Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer.

Background:Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer. Methods:The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics. Results:A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P < .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99). Conclusions:Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors

A Study on Topography Versus Sediment Yield Under Simulated Rainfall

This study investigates the effects of topography on the amount of sediment yield under simulated rainfall. The slope gradient and length would affect the runoff depth (V) and peak flow volume (Qp) and thus the amount of surface runoffs. In this study, the simulated 150mm/hour rainfall intensity was applied on triangular prism-shaped, cone-shaped and pyramid-shaped models for determination of the amount of respective sediment yields (tons/storm event). It was observed that the sediment yields of the triangular prism-, cone- and pyramid-shaped amounted to 0.144, 0.143 and 0.125 tons/storm event, respectively. The triangular prism-shaped topography has the highest sediment yield amount as it experiences highest runoff depth and highest surface runoff velocity at downslope. Based on the experimental outcomes, it was shown that MUSLE could over-estimate sediment yield as much as 3.6 times for areas characterized by hilly landscape

Testing the Concept of Mitigating Urban Flooding with Permeable Road: Case Study of Tong Wei Tah Street, Kuching City, Sarawak, Malaysia

This paper describes the investigation of permeable road as a mitigation measure for urban flooding. The study involves the reconstruction of a historical case of inundation, namely the 11 December 2019 flood event along the Tong Wei Tah Street in Greater Kuching City, Sarawak, Malaysia. The Storm Water Management Model version 5.0 was used as the platform to describe the flooding at the selected site and the functionality of permeable road to alleviate flooding. A permeable road with a dimension of 200 m long, 6 m wide and 1 m deep was used to simulate runoff after a structure was installed along the whole stretch of Tong Wei Tah Street. The model results show that flooding was caused by a backwater effect in the drainage system. Models predicted 0.1 to 0.5 m flood depths which matched the observed 0.3 m flood depth account of a local resident. The permeable road exhibited capability to absorb all the out-of-drain floodwaters, leaving no water due to the 11 December 2019 flood on the street. Modelling efforts demonstrated that the floodwater hydrographs in the drain rose and fell within 7 hours, while the underground storage, filled and drained within 13 hours. Moreover, the storage of permeable road was found to fill up to 75%, reserving the unfilled 25% for adverse weathers

CpG Island microarray probe sequences derived from a physical library are representative of CpG Islands annotated on the human genome

An effective tool for the global analysis of both DNA methylation status and protein–chromatin interactions is a microarray constructed with sequences containing regulatory elements. One type of array suited for this purpose takes advantage of the strong association between CpG Islands (CGIs) and gene regulatory regions. We have obtained 20 736 clones from a CGI Library and used these to construct CGI arrays. The utility of this library requires proper annotation and assessment of the clones, including CpG content, genomic origin and proximity to neighboring genes. Alignment of clone sequences to the human genome (UCSC hg17) identified 9595 distinct genomic loci; 64% were defined by a single clone while the remaining 36% were represented by multiple, redundant clones. Approximately 68% of the loci were located near a transcription start site. The distribution of these loci covered all 23 chromosomes, with 63% overlapping a bioinformatically identified CGI. The high representation of genomic CGI in this rich collection of clones supports the utilization of microarrays produced with this library for the study of global epigenetic mechanisms and protein–chromatin interactions. A browsable database is available on-line to facilitate exploration of the CGIs in this library and their association with annotated genes or promoter elements

Endometrial autotransplantation in rabbits: Potential for fertility restoration in severe Asherman's syndrome

