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Supplementary Figure 1. AZD5153 shows reduced BRD4 binding activity when BD2 function is abolished; Supplementary Figure 2. AZD5153 modulates MYC protein levels across hematologic cancer cell lines; Supplementary Figure 3. Gene Ontology (GO) analysis of the down-regulated transcripts by AZD5153 across all cell line types; Supplementary Figure 4. IC50 and percent maximal cell kill by AZD5153 and I-BET762 in five hematologic cell lines; Supplementary Figure 5. Tumor growth inhibition across six hematological xenograft Models

Protein modulation by AZD5153 in hematological cell lines

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The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting of BRD4 bromodomains by small molecule inhibitors has proven to be an effective means to disrupt aberrant transcriptional programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, and orally available BET/BRD4 bromodomain inhibitor possessing a bivalent binding mode. Unlike previously described monovalent inhibitors, AZD5153 ligates two bromodomains in BRD4 simultaneously. The enhanced avidity afforded through bivalent binding translates into increased cellular and antitumor activity in preclinical hematologic tumor models. In vivo administration of AZD5153 led to tumor stasis or regression in multiple xenograft models of acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma. The relationship between AZD5153 exposure and efficacy suggests that prolonged BRD4 target coverage is a primary efficacy driver. AZD5153 treatment markedly affects transcriptional programs of MYC, E2F, and mTOR. Of note, mTOR pathway modulation is associated with cell line sensitivity to AZD5153. Transcriptional modulation of MYC and HEXIM1 was confirmed in AZD5153-treated human whole blood, thus supporting their use as clinical pharmacodynamic biomarkers. This study establishes AZD5153 as a highly potent, orally available BET/BRD4 inhibitor and provides a rationale for clinical development in hematologic malignancies. Mol Cancer Ther; 15(11); 2563–74. ©2016 AACR.

Differentially expressed genes with AZD5153 treatment

Supplementary Figures 1-8 from The Mechanisms of Differential Sensitivity to an Insulin-like Growth Factor-1 Receptor Inhibitor (BMS-536924) and Rationale for Combining with EGFR/HER2 Inhibitors

Supplementary Tables 1-4 from The Mechanisms of Differential Sensitivity to an Insulin-like Growth Factor-1 Receptor Inhibitor (BMS-536924) and Rationale for Combining with EGFR/HER2 Inhibitors

Supplementary Information and Figures 1-3 from Identification of Candidate Molecular Markers Predicting Sensitivity in Solid Tumors to Dasatinib: Rationale for Patient Selection

Background and Aims According to the Nice Guidelines (NG89), for any person (over 16 years) undergoing abdominal surgery, pharmacological VTE prophylaxis must be added for a minimum of 7 days (if the risk of VTE outweighs the risk of bleeding). Also, mechanical VTE prophylaxis must commence on admission. We wanted to audit our adherence to these guidelines in the patients undergoing surgery for appendicitis. Methods A review of the electronic pharmacy records of the patients (over 16 years) who underwent surgery for appendicitis (proven with a CT scan or diagnosed intra-operatively) was performed from October to December 2021. We used the Department of Health VTE risk assessment form, and only the patients whose risk of VTE outweighed the bleeding risk were included. Results Of the 23 patients, 22 (95.6%) underwent laparoscopic appendicectomy and, open appendicectomy was done in 1 (4.4%) patient. 11 (47.8%) patients were females, and 12 (52.2%) were males. The mean age was 38.3 (±16) years, and the mean duration of hospital stay was 2.8 (±1.6) days. VTE risk assessment form was completed only for 12 (52.2%) patients. During the hospital stay, 15 of 23 (65.2%) patients received TEDS, and 18 (78.2%) patients received Enoxaparin. 4 (17.4%) patients did not receive any form of VTE prophylaxis. None of these patients was prescribed seven days of pharmacological prophylaxis. Conclusions VTE prophylaxis prescription in patients with short hospital stays is often missed. We must explore the necessary interventions to ensure that patients are given seven days of VTE prophylaxis and regularly audit this practice.

Quandle 2-cocycles define invariants of classical and virtual knots, and extensions of quandles. We show that the quandle 2-cocycle invariant with respect to a non-trivial [Formula: see text]-cocycle is constant, or takes some other restricted form, for classical knots when the corresponding extensions satisfy certain algebraic conditions. In particular, if an abelian extension is a conjugation quandle, then the corresponding cocycle invariant is constant. Specific examples are presented from the list of connected quandles of order less than 48. Relations among various quandle epimorphisms involved are also examined.

