Phase II randomized preoperative window-of-opportunity study of the PI3K inhibitor pictilisib plus anastrozole compared with anastrozole alone in patients with estrogen receptor-positive breast cancer

Purpose: Preclinical data support a key role for the PI3K pathway in estrogen receptor-positive breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. This preoperative window study assessed whether adding the PI3K inhibitor pictilisib (GDC-0941) can increase the antitumor effects of anastrozole in primary breast cancer and aimed to identify the most appropriate patient population for combination therapy. Patients and Methods: In this randomized, open-label phase II trial, postmenopausal women with newly diagnosed operable estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers were recruited. Participants were randomly allocated (2:1, favoring the combination) to 2 weeks of preoperative treatment with anastrozole 1 mg once per day (n = 26) or the combination of anastrozole 1 mg with pictilisib 260 mg once per day (n = 49). The primary end point was inhibition of tumor cell proliferation as measured by change in Ki-67 protein expression between tumor samples taken before and at the end of treatment. Results: There was significantly greater geometric mean Ki-67 suppression of 83.8% (one-sided 95% CI, ≥ 79.0%) for the combination and 66.0% (95% CI, ≤ 75.4%) for anastrozole (geometric mean ratio [combination: anastrozole], 0.48; 95% CI, ≤ 0.72; P = .004). PIK3CA mutations were not predictive of response to pictilisib, but there was significant interaction between response to treatment and molecular subtype (P =.03);for patients with luminal B tumors, the combination:anastrozole geometric mean ratio of Ki-67 suppression was 0.37 (95% CI, ≤ 0.67; P = .008), whereas no significant Ki-67 response was observed for pictilisib in luminal A tumors (1.01; P = .98). Multivariable analysis confirmed Ki-67 response to the combination treatment of patients with luminal B tumors irrespective of progesterone receptor status or baseline Ki-67 expression. Conclusion: Adding pictilisib to anastrozole significantly increases suppression of tumor cell proliferation in luminal B primary breast cancer

CamTrapAsia: a dataset of tropical forest vertebrate communities from 239 camera trapping studies

Information on tropical Asian vertebrates has traditionally been sparse, particularly when it comes to cryptic species inhabiting the dense forests of the region. Vertebrate populations are declining globally due to land-use change and hunting, the latter frequently referred as “defaunation.” This is especially true in tropical Asia where there is extensive land-use change and high human densities. Robust monitoring requires that large volumes of vertebrate population data be made available for use by the scientific and applied communities. Camera traps have emerged as an effective, non-invasive, widespread, and common approach to surveying vertebrates in their natural habitats. However, camera-derived datasets remain scattered across a wide array of sources, including published scientific literature, gray literature, and unpublished works, making it challenging for researchers to harness the full potential of cameras for ecology, conservation, and management. In response, we collated and standardized observations from 239 camera trap studies conducted in tropical Asia. There were 278,260 independent records of 371 distinct species, comprising 232 mammals, 132 birds, and seven reptiles. The total trapping effort accumulated in this data paper consisted of 876,606 trap nights, distributed among Indonesia, Singapore, Malaysia, Bhutan, Thailand, Myanmar, Cambodia, Laos, Vietnam, Nepal, and far eastern India. The relatively standardized deployment methods in the region provide a consistent, reliable, and rich count data set relative to other large-scale pressence-only data sets, such as the Global Biodiversity Information Facility (GBIF) or citizen science repositories (e.g., iNaturalist), and is thus most similar to eBird. To facilitate the use of these data, we also provide mammalian species trait information and 13 environmental covariates calculated at three spatial scales around the camera survey centroids (within 10-, 20-, and 30-km buffers). We will update the dataset to include broader coverage of temperate Asia and add newer surveys and covariates as they become available. This dataset unlocks immense opportunities for single-species ecological or conservation studies as well as applied ecology, community ecology, and macroecology investigations. The data are fully available to the public for utilization and research. Please cite this data paper when utilizing the data

CamTrapAsia: A dataset of tropical forest vertebrate communities from 239 camera trapping studies

