Association of common maternal infections with birth outcomes: a multinational cohort study.

PURPOSE: It is unclear whether common maternal infections during pregnancy are risk factors for adverse birth outcomes. We assessed the association between self-reported infections during pregnancy with preterm birth and small-for-gestational-age (SGA) in an international cohort consortium. METHODS: Data on 120,507 pregnant women were obtained from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA. Self-reported common infections during pregnancy included influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections, cystitis, urinary tract infection, and the symptoms fever and diarrhoea. Birth outcomes included preterm birth, low birth weight and SGA. Associations between maternal infections and birth outcomes were first assessed using Poisson regression in each cohort and then pooled using random-effect meta-analysis. Risk ratios (RR) and 95% confidence intervals (CI) were calculated, adjusted for potential confounders. RESULTS: Vaginal infections (pooled RR, 1.10; 95% CI, 1.02-1.20) and urinary tract infections (pooled RR, 1.17; 95% CI, 1.09-1.26) during pregnancy were associated with higher risk of preterm birth. Similar associations with low birth weight were also observed for these two infections. Fever during pregnancy was associated with higher risk of SGA (pooled RR, 1.07; 95% CI, 1.02-1.12). No other significant associations were observed between maternal infections/symptoms and birth outcomes. CONCLUSION: Vaginal infections and urinary infections during pregnancy were associated with a small increased risk of preterm birth and low birth weight, whereas fever was associated with SGA. These findings require confirmation in future studies with laboratory-confirmed infection diagnosis.

Lifestyle-based subtypes of childhood obesity and their association with cardiometabolic factors: A cluster analysis.

BACKGROUND: Lifestyle factors play an important role in the development and management of childhood obesity and its related cardiometabolic complications. OBJECTIVE/METHODS: We aimed to explore childhood obesity subtypes based on lifestyle factors and examine their association with cardiometabolic health. We included 1550 children with obesity from the National Health and Nutrition Examination Survey. Cluster analysis identified obesity subtypes based on four lifestyle factors (physical activity, diet quality, sedentary time and smoking). Multiple linear regression assessed their association with cardiometabolic factors. RESULTS: Five subtypes of childhood obesity were identified: unhealthy subtype (n = 571; 36.8%), physically active subtype (n = 185; 21.1%), healthy diet subtype (n = 404; 26.1%), smoking subtype (n = 125; 8.1%) and non-sedentary subtype (n = 265; 17.1%). Compared with the unhealthy subtype, the physically active subtype had lower insulin and HOMA-IR levels, and smoking subtype was associated with lower HDL levels. When compared with children with normal weight, all obesity subtypes had worse cardiometabolic profile, except the physically active subtype who had similar DBP, HbA1c and TC levels; smoking subtype who had similar TC levels; and healthy diet and non-sedentary subtypes who had similar DBP levels. CONCLUSION: Children of different lifestyle-based obesity subtypes might have different cardiometabolic risks. Our new classification system might help personalize assessment of childhood obesity.

Evaluation of Maternal Infection During Pregnancy and Childhood Leukemia Among Offspring in Denmark.

Importance: Maternal infection is common during pregnancy and is an important potential cause of fetal genetic and immunological abnormalities. Maternal infection has been reported to be associated with childhood leukemia in previous case-control or small cohort studies. Objective: To evaluate the association of maternal infection during pregnancy with childhood leukemia among offspring in a large study. Design, Setting, and Participants: This population-based cohort study used data from 7 Danish national registries (including the Danish Medical Birth Register, the Danish National Patient Registry, the Danish National Cancer Registry, and others) for all live births in Denmark between 1978 and 2015. Swedish registry data for all live births between 1988 and 2014 were used to validate the findings for the Danish cohort. Data were analyzed from December 2019 to December 2021. Exposures: Maternal infection during pregnancy categorized by anatomic locations identified from the Danish National Patient Registry. Main Outcomes and Measures: The primary outcome was any leukemia; secondary outcomes were acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML). Offspring childhood leukemia was identified in the Danish National Cancer Registry. Associations were first assessed in the whole cohort using Cox proportional hazards regression models, adjusted for potential confounders. A sibling analysis was performed to account for unmeasured familial confounding. Results: This study included 2 222 797 children, 51.3% of whom were boys. During the approximately 27 million person-years of follow-up (mean [SD], 12.0 [4.6] years per person), 1307 children were diagnosed with leukemia (ALL, 1050; AML, 165; or other, 92). Children born to mothers with infection during pregnancy had a 35% increased risk of leukemia (adjusted hazard ratio [HR], 1.35 [95% CI, 1.04-1.77]) compared with offspring of mothers without infection. Maternal genital and urinary tract infections were associated with a 142% and 65% increased risk of childhood leukemia, with HRs of 2.42 (95% CI, 1.50-3.92) and 1.65 (95% CI, 1.15-2.36), respectively. No association was observed for respiratory tract, digestive, or other infections. The sibling analysis showed comparable estimates to the whole-cohort analysis. The association patterns for ALL and AML were similar to that for any leukemia. No association was observed for maternal infection and brain tumors, lymphoma, or other childhood cancers. Conclusions and Relevance: In this cohort study of approximately 2.2 million children, maternal genitourinary tract infection during pregnancy was associated with childhood leukemia among offspring. If confirmed in future studies, our findings may have implications for understanding the etiology and developing preventive measures for childhood leukemia.

