Effect of taxane‐based neoadjuvant chemotherapy on fibroglandular tissue volume and percent breast density in the contralateral normal breast evaluated by 3T MR

The aim of this study was to evaluate the change of breast density in the normal breast of patients receiving neoadjuvant chemotherapy (NAC). Forty‐four breast cancer patients were studied. MRI acquisition was performed before treatment (baseline), and 4 and 12 weeks after treatment. A computer‐algorithm‐based program was used to segment breast tissue and calculate breast volume (BV), fibroglandular tissue volume (FV), and percent density (PD) (the ratio of FV over BV × 100%). The reduction of FV and PD after treatment was compared with baseline using paired t‐tests with a Bonferroni–Holm correction. The association of density reduction with age was analyzed. FV and PD after NAC showed significant decreases compared with the baseline. FV was 110.0 ml (67.2, 189.8) (geometric mean (interquartile range)) at baseline, 104.3 ml (66.6, 164.4) after 4 weeks (p < 0.0001), and 94.7 ml (60.2, 144.4) after 12 weeks (comparison with baseline, p < 0.0001; comparison with 4 weeks, p = 0.016). PD was 11.2% (6.4, 22.4) at baseline, 10.6% (6.6, 20.3) after 4 weeks (p < 0.0001), and 9.7% (6.2, 17.9) after 12 weeks (comparison with baseline, p = 0.0001; comparison with 4 weeks, p = 0.018). Younger patients tended to show a higher density reduction, but overall correlation with age was only moderate (r = 0.28 for FV, p = 0.07, and r = 0.52 for PD, p = 0.0003). Our study showed that breast density measured from MR images acquired at 3T MR can be accurately quantified using a robust computer‐aided algorithm based on non‐parametric non‐uniformity normalization (N3) and an adaptive fuzzy C‐means algorithm. Similar to doxorubicin and cyclophosphamide regimens, the taxane‐based NAC regimen also caused density atrophy in the normal breast and showed reduction in FV and PD. The effect of breast density reduction was age related and duration related. Copyright © 2013 John Wiley & Sons, Ltd.     

Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation

Calcium (Ca²⁺) acts as a ubiquitous second messenger, and normal cell and tissue physiology strictly depends on the precise regulation of Ca²⁺ entry, storage, and release. Store‐operated Ca²⁺ entry (SOCE) is a major mechanism controlling extracellular Ca²⁺ entry, and mainly relies on the accurate interplay between the Ca²⁺ sensor STIM1 and the Ca²⁺ channel ORAI1. Mutations in STIM1 or ORAI1 result in abnormal Ca²⁺ homeostasis and are associated with severe human disorders. Recessive loss‐of‐function mutations impair SOCE and cause combined immunodeficiency, while dominant gain‐of‐function mutations induce excessive extracellular Ca²⁺ entry and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK). TAM and STRMK are spectra of the same multisystemic disease characterized by muscle weakness, miosis, thrombocytopenia, hyposplenism, ichthyosis, dyslexia, and short stature. To date, 42 TAM/STRMK families have been described, and here we report five additional families for which we provide clinical, histological, ultrastructural, and genetic data. In this study, we list and review all new and previously reported STIM1 and ORAI1 cases, discuss the pathomechanisms of the mutations based on the known functions and the protein structure of STIM1 and ORAI1, draw a genotype/phenotype correlation, and delineate an efficient screening strategy for the molecular diagnosis of TAM/STRMK.     

Engaging participants in a complex intervention trial in Australian General Practice

Background  

The paper examines the key issues experienced in recruiting and retaining practice involvement in a large complex intervention trial in Australian General Practice.     

Event-related potentials to auditory and visual selective attention in schizophrenia.

BACKGROUND: Prior studies have shown a consistent reduction of the auditory P300 in schizophrenia, while the visual attention findings have been mixed. Both the auditory and visual N2b, an earlier, modality-specific attention index, are reduced in schizophrenia, sometimes despite sparing of the visual P300. Thus there may be a dissociation between the N2b and P300 attention effects in auditory and visual modalities in schizophrenia. METHODS: Thirteen patients and thirteen controls observed symbols appearing on a screen, paired with simultaneous tones. In some blocks subjects responded to one of the symbols, in others to one of the tones. The N2b was predicted to be reduced in the patient group in both auditory and visual attention but the P300 reduced only while attending to tones. RESULTS: Results showed a reduction of the N1 component in the patient group in the auditory condition but not in the visual. There was a reduction of the N2b target-minus-non-target difference wave in the patients in both auditory and visual target conditions. The P300 component was larger overall in the control group in both modalities, but did not show the usual enhancement to auditory targets in the control group. CONCLUSIONS: These findings suggest that the ability to selectively attend to a target in one modality while ignoring the other is compromised in patients with schizophrenia. Perceptual processing appears to be impacted in the auditory modality while remaining intact in the visual. The N2b appears more vulnerable than the P300 in both auditory and visual attention in schizophrenia.     

