Nutrient Management Approaches and Tools for Dairy Farms in Australia and the U.S.

Nutrient surpluses in industrialized nations like the U.S. and Australia are causing problems on dairy farms and posing a threat to the rest of the environment. This paper discusses tools that dairy farmers can use to manage the excess nutrients while continuing to meet demands and profit. The authors suggest improvements in these tools that will not only quantify the amount of nutrient balances on dairy farms, but also identify opportunities for enhanced nutrient use and reduced nutrient losses.Nutrient Management Tools, Australian Dairy Farms, U.S. Dairy Farms, Confinement-based Dairy Operations, Grazing-based Diary Operations, Environmental Economics and Policy, Farm Management, Land Economics/Use,

Reviews and contestability: new directions for Defence

Overview: The First Principles Review of Defence is arguably the most significant review of the defence establishment since the 1973 re-organisation led by Sir Arthur Tange. This Strategic Insights brings together a series of contributions to ASPI’s blog The Strategist written by ten experts with long experience and broad knowledge of Australia’s defence bureaucracy. They bring a wealth of different perspectives and point to significant challenges ahead for Defence if the reforms proposed by the First Principles Review are to succeed

FANCD2 expression affects platinum response and further characteristics of high grade serous ovarian cancer in cells with different genetic backgrounds

High-grade serous ovarian cancer (HGSOC) is the most prevalent subtype of ovarian cancer and demonstrates 5-year survival of just 40%. One of the major causes of mortality is the development of tumour resistance to platinum-based chemotherapy, which can be modulated by dysregulation of DNA damage repair pathways. We therefore investigated the contribution of the DNA interstrand crosslink repair protein FANCD2 to chemosensitivity in HGSOC. Increased FANCD2 protein expression was observed in some cell line models of platinum resistant HGSOC compared with paired platinum sensitive models. Knockdown of FANCD2 in some cell lines, including the platinum resistant PEO4, led to increased carboplatin sensitivity. Investigation into mechanisms of FANCD2 regulation showed that increased FANCD2 expression in platinum resistant cells coincides with increased expression of mTOR. Treatment with mTOR inhibitors resulted in FANCD2 depletion, suggesting that mTOR can mediate platinum sensitivity via regulation of FANCD2. Tumours from a cohort of HGSOC patients showed varied nuclear and cytoplasmic FANCD2 expression, however this was not significantly associated with clinical characteristics. Knockout of FANCD2 was associated with increased cell migration, which may represent a non-canonical function of cytoplasmic FANCD2. We conclude that upregulation of FANCD2, possibly mediated by mTOR, is a potential mechanism of chemoresistance in HGSOC and modulation of FANCD2 expression can influence platinum sensitivity and other tumour cell characteristics

RFWD3 modulates response to platinum chemotherapy and promotes cancer associated phenotypes in high grade serous ovarian cancer

Background: DNA damage repair is frequently dysregulated in high grade serous ovarian cancer (HGSOC), which can lead to changes in chemosensitivity and other phenotypic differences in tumours. RFWD3, a key component of multiple DNA repair and maintenance pathways, was investigated to characterise its impact in HGSOC.Methods: RFWD3 expression and association with clinical features was assessed using in silico analysis in the TCGA HGSOC dataset, and in a further cohort of HGSOC tumours stained for RFWD3 using immunohistochemistry. RFWD3 expression was modulated in cell lines using siRNA and CRISPR/cas9 gene editing, and cells were characterised using cytotoxicity and proliferation assays, flow cytometry, and live cell microscopy. Results: Expression of RFWD3 RNA and protein varied in HGSOCs. In cell lines, reduction of RFWD3 expression led to increased sensitivity to interstrand crosslinking (ICL) inducing agents mitomycin C and carboplatin. RFWD3 also demonstrated further functionality outside its role in DNA damage repair, with RFWD3 deficient cells displaying cell cycle dysregulation, reduced cellular proliferation and reduced migration. In tumours, low RFWD3 expression was associated with increased tumour mutational burden, and complete response to platinum chemotherapy. Conclusions: RFWD3 expression varies in HGSOCs, which can lead to functional effects at both the cellular and tumour levels.<br/

Plasma proteomic profiles from disease-discordant monozygotic twins suggest that molecular pathways are shared in multiple systemic autoimmune diseases*

Introduction: Although systemic autoimmune diseases (SAID) share many clinical and laboratory features, whether they also share some common features of pathogenesis remains unclear. We assessed plasma proteomic profiles among different SAID for evidence of common molecular pathways that could provide insights into pathogenic mechanisms shared by these diseases. Methods: Differential quantitative proteomic analyses (one-dimensional reverse-phase liquid chromatography-mass spectrometry) were performed to assess patterns of plasma protein expression. Monozygotic twins (four pairs discordant for systemic lupus erythematosus, four pairs discordant for juvenile idiopathic arthritis and two pairs discordant for juvenile dermatomyositis) were studied to minimize polymorphic gene effects. Comparisons were also made to 10 unrelated, matched controls. Results: Multiple plasma proteins, including acute phase reactants, structural proteins, immune response proteins, coagulation and transcriptional factors, were differentially expressed similarly among the different SAID studied. Multivariate Random Forest modeling identified seven proteins whose combined altered expression levels effectively segregated affected vs. unaffected twins. Among these seven proteins, four were also identified in univariate analyses of proteomic data (syntaxin 17, a-glucosidase, paraoxonase 1, and the sixth component of complement). Molecular pathway modeling indicated that these factors may be integrated through interactions with a candidate plasma biomarker, PON1 and the pro-inflammatory cytokine IL-6. Conclusions: Together, these data suggest that different SAID may share common alterations of plasma protein expression and molecular pathways. An understanding of the mechanisms leading to the altered plasma proteomes common among these SAID may provide useful insights into their pathogeneses