Association of Assisted Reproductive Technology With Offspring Growth and Adiposity From Infancy to Early Adulthood.

Importance: People conceived using assisted reproductive technology (ART) make up an increasing proportion of the world's population. Objective: To investigate the association of ART conception with offspring growth and adiposity from infancy to early adulthood in a large multicohort study. Design, Setting, and Participants: This cohort study used a prespecified coordinated analysis across 26 European, Asia-Pacific, and North American population-based cohort studies that included people born between 1984 and 2018, with mean ages at assessment of growth and adiposity outcomes from 0.6 months to 27.4 years. Data were analyzed between November 2019 and February 2022. Exposures: Conception by ART (mostly in vitro fertilization, intracytoplasmic sperm injection, and embryo transfer) vs natural conception (NC; without any medically assisted reproduction). Main Outcomes and Measures: The main outcomes were length / height, weight, and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared). Each cohort was analyzed separately with adjustment for maternal BMI, age, smoking, education, parity, and ethnicity and offspring sex and age. Results were combined in random effects meta-analysis for 13 age groups. Results: Up to 158 066 offspring (4329 conceived by ART) were included in each age-group meta-analysis, with between 47.6% to 60.6% females in each cohort. Compared with offspring who were NC, offspring conceived via ART were shorter, lighter, and thinner from infancy to early adolescence, with differences largest at the youngest ages and attenuating with older child age. For example, adjusted mean differences in offspring weight were -0.27 (95% CI, -0.39 to -0.16) SD units at age younger than 3 months, -0.16 (95% CI, -0.22 to -0.09) SD units at age 17 to 23 months, -0.07 (95% CI, -0.10 to -0.04) SD units at age 6 to 9 years, and -0.02 (95% CI, -0.15 to 0.12) SD units at age 14 to 17 years. Smaller offspring size was limited to individuals conceived by fresh but not frozen embryo transfer compared with those who were NC (eg, difference in weight at age 4 to 5 years was -0.14 [95% CI, -0.20 to -0.07] SD units for fresh embryo transfer vs NC and 0.00 [95% CI, -0.15 to 0.15] SD units for frozen embryo transfer vs NC). More marked differences were seen for body fat measurements, and there was imprecise evidence that offspring conceived by ART developed greater adiposity by early adulthood (eg, ART vs NC difference in fat mass index at age older than 17 years: 0.23 [95% CI, -0.04 to 0.50] SD units). Conclusions and Relevance: These findings suggest that people conceiving or conceived by ART can be reassured that differences in early growth and adiposity are small and no longer evident by late adolescence.

Common maternal infections during pregnancy and childhood leukaemia in the offspring: findings from six international birth cohorts.

