HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group

Time course and specificity of sensory-motor alpha modulation during the observation of hand motor acts and gestures: a high density EEG study

The main aim of the present study was to explore, by means of high-density EEG, the intensity and the temporal pattern of event-related sensory-motor alpha desynchronization (ERD) during the observation of different types of hand motor acts and gestures. In particular, we aimed to investigate whether the sensory-motor ERD would show a specific modulation during the observation of hand behaviors differing for goal-relatedness (hand grasping of an object and meaningless hand movements) and social relevance (communicative hand gestures and grasping within a social context). Time course analysis of alpha suppression showed that all types of hand behaviors were effective in triggering sensory-motor alpha ERD, but to a different degree depending on the category of observed hand motor acts and gestures. Meaningless gestures and hand grasping were the most effective stimuli, resulting in the strongest ERD. The observation of social hand behaviors such as social grasping and communicative gestures, triggered a more dynamic time course of ERD compared to that driven by the observation of simple grasping and meaningless gestures. These findings indicate that the observation of hand motor acts and gestures evoke the activation of a motor resonance mechanism that differs on the basis of the goal-relatedness and the social relevance of the observed hand behavior

Prevalence of adult ADHD in an all-female prison unit.

There is increasing evidence suggesting a link between ADHD and criminality, including a strong association between ADHD symptoms and the likelihood of being on probation or in prison. Most studies investigating the prevalence of ADHD in prison populations have focused on adult male offenders. In the current study, 69 female prisoners were screened for both childhood and adult ADHD symptoms using the Barkley Adult ADHD Rating Scale-IV. The results indicate that 41 % of the prisoners met the diagnostic criteria for ADHD in childhood and continued to meet criteria for ADHD as adults. More importantly, young female prisoners (aged 18-25) were significantly more likely to report symptoms of ADHD than older prisoners. Prisoners who reported symptoms of ADHD also reported high levels of impairment associated with these symptoms. A better understanding of the prevalence of ADHD in female prison units can highlight specific areas for intervention during rehabilitation, as well as the management of serious incidents within prison

Health service utilization patterns of primary care patients with osteoarthritis

Contains fulltext : 53455.pdf ( ) (Open Access)BACKGROUND: To assess factors associated with visits to GPs, orthopaedists, and non-physician practitioners of complementary medicine (alternative practitioners) by primary care patients with osteoarthritis (OA). METHODS: Cross-sectional survey among 1250 consecutively addressed patients from 75 primary care practices in Germany. All patients suffered from OA of the knee or hip according to ACR criteria. They received questionnaires collecting sociodemographic data, data about health service utilisation, prescriptions, comorbidities. They also included established instruments as the Arthritis Impact Measurement Scale (AIMS2-SF) to assess disease-specific quality of life and the Patient Health Questionnaire (PHQ-9) to assess depression. Hierarchical stepwise multiple linear regression models were used to reveal significant factors influencing health service utilization. RESULTS: 1021 of 1250 (81.6%) questionnaires were returned. Nonrespondents did not differ from participants. Factors associated with health service use (HSU) varied between providers of care. Not being in a partnership, achieving a high score on the PHQ-9, increased pain severity reflected in the "symptom" scale of the AIMS2-SF, and an increased number of drug prescriptions predicted a high frequency of GP visits. The PHQ-9 score was also a predictor for visits to orthopaedists, as were previous GP contacts, a high score in the "symptom" scale as well as a high score in the "lower limb scale" of the AIMS2-SF. Regarding visits to alternative practitioners, a high score in the AIMS -"social" scale was a positive predictor as older people were less likely to visit them. CONCLUSION: Our results emphasize the need for awareness of psychological factors contributing to the use of health care providers. Addressing the revealed factors associated with HSU appropriately may lead to decreased health care utilization. But further research is needed to assess how this can be done successfully

Non-Lytic, Actin-Based Exit of Intracellular Parasites from C. elegans Intestinal Cells

The intestine is a common site for invasion by intracellular pathogens, but little is known about how pathogens restructure and exit intestinal cells in vivo. The natural microsporidian parasite N. parisii invades intestinal cells of the nematode C. elegans, progresses through its life cycle, and then exits cells in a transmissible spore form. Here we show that N. parisii causes rearrangements of host actin inside intestinal cells as part of a novel parasite exit strategy. First, we show that N. parisii infection causes ectopic localization of the normally apical-restricted actin to the basolateral side of intestinal cells, where it often forms network-like structures. Soon after this actin relocalization, we find that gaps appear in the terminal web, a conserved cytoskeletal structure that could present a barrier to exit. Reducing actin expression creates terminal web gaps in the absence of infection, suggesting that infection-induced actin relocalization triggers gap formation. We show that terminal web gaps form at a distinct stage of infection, precisely timed to precede spore exit, and that all contagious animals exhibit gaps. Interestingly, we find that while perturbations in actin can create these gaps, actin is not required for infection progression or spore formation, but actin is required for spore exit. Finally, we show that despite large numbers of spores exiting intestinal cells, this exit does not cause cell lysis. These results provide insight into parasite manipulation of the host cytoskeleton and non-lytic escape from intestinal cells in vivo

Tendon–bone contact pressure and biomechanical evaluation of a modified suture-bridge technique for rotator cuff repair

The aim of the study was to evaluate the time-zero mechanical and footprint properties of a suture-bridge technique for rotator cuff repair in an animal model. Thirty fresh-frozen sheep shoulders were randomly assigned among three investigation groups: (1) cyclic loading, (2) load-to-failure testing, and (3) tendon–bone interface contact pressure measurement. Shoulders were cyclically loaded from 10 to 180 N and displacement to gap formation of 5- and 10-mm at the repair site. Cycles to failure were determined. Additionally, the ultimate tensile strength and stiffness were verified along with the mode of failure. The average contact pressure and pressure pattern were investigated using a pressure-sensitive film system. All of the specimens resisted against 3,000 cycles and none of them reached a gap formation of 10 mm. The number of cycles to 5-mm gap formation was 2,884.5 ± 96.8 cycles. The ultimate tensile strength was 565.8 ± 17.8 N and stiffness was 173.7 ± 9.9 N/mm. The entire specimen presented a unique mode of failure as it is well known in using high strength sutures by pulling them through the tendon. We observed a mean contact pressure of 1.19 ± 0.03 MPa, applied on the footprint area. The fundamental results of our study support the use of a suture-bridge technique for optimising the conditions of the healing biology of a reconstructed rotator cuff tendon. Nevertheless, an individual estimation has to be done if using the suture-bridge technique clinically. Further investigation is necessary to evaluate the cell biological healing process in order to achieve further sufficient advancements in rotator cuff repair

Sexual Priming, Gender Stereotyping, and Likelihood to Sexually Harass: Examining the Cognitive Effects of Playing a Sexually-Explicit Video Game

The present study examines the short-term cognitive effects of playing a sexually explicit video game with female “objectification” content on male players. Seventy-four male students from a university in California, U.S. participated in a laboratory experiment. They were randomly assigned to play either a sexually-explicit game or one of two control games. Participants’ cognitive accessibility to sexual and sexually objectifying thoughts was measured in a lexical decision task. A likelihood-to-sexually-harass scale was also administered. Results show that playing a video game with the theme of female “objectification” may prime thoughts related to sex, encourage men to view women as sex objects, and lead to self-reported tendencies to behave inappropriately towards women in social situations

Plasma phosphorylated-tau181 as a predictive biomarker for Alzheimer’s amyloid, tau and FDG PET status

Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer’s diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could serve as a marker for Alzheimer’s pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET were included from ADNI. Cross-sectional relationships of plasma p-tau181 with PET biomarkers were tested. Longitudinally, we further investigated whether different p-tau181 levels at baseline predicted different progression of Alzheimer’s pathological changes in the brain. We found plasma p-tau181 significantly correlated with brain amyloid (Spearman ρ = 0.45, P 18.85 pg/ml) at baseline had a higher risk of pathological progression in brain amyloid (HR: 2.32, 95%CI 1.32–4.08) and FDG PET (3.21, 95%CI 2.06–5.01) status. Plasma p-tau181 may be a sensitive screening test for detecting brain pathologies, and serve as a predictive biomarker for Alzheimer’s pathophysiology

Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes

BACKGROUND: Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers. METHODS: A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry. RESULTS: During 122,304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56). CONCLUSION: Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers