Cereal, pasture legume and water supply prospects at Forrestania : results of experimental work east of Hyden, Western Australia

The agricultural potential of the Forrestania area appears at least equal to that of much of the settled eastern wheatbelt. The scrubplain soils of the Forrestania area have an average yield potential of at least 1 000 kg/ha wheat and carrying capacity of 1.8 to 3.7 sheep per hectare on improved pastures. The use of clover ley rotations would maintain these levels of potential yield. Partial crop failures caused by adverse seasonal conditions could be expected 10 years in every 100

Tumour-derived alkaline phosphatase regulates tumour growth, epithelial plasticity and disease-free survival in metastatic prostate cancer

BACKGROUND: Recent evidence suggests that bone-related parameters are the main prognostic factors for overall survival in advanced prostate cancer (PCa), with elevated circulating levels of alkaline phosphatase (ALP) thought to reflect the dysregulated bone formation accompanying distant metastases. We have identified that PCa cells express ALPL, the gene that encodes for tissue nonspecific ALP, and hypothesised that tumour-derived ALPL may contribute to disease progression. METHODS: Functional effects of ALPL inhibition were investigated in metastatic PCa cell lines. ALPL gene expression was analysed from published PCa data sets, and correlated with disease-free survival and metastasis. RESULTS: ALPL expression was increased in PCa cells from metastatic sites. A reduction in tumour-derived ALPL expression or ALP activity increased cell death, mesenchymal-to-epithelial transition and reduced migration. Alkaline phosphatase activity was decreased by the EMT repressor Snail. In men with PCa, tumour-derived ALPL correlated with EMT markers, and high ALPL expression was associated with a significant reduction in disease-free survival. CONCLUSIONS: Our studies reveal the function of tumour-derived ALPL in regulating cell death and epithelial plasticity, and demonstrate a strong association between ALPL expression in PCa cells and metastasis or disease-free survival, thus identifying tumour-derived ALPL as a major contributor to the pathogenesis of PCa progression.British Journal of Cancer advance online publication, 22 December 2016; doi:10.1038/bjc.2016.402 www.bjcancer.com

Lesbian and Heterosexual Two-Parent Families: Adolescent–Parent Relationship Quality and Adolescent Well-Being

This study compared 51 adolescents from intact two-mother planned lesbian families (all conceived through donor insemination) with 51 adolescents from intact mother-father families on their relationships with their parents (parental control, disclosure to parents, and adolescent-parent relationship quality), psychological adjustment (self-esteem, social anxiety, and conduct problems), and substance usage (consumption of tobacco, alcohol, and marijuana/hashish). The adolescents (average age 16 years) were matched on demographic characteristics (age, gender, educational level, country of birth, parental birth country) with a sample from a large school-based survey, and data were collected by means of adolescent self-reports. Analyses indicated that adolescents in both family types had positive relationships with their parents, which were favorably associated with psychological well-being. On the assessments of psychological adjustment and substance use, family type was significantly associated only with self-esteem and conduct problems: Adolescents with lesbian mothers had higher levels of self-esteem and lower levels of conduct problems than their counterparts in heterosexual-parent families. Overall, the findings indicate that adolescents from intact two-mother lesbian families are comparable to those in a matched comparison group with intact mother-father families. The few differences found on psychological well-being favored the adolescents in lesbian two-mother families

Association Between Androgen Deprivation Therapy and Mortality Among Patients With Prostate Cancer and COVID-19

