Refinement Reflection:Complete Verification with SMT

We introduce Refinement Reflection, a new framework for building SMT-based deductive verifiers. The key idea is to reflect the code implementing a user-defined function into the function's (output) refinement type. As a consequence, at uses of the function, the function definition is instantiated in the SMT logic in a precise fashion that permits decidable verification. Reflection allows the user to write equational proofs of programs just by writing other programs using pattern-matching and recursion to perform case-splitting and induction. Thus, via the propositions-as-types principle, we show that reflection permits the specification of arbitrary functional correctness properties. Finally, we introduce a proof-search algorithm called Proof by Logical Evaluation that uses techniques from model checking and abstract interpretation, to completely automate equational reasoning. We have implemented reflection in Liquid Haskell and used it to verify that the widely used instances of the Monoid, Applicative, Functor, and Monad typeclasses actually satisfy key algebraic laws required to make the clients safe, and have used reflection to build the first library that actually verifies assumptions about associativity and ordering that are crucial for safe deterministic parallelism.Comment: 29 pages plus appendices, to appear in POPL 2018. arXiv admin note: text overlap with arXiv:1610.0464

Newer Clinical Strategies for Combining Interferon and Cytotoxic Agents Against Solid Tumours and Hematological Malignancies

The role of interferons in the treatment of cancer continues to evolve. Despite limited single agent activity against solid tumours, interferons now appear to have an important role as modulators of the activity of a variety of cytotoxic drugs. Clinical benefits have been observed for combinations of interferons and alkylating agents against low grade lymphomas, interferons and dacarbazine against malignant melanoma, and interferons and 5-fluorouracil against gastrointestinal and genitourinary malignancies. Further progress will depend on a grealer understanding of the biology of the interaction

Phase II/Pharmacodynamic Trial of Dose-Intensive, Weekly Parenteral Hydroxyurea and Fluorouracil Administered With Interferon Alfa-2a in Patients With Refractory Malignancies of the Gastrointestinal Tract

PURPOSE: Combined depletion of pyrimidine and purine DNA precursors has resulted in therapeutic synergism in vitro. The aims of the current study were to test this strategy in patients with refractory tumors and to assess its effects on selected nucleotide pools.PATIENTS AND METHODS: A single-institution phase II trial was initiated in patients with advanced carcinomas of the stomach and pancreas. Patients had measurable disease and had no prior chemotherapy except adjuvant fluorouracil (5FU) or gemcitabine. 5FU was administered by CADD + pump at 2.6 g/m(2) intravenously by 24-hour infusion on days 1, 8, 15, 22, 29, and 36. Parenteral hydroxyurea (HU) was administered at 4.3 g/m(2) as a 24-hour infusion concurrently with 5FU. Interferon alfa-2a (IFN-alpha2a) was administered at 9 million units subcutaneously on days 1, 3, and 5 each week. No drug was administered in weeks 7 and 8. Pharmacodynamic studies were performed to assess drug effects on levels of deoxyuridine triphosphate (dUTP) and thymidine triphosphate (TTP) pools in peripheral-blood mononuclear cells (PBMCs) before and 6 hours after treatment using a highly sensitive DNA polymerase assay.RESULTS: There were 53 patients enrolled onto the study (gastric carcinoma, 31; pancreatic carcinoma, 22). The median age was 61 years, with 22% of patients &gt; or = 70 years old. The predominant grade 3 to 4 toxicities were leukopenia (49%), granulocytopenia (55%), and thrombocytopenia (22%). Severe diarrhea occurred in 12%, mucositis in 0%, and vomiting in 10% of patients. Patients &gt; or = 70 years had no greater incidence of toxicities. Among the 30 assessable patients with gastric carcinoma, there were two (7%) complete responders and 11 (37%) partial responders (median duration, 7 months). Among the 21 assessable patients with pancreatic carcinoma, there was one responder. Median survival among all patients with gastric carcinoma was 10 months and 13 months for patients with pancreatic carcinoma. Twenty-three patients had samples studied for levels of dUTP and TTP. There was no change in the levels of TTP before and after treatment. Furthermore, dUTP was detected in only five of 28 samples after treatment with no increase in the dUTP/TTP ratio.CONCLUSION: Combination therapy with high-dose, weekly infusional HU and 5FU with IFN-alpha2a modulation was well-tolerated with activity in gastric cancer. Patients &gt; or = 70 years tolerated therapy as well as younger patients. This was the first study to correlate levels of TTP and dUTP after treatment with clinical outcome. In PBMCs used as a surrogate tissue, HU abrogated the 5FU-induced increase in dUTP levels without reversing the overall efficacy of the regimen.</p