BACKGROUND: Previous epidemiological studies have found positive associations between maternal infections and childhood leukaemia; however, evidence from prospective cohort studies is scarce. We aimed to examine the associations using large-scale prospective data. METHODS: Data were pooled from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA (recruitment 1950s-2000s). Primary outcomes were any childhood leukaemia and acute lymphoblastic leukaemia (ALL); secondary outcomes were acute myeloid leukaemia (AML) and any childhood cancer. Exposures included maternal self-reported infections [influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections and urinary tract infection (including cystitis)] and infection-associated symptoms (fever and diarrhoea) during pregnancy. Covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using multilevel Cox models. RESULTS: Among 312 879 children with a median follow-up of 13.6 years, 167 leukaemias, including 129 ALL and 33 AML, were identified. Maternal urinary tract infection was associated with increased risk of any leukaemia [HR (95% CI) 1.68 (1.10-2.58)] and subtypes ALL [1.49 (0.87-2.56)] and AML [2.70 ([0.93-7.86)], but not with any cancer [1.13 (0.85-1.51)]. Respiratory tract infection was associated with increased risk of any leukaemia [1.57 (1.06-2.34)], ALL [1.43 (0.94-2.19)], AML [2.37 (1.10-5.12)] and any cancer [1.33 (1.09-1.63)]; influenza-like illness showed a similar pattern but with less precise estimates. There was no evidence of a link between other infections and any outcomes. CONCLUSIONS: Urinary tract and respiratory tract infections during pregnancy may be associated with childhood leukaemia, but the absolute risk is small given the rarity of the outcome.

Long non-coding RNA ARHGAP5-AS1 inhibits migration of breast cancer cell via stabilizing SMAD7 protein.

PURPOSE: Tumor metastasis is the main cause of death from breast cancer patients and cell migration plays a critical role in cancer metastasis. Recent studies have shown long non-coding RNAs (lncRNAs) play an essential role in the initiation and progression of cancer. In the present study, the role of an LncRNA, Rho GTPase Activating Protein 5- Antisense 1 (ARHGAP5-AS1) in breast cancer was investigated. METHODS: RNA sequencing was performed to find out dysregulated LncRNAs in MDA-MB-231-LM2 cells. Transwell migration assays and F-actin staining were utilized to estimate cell migration ability. RNA pulldown assays and RNA immunoprecipitation were used to prove the interaction between ARHGAP5-AS1 and SMAD7. Western blot and immunofluorescence imaging were used to examine the protein levels. Dual luciferase reporter assays were performed to evaluate the activation of TGF-ß signaling. RESULTS: We analyzed the RNA-seq data of MDA-MB-231 and its highly metastatic derivative MDA-MB-231-LM2 cell lines (referred to as LM2) and identified a novel lncRNA (NR_027263) named as ARHGAP5-AS1, which expression was significantly downregulated in LM2 cells. Further functional investigation showed ARHGAP5-AS1 could inhibit cell migration via suppression of stress fibers in breast cancer cell lines. Afterwards, SMAD7 was further identified to interact with ARHGAP5-AS1 by its PY motif and thus its ubiquitination and degradation was blocked due to reduced interaction with E3 ligase SMURF1 and SMURF2. Moreover, ARHGAP5-AS1 could inhibit TGF-ß signaling pathway due to its inhibitory role on SMAD7. CONCLUSION: ARHGAP5-AS1 inhibits breast cancer cell migration via stabilization of SMAD7 protein and could serve as a novel biomarker and a potential target for breast cancer in the future.

Association between serum progesterone concentration in early pregnancy and duration of pregnancy: a cohort study.

Objective: To examine the association between progesterone concentration in early pregnancy and duration of pregnancy and risk of preterm delivery.Methods: Women enrolled in the Born in Guangzhou Cohort Study from 2013-2014, with a singleton pregnancy, who had serum progesterone measured at least one time between 4 and 10 weeks of gestation were included. The association between progesterone concentration both continuous and as categorical variable (quartile) and the risk of preterm delivery was assessed with Cox proportional hazards regression. Differences of length of gestation in four progesterone concentration quartiles were assessed using the Log-rank test.Results: We studied 1860 mother-newborn pairs. The mean overall progesterone concentration was 65.7 ± 21.3 nmol/L, with mean progesterone concentrations in the four quartiles of 42.4 ± 6.2 nmol/L (n = 463), 56.2 ± 3.3 nmol/L (n = 462), 68.9 ± 4.5 nmol/L (n = 470), and 95.1 ± 15.3 nmol/L (n = 465). There was no significantly difference in duration of gestation in four progesterone concentration groups (p=.511). There was no relation between progesterone level and preterm delivery (adjusted hazard ratio (HR) per 10 nmol/l progesterone level 1.00 (95% confidence interval (CI) 0.90, 1.11)). After adjusting for potential confounders, the HR of any preterm delivery for quartiles 1, 2 and 3 versus the highest quartile of progesterone level (> 77.3 nmol/L) was 1.04 (95% CI 0.52, 2.07), 1.17 (95% CI 0.60, 2.28), and 1.46 (95% CI 0.76, 2.78), respectively. When analysis was done for spontaneous preterm delivery only, also no association with first trimester progesterone was found.Conclusion: Lower first trimester serum progesterone concentration is not associated with reduction of length of gestation or increased risk of preterm delivery.