Importance: Androgen deprivation therapy (ADT) has been theorized to decrease the severity of SARS-CoV-2 infection in patients with prostate cancer owing to a potential decrease in the tissue-based expression of the SARS-CoV-2 coreceptor transmembrane protease, serine 2 (TMPRSS2). Objective: To examine whether ADT is associated with a decreased rate of 30-day mortality from SARS-CoV-2 infection among patients with prostate cancer. Design, Setting, and Participants: This cohort study analyzed patient data recorded in the COVID-19 and Cancer Consortium registry between March 17, 2020, and February 11, 2021. The consortium maintains a centralized multi-institution registry of patients with a current or past diagnosis of cancer who developed COVID-19. Data were collected and managed using REDCap software hosted at Vanderbilt University Medical Center in Nashville, Tennessee. Initially, 1228 patients aged 18 years or older with prostate cancer listed as their primary malignant neoplasm were included; 122 patients with a second malignant neoplasm, insufficient follow-up, or low-quality data were excluded. Propensity matching was performed using the nearest-neighbor method with a 1:3 ratio of treated units to control units, adjusted for age, body mass index, race and ethnicity, Eastern Cooperative Oncology Group performance status score, smoking status, comorbidities (cardiovascular, pulmonary, kidney disease, and diabetes), cancer status, baseline steroid use, COVID-19 treatment, and presence of metastatic disease. Exposures: Androgen deprivation therapy use was defined as prior bilateral orchiectomy or pharmacologic ADT administered within the prior 3 months of presentation with COVID-19. Main Outcomes and Measures: The primary outcome was the rate of all-cause 30-day mortality after COVID-19 diagnosis for patients receiving ADT compared with patients not receiving ADT after propensity matching. Results: After exclusions, 1106 patients with prostate cancer (before propensity score matching: median age, 73 years [IQR, 65-79 years]; 561 (51%) self-identified as non-Hispanic White) were included for analysis. Of these patients, 477 were included for propensity score matching (169 who received ADT and 308 who did not receive ADT). After propensity matching, there was no significant difference in the primary end point of the rate of all-cause 30-day mortality (OR, 0.77; 95% CI, 0.42-1.42). Conclusions and Relevance: Findings from this cohort study suggest that ADT use was not associated with decreased mortality from SARS-CoV-2 infection. However, large ongoing clinical trials will provide further evidence on the role of ADT or other androgen-targeted therapies in reducing COVID-19 infection severity

Quantitative analysis of a footwall‐scarp degradation complex and syn‐rift stratigraphic architecture, Exmouth Plateau, NW Shelf, offshore Australia

Interactions between footwall‐, hangingwall‐ and axial‐derived depositional systems make syn‐rift stratigraphic architecture difficult to predict, and preservation of net‐erosional source landscapes is limited. Distinguishing between deposits derived from fault‐scarp degradation (consequent systems) and those derived from long‐lived catchments beyond the fault block crest (antecedent systems) is also challenging, but important for hydrocarbon reservoir prospecting. We undertake geometric and volumetric analysis of a fault‐scarp degradation complex and adjacent hangingwall‐fill associated with the Thebe‐2 fault block on the Exmouth Plateau, NW Shelf, offshore Australia, using high resolution 3D seismic data. Vertical and headward erosion of the complex and fault throw are measured. Seismic‐stratigraphic and seismic facies mapping allow us to constrain the spatial and architectural variability of depositional systems in the hangingwall. Footwall‐derived systems interacted with hangingwall‐ and axial‐derived systems, through diversion around topography, interfingering or successive onlap. We calculate the volume of footwall‐sourced hangingwall fans (VHW) for nine quadrants along the fault block, and compare this to the volume of material eroded from the immediately up‐dip fault‐scarp (VFW). This analysis highlights areas of sediment bypass (VFW > VHW) and areas fed by sediment sources beyond the degraded fault scarp (VHW > VFW). Exposure of the border fault footwall and adjacent fault terraces produced small catchments located beyond the fault block crest that fed the hangingwall basin. One source persisted throughout the main syn‐rift episode, and its location coincided with: (a) an intra‐basin topographic high; (b) a local fault throw minimum; (c) increased vertical and headward erosion within the fault‐scarp degradation complex; and (d) sustained clinoform development in the immediate hangingwall. Our novel quantitative volumetric approach to identify through‐going sediment input points could be applied to other rift basin‐fills. We highlight implications for hydrocarbon exploration and emphasize the need to incorporate interaction of multiple sediment sources and their resultant architecture in tectono‐stratigraphic models for rift basins

Children and Their Parents: A Comparative Study of the Legal Position of Children with Regard to Their Intentional and Biological Parents in English and Dutch Law

This is a book about children and their parents. There are many different kinds of children and at least about as many different kinds of parents. In addition to the many different disciplines that study children and their parents, such as sociology, psychology, child studies and gender studies, to name but a few, this study concerns a legal question with regard to the parent-child relationship, namely how the law assigns parents to children. This subject is approached in a comparative legal perspective and covers England and The Netherlands. The book contains a detailed comparison and analysis of the manner in which the law in the two jurisdictions assigns the status of legal parent and/or attributes parental responsibility to the child’s biological and intentional parents. The concept ‘procreational responsibility’, which is introduced in the concluding chapter of the book, may be used as a tool to assess and reform existing regulations on legal parent-child relationships. The structure of the book, which is based on a categorisation of different family types in a ‘family tree’, enables the reader to have easy access to family-specific information.FdR – Publicaties zonder aanstelling Universiteit Leide

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival