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Metastatic dissemination in breast cancer patients occurs early in malignant transformation, raising questions about how disseminated cancer cells (DCC) progress at distant sites. Here, the authors show that DCCs in bone marrow are activated via IL6-trans-signaling and thereby acquire stemness traits relevant for metastasis formation.

Abstract Background The sensitivity of estrogen receptor-positive breast cancers to tamoxifen treatment varies considerably, and the molecular mechanisms affecting the response rates are manifold. The human epidermal growth factor receptor-related receptor HER2 is known to trigger intracellular signaling cascades that modulate the activity of coregulators of the estrogen receptor which, in turn, reduces the cell sensitivity to tamoxifen treatment. However, the impact of HER2-related receptor tyrosine kinases HER1, HER3, and, in particular, HER4 on endocrine treatment is largely unknown. Methods Here, we retrospectively evaluated the importance of HER4 expression on the outcome of tamoxifen- and aromatase inhibitor-treated estrogen receptor-positive breast cancer patients (n = 258). In addition, we experimentally analyzed the efficiency of tamoxifen treatment as a function of HER4 co-expression in vitro. Results We found a significantly improved survival in tamoxifen-treated postmenopausal breast cancer patients in the absence of HER4 compared with those with pronounced HER4 expression. In accordance with this finding, the sensitivity to tamoxifen treatment of estrogen and HER4 receptor-positive ZR-75-1 breast cancer cells can be significantly enhanced by HER4 knockdown. Conclusion We suggest an HER4/estrogen receptor interaction that impedes tamoxifen binding to the estrogen receptor and reduces treatment efficiency. Whether the sensitivity to tamoxifen treatment can be enhanced by anti-HER4 targeting needs to be prospectively evaluated.

Background: There has been increasing research on posttraumatic stress disorder (PTSD) following childbirth in the last two decades. The literature on predictors of who develops posttraumatic stress symptoms (PSS) suggests that both vulnerability and birth factors have an influence, but many studies measure predictors and outcomes simultaneously. Objective: In this context, we aimed to examine indirect and direct effects of predictors of PSS, which were measured longitudinally. Method: We assessed women within the first days (n=353), 6 weeks, and 12 months (n=183) after having given birth to a healthy infant. The first assessment included questions on demographics, pregnancy, and birth experience. The second and third assessments contained screenings for postpartum depression, PTSD, and general mental health problems, as well as assessing social support and physical well-being. We analysed our data using structural equation modelling techniques (n=277). Results: Our final model showed good fit and was consistent with a diathesis-stress model of PSS. Women who had used antidepressant medication in the 10 years before childbirth had higher PSS at 6 weeks, independent of birth experiences. Subjective birth experience was the early predictor with the highest total effect on later PSS. Interestingly, a probable migration background also had a small but significant effect on PSS via more episiotomies. The null results for social support may have been caused by a ceiling effect. Conclusions: Given that we measured predictors at different time points, our results lend important support to the etiological model, namely, that there is a vulnerability pathway and a stress pathway leading to PSS. PSS and other psychological measures stayed very stable between 6 weeks and 1 year postpartum, indicating that it is possible to identify women developing problems early.

Cardiac myxoma is a benign primary cardiac tumour which can present with nonspecific symptoms of right heart failure, syncope, exertional dyspnea, and pulmonary embolism. We describe a case of a right ventricular myxoma complicated with bilateral pulmonary embolism, with an incidental right coronary artery fistula but otherwise normal coronary anatomy on coronary angiogram. This case report emphasizes the importance of performing a transesophageal echo in the setting of pulmonary embolism to search for the origin of thrombus/tumour, and performing a comprehensive assessment is also necessary to rule out coronary artery disease, coronary artery fistula that may also represent a tumour blush.

Abstract We report a case of an idiopathic coronary artery rupture in a 41-year-old male patient who was admitted to the hospital with cardiac tamponade. On opening the chest via a median sternotomy and establishing cardiopulmonary bypass the hemopericardium's cause could be identified as a perforation of the right posterior descending coronary artery which was treated with a saphenous vein patch plasty. With idiopathic coronary artery rupture being a rare diagnosis, one should always consider it in a young patient presenting with cardiac tamponade.