Maternal Infection in Pregnancy and Childhood Leukemia: A Systematic Review and Meta-analysis.

OBJECTIVE: To summarize the published evidence regarding the association between maternal infection during pregnancy and childhood leukemia. STUDY DESIGN: In this systematic review and meta-analysis (PROSPERO number, CRD42018087289), we searched PubMed and Embase to identify relevant studies. We included human studies that reported associations of at least one measure of maternal infection during pregnancy with acute lymphoblastic leukemia (ALL) or all childhood leukemias in the offspring. One reviewer extracted the data first using a standardized form, and the second reviewer independently checked the data for accuracy. Two reviewers used the Newcastle-Ottawa Scale to assess the quality of included studies. We conducted random effects meta-analyses to pool the ORs of specific type of infection on ALL and childhood leukemia. RESULTS: This review included 20 studies (ALL, n = 15; childhood leukemia, n = 14) reported in 32 articles. Most (>65%) included studies reported a positive association between infection variables and ALL or childhood leukemia. Among specific types of infection, we found that influenza during pregnancy was associated with higher risk of ALL (pooled OR, 3.64; 95% CI, 1.34-9.90) and childhood leukemia (pooled OR, 1.77; 95% CI, 1.01-3.11). Varicella (pooled OR, 10.19; 95% CI, 1.98-52.39) and rubella (pooled OR, 2.79; 95% CI, 1.16-6.71) infections were also associated with higher childhood leukemia risk. CONCLUSIONS: Our findings suggest that maternal infection during pregnancy may be associated with a higher risk of childhood leukemia.

Insulin-like growth factor-1, metabolic abnormalities, and pathological complete remission rate in HER2-positive breast cancer patients receiving neoadjuvant therapy.

Purpose: HER2-positive breast cancer (BC) achieving pathological complete remission (pCR) after neoadjuvant therapy (NAT) had a superior disease outcome. Dysmetabolism and stimulation of insulin-like growth factor 1 (IGF-1)-axis would increase BC risk, but we are lacking data for their association with pCR in HER2-positive+ BC. We aim to evaluate the pCR predictive value of above factors in HER2-positive BC patients receiving NAT. Patients and methods: HER2-positive BC patients receiving NAT ± trastuzumab were retrospectively included between January 2013 and December 2016. Data were compared between baseline at biopsy and surgery. Median value of IGF-1 expression was used as cutoff value to classify patients into low or high group. pCR was defined as no residual invasive carcinoma in breast and axilla. Results: Overall, 101 patients were included. Metabolic syndrome was diagnosed in 29 (28.71%) with an average of 1.71±1.51 metabolic disorders at baseline, significantly increased after NAT (2.12±1.54, P<0.001). Lipid metabolism factors, including triglycerides, TC, HDL-C and LDL-C significantly worsened after NAT (all P<0.05). Average post-NAT IGF-1 was 196.14±86.03 ng/mL (vs preNAT 186.41±75.03 ng/mL, P=0.182). pCR was achieved in 29 (28.71%) patients. pCR rate was 40.00% and 17.65% for those with low or high preIGF-1 level (P=0.013). Multivariate analysis found that low IGF-1 expression, but not any other metabolic variable, was significantly associated with higher pCR rate in whole population (OR: 3.83, 95%CI: 1.32-11.11, P=0.014) or in patients receiving NAT + trastuzumab (OR: 3.93, 95%CI: 1.13-13.63, P=0.031). With a median follow-up of 29.03 (range: 10.42-56.98) months, IGF-1 level was not associated with overall survival (P=0.328) or disease-free survival (P=0.288). Conclusion: Low IGF-1 level was related with higher pCR rate in HER2-positive BC patients receiving NAT, which deserves further clinical evaluation.

The International Childhood Cancer Cohort Consortium (I4C): A research platform of prospective cohorts for studying the aetiology of childhood cancers.

