Current and emerging therapies of HER2-positive metastatic breast cancer

The HER2 receptor as measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) is overexpressed in 15–20% of all breast cancers and traditionally represents adverse biology and a guarded prognosis, particularly in HER2 positive metastatic breast cancer (MBC). Trastuzumab and newer anti-HER2 targeting agents have significantly improved the clinical outcomes of patients with HER2 positive MBC. The development of new techniques has led to discovery of promising biomarkers that can lead to more precise selection of patients for anti-HER2 therapies. This paper summarizes these new biomarkers, useful in selecting patients for treatment with new and emerging therapies for HER2 positive MBC. Emerging next generation sequencing techniques have truly changed the landscape of HER2 positive MBC. Deployment of multiple anti-HER2 therapies in combination is a strategy which has yielded additive or even synergistic effects and has led to markedly improved patient outcomes in HER2+ MBC. In the future, in order to further improve the treatment of these patients and to reduce toxicities, we need to improve our understanding of HER2-dependent pathways and their function, and to develop further treatment combinations while optimizing selection of patients by identifying new biomarkers. The results of prospective studies using CTCs, cDNA and other promising new biomarkers are awaited with great interest.     

Role of spinal metabotropic glutamate receptors in regulation of lower urinary tract function in the decerebrate unanesthetized rat

Biomarker levels in cerebrospinal fluid (CSF) may serve as surrogate markers for treatment efficacy in clinical trials of disease-modifying drugs against Alzheimer's disease (AD). A prerequisite, however, is that the marker is sufficiently stable over time in individual patients. Here, we tested the stability of the three established CSF biomarkers for AD, total tau (T-tau), tau phosphorylated at threonine 181 (P-tau(181)) and the 42 amino acid isoform of beta-amyloid (Abeta42), over 6 months in a cohort of AD patients on stable treatment with acetylcholinesterase (AChE) inhibitors. Fifty-three patients completed the study, 29 men and 24 women, mean age (+/-S.D.) 76.1+/-7.9 years. Mean levels of CSF biomarkers were very stable between baseline and endpoint, with coefficients of variation (CVs) of 4.4-6.1%. Intra-individual biomarker levels at baseline and endpoint were also highly correlated with Pearson r-values above 0.95 (p<0.0001), for all three markers. We conclude that T-tau, P-tau and Abeta42 concentrations in CSF are remarkably stable over a 6-month period in individual AD patients. This suggest that these biomarkers may have a potential to identify and monitor very minor biochemical changes induced by treatment, and thus support their possible usefulness as surrogate markers in clinical trials with drug candidates with disease-modifying potential, such as secretase inhibitors, Abeta immunotherapy and tau phosphorylation inhibitors.     

Urinary metal concentrations among mothers and children in a Mexico City birth cohort study

Personal care product use is a potential source of metals exposure among children, but studies have been limited. We measured urinary concentrations of 10 metals (aluminum, arsenic [As], barium [Ba], cadmium, cobalt [Co], lead [Pb], manganese [Mn], molybdenum [Mo], nickel, and zinc [Zn]) in third trimester pregnant women (n?=?212) and their children at 8–14 years of age (n?=?250). Demographic factors (child sex, age, socioeconomic status, and maternal education), body mass index (BMI) z-score, and child personal care product use in the 24?h prior to urine collection were examined as predictors of urinary metal concentrations. Metals were detected in 80–100% of urine samples, with significant differences in maternal versus childhood levels. However, metal concentrations were not strongly correlated within or between time points. In linear regression models including all demographic characteristics, BMI z-score, and specific gravity, age was associated with higher Co (6% [95% CI: 2, 10]), while BMI z-score was associated with lower Mo (-6% [95% CI: -11, -1). In addition, significantly higher metal concentrations were observed among users of colored cosmetics (Mo: 42% [95% CI: 1, 99]), deodorant (Ba: 28% [3, 58]), hair spray/hair gel (Mn: 22% [3, 45]), and other toiletries (As: 50% [9, 108]), as well as with an increasing number of personal care products used (As: 7% [3, 11]) after adjustment for child sex, age, total number of products used, and specific gravity. However, significantly lower metal concentrations were noted for users of hair cream (As and Zn: -20% [-36, -2] and -21% [-35, -2], respectively), shampoo (Pb: -40% [-62, -7]), and other hair products (Pb: -44% [-65, -9]). We found that personal care product use may be a predictor of exposure to multiple metals among children. Further research is recommended to inform product-specific exposure source identification and related child health risk assessment efforts.     

