The impact of HER2-directed targeted therapy on HER2-positive DCIS of the breast

BACKGROUND: In invasive breast cancer, HER2 is a well-established negative prognostic factor. However, its significance on the prognosis of ductal carcinoma in situ (DCIS) of the breast is unclear. As a result, the impact of HER2-directed therapy on HER2-positive DCIS is unknown and is currently the subject of ongoing clinical trials. In this study, we aim to determine the possible impact of HER2-directed targeted therapy on survival outcomes for HER2-positive DCIS patients. MATERIALS AND METHODS: The National Cancer Data Base (NCDB) was used to retrieve patients with biopsy-proven DCIS diagnosed from 2004–2015. Patients were divided into two groups based on the adjuvant therapy they received: systemic HER2-directed targeted therapy or no systemic therapy. Statistics included multivariable logistic regression to determine factors predictive of receiving systemic therapy, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling to determine variables associated with OS. RESULTS: Altogether, 1927 patients met inclusion criteria; 430 (22.3%) received HER2-directed targeted therapy; 1497 (77.7%) did not. Patients who received HER2-directed targeted therapy had a higher 5-year OS compared to patients that did not (97.7% vs. 95.8%, p = 0.043). This survival benefit remained on multivariable analysis. Factors associated with worse OS on multivariable analysis included Charlson-Deyo Comorbidity Score ≥ 2 and no receipt of hormonal therapy. CONCLUSION: In this large study evaluating HER2-positive DCIS patients, the receipt of HER2-directed targeted therapy was associated with an improvement in OS. The results of currently ongoing clinical trials are needed to confirm this finding

Conserved molecular interactions in centriole-to-centrosome conversion.

Centrioles are required to assemble centrosomes for cell division and cilia for motility and signalling. New centrioles assemble perpendicularly to pre-existing ones in G1-S and elongate throughout S and G2. Fully elongated daughter centrioles are converted into centrosomes during mitosis to be able to duplicate and organize pericentriolar material in the next cell cycle. Here we show that centriole-to-centrosome conversion requires sequential loading of Cep135, Ana1 (Cep295) and Asterless (Cep152) onto daughter centrioles during mitotic progression in both Drosophila melanogaster and human. This generates a molecular network spanning from the inner- to outermost parts of the centriole. Ana1 forms a molecular strut within the network, and its essential role can be substituted by an engineered fragment providing an alternative linkage between Asterless and Cep135. This conserved architectural framework is essential for loading Asterless or Cep152, the partner of the master regulator of centriole duplication, Plk4. Our study thus uncovers the molecular basis for centriole-to-centrosome conversion that renders daughter centrioles competent for motherhood.J.F., Z.L., S.S. and N.S.D. are supported from Programme Grant to D.M.G. from Cancer Research UK. H.R. is supported from MRC Programme Grant to D.M.G. J.F. thank the British Academy and the Royal Society for Newton International Fellowship and Z.L. thanks the Federation of European Biochemical Societies for the Long-Term postdoctoral Fellowship. The authors thank Nicola Lawrence and Alex Sossick for assistance with 3D-SIM.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ncb327

Factorial validity of the Toronto Alexithymia Scale (TAS-20) in clinical samples: A critical examination of the literature and a psychometric study in anorexia nervosa

There is extensive use of the 20-item Toronto Alexithymia Scale (TAS-20) in research and clinical practice in anorexia nervosa (AN), though it is not empirically established in this population. This study aims to examine the factorial validity of the TAS-20 in a Portuguese AN sample (N = 125), testing four different models (ranging from 1 to 4 factors) that were identified in critical examination of existing factor analytic studies. Results of confirmatory factor analysis (CFA) suggested that the three-factor solution, measuring difficulty identifying (DIF) and describing feelings (DDF), and externally oriented thinking (EOT), was the best fitting model. The quality of measurement improves if two EOT items (16 and 18) are eliminated. Internal consistency of EOT was low and decreased with age. The results provide support for the factorial validity of the TAS-20 in AN. Nevertheless, the measurement of EOT requires some caution and may be problematic in AN adolescents.Center for Psychology at the University of Porto, Portuguese Science Foundation (FCT UID/PSI/00050/2013) and EU FEDER through COMPETE 2020 program (POCI-01-0145-FEDER-007294info:eu-repo/semantics/acceptedVersio

Orally Ingested Probiotic, Prebiotic, and Synbiotic Interventions as Countermeasures for Gastrointestinal Tract Infections in Non-elderly Adults: A Systematic Review and Meta-analysis

Meta-analyses have not examined the prophylactic use of orally ingested probiotics, prebiotics, or synbiotics for preventing gastrointestinal tract infections (GTI) of various etiologies in adult populations despite evidence that these gut microbiota-targeted interventions can be effective in treating certain GTI. This systematic review and meta-analysis aimed to estimate the effects of prophylactic use of orally ingested probiotics, prebiotics, and synbiotics on GTI incidence, duration, and severity in non-elderly, non-hospitalized adults. CENTRAL, PubMed, Scopus, and Web of Science were searched through January 2022. English-language, peer-reviewed publications of randomized, placebo-controlled studies testing an orally ingested probiotic, prebiotic, or synbiotic intervention of any dose for ≥1 week in adults who were not hospitalized, immunosuppressed, or taking antibiotics were included. Results were analyzed using random-effects meta-analyses of intention-to-treat (ITT) and complete case (CC) cohorts. Heterogeneity was explored by subgroup meta-analysis and meta-regression. Risk of bias was assessed using the Cochrane RoB2 tool. Seventeen publications reporting 20 studies of probiotics (n=16), prebiotics (n=3), and synbiotics (n=1) were identified (n\u3e6,994 subjects). In CC and ITT analyses, risk of experiencing ≥1 GTI was reduced with probiotics (CC analysis: risk ratio=0.86 [95%CI: 0.73, 1.01]) and prebiotics (risk ratio=0.80 [95%CI: 0.66, 0.98]). No effects on GTI duration or severity were observed. Sources of heterogeneity included study population and number of probiotic strains administered, but were often unexplained, and a high risk of bias was observed for most studies. Specific effects of individual probiotic strains and prebiotic types could not be assessed due to a lack of confirmatory studies. Findings indicated that orally ingested probiotics and prebiotics, relative to placebo, both demonstrated modest benefit for reducing GTI risk in non-elderly adults. However, results should be interpreted cautiously due to the low number of studies, high risk of bias, and unexplained heterogeneity that may include probiotic strain- or prebiotic-specific effects. PROSPERO REGISTRATION: CRD42020200670