BACKGROUND: Childhood cancer is a rare but leading cause of morbidity and mortality. Established risk factors, accounting for <10% of incidence, have been identified primarily from case-control studies. However, recall, selection and other potential biases impact interpretations particularly, for modest associations. A consortium of pregnancy and birth cohorts (I4C) was established to utilise prospective, pre-diagnostic exposure assessments and biological samples. METHODS: Eligibility criteria, follow-up methods and identification of paediatric cancer cases are described for cohorts currently participating or planning future participation. Also described are exposure assessments, harmonisation methods, biological samples potentially available for I4C research, the role of the I4C data and biospecimen coordinating centres and statistical approaches used in the pooled analyses. RESULTS: Currently, six cohorts recruited over six decades (1950s-2000s) contribute data on 388 120 mother-child pairs. Nine new cohorts from seven countries are anticipated to contribute data on 627 500 additional projected mother-child pairs within 5 years. Harmonised data currently includes over 20 "core" variables, with notable variability in mother/child characteristics within and across cohorts, reflecting in part, secular changes in pregnancy and birth characteristics over the decades. CONCLUSIONS: The I4C is the first cohort consortium to have published findings on paediatric cancer using harmonised variables across six pregnancy/birth cohorts. Projected increases in sample size, expanding sources of exposure data (eg, linkages to environmental and administrative databases), incorporation of biological measures to clarify exposures and underlying molecular mechanisms and forthcoming joint efforts to complement case-control studies offer the potential for breakthroughs in paediatric cancer aetiologic research.

Predictions of Preterm Birth from Early Pregnancy Characteristics: Born in Guangzhou Cohort Study.

Preterm birth (PTB, <37 weeks) is the leading cause of death in children <5 years of age. Early risk prediction for PTB would enable early monitoring and intervention. However, such prediction models have been rarely reported, especially in low- and middle-income areas. We used data on a number of easily accessible predictors during early pregnancy from 9044 women in Born in Guangzhou Cohort Study, China to generate prediction models for overall PTB and spontaneous, iatrogenic, late (34⁻36 weeks), and early (<34 weeks) PTB. Models were constructed using the Cox proportional hazard model, and their performance was evaluated by Harrell's c and D statistics and calibration plot. We further performed a systematic review to identify published models and validated them in our population. Our new prediction models had moderate discrimination, with Harrell's c statistics ranging from 0.60⁻0.66 for overall and subtypes of PTB. Significant predictors included maternal age, height, history of preterm delivery, amount of vaginal bleeding, folic acid intake before pregnancy, and passive smoking during pregnancy. Calibration plots showed good fit for all models except for early PTB. We validated three published models, all of which were from studies conducted in high-income countries; the area under receiver operating characteristic for these models ranged from 0.50 to 0.56. Based on early pregnancy characteristics, our models have moderate predictive ability for PTB. Future studies should consider inclusion of laboratory markers for the prediction of PTB.

MiR-133b targets Sox9 to control pathogenesis and metastasis of breast cancer.

The miR-133b, a commonly recognized muscle-specific miRNA, was reported to be deregulated in many kinds of cancers. However, its potential roles in tumorigenesis remain greatly elusive. Herein, we demonstrate that miR-133b is significantly suppressed in human breast cancer specimens, which is reversely correlated to histological grade of the cancer. Ectopic expression of miR-133b suppresses clonogenic ability and metastasis-relevant traits in vitro, as well as carcinogenesis and pulmonary metastasis in vivo. Further studies have identified Sox9, c-MET, and WAVE2 as direct targets of miR-133b, in which Sox9 contributes to all miR-133b-endowed effects including cell proliferation, colony formation, as well as cell migration and invasion in vitro. Moreover, re-expression of Sox9 reverses miR-133b-mediated metastasis suppression in vivo. Taken together, these findings highlight an important role for miR-133b in the regulation of tumorigenesis and metastatic potential of breast cancer and suggest a potential application of miR-133b in cancer treatment.

The impact of surgical excision of the primary tumor in stage IV breast cancer on survival: a meta-analysis.