呼出气冷凝液生物标志物检测在呼吸系统疾病中的应用现状及前景

呼吸系统疾病越发受到人们广泛关注,其复杂多变的病征给医疗领域带来一系列挑战,许多临床常用的检查方法已不足以应对该局面,临床亟需更加方便快捷的检查方法为诊疗提供准确有效的依据。呼出气冷凝液（EBC）是以无创方式获得的呼吸道内衬液,是呼吸系统疾病生物标志物的一种新的重要来源,具有较高的临床研究价值。基于EBC的生物标志物检测方法,能有效反映患者病情变化,优化治疗方案。该方法以其操作简单、安全无创、重复性高、依从性好等优点,日益受到临床重视。本文系统分析了EBC中生物标志物检测方法在呼吸系统疾病中的诊断、监测、疗效评价及预后中的应用现状,并对其收集、检测规范及临床应用等提出相应问题,为其在临床上广泛应用提供有力依据。     

Suicidal behavior-advances in clinical and neurobiological research and improvement of prevention strategies

Suicide is the 14^th leading cause of death worldwide. It is responsible for 1%-5% of all mortality. This article highlights the latest developments in universal, selective, and indicated prevention strategies. Concerning universal suicide prevention, current research has shown that strategies such as restricting access to lethal means (e.g., control of analgesics and hot-spots for suicide by jumping) and school-based awareness programs are most efficacious. Regarding selective prevention, substantial progress can be expected in psychological screening methods for suicidal behavior. The measurement of implicit cognition proved to be more valid in predicting future suicide attempts than classic clinical assessment. Latest developments are smartphone-based interventions and real-time monitoring of suicidal behavior. Great effort has been made to establish valid neurobiological screening methods (e.g., genetic and epigenetic risk factors for suicide, hypothalamic-pituitary-adrenal axis) without yielding a major bre-akthrough. Potentially, multiple biomarkers rather than a single one are necessary to identify individuals at risk. With regard to indicated prevention in form of psychopharmacological treatment, recent pharmacoepidemiological studies and meta-analyses have supported a protective role of antidepressants, lithium, and clozapine. However, the data concerning a specific anti-suicidal effect of these drugs are currently not consistent. Promising results exist for ketamine in reducing suicidal ideation, independently of its antidepressant effect. Concerning psychotherapy, recent findings suggest that psychotherapeutic interventions specifically designed to prevent suicide re-attempts are most efficacious. Specifically, cognitive behavioral therapy and psychodynamic therapy approaches proved to decrease the number of suicide re-attempts significantly.     

An organizational approach for the assessment of DNA adduct data in risk assessment: case studies for aflatoxin B1, tamoxifen and vinyl chloride

The framework analysis previously presented for using DNA adduct information in the risk assessment of chemical carcinogens was applied in a series of case studies which place the adduct information into context with the key events in carcinogenesis to determine whether they could be used to support a mutagenic mode of action (MOA) for the examined chemicals. Three data-rich chemicals, aflatoxin B₁ (AFB₁), tamoxifen (Tam) and vinyl chloride (VCl) were selected for this exercise. These chemicals were selected because they are known human carcinogens and have different characteristics: AFB₁ forms a unique adduct and human exposure is through contaminated foods; Tam is a pharmaceutical given to women so that the dose and duration of exposure are known, forms unique adducts in rodents, and has both estrogenic and genotoxic properties; and VCl, to which there is industrial exposure, forms a number of adducts that are identical to endogenous adducts found in unexposed people. All three chemicals produce liver tumors in rats. AFB₁ and VCl also produce liver tumors in humans, but Tam induces human uterine tumors, only. To support a mutagenic MOA, the chemical-induced adducts must be characterized, shown to be pro-mutagenic, be present in the tumor target tissue, and produce mutations of the class found in the tumor. The adducts formed by AFB₁ and VCl support a mutagenic MOA for their carcinogenicity. However, the data available for Tam shows a mutagenic MOA for liver tumors in rats, but its carcinogenicity in humans is most likely via a different MOA.