (B)-, platinum salts (P)-, B plus P (BP)-, poly(ADP-ribose) polymerase inhibitors (Pi)-, P plus Pi (PPi)-, capecitabine (Ca)-, gemcitabine (Ge)-, zoledronic acid (Za)-, everolimus (E)-, P plus E (PE)-, and gefitinib (G)-containing regimens. The results showed that P-, B-, PPi-, and Za-containing regimens achieved higher pCR than standard chemotherapeutic agents. BP-containing regimens had a better pCR than B-containing regimens. In indirect comparisons, Za-, BP-, P-, and B-containing regimens were the top four strategies with the highest probability for pCR. Benefit-risk analysis showed that B-containing regimens had the highest acceptability of being the best treatment for better pCR achievement with fewer SAEs. The addition of P, B, BP, PPi, and Za to standard chemotherapeutic agents enhanced the pCR, but a balance between efficacy and safety should be carefully considered. B-containing regimens might be the best choice for neoadjuvant chemotherapy due to its better efficacy and tolerability.

Paired box 5 is a novel marker of breast cancers that is frequently downregulated by methylation.

Identifying markers for breast cancer is important for both diagnosis and the design of treatment strategies. Recent studies have implicated Paired box 5 (PAX5) as a suppressor in various cancer types, where it is silenced by hypermethylation. However, determining the role of PAX5 in breast cancer requires further study, and the relationship between PAX5 methylation and breast cancer remains unclear. In this study, we found that PAX5 expression was frequently silenced or reduced by methylation in breast cancer cell lines as well as in breast cancer tissues. Restoring expression of PAX5 in breast cancer cells led to tumor suppression through inhibited proliferation and invasion, which resulted from modulation of the cell cycle and altered vascular endothelial growth factor (VEGF) expression. Most importantly, we found that PAX5 methylation status in breast cancer tissues was significantly correlated with patients' age, estrogen receptor (ER) status, progesterone receptor (PR) status, indicating that PAX5 could serve as a marker for breast cancer diagnosis and treatment strategy design.

Poly(ADP-ribose) polymerase-1 promotes recruitment of meiotic recombination-11 to chromatin and DNA double-strand break repair in Ku70-deficient breast cancer cells.

Poly(ADP-ribose) polymerase (PARP)-1 may act in an error-prone pathway called alternative end joining (Alt-EJ) for DNA double-strand break (DSB) repair when nonhomologous end joining is defective. We examined the recruitment of PARP-1 to chromatin in response to radiomimetic agents and the effects of PARP-1 inhibition on DSB repair and recruitment of the meiotic recombination (MRE)-11-double-strand break repair (RAD50) protein-Nijmegen breakage syndrome (NSB)-1 (MRN) complex to the chromatin in Ku70-deficient breast cancer cells. The chromatin-binding affinity of PARP-1 was enhanced in response to neocarzinostatin (NCS) or calicheamicin treatment in the absence of Ku70. PARP-1 inhibition impaired the repair of both NCS-induced DSBs and intron-encoded endonuclease from Physarum polycephalum-induced site-specific DSB. Both fractionation and chromatin immunoprecipitation assays demonstrated that chromatin recruitment of MRN was PARP-1 dependent. These data suggest that PARP-1 is vital for DSB repair in breast cancer cells when Alt-EJ is activated.-Huang, Y., Shao, Q., Luo, X., Yang, D., Zeng, B., Xiang, T., Ren, G., Cheng, Q. Poly(ADP-ribose) polymerase-1 promotes recruitment of meiotic recombination-11 to chromatin and DNA double-strand break repair in Ku70-deficient breast cancer cells.

Utilization of adipocyte-derived lipids and enhanced intracellular trafficking of fatty acids contribute to breast cancer progression.