INTRODUCTION: Approximately 5% of primary breast cancer patients present de novo stage IV breast cancer, for whom systematic therapy is the mainstream treatment. The role of surgical excision of the primary tumor has been controversial due to inconsistent results of relevant studies. Recently, with the reports of some relevant preclinical data, retrospective studies and randomized clinical trials, we've got more evidence to reexamine the issue. Based on those above, a literature review and meta-analysis was performed to determine whether surgery of the primary tumor could improve overall survival in the setting of stage IV breast cancer. MATERIALS AND METHODS: A comprehensive search of PubMed, OVID, American Society of Clinical Oncology (ASCO) symposium documents, European Society for Medical Oncology (ESMO) symposium documents and San Antonio Breast Cancer Symposium (SABCS) symposium documents was performed to identify published literature that evaluated survival benefits from excision of the primary tumor in the setting of stage IV breast cancer. Data were extracted in review of appropriate studies by the authors independently. The primary endpoint was overall survival following surgical removal of the primary tumor. Secondary endpoints were the impacts of surgery on progression free survival (PFS) and time to progression (TTP). RESULTS: Data from 19 retrospective studies showed a pooled hazard ratio of 0.65 (95% confidence interval (95% CI), 0.60-0.71, P < 0.01= for overall survival (OS), indicating a 35% reduction in risk of mortality in patients who underwent surgical excision of the primary tumor. Nevertheless, the analysis of 3 randomized clinical trials revealed a pooled hazard ratio of 0.85 (95% CI, 0.59-1.21, P = 0.359) for OS in the surgical group. According to the meta-regression, the survival benefit was independent of age, tumor size, site of the metastases, and PR or HER-2 status, acceptance of systematic therapies and radiotherapy and inversely correlated with the ER+ status of the population included. CONCLUSIONS: This is the first meta-analysis that includes both retrospective and prospective studies regarding the impact of surgery of the primary tumor on survival in stage IV breast cancer patients. According to the analytical results, we do not recommend surgery of the primary tumor as routine therapy for stage IV breast cancer. However, for those who are supposed to have long life expectancy, physicians could discuss it with these patients, put forward surgery as a therapy choice and perform the operation under deliberation.

Associations between maternal exposure to incense burning and blood pressure during pregnancy.

Incense burning is a popular practice in Asian and Arabic countries. Previous studies show that incense burning was associated with increased risks of adverse outcomes among non-pregnant population. However, very few studies explored its health effects among pregnant women, who are more susceptible to environmental stressor. We aimed to examine the association between incense burning at home and hypertensive disorders as well as blood pressure levels during pregnancy, using data from 10,563 pregnant women recruited in Born in Guangzhou Cohort Study, China between January 2013 and December 2015. Information on frequency and duration of exposure to incense burning were collected at early and late pregnancy using questionnaire. Data on outcome variables, including hypertensive disorders diagnosis and blood pressure levels at the final antenatal visit before delivery, were extracted from medical records. We used Poisson regression model and general linear model to examine the associations between incense exposure and the outcomes. We found incense use at early pregnancy was not significantly associated with outcomes. Pregnant women who frequently smelled the incense burning at late pregnancy was associated with higher risk of hypertensive disorders (relative risk, 1.84; 95% confidence interval, 1.14-2.98) and higher levels of blood pressure (1.6mmHg increase of systolic blood pressure; 95% confidence interval, 0.4-2.8mmHg) before delivery, compared to those did not burn incense. These associations tended to more evident among women without active and passive smoking. We did not observe significant dose-response relationship between exposure duration and the risk of hypertensive disorders. We firstly reported exposure to incense burning was associated with the risk of hypertensive disorders and blood pressure levels during pregnancy. Given hypertensive disorders in pregnancy are well-established risk factors for a variety of adverse outcomes and the incense burning is a modifiable factor, our finding may have important public health significance.

MicroRNA-630 inhibits breast cancer progression by directly targeting BMI1.

MicroRNAs (miRNAs) play critical roles in breast cancer cell biological processes, including proliferation and apoptosis by inhibiting the expression of their target genes. Herein, we reported that miR-630 overexpression initiates apoptosis, blocks cell cycle progression and suppresses cell proliferation in breast cancer cells. Furthermore, BMI1, a member of polycomb group family, was identified as a direct target of miR-630, and there was a negative correlation between the expression levels of BMI1 and miR-630 in human breast cancer samples. With a series of biology approaches, subsequently, we proved that BMI1 was a functional downstream target of miR-630 and mediated the property of miR-630-dependent inhibition of breast cancer progression. Taken together, these findings provide further evidence on the tumor-suppression function of miR-630 in breast cancer, and clarify BMI1 as a novel functional target gene of miR-630.

Modification effects of genetic polymorphisms in FTO, IL-6, and HSPD1 on the associations of diabetes with breast cancer risk and survival.

