Citations

AbstractEpidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg = 0.23, P = 9.3 × 10−3), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10−3) and concordance in effect direction (P = 2.0 × 10−3) between the two diseases. Cross‐disease GWAS meta‐analysis highlighted 13 distinct loci associated at P ≤ 10−5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10−8, OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross‐disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.

TPS389 Background: Recent data have shown that up to 25% of patients with advanced prostate cancer, including mCRPC, have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or another homologous recombination DNA repair gene. Such mutations can be used as a molecular marker to select patients for targeted treatment with poly(ADP-ribose) polymerase inhibitors (PARPis), which are lethal to cells with HRD. Treatment with PARPis has shown preliminary evidence of antitumor activity in patients with mCRPC and a mutation in a homologous recombination DNA repair gene (Mateo et al. N Engl J Med. 2015;373:1697-708). These data provide a compelling rationale for evaluating rucaparib, a potent inhibitor of PARP1, PARP2, and PARP3, in patients with mCRPC associated with HRD. Methods: TRITON3 (NCT02975934) is a randomized, phase 3 study evaluating rucaparib 600 mg BID vs physician’s choice of abiraterone, enzalutamide, or docetaxel in patients with mCRPC and a deleterious germline or somatic BRCA1, BRCA2, or ATM mutation (identified by prior local testing or central testing during screening). Patients must have progressed on androgen receptor signaling–directed therapy in the mCRPC setting; prior PARPi treatment or chemotherapy for mCRPC are exclusion criteria. Patients will be randomly assigned in a 2:1 ratio to either rucaparib or physician’s choice, with the possibility for cross over from the comparator treatment to rucaparib upon radiographic progression confirmed by independent radiology review. The primary endpoint is radiographic progression-free survival (modified RECIST v1.1/PCWG3 criteria) assessed by independent radiology review. Secondary endpoints include objective response rate, duration of response, patient-reported outcomes, overall survival, and safety. Pretreatment blood samples collected from all patients will enable development of a noninvasive plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈400) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02975934.

TPS388 Background: Up to 25% of patients with advanced prostate cancer, including mCRPC, have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM or another homologous recombination (HR) DNA repair gene that can serve as a molecular marker to select those who may respond to poly(ADP-ribose) polymerase inhibitors (PARPis). PARPis are lethal to cells with HRD, and PARPi treatment has shown preliminary evidence of an antitumor effect in patients with mCRPC who harbor a mutation in an HR DNA repair gene (Mateo et al. N Engl J Med. 2015;373:1697-708). These data provide a compelling rationale for evaluating rucaparib, a potent PARP1, PARP2 and PARP3 inhibitor, in patients with mCRPC associated with HRD. Methods: TRITON2 (NCT02952534) is a phase 2 study evaluating rucaparib 600 mg BID in patients with mCRPC. Patients with a deleterious germline or somatic BRCA1, BRCA2 or ATM mutation (per prior local test or central test during screening) will be enrolled into 1 of 2 cohorts based on the presence or absence of measurable visceral and/or nodal disease. An exploratory cohort will enroll patients with an alteration in any of 12 other prespecified HR genes (eg, RAD51C, RAD51D and PALB2), with or without measurable visceral and/or nodal disease. Patients must have progressed on androgen receptor signaling–directed therapy and 1 prior taxane-based chemotherapy for mCRPC. Patients who received prior treatment with a PARPi, mitoxantrone, cyclophosphamide or platinum-based chemotherapy are excluded. The primary endpoint is objective response rate measured using modified RECIST v1.1/PCWG3 for patients with soft-tissue disease and prostate-specific antigen response for patients with nonmeasurable disease. Secondary endpoints include duration of response, radiographic progression-free survival, overall survival, clinical benefit rate and safety. Pretreatment blood samples collected from all patients will enable development of a plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈160) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02952534.

scikit-image is an image processing library that implements algorithms and utilities for use in research, education and industry applications. It is released under the liberal "Modified BSD" open source license, provides a well-documented API in the Python programming language, and is developed by an active, international team of collaborators. In this paper we highlight the advantages of open source to achieve the goals of the scikit-image library, and we showcase several real-world image processing applications that use scikit-image.

scikit-image is an image processing library that implements algorithms and utilities for use in research, education and industry applications. It is released under the liberal "Modified BSD" open source license, provides a well-documented API in the Python programming language, and is developed by an active, international team of collaborators. In this paper we highlight the advantages of open source to achieve the goals of the scikit-image library, and we showcase several real-world image processing applications that use scikit-image.

