No abstract

About 3ie The International Initiative for Impact Evaluation (3ie) promotes evidence-informed, equitable, inclusive and sustainable development. We support the generation and effective use of high-quality evidence to inform decision-making and improve the lives of people living in poverty in low-and middle-income countries. We provide guidance and support to produce, synthesise and quality assure evidence of what works, for whom, how, why and at what cost. 3ie impact evaluations 3ie-supported impact evaluations assess the difference a development intervention has made to social and economic outcomes. 3ie is committed to funding rigorous evaluations that include a theory-based design and that use the most appropriate mix of methods to capture outcomes and are useful in complex development contexts. About this report 3ie accepted the final version of the report, Rebuilding the social compact: urban service delivery and property taxes in Pakistan, as partial fulfilment of requirements under grant DPW1.1005 awarded through Development Priorities Window 1. The report is technically sound and 3ie is making it available to the public in this final report version as it was received. No further work has been done. The 3ie technical quality assurance team for this report comprises Francis Rathinam, Neeta Goel, Kanika Jha Kingra and Deeksha Ahuja, an anonymous external impact evaluation design expert reviewer and an anonymous external sector expert reviewer, with overall technical supervision by Marie Gaarder. The 3ie editorial production team for this report comprises Anushruti Ganguly and Akarsh Gupta.

We report a rare and interesting case of a pericecal hernia. A 34-year-old male presented to the emergency department with severe periumbilical pain, emesis and a prior syncopal episode. He noted a 3-month history of intermittent, colicky periumbilical pain. His abdominal examination demonstrated a palpable mass in the right lower quadrant, involuntary guarding and rebound tenderness. CT demonstrated dilated small-bowel loops and findings suggestive of ischemia. The patient was immediately taken to the operating room where a diagnosis of pericecal hernia was made. The patient underwent a reduction of the hernia and a repair of the mesenteric defect.

Purpose: STING (stimulator of interferon genes) plays an important role in innate immunity by activating type I interferons in response to cytosolic nucleic acid ligands such as cyclic dinucleotides (CDNs). In recent years, STING has become an attractive therapeutic target for cancer immune therapy and hydrolysis resistant CDNs have been developed as a new class of cancer therapeutics. These CDNs have been shown to possess potent preclinical efficacy but early results from phase I trials have been disappointing. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1 or NPP1) is natural antagonist of STING pathway. ENPP1 constitutively hydrolyzes 2′3′-cGAMP, a CDN that is the natural ligand for STING. Previously, we reported that SR-8291, a highly selective ENPP1 inhibitor, induces STING activity and demonstrates anti-tumor activity in B16F10 melanoma and CT26 colorectal models. In this study, we extend these findings and report the discovery of SR-8314, an analog of SR-8291 that shows improved physiochemical and developability properties. Methods: With the application of computational techniques (ICM, Maestro), human NPP1 homology model was built by utilizing the crystal structure of mouse NPP1 (PDB: 4GTW). Series of docking simulations on built in ligands were performed within the substrate binding pocket and that led to the identification of lead NPP1 inhibitor SR-8314. Binding of SR-8314 to ENPP1 was evaluated using thermal shift assay. Activity of recombinant human ENPP1 using ATP as a substrate was measured using Cell Titer Glo (Promega) reagent. IRF-Lucia reporter activity, RT-PCR and Western Blotting were performed to evaluate the effect of SR-8314 in 2′3′-cGAMP primed THP1 dual reporter cells (Invivogen). In vivo efficacy studies of intraperitoneally-dosed SR-8314 and SR-8291 were performed in a syngeneic murine tumor model. Tumor T cell infiltration, tumor and plasma pharmacokinetics were assessed by flow cytometry and mass-spectrometry, respectively. Results: SR-8314 has higher binding affinity towards ENPP1 and it potently inhibits ENPP1 activity with a Ki value of 0.079µM. A significant increase in gene expression of IFNβ, ISG15 and CXCL10 along with an increase in the secretion of IFNβ was observed in SR-8314 treated THP1 cells. We show anti-tumor activity as well as an increase in CD3+, CD4+ and CD8+ T cells in both SR-8314 and SR-8291 treated tumors. In addition, there was a decrease in tumor associated macrophages in SR-8314 treated tumors. Conclusions: In summary, we show SR-8314 as a potent inhibitor of ENPP1 that promotes STING activity in vitro. SR-8314 displays promising anti-tumor activity and has ideal candidate properties that warrant further evaluation. Citation Format: Alexis Weston, Trason Thode, Ruben Munoz, Sherin Daniel, Raffaella Soldi, Mohan Kaadige, Haiyong Han, Hariprasad Vankayalapti, Sunil Sharma. Preclinical studies of SR-8314, a highly selective ENPP1 inhibitor and an activator of STING pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3077.

Neuroendocrine tumours (NETs) of the urinary tract are rare, and the urinary bladder is the the most common primary site. Primary ureteric NET is rarer with under 80 cases reported in the literature thus far. Most of these tumours are of the high-grade small cell neuroendocrine carcinoma subtype, which has a worse prognosis. Neoadjuvant chemotherapy has a proven role in the management of NET of the bladder as it downstages the tumour, which may add to significant recurrence-free survival and overall survival. We report the successful management of a patient with locally advanced small cell neuroendocrine carcinoma of the ureter, who had a pathological complete response after neoadjuvant chemotherapy with etoposide and cisplatin. He subsequently received adjuvant chemotherapy followed by radiation and is recurrence-free at a follow-up of 1 year.