Estrogen receptor and progesterone receptor expression in normal terminal duct lobular units surrounding invasive breast cancer

Molecular and morphological alterations related to carcinogenesis have been found in terminal duct lobular units (TDLUs), the microscopic structures from which most breast cancer precursors and cancers develop, and therefore, analysis of these structures may reveal early changes in breast carcinogenesis and etiologic heterogeneity. Accordingly, we evaluated relationships of breast cancer risk factors and tumor pathology to estrogen receptor (ER) and progesterone receptor (PR) expression in TDLUs surrounding breast cancers. We analyzed 270 breast cancer cases included in a population-based breast cancer case–control study conducted in Poland. TDLUs were mapped in relation to breast cancer: within the same block as the tumor (TDLU-T), proximal to tumor (TDLU-PT), or distant from (TDLU-DT). ER/PR was quantitated using image analysis of immunohistochemically stained TDLUs prepared as tissue microarrays. In surgical specimens containing ER-positive breast cancers, ER and PR levels were significantly higher in breast cancer cells than in normal TDLUs, and higher in TDLU-T than in TDLU-DT or TDLU-PT, which showed similar results. Analyses combining DT?/PT TDLUs within subjects demonstrated that ER levels were significantly lower in premenopausal women versus postmenopausal women (odds ratio [OR] = 0.38, 95 % confidence interval [CI] = 0.19, 0.76, P = 0.0064) and among recent or current menopausal hormone therapy users compared with never users (OR = 0.14, 95 % CI = 0.046–0.43, P _trend = 0.0006). Compared with premenopausal women, TDLUs of postmenopausal women showed lower levels of PR (OR = 0.90, 95 % CI = 0.83–0.97, P _trend = 0.007). ER and PR expression in TDLUs was associated with epidermal growth factor receptor (EGFR) expression in invasive tumors (P = 0.019 for ER and P = 0.03 for PR), but not with other tumor features. Our data suggest that TDLUs near breast cancers reflect field effects, whereas those at a distance demonstrate influences of breast cancer risk factors on at-risk breast tissue. Analyses of mapped TDLUs may provide information about the sequence of molecular changes occurring in breast carcinogenesis.     

State-of-the-art reperfusion strategies for acute ischemic stroke

Timely recanalization of the occluded artery is the only effective treatment for acute ischemic stroke. Intravenous tissue plasminogen activator (IV tPA), administered within 3 hours of symptom onset, is the only United States Food and Drug Administration-approved treatment. This short window often precludes effective intervention, and IV tPA often fails to recanalize major and mid-sized arteries. Intra-arterial thrombolysis has been used for decades, but its safety and effectiveness in cerebrovascular occlusions is also limited. Recently, new mechanical neuroendovascular devices have shown high recanalization rates with acceptable safety in early studies. Multi-modal reperfusion therapy (MMRT) - including intra-arterial infusion of thrombolytics and/or antiplatelet agents, mechanical clot disruption and retrieval, and balloon angioplasty with stent placement - is the prevailing concept for the management of major acute stroke. Recent results suggest that MMRT results in higher chances for both recanalization of the occluded artery and reperfusion of the ischemic tissue.     

Adipose tissue-derived FABP4 mediates glucagon-stimulated hepatic glucose production in gestational diabetes

Aims

One of the most common complications of pregnancy is gestational diabetes mellitus (GDM), which may result in significant health threats of the mother, fetus and the newborn. Fatty acid-binding protein 4 (FABP4) is an adipokine that regulates glucose homeostasis by promoting glucose production and liver insulin resistance in mouse models. FABP4 levels are increased in GDM and correlates with maternal indices of insulin resistance, with a rapid decline post-partum. We therefore aimed to determine the tissue origin of elevated circulating FABP4 levels in GDM and to assess its potential contribution in promoting glucagon-induced hepatic glucose production.

Materials and Methods

FABP4 protein and gene expression was determined in biopsies from placenta, subcutaneous (sWAT) and visceral (vWAT) white adipose tissues from GDM and normoglycaemic pregnant women. FABP4 differential contribution in glucagon-stimulated hepatic glucose production was tested in conditioned media before and after its immune clearance.

Results

We showed that FABP4 is expressed in placenta, sWAT and vWAT of pregnant women at term, with a significant increase in its secretion from vWAT of women with GDM compared with normoglycaemic pregnant women. Neutralizing FABP4 from both normoglycaemic pregnant women and GDM vWAT secretome, resulted in a decrease in glucagon-stimulated hepatic glucose production.

Conclusions

This study provides new insights into the role of adipose tissue-derived FABP4 in GDM, highlighting this adipokine, as a potential co-activator of glucagon-stimulated hepatic glucose production during pregnancy.     