Methods developed previously for studying the effect of cerebroventricular injection or ventriculocisternal perfusion of test substances are unsatisfactory because the test substance is not confined to the central compartment. Most likely the test substance enters the peripheral circulation via the arachnoid villi. The purpose of this paper is to describe a method for perfusing the cerebroventricular system of conscious dogs without passage of test substances to the peripheral circulation. With the method described, the mean (+/- SE) cerebroventricular pressure in conscious dogs was 7.4 +/- 0.8 cmH2O (n = 16), and the mean (+/- SE) production of cerebrospinal fluid (CSF) was 25 +/- 0.3 microliter/min (n = 16). Endogenously occurring migrating myoelectric complexes (MMCs) of the small intestine were recorded in dogs before catheters were implanted in the left and right lateral ventricles and the fourth ventricle and after catheter implantation during cerebroventricular perfusion with artificial CSF alone or with CSF containing sulfated (S-CCK-OP) or nonsulfated cholecystokinin octapeptide (NS-CCK-OP). Only cerebroventricular perfusion with S-CCK-OP (1.2 pmol.kg-1.min-1; n = 20) replaced spontaneously occurring MMCs with a fed-like pattern of myoelectric activity. The results suggest that replacement of the fasting pattern of myoelectric activity with a fed-like pattern in the fasted dog was mediated by CCK-A receptors located in one or more brain nuclei surrounding the third ventricle.

Systemic cholecystokinin (CCK) suppresses food intake in various species and has therefore been proposed to act as a satiety factor. Because CCK is also present in the hypothalamus and furthermore meets neurotransmitter criteria, the hypothesis was tested whether CCK participates in the transmission of satiety messages at the lateral hypothalamic (LH) level. The results of this study demonstrate that in halothane-anesthetized cats, neurons located in the LH will indeed release CCK-like material after a carbohydrate-protein meal in a time-dependent fashion. This release, as water loads demonstrate, is most likely due to volumetric distension rather than to the nutrient content. The releasable CCK does not originate from peripheral sources, since intravenously infused CCK octapeptide (CCK-8) does not appear in the perfusate. The release occurs only in discrete neurons and is not universal to CCK-releasing systems within the LH, and also, CCK-releasing systems are not present at all locations. The molecular form of CCK in feline hypothalamus is the COOH-terminal octapeptide (CCK-8) as shown by high-performance liquid chromatography. No gastrin-17 is present. CCK-8 is also the predominant form found in meal-induced as well as in KCl-induced CCK released from hypothalamic neurons. These results suggest a correlated role for hypothalamic CCK in the termination of food intake.

The tissue content and overflow of norepinephrine (NE), epinephrine (Epi), dopamine (DA), Met-enkephalin (Met-Enk), and neuropeptide Y (NPY) from isolated, retrogradely perfused dog adrenal glands were studied. Under resting conditions, approximately 25% of the overflow of autocoids from the glands was Ca2+ dependent; the cholinergic antagonists hexamethonium and atropine had no effects on basal efflux. Stimulation with the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP; 3 or 50 microM) or with the muscarinic agonist pilocarpine (50 microM or 1 mM) evoked releases of autocoids. These releases were blocked or dramatically reduced by appropriate antagonists or by the removal of Ca2+ from the perfusate. Expressed as percentages of tissue stores, the rank order of overflow of autocoids was E approximately DA much greater than NE during resting conditions, DA much greater than E approximately NE during stimulation with 50 microM DMPP, and DA greater than Epi greater than NE during stimulation with 1 mM pilocarpine. These data are consistent with different mechanisms of release for the catecholamines, perhaps from different cell populations. The data support corelease of peptides and catecholamines, although clear pairing of autocoids could not be confirmed.