The contribution of diabetes to breast cancer remains uncertain among Chinese females, which may result from different genetic factors. We evaluated the associations of diabetes, combined with the polymorphisms in the genes of fat mass and obesity-associated gene (FTO), interleukin 6 (IL-6), and heat shock protein 60 (HSPD1), with breast cancer risk and survival in a Chinese Han population. The information on the history of diabetes was collected from 1551 incident breast cancer cases and 1605 age-frequency matched controls in Guangzhou, China. In total, 1168 cases were followed up. Diabetes was associated with both an increased risk of breast cancer [OR (95%CI): 1.67 (1.11, 2.52)] and a poor overall survival and progression free survival for breast cancer patients [HRs (95%CIs): 2.66 (1.10, 6.44) and 2.46 (1.29, 4.70), respectively]. IL-6 rs1800796 and HSPD1 rs2605039 had interactions with diabetes on breast cancer risk. Among women with CC genotype of IL-6 rs1800796 or GG genotype of HSPD1 rs2605039, diabetic individuals had a remarkably increased risk of breast cancer compared to non-diabetic women with ORs and 95%CIs of 2.53 (1.45, 4.41) and 6.40 (2.29, 17.87), respectively. GT/TT genotypes of HSPD1 rs2605039 was also associated with a better progression free survival for breast cancer patients [HR (95%CI): 0.70 (0.49, 0.99)]. Our results suggest that the contribution of diabetes to breast cancer risk might be modified by IL-6 rs1800796 and HSPD1 rs2605039. Diabetes and HSPD1 rs2605039 might also influence breast cancer prognosis.

MicroRNA-494 inhibits breast cancer progression by directly targeting PAK1.

MicroRNA (miRNA) is involved in the progression and metastasis of diverse human cancers, including breast cancer, as strong evidence has been found that miRNAs can act as oncogenes or tumor suppressor genes. Here, we show that miR-494 is decreased in human breast cancer specimens and breast cancer cell lines. Ectopic expression of miR-494 in basal-like breast cancer cell lines MDA-MB-231-LUC-D2H3LN and BT-549 inhibits clonogenic ability and metastasis-relevant traits in vitro. Moreover, ectopic expression of miR-494 suppresses neoplasm initiation as well as pulmonary metastasis in vivo. Further studies have identified PAK1, as a direct target gene of miR-494, contributes to the functions of miR-494. Remarkably, the expression of PAK1 is inversely correlated with the level of miR-494 in human breast cancer samples. Furthermore, re-expression of PAK1 partially reverses miR-494-mediated proliferative and clonogenic inhibition as well as migration and invasion suppression in breast cancer cells. Taken together, these findings highlight an important role for miR-494 in the regulation of progression and metastatic potential of breast cancer and suggest a potential application of miR-494 in breast cancer treatment.

Three-dimensional Contrast-enhanced Ultrasound in Response Assessment for Breast Cancer: A Comparison with Dynamic Contrast-enhanced Magnetic Resonance Imaging and Pathology.

To compare the capabilities of three-dimensional contrast enhanced ultrasound (3D-CEUS) and dynamic contrast-enhanced magnetic resonance (DCE-MRI) in predicting the response to neoadjuvant chemotherapy (NAC) among breast cancer patients, 48 patients with unilateral breast cancer were recruited for 3D-CEUS and DCE-MRI examinations both before and after NAC; pathology was used to validate the results. This study was approved by the institutional review board, and written informed consent was obtained from each patient. Imaging feature changes and pathological vascularity response, including microvessel density (MVD) and vascular endothelial growth factor (VEGF), were calculated. Pathological complete response (pCR) and major histological response (MHR) were used as references. The 3D-CEUS score, DCE-MRI score, MVD and VEGF significantly decreased (P < 0.0001) after NAC. The correlations between Δ3D-CEUS and ΔDCE-MRI with pCR (r = 0.649, P < 0.0001; r = 0.639, P < 0.0001) and MHR (r = 0.863, P < 0.0001; r = 0.836, P < 0.0001) were significant. All scores showed significant differences between the pCR and non-pCR groups with folder changes of 0.1, 0.1, 2.4, and 2.3, respectively (P = 0.0001, <0.0001, <0.0001 and <0.0001). In conclusion, 3D-CEUS is effective in assessing the response of breast cancer patients undergoing NAC.