[EN] Objective: Uterine transplantation is now considered a feasible treatment for women with absolute uterine factor infertility and has been successfully performed for a woman with Asherman's syndrome (AS). The endometrium is a clinically and histologically distinct entity from the surrounding myometrium. Endometrial transplantation (ETx) may offer a less invasive option, with less immunogenic impact, to restore fertility in women with severe AS. The objective of this study was to assess the feasibility of ETx by evaluating surgical and reproductive outcomes following endometrial autotransplantation in a rabbit model. Study design: A longitudinal study assessing surgical, biochemical, radiological, reproductive and histological outcomes following endometrial autotransplantation in ten New Zealand white rabbits. Results: Ten procedures were performed, including 8 endometrial auto-transplants (ETx) and 2 endometrial resections (ER), to control against endometrial regeneration. Eight procedures were successful, whereas two rabbits from the ETx group died intra-operatively. Three rabbits were euthanised at 48, 72 and 96 h post-operatively to assess gross and histological appearances. Two rabbits, one from the ETx group and one from the ER group, died four weeks and eight weeks post-operatively. Three rabbits subsequently underwent two cycles of in-vitro fertilization. The first cycle resulted in an implantation rate of 57% in the un-operated uteri. In two rabbits who underwent ETx, an implantation rate of 28.6% was seen. In the second cycle, an implantation rate of 61.9 % (13 implantations) was observed in the control uteri. In the two ETx females, an implantation rate of 14.3 % was seen. No pregnancies were seen in either cycle in the animals who underwent ER. Despite successful implantations in both cycles in the ETx rabbits, no livebirths were achieved. Following death or euthanasia there was gross and microscopic evidence of viable endometrium following ETx, but not following ER. Conclusion: This study has revealed, for the first time, the feasibility of ETx with gross and microscopic evidence of viable endometrium, and the demonstration of clinical pregnancies. Whilst further studies are essential, and the achievement of successful livebirths fundamental, ETx may offer a potential fertility restoring opportunity for women with severe, treatment refractory cases of AS.The study was funded by registered charity Womb Transplant UK (1138559).Jones, BP.; Vali, S.; Saso, S.; Garcia-Dominguez, X.; Chan, M.; Thum, M.; Ghaem-Maghami, S.... (2020). Endometrial autotransplantation in rabbits: Potential for fertility restoration in severe Asherman's syndrome. European Journal of Obstetrics & Gynecology and Reproductive Biology. 248:14-23. https://doi.org/10.1016/j.ejogrb.2020.03.011S1423248Asherman, J. G. (1950). TRAUMATIC INTRA-UTERINE ADHESIONS. BJOG: An International Journal of Obstetrics and Gynaecology, 57(6), 892-896. doi:10.1111/j.1471-0528.1950.tb06053.xHooker, A. B., de Leeuw, R., van de Ven, P. M., Bakkum, E. A., Thurkow, A. L., Vogel, N. E. A., … Huirne, J. A. F. (2017). Prevalence of intrauterine adhesions after the application of hyaluronic acid gel after dilatation and curettage in women with at least one previous curettage: short-term outcomes of a multicenter, prospective randomized controlled trial. Fertility and Sterility, 107(5), 1223-1231.e3. doi:10.1016/j.fertnstert.2017.02.113Wallach, E. E., Schenker, J. G., & Margalioth, E. J. (1982). Intrauterine adhesions: an updated appraisal. Fertility and Sterility, 37(5), 593-610. doi:10.1016/s0015-0282(16)46268-0Westendorp, I. C., Ankum, W. M., Mol, B. W., & Vonk, J. (1998). Prevalence of Asherman’s syndrome after secondary removal of placental remnants or a repeat curettage for incomplete abortion. Human Reproduction, 13(12), 3347-3350. doi:10.1093/humrep/13.12.3347Wallach, E., & Czernobilsky, B. (1978). Endometritis and Infertility. Fertility and Sterility, 30(2), 119-130. doi:10.1016/s0015-0282(16)43448-5Baradwan, S., Baradwan, A., & Al-Jaroudi, D. (2018). The association between menstrual cycle pattern and hysteroscopic march classification with endometrial thickness among infertile women with Asherman syndrome. Medicine, 97(27), e11314. doi:10.1097/md.0000000000011314Hooker, A. B., Lemmers, M., Thurkow, A. L., Heymans, M. W., Opmeer, B. C., Brolmann, H. A. M., … Huirne, J. A. F. (2013). Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome. Human Reproduction Update, 20(2), 262-278. doi:10.1093/humupd/dmt045Yu, D., Wong, Y.-M., Cheong, Y., Xia, E., & Li, T.