The Simplified Comorbidity Index predicts non-relapse mortality in reduced-intensity conditioning allogeneic haematopoietic cell transplantation

Comorbidity assessment before allogeneic haematopoietic cell transplantation (allo-HCT) is essential for estimating non-relapse mortality (NRM) risk. We previously developed the Simplified Comorbidity Index (SCI), which captures a small number of ‘high-yield’ comorbidities and older age. The SCI was predictive of NRM in myeloablative CD34-selected allo-HCT. Here, we evaluated the SCI in a single-centre cohort of 327 patients receiving reduced-intensity conditioning followed by unmanipulated allografts from HLA-matched donors. Among the SCI factors, age above 60, mild renal impairment, moderate pulmonary disease and cardiac disease were most frequent. SCI scores ranged from 0 to 8, with 39%, 20%, 20% and 21% having scores of 0–1, 2, 3 and ≥4 respectively. Corresponding cumulative incidences of 3-year NRM were 11%, 16%, 22% and 27%; p = 0.03. In multivariable models, higher SCI scores were associated with incremental risks of all-cause mortality and NRM. The SCI had an area under the receiver operating characteristic curve of 65.9%, 64.1% and 62.9% for predicting 1-, 2- and 3-year NRM versus 58.4%, 60.4% and 59.3% with the haematopoietic cell transplantation comorbidity index. These results demonstrate for the first time that the SCI is predictive of NRM in patients receiving allo-HCT from HLA-matched donors after reduced-intensity conditioning.     

Clinical efficacy and safety of chimeric antigen receptor T-cell therapy for mantle cell lymphoma with secondary central nervous system involvement

Data describing outcomes of chimeric antigen receptor (CAR) T-cell therapy in patients with secondary central nervous system (SCNS) involvement of mantle cell lymphoma (MCL) are limited. We identified 10 patients with MCL and SCNS involvement treated with anti-CD19 CAR T-cell therapy at three US academic centres. Frequent objective responses were observed in the CNS (86%) and systemically (90%), and the 1-year progression-free survival was 47%. Seven patients developed immune-effector-cell-associated-neurotoxicity-syndrome (n = 2 Grade 1, n = 5 Grade 3). Our results suggest that anti-CD19 CAR T-cell therapy in this setting is feasible and additional data regarding neurotoxicity in this population may be warranted.     

Effects of emotion and semantic relatedness on recognition memory: Behavioral and electrophysiological evidence

Some aspects of our memory are enhanced by emotion, whereas others can be unaffected or even hindered. Previous studies reported impaired associative memory of emotional content, an effect termed associative “emotional interference”. The current study used EEG and an associative recognition paradigm to investigate the cognitive and neural mechanisms associated with this effect. In two experiments, participants studied negative and neutral stimulus-pairs that were either semantically related or unrelated. In Experiment 1 emotions were relevant to the encoding task (valence judgment) whereas in Experiment 2 emotions were irrelevant (familiarity judgment). In a subsequent associative recognition test, EEG was recorded while participants discriminated between intact, rearranged, and new pairs. An associative emotional interference effect was observed in both experiments, but was attenuated for semantically related pairs in Experiment 1, where valence was relevant to the task. Moreover, a modulation of an early associative memory ERP component (300–550 ms) occurred for negative pairs when valence was task-relevant (Experiment 1), but for semantically related pairs when valence was irrelevant (Experiment 2). A later ERP component (550–800 ms) showed a more general pattern, and was observed in all experimental conditions. These results suggest that both valence and semantic relations can act as an organizing principle that promotes associative binding. Their ability to contribute to successful retrieval depends on specific task demands.     

Attention bias modification add-on to inpatient treatment for young women with anorexia nervosa—A randomized controlled trial

Patients with anorexia nervosa (AN) display elevated anxiety and attention biases (ABs) in threat processing. Attention bias modification treatment (ABMT) is considered promising for anxiety disorders, but its potential for AN is limited. In this study, 154 young women hospitalised because of AN were assigned to ED-related and anxiety-related threat stimuli, or to a non-ABMT intervention control condition in a randomized control trial. Hundred-and-ten patients completed the study. ABMT was an add-on to the regular inpatient treatment. Research participants completed two pretreatment training sessions and eight biweekly sessions of ABMT. AB, ED-related symptoms, depression, anxiety and stress were assessed before and after ABMT in the research groups, and, similarly, 5 weeks apart, in the controls. We found that despite the different patterns of change in AB between the three groups following ABMT, the reduction in AB, or the between-group differences in AB-reduction, were not significant. While the severity of ED-symptoms, depression, anxiety and stress was reduced following ABMT, or control condition, in all groups, there were no between-group differences in these changes. Changes in AB were not correlated with baseline and pre-post-treatment changes in ED-related and comorbid symptomatology. Methodological and inpatient treatment-related considerations may explain our negative ABMT-related results.