Identifying and overcoming mechanisms of PARP 2 inhibitor resistance in homologous recombination 3 repair-deficient and repair-proficient high grade 4 serous ovarian cancer cells

High grade serous ovarian cancer (HGSOC) is a major cause of female cancer mortality. The approval of poly (ADP-ribose) polymerase (PARP) inhibitors for clinical use has greatly improved treatment options for patients with homologous recombination repair (HRR)-deficient HGSOC, although the development of PARP inhibitor resistance in some patients is revealing limitations to outcome. A proportion of patients with HRR-proficient cancers also benefit from PARP inhibitor therapy. Our aim is to compare mechanisms of resistance to the PARP inhibitor olaparib in these two main molecular categories of HGSOC and investigate a way to overcome resistance that we considered particularly suited to a cancer like HGSOC, where there is a very high incidence of TP53 gene mutation, making HGSOC cells heavily reliant on the G2 checkpoint for repair of DNA damage and survival. We identified alterations in multiple factors involved in resistance to PARP inhibition in both HRR-proficient and -deficient cancers. The most frequent change was a major reduction in levels of poly (ADP-ribose) glycohydrolase (PARG), which would be expected to preserve a residual PARP1-initiated DNA damage response to DNA single-strand breaks. Other changes seen would be expected to boost levels of HRR of DNA double-strand breaks. Growth of all olaparib-resistant clones isolated could be controlled by WEE1 kinase inhibitor AZD1775, which inactivates the G2 checkpoint. Our work suggests that use of the WEE1 kinase inhibitor could be a realistic therapeutic option for patients that develop resistance to olaparib

Multisite gynecologic endometrioid adenocarcinomas: Can mutation profiling be used to distinguish synchronous primary cancers from metastases?

It is well recognized that some patients with endometrioid gynecological cancers have tumors arising in multiple sites (ovary, endometrium, and endometriosis) at the time of diagnosis. Molecular analysis has helped discern whether these multisite cancers represent synchronous primary tumors or alternatively metastatic disease. We present a complex case of a patient with endometrioid carcinomas arising in multiple sites. We discuss the use of mutation profiling to discern clonality and highlight how this information may inform the clinical management of such cases

MAJOR DEPRESSION AND SURVIVAL IN PEOPLE WITH CANCER

OBJECTIVE: The question of whether depression is associated with worse survival in people with cancer remains unanswered because of methodological criticism of the published research on the topic. We aimed to study the association in a large methodologically robust study. METHODS: We analyzed data on 20,582 patients with breast, colorectal, gynecological, lung, and prostate cancers who had attended cancer outpatient clinics in Scotland, United Kingdom. Patients had completed two-stage screening for major depression as part of their cancer care. These data on depression status were linked to demographic, cancer, and subsequent mortality data from national databases. We estimated the association of major depression with survival for each cancer using Cox regression. We adjusted for potential confounders and interactions between potentially time-varying confounders and the interval between cancer diagnosis and depression screening, and used multiple imputation for missing depression and confounder data. We pooled the cancer-specific results using fixed-effects meta-analysis. RESULTS: Major depression was associated with worse survival for all cancers, with similar adjusted hazard ratios (HRs): breast cancer (HR = 1.42, 95% confidence interval [CI] = 1.15-1.75), colorectal cancer (HR = 1.47, 95% CI = 1.11-1.94), gynecological cancer (HR = 1.36, 95% CI = 1.08-1.71), lung cancer (HR = 1.39, 95% CI = 1.24-1.56), and prostate cancer (HR = 1.76, 95% CI = 1.08-2.85). The pooled HR was 1.41 (95% CI = 1.29-1.54, p < .001, I2 = 0%). These findings were not materially different when we only considered the deaths (90%) that were attributed to cancer. CONCLUSIONS: Major depression is associated with worse survival in patients with common cancers. The mechanisms of this association and the clinical implications require further study

Antibodies to C1q in systemic lupus erythematosus: Characteristics and relation to FcγRIIA alleles

Antibodies to C1q in systemic lupus erythematosus: Characteristics and relation to FcγRIIA alleles. Autoantibodies to the collagen-like region of the first complement component (C1qAB) are found in patients with systemic lupus erythematosus (SLE), particularly those with renal disease. In a cohort of 46 SLE patients with diffuse proliferative glomerulonephritis, we found declining C1qAB titers in 77% of treatment responders and in only 38% of treatment non-responders (P < 0.03). To further characterize this autoantibody, we tested 240 SLE patients for the presence of C1qAB. Positive titers were found in 44% of patients with renal disease and 18% of patients without renal disease (χ2 P < 0.0003). Analysis of IgG subclass revealed IgG2 C1qAB alone in 34%, IgG1 C1qAB alone in 20%, and both IgG1 and IgG2 in 46% of patients. Fewer than 10% of patients had measurable titers of IgG3 or IgG4 C1qAB. The pathogenic role of these IgG2-skewed C1qAB may relate to impaired immune complex clearance by the mononuclear phagocyte system: IgG2 antibodies are efficiently recognized by only one IgG receptor, the H131 allele of FcγRIIa (FcγRIIa-H131). In contrast, FcγRIIa-R131, which is characterized by minimal IgG2 binding, has recently been associated with lupus nephritis. In our C1qAB positive patients, the presence of FcγRIIA-R131 was associated with an increased risk for renal disease. Autoantibodies to C1q may have pathogenic significance in SLE patients with genetic defects in the ability to clear IgG2 containing immune complexes