-C. (2008). Asherman syndrome—one century later. Fertility and Sterility, 89(4), 759-779. doi:10.1016/j.fertnstert.2008.02.096Yamamoto, N., Takeuchi, R., Izuchi, D., Yuge, N., Miyazaki, M., Yasunaga, M., … Inoue, Y. (2013). Hysteroscopic adhesiolysis for patients with Asherman’s syndrome: menstrual and fertility outcomes. Reproductive Medicine and Biology, 12(4), 159-166. doi:10.1007/s12522-013-0149-xThomson, A. J. M., Abbott, J. A., Kingston, A., Lenart, M., & Vancaillie, T. G. (2007). Fluoroscopically guided synechiolysis for patients with Asherman’s syndrome: menstrual and fertility outcomes. Fertility and Sterility, 87(2), 405-410. doi:10.1016/j.fertnstert.2006.06.035Deans, R., & Abbott, J. (2010). Review of Intrauterine Adhesions. Journal of Minimally Invasive Gynecology, 17(5), 555-569. doi:10.1016/j.jmig.2010.04.016Song, D., Liu, Y., Xiao, Y., Li, T.-C., Zhou, F., & Xia, E. (2014). A Matched Cohort Study Comparing the Outcome of Intrauterine Adhesiolysis for Asherman’s Syndrome After Uterine Artery Embolization or Surgical Trauma. Journal of Minimally Invasive Gynecology, 21(6), 1022-1028. doi:10.1016/j.jmig.2014.04.015Panchal, S., Patel, H., & Nagori, C. (2011). Endometrial regeneration using autologous adult stem cells followed by conception by in vitro fertilization in a patient of severe Asherman′s syndrome. Journal of Human Reproductive Sciences, 4(1), 43. doi:10.4103/0974-1208.82360Singh, N., Mohanty, S., Seth, T., Shankar, M., Dharmendra, S., & Bhaskaran, S. (2014). Autologous stem cell transplantation in refractory Asherman′s syndrome: A novel cell based therapy. Journal of Human Reproductive Sciences, 7(2), 93. doi:10.4103/0974-1208.138864Tan, J., Li, P., Wang, Q., Li, Y., Li, X., Zhao, D., … Kong, L. (2016). Autologous menstrual blood-derived stromal cells transplantation for severe Asherman’s syndrome. Human Reproduction, 31(12), 2723-2729. doi:10.1093/humrep/dew235Santamaria, X., Cabanillas, S., Cervelló, I., Arbona, C., Raga, F., Ferro, J., … Simón, C. (2016). Autologous cell therapy with CD133+ bone marrow-derived stem cells for refractory Asherman’s syndrome and endometrial atrophy: a pilot cohort study. Human Reproduction, 31(5), 1087-1096. doi:10.1093/humrep/dew042Puntambekar, S., Telang, M., Kulkarni, P., Puntambekar, S., Jadhav, S., Panse, M., … Phadke, U. (2018). Laparoscopic-Assisted Uterus Retrieval From Live Organ Donors for Uterine Transplant: Our Experience of Two Patients. Journal of Minimally Invasive Gynecology, 25(4), 622-631. doi:10.1016/j.jmig.2018.01.009Saso, S., Haddad, J., Ellis, P., Lindsay, I., Sebire, N., McIndoe, A., … Smith, J. (2011). Placental site trophoblastic tumours and the concept of fertility preservation. BJOG: An International Journal of Obstetrics & Gynaecology, 119(3), 369-374. doi:10.1111/j.1471-0528.2011.03230.xViudes‐de‐Castro, M. P., Marco‐Jiménez, F., Más Pellicer, A., García‐Domínguez, X., Talaván, A. M., & Vicente, J. S. (2019). A single injection of corifollitropin alfa supplemented with human chorionic gonadotropin increases follicular recruitment and transferable embryos in the rabbit. Reproduction in Domestic Animals, 54(4), 696-701. doi:10.1111/rda.13411Garcia-Dominguez, X., Marco-Jimenez, F., Viudes-de-Castro, M. P., & Vicente, J. S. (2019). Minimally Invasive Embryo Transfer and Embryo Vitrification at the Optimal Embryo Stage in Rabbit Model. Journal of Visualized Experiments, (147). doi:10.3791/58055Esteves, P. J., Abrantes, J., Baldauf, H.-M., BenMohamed, L., Chen, Y., Christensen, N., … Mage, R. (2018). The wide utility of rabbits as models of human diseases. Experimental & Molecular Medicine, 50(5), 1-10. doi:10.1038/s12276-018-0094-1Graur, D., Duret, L., & Gouy, M. (1996). Phylogenetic position of the order Lagomorpha (rabbits, hares and allies). Nature, 379(6563), 333-335. doi:10.1038/379333a0Saso, S., Petts, G., David, A. L., Thum, M.-Y., Chatterjee, J., Vicente, J. S., … Smith, J. R. (2015). Achieving an early pregnancy following allogeneic uterine transplantation in a rabbit model. European Journal of Obstetrics & Gynecology and Reproductive Biology, 185, 164-169. doi:10.1016/j.ejogrb.2014.12.017Saso, S., Petts, G., Chatterjee, J., Thum, M.-Y., David, A. L., Corless, D., … Smith, J. R. (2014). Uterine allotransplantation in a rabbit model using aorto-caval anastomosis: a long-term viability study. European Journal of Obstetrics & Gynecology and Reproductive Biology, 182, 185-193. doi:10.1016/j.ejogrb.2014.09.029Ozsoy, M., Gonul, Y., Bal, A., Ozkececi, Z. T., Celep, R. B., Adali, F., … Tosun, M. (2015). Effect of IL-18 binding protein on hepatic ischemia-reperfusion injury induced by infrarenal aortic occlusion. Annals of Surgical Treatment and Research, 88(2), 92. doi:10.4174/astr.2015.88.2.92Hare, A., & Olah, K. (2005). Pregnancy following endometrial ablation: a review article. Journal of Obstetrics and Gynaecology, 25(2), 108-114. doi:10.1080/01443610500040745Johannesson, L., Enskog, A., Molne, J., Diaz-Garcia, C., Hanafy, A., Dahm-Kahler, P., … Brannstrom, M. (2012). Preclinical report on allogeneic uterus transplantation in non-human primates. Human Reproduction, 28(1), 189-198. doi:10.1093/humrep/des381Brännström, M., Johannesson, L., Dahm-Kähler, P., Enskog, A., Mölne, J., Kvarnström, N., … Olausson, M. (2014). First clinical uterus transplantation trial: a six-month report. Fertility and Sterility, 101(5), 1228-1236. doi:10.1016/j.fertnstert.2014.02.02

Predictors of contemporary coronary artery bypass grafting outcomes

n/

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand

Objective Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism. Methods We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage. Results We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10⁻¹⁰) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10⁻⁹) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Betameta=0.83, Pmeta=1.8*10⁻¹⁵). This variant is high linkage disequilibrium with a coding variant in MGP, a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10⁻¹⁶). Conclusions Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP, which may increase the burden of hand OA by decreased inhibition of cartilage calcification

Impact of an Expanded Definition of Family History on Outcomes of Active Surveillance for Prostate Cancer

PURPOSE: Despite family history being an established risk factor for prostate cancer, the role of a broader definition of family history inclusive of not just prostate cancer but other genetically related malignancies has not been investigated in the active surveillance population. Here, we evaluate the impact of an expanded definition of family history on active surveillance outcomes. MATERIALS AND METHODS: Patients undergoing active surveillance for prostate cancer at Massachusetts General Hospital from 1997-2019 with detailed data available on family cancer history were identified. Primary outcome was biopsy progression-free survival, and secondary outcomes were treatment-free survival, adverse pathological features at prostatectomy, and biochemical recurrence after treatment. Statistical analyses were conducted using the Kaplan-Meier method and Cox regression. RESULTS: Among 855 evaluable patients, 300 (35.1%) patients had any family history of prostate cancer, and 95 (11.1%) had a family history of related malignancies suggestive of a hereditary cancer syndrome. Family history of prostate cancer alone was not associated with biopsy progression, whereas family history suggestive of a hereditary cancer syndrome was associated with a significantly increased risk of biopsy progression (HR 1.43, 95%CI 1.01-2.02), independent of other known clinicopathological risk factors in multivariable analysis. Similarly, family history suggestive of a hereditary cancer syndrome was associated with significantly lower treatment-free survival (HR 1.58, 95%CI 1.14-2.18) in multivariable analysis. No significant association was found between family history and adverse features on surgical pathology or biochemical recurrence. CONCLUSIONS: An expanded family history suggestive of a hereditary cancer syndrome is an independent predictor of biopsy progression during active surveillance. Men with such a family history may still be offered active surveillance but should be counseled regarding the higher risk of disease progression

Predicting breast cancer response to neoadjuvant treatment using multi-feature MRI: results from the I-SPY 2 TRIAL.

Dynamic contrast-enhanced (DCE) MRI provides both morphological and functional information regarding breast tumor response to neoadjuvant chemotherapy (NAC). The purpose of this retrospective study is to test if prediction models combining multiple MRI features outperform models with single features. Four features were quantitatively calculated in each MRI exam: functional tumor volume, longest diameter, sphericity, and contralateral background parenchymal enhancement. Logistic regression analysis was used to study the relationship between MRI variables and pathologic complete response (pCR). Predictive performance was estimated using the area under the receiver operating characteristic curve (AUC). The full cohort was stratified by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status (positive or negative). A total of 384 patients (median age: 49 y/o) were included. Results showed analysis with combined features achieved higher AUCs than analysis with any feature alone. AUCs estimated for the combined versus highest AUCs among single features were 0.81 (95% confidence interval [CI]: 0.76, 0.86) versus 0.79 (95% CI: 0.73, 0.85) in the full cohort, 0.83 (95% CI: 0.77, 0.92) versus 0.73 (95% CI: 0.61, 0.84) in HR-positive/HER2-negative, 0.88 (95% CI: 0.79, 0.97) versus 0.78 (95% CI: 0.63, 0.89) in HR-positive/HER2-positive, 0.83 (95% CI not available) versus 0.75 (95% CI: 0.46, 0.81) in HR-negative/HER2-positive, and 0.82 (95% CI: 0.74, 0.91) versus 0.75 (95% CI: 0.64, 0.83) in triple negatives. Multi-feature MRI analysis improved pCR prediction over analysis of any individual feature that we examined. Additionally, the improvements in prediction were more notable when analysis was conducted according to cancer subtype