The sensitivity of a nanoscale crack-based sensor is enhanced markedly by modulating the crack depth. The crack-depth-propagated sensor exhibits ≈16 000 gauge factor at 2% strain and a superior signal-to-noise ratio of ≈35, which facilitates detection of target signals for voice-pattern recognition.

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Oncogenic Ras mutants, frequently detected in human cancers, are high-priority anticancer drug targets. However, direct inhibition of oncogenic Ras mutants with small molecules has been extremely challenging. Here we report the development of a human IgG1 format antibody, RT11, which internalizes into the cytosol of living cells and selectively binds to the activated GTP-bound form of various oncogenic Ras mutants to block the interactions with effector proteins, thereby suppressing downstream signalling and exerting anti-proliferative effects in a variety of tumour cells harbouring oncogenic Ras mutants. When systemically administered, an RT11 variant with an additional tumour-associated integrin binding moiety for tumour tissue targeting significantly inhibits the in vivo growth of oncogenic Ras-mutated tumour xenografts in mice, but not wild-type Ras-harbouring tumours. Our results demonstrate the feasibility of developing therapeutic antibodies for direct targeting of cytosolic proteins that are inaccessible using current antibody technology.

IntroductionAnti-estrogen therapy has been shown to reduce mammographic breast density (MD). We hypothesized that a short-term change in breast density may be a surrogate biomarker predicting response to adjuvant endocrine therapy (ET) in breast cancer.MethodsWe analyzed data for 1,065 estrogen receptor (ER)-positive breast cancer patients who underwent surgery between 2003 and 2006 and received at least 2 years of ET, including tamoxifen and aromatase inhibitors. MD was measured using Cumulus software 4.0 and expressed as a percentage. MD reduction (MDR) was defined as the absolute difference in MD of mammograms taken preoperatively and 8-20 months after the start of ET.ResultsAt a median follow-up of 68.8 months, the overall breast cancer recurrence rate was 7.5% (80/1065). Mean MDR was 5.9% (range, -17.2% to 36.9%). Logistic regression analysis showed that age < 50 years, high preoperative MD, and long interval between start of ET to follow-up mammogram were significantly associated with larger MDR (p < 0.05). In a survival analysis, tumor size, lymph node positivity, high Ki-67 (≥ 10%), and low MDR were independent factors significantly associated with recurrence-free survival (p < 0.05). Compared with the group showing the greatest MDR (≥ 10%), the hazard ratios for MDRs of 5-10%, 0-5%, and < 0% were 1.33, 1.92, and 2.26, respectively.ConclusionsMD change during short-term use of adjuvant ET was a significant predictor of long-term recurrence in women with ER-positive breast cancer. Effective treatment strategies are urgently needed in patients with low MDR despite about 1 year of ET.

BackgroundMammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known.Methods and findingsWe examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35–85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (–0.46 cm [95% CI: −0.53, −0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was −0.24 cm (95% CI: −0.34, −0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (−0.38 cm [95% CI: −0.44, −0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature.ConclusionsDeclines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.

The pioneer microbiota of the neonatal gut are essential for gut maturation, and metabolic and immunologic programming. Recent research has shown that early bacterial colonization may impact the occurrence of disease later in life (microbial programming). Despite early conflicting evidence, it has long been considered that the womb is a sterile environment and human microbial colonization begins at birth. In the last few years, several findings have reiterated the presence of microbes in infant first stool (meconium) and pointed to the existence of in utero microbial colonization of the infant gut. The dominant bacterial taxa detected in meconium specimens belong to the Enterobacteriaceae family (Escherichia genus) and lactic acid bacteria (notably members of the genera Leuconostoc, Enterococcus, and Lactococcus). Maternal atopy promotes dominance of Enterobacteriaceae in newborn meconium, which in turn may lead to respiratory problems in the infant. This microbial interaction with the host immune system may in fact, originate during fetal life. Our review evaluates the evidence for an intrauterine origin of meconium microbiota, their composition and influences, and potential clinical implications on infant health.

A vanadium pentoxide electrode is prepared in the amorphous form (a-V2O5), and its electrode performances are compared to those for its crystalline counterpart (c-V2O5). The a-V2O5 electrode outperforms c-V2O5 in several ways. First, it is free from irreversible phase transitions and Li trapping, which evolve in c-V2O5, probably due to the lack of interactions between the inserted Li+ ions/electrons and V2O5 matrix. Second, the absence of Li trapping allows a reversible capacity amounting to >600 mA h g–1, which is larger than that given by c-V2O5. Third, it shows an excellent rate property. The notably high reversible capacity and rate capability seem to be due to Li storage at vacant sites that are ill-defined but numerous in a-V2O5, which Li+ ions can easily access. However, irreversible capacity of a-V2O5 is appreciable in the first cycle due to a parasitic Li reaction with surface hydroxyl groups. Treatment with n-butyllithium can suppress the irreversible capacity by removing the surface hydroxyl groups.

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