RATIONALE:To address the inaccessibility of interventional cardiac services in North Queensland a new cardiac catheterisation laboratory (CCL) was established in Mackay Base Hospital (MBH) in February 2014. OBJECTIVE:To determine whether the provision of in-house angiography and/or percutaneous coronary intervention (PCI) 1) minimises treatment delays 2) further reduces the risk of mortality, recurrent myocardial infarction (MI) and recurrent ischaemia 3) improves patient satisfaction and 4) minimises cost expenditure compared with inter-hospital transfer for patients with acute coronary syndrome (ACS). METHODS:We compared ACS patients who were transferred to tertiary centres from July 2012 to June 2013 with those who received in-house angiography and/or PCI from February 2015 to January 2016. The primary outcome was the composite of all-cause mortality, recurrent myocardial infarction (MI) or recurrent ischaemia at six months. Pre-specified secondary outcomes were the composite of all-cause mortality, recurrent MI or recurrent ischaemia at one month, a summated patient satisfaction score and the proportional cost savings generated between 2015 and 2016. RESULTS:We included consecutive samples of 203 patients from July 2012 to June 2013 and 229 patients from February 2015 to January 2016. There was a reduction in the median time to treatment of 3.2 days and a reduction in the median length of stay of four days amongst all ACS patients receiving in-house angiography and/or PCI. The primary outcome occurred in 14 (6.9%) patients in the 2012 to 2013 group, as compared with 18 (7.9%) patients in the 2015 to 2016 group (OR = 0.71, 95% CI 0.24-2.1, P = 0.54). The secondary outcome at one month occurred in four (2.0%) patients in the 2012 to 2013 group, as compared with three (1.3%) patients in the 2015 to 2016 group (OR = 1.2, 95% CI 0.11-13.1, P = 0.87). There was a statistically significant improvement in the summated patient satisfaction score amongst patients who received in-house angiography and/or PCI (U = 1918, P

The hydroxylation of n-alkanes, which proceeds in the presence of a P450-monooxygenase advantageously at temperatures significantly below room temperature, is described. In addition, an enzymatic hydroxylation of the “liquid gas” n-butane with in situ cofactor regeneration, which does not require high-pressure conditions, was developed. The resulting 2-butanol was obtained as the only regioisomer, at a product concentration of 0.16 g/L.

BACKGROUND: The cardiovascular impact of cocaine use in otherwise healthy individuals who consider themselves 'social' users is not well established. METHODS/RESULTS: Twenty regular cocaine users and 20 control subjects were recruited by word-of-mouth. Cardiovascular magnetic resonance was performed to assess cardiac and vascular structure and function. Cocaine users had higher systolic blood pressure compared to non-users (134±11 vs 126±11 mmHg, p = 0.036), a finding independent of age, body surface area, smoking and alcohol consumption. Cocaine use was associated with increased arterial stiffness - reflected by reduced aortic compliance (1.3±0.2 vs 1.7±0.5 cm2×10-2.mmHg-1, p = 0.004), decreased distensibility (3.8±0.9 vs 5.1±1.4 mmHg-1.10-3, p = 0.001), increased stiffness index (2.6±0.6 vs 2.1±0.6, p = 0.005), and higher pulse wave velocity (5.1±0.6 vs 4.4±0.6 m.s-1, p = 0.001). This change in aortic stiffness was independent of vessel wall thickness. Left ventricular mass was 18% higher in cocaine users (124±25 vs 105±16 g, p = 0.01), a finding that was independent of body surface area, and left atrial diameter was larger in the user group than controls (3.8±0.6 vs 3.5±0.3 cm, p = 0.04). The increased left ventricular mass, systolic blood pressure and vascular stiffness measures were all associated with duration and/or frequency of cocaine use. No late gadolinium enhancement or segmental wall motion abnormalities were seen in any of the subjects. CONCLUSIONS: Compared with the non-user control cohort, cocaine users had increased aortic stiffness and systolic blood pressure, associated with greater left ventricular mass. These measures are all well known risk factors for premature cardiovascular events, highlighting the dangers of cocaine use, even in a 'social' setting, and have important public health implications.

Tumor xenografts in immunodeficient mice, while routinely used in cancer research, preclude studying interactions of immune and cancer cells or, if humanized by allogeneic immune cells, are of limited use for tumor-immunological questions. Here, we explore a novel way to generate cancer models with an autologous humanized immune system. We demonstrate that hematopoietic stem and progenitor cells (HSPCs) from bone marrow aspirates of non-metastasized carcinoma patients, which are taken at specialized centers for diagnostic purposes, can be used to generate a human immune system in NOD-scid IL2rγ(null) (NSG) and HLA-I expressing NSG mice (NSG-HLA-A2/HHD) comprising both, lymphoid and myeloid cell lineages. Using NSG-HLA-A2/HHD mice, we show that responsive and self-tolerant human T cells develop and human antigen presenting cells can activate human T cells. As critical factors we identified the low potential of bone marrow HSPCs to engraft, generally low HSPC numbers in patient-derived bone marrow samples, cryopreservation and routes of cell administration. We provide here an optimized protocol that uses a minimum number of HSPCs, preselects high-quality bone marrow samples defined by the number of initially isolated leukocytes and intra-femoral or intra-venous injection. In conclusion, the use of diagnostic bone marrow aspirates from non-metastasized carcinoma patients for the immunological humanization of immunodeficient mice is feasible and opens the chance for individualized analyses of anti-tumoral T cell responses.