Purpose Patients with advanced papillary renal cell carcinoma (PRCC) have limited therapeutic options. PRCC may involve activation of the MET pathway, for example, through gene amplification or mutations. Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective MET tyrosine kinase inhibitor. We report results of a single-arm, multicenter, phase II study evaluating the safety and efficacy of savolitinib in patients with PRCC according to MET status. Patients and Methods Patients with histologically confirmed locally advanced or metastatic PRCC were enrolled and received savolitinib 600 mg orally once daily. MET-driven PRCC was defined as any of the following: chromosome 7 copy gain, focal MET or HGF gene amplification, or MET kinase domain mutations. Efficacy was assessed according to MET status. Safety, toxicity, and patient-reported health-related quality-of-life outcomes were assessed in all patients. Results Of 109 patients treated, PRCC was MET driven in 44 (40%) and MET independent in 46 (42%); MET status was unknown in 19 (17%). MET-driven PRCC was strongly associated with response; there were eight confirmed partial responders with MET-driven disease (18%), but none with MET-independent disease ( P = .002). Median progression-free survival for patients with MET-driven and MET-independent PRCC was 6.2 months (95% CI, 4.1 to 7.0 months) and 1.4 months (95% CI, 1.4 to 2.7 months), respectively (hazard ratio, 0.33; 95% CI, 0.20 to 0.52; log-rank P < .001). The most frequent adverse events associated with savolitinib were nausea, fatigue, vomiting, and peripheral edema. Conclusion These data show activity and tolerability of savolitinib in the subgroup of patients with MET-driven PRCC. Furthermore, molecular characterization of MET status was more predictive of response to savolitinib than a classification based on pathology. These findings justify investigating savolitinib in MET-driven PRCC.

In this work, we evaluate the potential risk of thrombocytopenia in man for a BRD4 inhibitor, AZD5153, based on the platelet count decreases from a Han Wistar rat study. The effects in rat were modeled and used to make clinical predictions for human populations with healthy baseline blood counts. At doses >10 mg, a dose-dependent effect on circulating platelets is expected, with similar predicted changes for both q.d. and b.i.d. dose schedules. These results suggest that at predicted efficacious doses, AZD5153 is likely to have some reductions in the clinical platelet counts, but within the normal range at projected efficacious doses. The model was then extended to incorporate preexisting myelosuppression where bone marrow function is inhibited by acute myeloid leukemia. Under these conditions, duration of platelet count recovery has the potential to be prolonged due to drug-induced myelosuppression.

Quandle homology theories have been developed and cocycles have been used to construct invariants in state-sum form for knots using colorings of knot diagrams by quandles. Quandle 2-cocycles can be also used to define extensions as in the case of groups. There are relations among algebraic properties of quandles, their homology theories, and cocycle invariants; certain algebraic properties of quandles affect the values of the cocycle invariants, and identities satisfied by quandles induce subcomplexes of homology theory. Recent developments in these matters, as well as computational aspects of the invariant, are reviewed. Problems and conjectures pertinent to the subject are also listed.

Proteins of the bromodomain and extraterminal (BET) family, in particular bromodomain-containing protein 4 (BRD4), are of great interest as biological targets. BET proteins contain two separate bromodomains, and existing inhibitors bind to them monovalently. Here we describe the discovery and characterization of probe compound biBET, capable of engaging both bromodomains simultaneously in a bivalent, in cis binding mode. The evidence provided here was obtained in a variety of biophysical and cellular experiments. The bivalent binding results in very high cellular potency for BRD4 binding and pharmacological responses such as disruption of BRD4-mediator complex subunit 1 foci with an EC50 of 100 pM. These compounds will be of considerable utility as BET/BRD4 chemical probes. This work illustrates a novel concept in ligand design-simultaneous targeting of two separate domains with a drug-like small molecule-providing precedent for a potentially more effective paradigm for developing ligands for other multi-domain proteins.

Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency.