Information on tropical Asian vertebrates has traditionally been sparse, particularly when it comes to cryptic species inhabiting the dense forests of the region. Vertebrate populations are declining globally due to land‐use change and hunting, the latter frequently referred as “defaunation.” This is especially true in tropical Asia where there is extensive land‐use change and high human densities. Robust monitoring requires that large volumes of vertebrate population data be made available for use by the scientific and applied communities. Camera traps have emerged as an effective, non‐invasive, widespread, and common approach to surveying vertebrates in their natural habitats. However, camera‐derived datasets remain scattered across a wide array of sources, including published scientific literature, gray literature, and unpublished works, making it challenging for researchers to harness the full potential of cameras for ecology, conservation, and management. In response, we collated and standardized observations from 239 camera trap studies conducted in tropical Asia. There were 278,260 independent records of 371 distinct species, comprising 232 mammals, 132 birds, and seven reptiles. The total trapping effort accumulated in this data paper consisted of 876,606 trap nights, distributed among Indonesia, Singapore, Malaysia, Bhutan, Thailand, Myanmar, Cambodia, Laos, Vietnam, Nepal, and far eastern India. The relatively standardized deployment methods in the region provide a consistent, reliable, and rich count data set relative to other large‐scale pressence‐only data sets, such as the Global Biodiversity Information Facility (GBIF) or citizen science repositories (e.g., iNaturalist), and is thus most similar to eBird. To facilitate the use of these data, we also provide mammalian species trait information and 13 environmental covariates calculated at three spatial scales around the camera survey centroids (within 10‐, 20‐, and 30‐km buffers). We will update the dataset to include broader coverage of temperate Asia and add newer surveys and covariates as they become available. This dataset unlocks immense opportunities for single‐species ecological or conservation studies as well as applied ecology, community ecology, and macroecology investigations. The data are fully available to the public for utilization and research. Please cite this data paper when utilizing the data

Investigations on the role of haemocytes in drosophila host defence

Innate immunity in Drosophila is mediated via two major responses, humoral and cellular immunity. Induction of the former is characterised by the production of antimicrobial peptides (AMP) via the Toll and Imd pathway. The cellular response is mediated via the haemocytes (blood cells), which engage in phagocytosis and the melanisation cascade. In parallel to the mammalian system, the possibility of haemocytes bridging the gap between pathogen recognition in the haemolymph and AMP gene induction in fat body cells was explored. To analyse their role, the haemocytes were ablated and various parameters for AMP gene expression were defined. The reduction in haemocytes was found to reduce AMP gene expression quantitatively as well causing a spatial restriction in the spreading of AMP expression in the fat body. To determine whether cytokine signals such as Spaetzle (Spz) or unpaired3 (upd3) were involved in transducing the signal, they were knocked down in the haemocytes via RNA interference. The transcriptional reduction of Spz, the ligand for the Toll receptor, was shown to quantitatively reduce the expression of AMP while the reduction of upd3, the cytokine ligand for the JAK/STAT pathway, resulted in the same spatial restriction as larvae with reduced haemocyte counts. The reduction of upd3 in the haemocytes also caused a reduction to signalling in the JNK pathway. The results here show that the haemocytes relay signal(s) to the fat body through the use of cytokines, a process surprisingly similar to the mammalian system

Investigations on the role of haemocytes in Drosophila host defence

upd3 in the haemocytes also caused a reduction to signalling in the JNK pathway. The results here show that the haemocytes relay signal(s) to the fat body through the use of cytokines, a process surprisingly similar to the mammalian system.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Investigations on the role of haemocytes in drosophila host defence

upd3 in the haemocytes also caused a reduction to signalling in the JNK pathway. The results here show that the haemocytes relay signal(s) to the fat body through the use of cytokines, a process surprisingly similar to the mammalian system

Toll-dependent antimicrobial responses in Drosophila larval fat body require Spätzle secreted by haemocytes

In Drosophila, the humoral response characterised by the synthesis of antimicrobial peptides (AMPs) in the fat body (the equivalent of the mammalian liver) and the cellular response mediated by haemocytes (blood cells) engaged in phagocytosis represent two major reactions that counter pathogens. Although considerable analysis has permitted the elucidation of mechanisms pertaining to the two responses individually, the mechanism of their coordination has been unclear. To characterise the signals with which infection might be communicated between blood cells and fat body, we ablated circulating haemocytes and defined the parameters of AMP gene activation in larvae. We found that targeted ablation of blood cells influenced the levels of AMP gene expression in the fat body following both septic injury and oral infection. Expression of the AMP gene drosomycin (a Toll target) was blocked when expression of the Toll ligand Spätzle was knocked down in haemocytes. These results show that in larvae, integration of the two responses in a systemic reaction depend on the production of a cytokine (spz), a process that strongly parallels the mammalian immune response