Chronically increased transforming growth factor-beta1 strongly inhibits hippocampal neurogenesis in aged mice

There is increasing evidence that hippocampal learning correlates strongly with neurogenesis in the adult brain. Increases in neurogenesis after brain injury also correlate with improved outcomes. With aging the capacity to generate new neurons decreases dramatically, both under normal conditions and after injury. How this decrease occurs is not fully understood, but we hypothesized that transforming growth factor (TGF)-beta1, a cell cycle regulator that rapidly increases after injury and with age, might play a role. We found that chronic overproduction of TGF-beta1 from astrocytes almost completely blocked the generation of new neurons in aged transgenic mice. Even young adult TGF-beta1 mice had 60% fewer immature, doublecortin-positive, hippocampal neurons than wild-type littermate controls. Bromodeoxyuridine labeling of dividing cells in 2-month-old TGF-beta1 mice confirmed this decrease in neuro-genesis and revealed a similar decrease in astrogenesis. Treatment of early neural progenitor cells with TGF-beta1 inhibited their proliferation. This strongly suggests that TGF-beta1 directly affects these cells before their differentiation into neurons and astrocytes. Together, these data show that TGF-beta1 is a potent inhibitor of hippocampal neural progenitor cell proliferation in adult mice and suggest that it plays a key role in limiting injury and age-related neurogenesis.     

Improving Care of Upper Respiratory Infections Among Latino Early Head Start Parents

Misconceptions about upper respiratory infections (URI) and their treatment are widely held, especially among Latino parents, and are associated with increased health care visits. The Centers for Disease Control and Prevention recommends community based interventions to educate families about URI. We designed a community-based, culturally competent health literacy intervention regarding URI, which was pilot tested with Latino Early Head Start (EHS) parents. In depth interviews were conducted to understand parents’ perceptions. A paired-sample Wilcoxon signed rank test was used to assess change in pre-post knowledge/attitudes scores. Changes in care practices are described. Parents were very positive about this education, were open to non-antibiotic URI care, and reported that materials were helpful. Following the intervention, the mean composite knowledge/attitude score increased from 4.1 (total: 10) to 6.6 (P < .05). Families also reported improved care practices. EHS sites are promising locations for health literacy interventions regarding URI.     

Impact of breast density on computer-aided detection for breast cancer

OBJECTIVE: Our aim was to determine whether breast density affects the performance of a computer-aided detection (CAD) system for the detection of breast cancer. MATERIALS AND METHODS: Nine hundred six sequential mammographically detected breast cancers and 147 normal screening mammograms from 18 facilities were classified by mammographic density. BI-RADS 1 and 2 density cases were classified as nondense breasts; BI-RADS 3 and 4 density cases were classified as dense breasts. Cancers were classified as either masses or microcalcifications. All mammograms from the cancer and normal cases were evaluated by the CAD system. The sensitivity and false-positive rates from CAD in dense and nondense breasts were evaluated and compared. RESULTS: Overall, 809 (89%) of 906 cancer cases were detected by CAD; 455/505 (90%) cancers in nondense breasts and 354/401 (88%) cancers in dense breasts were detected. CAD sensitivity was not affected by breast density (p=0.38). Across both breast density categories, 280/296 (95%) microcalcification cases and 529/610 (87%) mass cases were detected. One hundred fourteen (93%) of the 122 microcalcifications in nondense breasts and 166 (95%) of 174 microcalcifications in dense breasts were detected, showing that CAD sensitivity to microcalcifications is not dependent on breast density (p=0.46). Three hundred forty-one (89%) of 383 masses in nondense breasts, and 188 (83%) of 227 masses in dense breasts were detected-that is, CAD sensitivity to masses is affected by breast density (p=0.03). There were more false-positive marks on dense versus nondense mammograms (p=0.04). CONCLUSION: Breast density does not impact overall CAD detection of breast cancer. There is no statistically significant difference in breast cancer detection in dense and nondense breasts. However, the detection of breast cancer manifesting as masses is impacted by breast density. The false-positive rate is lower in nondense versus dense breasts. CAD may be particularly advantageous in patients with dense breasts, in which mammography is most challenging.     

MK-2206 Causes Growth Suppression and Reduces Neuroendocrine Tumor Marker Production in Medullary Thyroid Cancer Through Akt Inhibition

Background

Development of targeted therapies for medullary thyroid cancer (MTC) has focused on inhibition of the rearranged during transfection (RET) proto-oncogene. Akt has been demonstrated to be a downstream target of RET via the key mediator phosphoinositide-3-kinase. MK-2206 is an orally administered allosteric Akt inhibitor that has exhibited minimal toxicity in phase I trials. We explored the antitumor effects of this compound in MTC.

Methods

Human MTC-TT cells were treated with MK-2206 (0–20 μM) for 8 days. Assays for cell viability were performed at multiple time points with MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide). The mechanism of action, mechanism of growth inhibition, and production of neuroendocrine tumor markers were assessed with Western blot analysis.

Results

MK-2206 suppressed MTC cell proliferation in a dose-dependent manner (p ≤ 0.001). Levels of Akt phosphorylated at serine 473 declined with increasing doses of MK-2206, indicating successful Akt inhibition. The apoptotic proteins cleaved poly (ADP-ribose) polymerase and cleaved caspase-3 increased in a dose-dependent manner with MK-2206, while the apoptosis inhibitor survivin was markedly reduced. Importantly, the antitumor effects of MK-2206 were independent of RET inhibition, as the levels of RET protein were not blocked.

Conclusions

MK-2206 significantly suppresses MTC proliferation without RET inhibition. Given its high oral bioavailability and low toxicity profile, phase II studies with this drug alone or in combination with RET inhibitors are warranted.