Robustness of GNSS integer ambiguity resolution in the presence of atmospheric biases

Both the underlying model strength and biases are two crucial factors for successful integer GNSS ambiguity resolution (AR) in real applications. In some cases, the biases can be adequately parameterized and an unbiased model can be formulated. However, such parameterization will, as trade-off, reduce the model strength as compared to the model in which the biases are ignored. The AR performance with the biased model may therefore be better than with the unbiased model, if the biases are sufficiently small. This would allow for faster AR using the biased model, after which the unbiased model can be used to estimate the remaining unknown parameters. We assess the bias-affected AR performance in the presence of tropospheric and ionospheric biases and compare it with the unbiased case. As a result, the maximum allowable biases are identified for different situations where CORS, static and kinematic baseline models are considered with different model settings. Depending on the size of the maximum allowable bias, a user may decide to use the biased model for AR or to use the unbiased model both for AR and estimating the other unknown parameters

Individual socio-demographic factors and perceptions of the environment as determinants of inequalities in adolescent physical and psychological health: the Olympic Regeneration in East London (ORiEL) study.

BACKGROUND: Populations living in urban areas experience greater health inequalities as well as higher absolute burdens of illness. It is well-established that a range of social and environmental factors determine these differences. Less is known about the relative importance of these factors in determining adolescent health within a super diverse urban context. METHODS: A cross-sectional sample of 3,105 adolescent participants aged 11 to 12 were recruited from 25 schools in the London boroughs of Newham, Tower Hamlets, Hackney and Barking & Dagenham. Participants completed a pseudo-anonymised paper-based questionnaire incorporating: the Warwick-Edinburgh Mental Well-being Scale used for assessing positive mental well-being, the Short Moods and Feelings Questionnaire based on the DSM III-R criteria for assessment of depressive symptoms, the Youth-Physical Activity Questionnaire and a self-assessment of general health and longstanding illness. Prevalence estimates and unadjusted linear models estimate the extent to which positive well-being scores and time spent in physical/sedentary activity vary by socio-demographic and environmental indicators. Logistic regression estimated the unadjusted odds of having fair/(very)poor general health, a long standing illness, or depressive symptoms. Fully adjusted mixed effects models accounted for clustering within schools and for all socio-demographic and environmental indicators. RESULTS: Compared to boys, girls had significantly lower mental well-being and higher rates of depressive symptoms, reported fewer hours physically active and more hours sedentary, and had poorer general health after full adjustment. Positive mental well-being was significantly and positively associated with family affluence but the overall relationship between mental health and socioeconomic factors was weak. Mental health advantage increased as positive perceptions of the neighbourhood safety, aesthetics, walkability and services increased. Prevalence of poor health varied by ethnic group, particularly for depressive symptoms, general health and longstanding illness suggesting differences in the distribution of the determinants of health across ethnic groups. CONCLUSIONS: During adolescence perceptions of the urban physical environment, along with the social and economic characteristics of their household, are important factors in explaining patterns of health inequality

A randomized trial of adjunct testosterone for cancer‐related muscle loss in men and women

Abstract Background Cancer cachexia negatively impacts cancer‐related treatment options, quality of life, morbidity, and mortality, yet no established therapies exist. We investigated the anabolic properties of testosterone to limit the loss of body mass in late stage cancer patients undergoing standard of care cancer treatment. Methods A randomized, double‐blind, placebo‐controlled phase II clinical trial was undertaken to assess the potential therapeutic role of adjunct testosterone to limit loss of body mass in patients with squamous cell carcinoma of the cervix or head and neck undergoing standard of care treatment including chemotherapy and chemoradiation. Patients were randomly assigned in blocks to receive weekly injections of either 100 mg testosterone enanthate or placebo for 7 weeks. The primary outcome was per cent change in lean body mass, and secondary outcomes included assessment of quality of life, tests of physical performance, muscle strength, daily activity levels, resting energy expenditure, nutritional intake, and overall survival. Results A total of 28 patients were enrolled, 22 patients were studied to completion, and 21 patients were included in the final analysis (12 placebo, nine testosterone). Adjunct testosterone increased lean body mass by 3.2% (95% confidence interval [CI], 0–7%) whereas those receiving placebo lost 3.3% (95% CI, −7% to 1%, P = 0.015). Although testosterone patients maintained more favourable body condition, sustained daily activity levels, and showed meaningful improvements in quality of life and physical performance, overall survival was similar in both treatment groups. Conclusions In patients with advanced cancer undergoing the early phase of standard of care therapy, adjunct testosterone improved lean body mass and was also associated with increased quality of life, and physical activity compared with placebo