BACKGROUND: To determine whether adipocyte-derived lipids could be transferred into breast cancer cells and investigate the underlying mechanisms of subsequent lipolysis and fatty acid trafficking in breast cancer cells. METHODS: A Transwell co-culture system was used in which human breast cancer cells were cultured in the absence or presence of differentiated murine 3 T3-L1 adipocytes. Migration/invasion and proliferation abilities were compared between breast cancer cells that were cultivated alone and those co-cultivated with mature adipocytes. The ability of lipolysis in breast cancer cells were measured, as well as the expression of the rate-limiting lipase ATGL and fatty acid transporter FABP5. ATGL and FABP5 were then ablated to investigate their impact on the aggressiveness of breast cancer cells that were surrounded by adipocytes. Further, immunohistochemistry was performed to detect differential expression of ATGL and FABP5 in breast cancer tissue sections. RESULTS: The migration and invasion abilities of cancer cells were significantly enhanced after co-culture with adipocytes, accompanied by elevated lipolysis and expression of ATGL and FABP5. Abrogation of ATGL and FABP5 sharply attenuated the malignancy of co-cultivated breast cancer cells. However, this phenomenon was not observed if a lipid emulsion was added to the culture medium to substitute for adipocytes. Furthermore, epithelial-mesenchymal transaction was induced in co-cultivated breast cancer cells. That may partially due to the stimulation of PPARß/δ and MAPK, which was resulted from upregulation of FABP5. As evidenced by immunohistochemistry, ATGL and FABP5 also had higher expression levels at the invasive front of the breast tumor, in where the adipocytes abound, compared to the central area in tissue specimens. CONCLUSIONS: Lipid originating from tumor-surrounding adipocytes could be transferred into breast cancer cells. Adipocyte-cancer cell crosstalk rather than lipids alone induced upregulation of lipases and fatty acid transport protein in cancer cells to utilize stored lipids for tumor progression. The increased expression of the key lipase ATGL and intracellular fatty acid trafficking protein FABP5 played crucial roles in this process via fueling or signaling.

Expression patterns of E2F transcription factors and their potential prognostic roles in breast cancer.

E2Fs, as a family of pivotal transcription factors, have been implicated in multiple biological functions in human cancer; however, the expression and prognostic significance of E2Fs in breast cancer remains unknown. In the present study, the mRNA expression patterns of E2Fs in breast cancer were investigated with Oncomine and The Cancer Genome Atlas data. Prognostic values of E2Fs for patients with breast cancer were determined using the Kaplan-Meier plotter database. The results strongly indicated that E2F1, E2F2, E2F3, E2F5, E2F7 and E2F8 were overexpressed in patients with breast cancer, whereas E2F4 and E2F6 exhibited no expression difference between patients with cancer and healthy controls. In survival analyses, elevated E2F1, E2F3, E2F5, E2F7 and E2F8 expression levels were significantly associated with lower overall survival, relapse-free survival (RFS), distant metastasis-free survival (DMFS) or post-progression survival for patients with breast cancer. Furthermore, high expression of E2F4 indicated improved RFS but reduced DMFS. Subgroup analyses based on four clinicopathological factors further revealed that E2Fs were associated with the prognosis of patients with breast cancer in an estrogen receptor-, progesterone receptor-, human epidermal growth factor 2- and lymph node status-specific manner. These data indicated that E2Fs may serve as promising biomarkers and therapeutic targets for breast cancer.

PSMD2 regulates breast cancer cell proliferation and cell cycle progression by modulating p21 and p27 proteasomal degradation.

Alterations in the ubiquitin-proteasome system (UPS) and UPS-associated proteins have been implicated in the development of many human malignancies. In this study, we investigated the expression profiles of 797 UPS-related genes using HiSeq data from The Cancer Genome Atlas and identified that PSMD2 was markedly upregulated in breast cancer. High PSMD2 expression was significantly correlated with poor prognosis. Gene set enrichment analysis revealed that transcriptome signatures involving proliferation, cell cycle, and apoptosis were critically enriched in specimens with elevated PSMD2. Consistently, PSMD2 knockdown inhibited cell proliferation and arrested cell cycle at G0/G1 phase in vitro, as well as suppressed tumor growth in vivo. Rescue assays demonstrated that the cell cycle arrest caused by silencing PSMD2 partially resulted from increased p21 and/or p27. Mechanically, PSMD2 physically interacted with p21 and p27 and mediated their ubiquitin-proteasome degradation with the cooperation of USP14. Notably, intratumor injection of therapeutic PSMD2 small interfering RNA effectively delayed xenograft tumor growth accompanied by p21 and p27 upregulation. These data provide novel insight into the role of PSMD2 in breast cancer and suggest that PSMD2 may be a potential therapeutic target.

The 3p14.2 tumour suppressor ADAMTS9 is inactivated by promoter CpG methylation and inhibits tumour cell growth in breast cancer.

Chromosome region 3p12-14 is an important tumour suppressor gene (TSG) locus for multiple cancers. ADAMTS9, a member of the metalloprotease large family, has been identified as a candidate 3p14.2 TSG inactivated by aberrant promoter CpG methylation in several carcinomas, but little known about its expression and function in breast cancer. In this report, ADAMTS9 expression and methylation was analysed in breast cancer cell lines and tissue samples. ADAMTS9 RNA was significantly down-regulated in breast cancer cell lines (6/8). After treating the cells with demethylation agent Aza and TSA, ADAMTS9 expression was dramatically increased. Bisulphite genomic sequencing and methylation-specific PCR detected promoter methylation, which was associated with decreased ADAMTS9 expression. Hypermethylation was also detected in 130/219 (59.4%) of primary tumours but only in 4.5% (2/44) of paired surgical margin tissues. Ectopic expression of ADAMTS9 in tumor cells induced significant growth suppression, cell cycle arrest at the G0/G1 phase, enhanced apoptosis and reduced cell migration and invasion. Conditioned culture medium from ADAMTS9-transfected BT549 cells markedly disrupted tube formation ability of human umbilical vein endothelial cell (HUVEC) in Matrigel. Furthermore, ADAMTS9 inhibited AKT signaling and its downstream targets (MDM2, p53, p21, p27, E-cadherin, VIM, SNAIL, VEGFA, NFκB-p65 and MMP2). In addition, we demonstrated, for the first time, that ADAMTS9 inhibits AKT signaling, through suppressing its upstream activators EGFR and TGFß1/TßR(I/II) in breast cancer cells. Our results suggest that ADAMTS9 is a TSG epigenetically inactivated in breast cancer, which functions through blocking EGFR- and TGFß1/TßR(I/II)-activated AKT signaling.

PSME3 induces epithelial-mesenchymal transition with inducing the expression of CSC markers and immunosuppression in breast cancer.

Proteasome activator subunit 3 (PSME3) plays a key role in breast cancer by regulating the cell cycle. However, its role in other pathogenesis-related features of breast cancer is unclear. In this study, we found that overexpression of PSME3 induced the epithelial-mesenchymal transition and contributed to induce the expression of cancer stem cell markers of the MDA-MB-231 cell line, thus increasing the migration, and invasion of the cells. Moreover, overexpression of PSME3 reduced the chemotaxis of CD8+ T cells and induced the apoptosis of T cells in vitro. Furthermore, PSME3 knockdown increased the number of CD8+ T cells in vivo and reduced the subcutaneous tumor growth rate. These findings revealed that PSME3 induces epithelial-mesenchymal transition with inducing the expression of CSC markers and influencing the tumor immune microenvironment in breast cancer.

Phospholipase Cδ1 suppresses cell migration and invasion of breast cancer cells by modulating KIF3A-mediated ERK1/2/ß- catenin/MMP7 signalling.

Phospholipase C δ1 (PLCD1) encodes an enzyme involved in energy metabolism, calcium homeostasis and intracellular movement. It is located at 3p22 in a region that is frequently deleted in multiple cancers, and the PLCD1 enzyme is a potential tumour suppressor in breast cancer that inhibits matrix metalloprotease (MMP) 7, but the detailed mechanism remains elusive. In this study, we found that PLCD1 was downregulated in breast cancers, and the gain-or-loss functional assay revealed that PLCD1 inhibited cell migration and invasion in vitro via the ERK1/2/ß-catenin/MMP7 signalling pathway. Furthermore, KIF3A was identified as a downstream mediator of PLCD1, and there was an inverse correlation between the expression of PLCD1 and KIF3A. Knockdown of KIF3A expression alone suppressed cell migration and invasion, and attenuated ERK1/2/ß-catenin/MMP7 signalling that was reactivated by knocking down PLCD1 in vitro. Collectively, our findings suggest that PLCD1 acts as a tumour suppressor, by KIF3A-mediated suppression of ERK1/2/ß-catenin/MMP7 signalling, at least in part, in breast cancer.

The transcription levels and prognostic values of seven proteasome alpha subunits in human cancers.

Proteasome alpha subunits (PSMAs) have been shown to participate in the malignant progression of human cancers. However, the expression patterns and prognostic values of individual PSMAs remain elusive in most cancers. In the present study, we investigated the mRNA expression levels of seven PSMAs in different kinds of cancers using Oncomine and The Cancer Genome Atlas (TCGA) databases. The prognostic significance of PSMAs was also determined by Kaplan-Meier Plotter and PrognScan databases. Combined with Oncomine and TCGA, the mRNA expression levels of PSMA1-7 were significantly upregulated in breast, lung, gastric, bladder and head and neck cancer compared with normal tissues. Moreover, only PSMA6 and PSMA5 were not overexpressed in colorectal and kidney cancer, respectively. In survival analyses based on Kaplan-Meier Plotter, PSMA1-7 showed significant prognostic values in breast, lung and gastric cancer. Furthermore, potential correlations between PSMAs and survival outcomes were also observed in ovarian cancer, colorectal cancer and melanoma by Kaplan-Meier Plotter and PrognScan. These data indicated that PSMAs might serve as novel biomarkers and potential therapeutic targets for multiple human cancers. However, further studies are needed to explore the detailed biological functions and molecular mechanisms involved in tumor progression.