Abstract S2-03: Preoperative window of opportunity study of the PI3K inhibitor pictilisib (GDC-0941) plus anastrozole vs anastrozole alone in patients with ER+, HER2-negative operable breast cancer (OPPORTUNE study)

Abstract Background: Preclinical and clinical data support a key role for the PI3K pathway in resistance to endocrine therapy in patients with ER+ breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. Short-term preoperative window of opportunity (WOO) studies are a validated strategy for novel treatments to provide proof-of-concept and define the most appropriate patient population by directly assessing treatment effects in tumour tissue before and after treatment. This is the first WOO study with the PI3K inhibitor pictilisib (GDC-0941) in combination with anastrozole (ANA). Methods: 73 postmenopausal patients (pts) have been randomized (2:1 in favour of the combination) to receive 2-week preoperative treatment with ANA plus pictilisib (n=50, "ANA+PIC" arm) or ANA alone (n=23, "ANA" arm). Pts had newly diagnosed, operable, ER+, HER2-negative breast cancer of ≥1 cm size. Pts receiving HRT were excluded. Treatment effects and correlative studies were assessed using FFPE and frozen tumour biopsies taken before and after 14 days of study treatment. The primary endpoint was inhibition of tumour-cell proliferation, as measured by change in Ki67 expression, determined centrally by 2 investigators. Secondary endpoints include induction of apoptosis (Caspase3) and safety. Comprehensive biomarkers analyses include targeted NGS of a comprehensive cancer panel of &amp;gt;400 genes, copy number analyses, and pre- and post-treatment reverse-phase protein arrays (RPPA) and RNA profiling. Results: Baseline (BL) disease characteristics were similar between both study arms. PAM50 analysis showed that 53% and 47% of tumors were Luminal (Lum) A and B, respectively. 65% of tumors had &amp;gt;14% Ki67-positive cells. Observed treatment-emergent AEs were consistent with those previously described for single-agent pictilisib and anastrozole. Mean post-treatment percentage reduction of Ki67 was 84% (95% CI, 75%-89%) for ANA+PIC and 72% (54%-87%) for ANA. Ki67-response (≥50% drop in % of Ki67+ cells) was 86% for ANA+PIC and 60% for ANA. By using the definition that pts with a natural logarithm of %Ki67+ cells of ≤1 or 1-2 have a day 15 anti-proliferative response, 93% [ln(ki67): &amp;lt;1, 46%; 1-2, 46%] of ANA+PIC were responders compared with 60% [&amp;lt;1, 47%; 1-2, 13%] of ANA-treated pts (p = 0.01). Preplanned subgroup analyses showed a significant interaction of response to ANA+PIC with molecular subtype and Ki67 levels. Patients with LumB tumors or high BL Ki67 (&amp;gt;14%) had a higher Ki67 response with ANA+PIC compared to ANA (LumB, 83% vs 38%; Ki67&amp;gt;14%, 94% vs 55%), whereas Ki67 response was similar for both treatments for LumA tumors (ANA, 75%; ANA+PIC, 73%) or tumors with low BL Ki67. Mean post-treatment % reduction of Ki67 in LumB tumors was 87% (95% CI, 49%-96%) for ANA+PIC and 56% (16%-77%) for ANA (p=0.03). Additional data on apoptosis and comprehensive pre- and post-treatment biomarkers analyses will be presented. Conclusions: This first report of a preoperative WOO study evaluating a PI3K inhibitor in early breast cancer demonstrated addition of pictilisib to ANA was associated with increased anti-proliferative response over single-agent ANA. Citation Format: Peter Schmid, Sarah E Pinder, Duncan Wheatley, Jane Macaskill, Charles Zammit, Jennifer Hu, Robert Price, Nigel Bundred, Sirwan Hadad, Alice Shia, Louise Lim, Shah-Jalal Sarker, Patrycja Gazinska, Natalie Woodman, Darren Korbie, Matt Trau, Paul Mainwaring, Peter Parker, Arnie Purushotham, Alastair M Thompson. Preoperative window of opportunity study of the PI3K inhibitor pictilisib (GDC-0941) plus anastrozole vs anastrozole alone in patients with ER+, HER2-negative operable breast cancer (OPPORTUNE study) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S2-03.</jats:p