Aggressive B-cell lymphomas are genetically and clinically heterogeneous. Standard clinical trial designs do not efficiently evaluate the safety and efficacy of multiple drug combinations within the context of underlying molecular biology. The rapid identification of oncogenic driver pathways and development of multiple targeted drugs in lymphomas create many potential combinations. To address this need, we developed a Phase 1 master protocol termed PRISM (NCT03527147) to evaluate multiple targeted therapies alone or in combination for the treatment of relapsed/refractory (R/R) aggressive B-cell lymphoma. Each study arm is conducted in a predefined disease subset with the aim of addressing clinical and translational questions within an overarching protocol. All study arms are open label and not randomized. Enrolment of subjects into a given study arm is based on meeting inclusion/exclusion criteria and available slots. Pertinent inclusion criteria for the master protocol are: (a) a diagnosis of R/R non-Hodgkin lymphoma based on established World Health Organization criteria; (b) ≥1 prior line of therapy for the treatment of current histology, no known curative treatment options available, or the subject is ineligible for potential curative options; (c) the presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy and; (d) an ECOG performance status ≤2. Exclusion criteria for the master protocol include: (a) a history of prior malignancy, severe or uncontrolled disease or conditions; (b) use of anti-lymphoma therapy within 14 days of the first dose of study drug and; (c) a requirement for ongoing immunosuppressive therapy. Treatment-specific inclusion/exclusion criteria are also provided (see www.clinicaltrials.gov). As PRISM has multiple study arms, subjects can be simultaneously screened for multiple arms. In each arm, a safety review for dose-limiting toxicity (DLT) is performed after 6 subjects have completed the protocol-defined DLT window. Further enrolment will only proceed in that arm if ≤1 subject experiences a DLT (Figure 1). The sample size for each respective arm is determined based on prior clinical/experimental data on anticipated/clinically meaningful activity of each drug combination. This determines a minimally acceptable response and a desirable response. For each arm, a futility analysis occurs after approximately 10 sequentially enrolled subjects. An arm is considered futile if there is 80% chance for the response rate to be above the minimally acceptable response. The study endpoints include safety, ORR, duration of response, progression-free survival, overall survival, and standard pharmacokinetic parameters. Exploratory analyses include in depth translational studies employing peripheral blood and tumor tissue collected at screening and during treatment. These investigations aim to discover predictive biomarkers, identify the molecular correlates of response based on known genetic subtypes, investigate pharmacodynamic and pathway changes and define the depth of response using assays for measurable residual disease (MRD). Exploratory translational endpoints may inform additional biomarker selection strategies for future arms of the PRISM study. All study arms within PRISM to date have combined acalabrutinib, a highly selective BTK inhibitor, with additional targeted agents in subjects with R/R diffuse large B-cell lymphoma. The mechanism of action of the drugs combined with acalabrutinib are as follows: 1. AZD9150 is a 16-nucleotide antisense oligonucleotide designed to target and down-regulate expression of human STAT3 mRNA; administered intravenously. 2. AZD6738 is an inhibitor of ATR; administered orally. 3. Hu5F9-G4 is an anti-CD47 antibody and rituximab is an anti-CD20 antibody; both administered intravenously. 4. AZD5153 is a BRD4 inhibitor; administered orally. In summary, PRISM is a unique platform protocol designed to efficiently evaluate targeted agents in R/R aggressive B-cell lymphoma with an emphasis on comprehensive translational and molecular investigations. Disclosures Izumi: AstraZeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acalabrutinib patents. Hamdy:AstraZeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acalabrutinib patents. Arkenau:Acerta Pharma: Research Funding. de Vos:Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Verastem: Consultancy. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Zinzani:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Davies:BioInvent: Research Funding; ADCT Therapeutics: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Pfizer: Honoraria, Research Funding; Acerta Pharma: Honoraria, Research Funding; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pagel:AstraZeneca: Consultancy; Pharmacyclics, Inc.: Consultancy. Vose:Legend Pharmaceuticals: Honoraria; Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria. Bitman:Acerta Pharma: Employment; AstraZeneca: Equity Ownership. Brock:Acerta Pharma: Employment; AstraZeneca: Equity Ownership. Clark:AstraZeneca: Employment, Equity Ownership. Frigault:Acerta Pharma: Employment; AstraZeneca: Employment, Equity Ownership. Ware:Acerta Pharma: Employment; Astrazeneca: Employment, Equity Ownership. Yang:Acerta Pharma: Employment; AstraZeneca: Equity Ownership. Staudt:Nanostring: Patents & Royalties. Flinn:TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. OffLabel Disclosure: acalabrutinib in DLBCL

Acute myeloid leukemia (AML) is an aggressive, heterogeneous malignancy. AML patients whose disease relapses on chemotherapy or are unfit for aggressive induction regimens have limited therapeutic options. Many patients benefit from the combination of venetoclax (BCL2i) and a hypomethylating agent (HMA) but this regimen is rarely curative. The addition of novel agents could provide improved benefit for relapsed/refractory patients. To identify such regimens, we screened a panel of 10 AML cell lines with combinations of venetoclax and novel targeted agents. The agents used spanned multiple mechanisms of action (e.g. DNA damage response, kinase signaling, pro-apoptotic agents) and are all in early clinical development. Cells were treated for 72hrs and viability was assessed by CellTiter-Glo. In several of the cell lines that were insensitive or partially sensitive to venetoclax (OCI-AML3, KG1a, MonoMac6, THP1), combinations with inhibitors of MCL1 (AZD5991), AURKB (AZD2811), and BRD4 (AZD5153) showed synergistic activity (Loewe synergy score >5, growth inhibition > 180%) (Table 1). We next asked if these combinations were active in patient-derived xenograft (PDX) models of AML. We established an ex vivo co-culture assay using the HS-5 bone marrow stromal cell line. AML PDX cells were isolated from mouse spleens and plated in 96-well format in direct co-culture with HS-5 cells or in HS-5-derived conditioned media. Cells were treated with three doses of each monotherapy and three doses of fixed ratio combination. Replicate screens using cells from individual mice on different days confirmed data were reproducible (r2=0.687) across animals engrafted with the same PDX. Drug response was similar between conditioned media and direct co-culture assays (r2=0.81). Venetoclax sensitivity varied across PDX models ex vivo. Notably, 2/5 PDX models screened (DFAM-68555 and DFAM-10360) were insensitive to both venetoclax and the combination of venetoclax + 5-azacytidine (HMA) ex vivo. Both models were established from untreated/1L patients and harbor TP53 mutations. Combination treatments did not add additional benefit over venetoclax monotherapy in the DFAM-10360 model. However, in DFAM-68555, AZD5153, AZD5991, and AZD2811 showed improved activity over venetoclax alone (67%, 54%, and 67% vs. 26% decrease in viability for venetoclax alone, respectively). Since combination strategies will likely be most impactful in patients refractory to or relapsed after venetoclax, we chose this venetoclax insensitive model to prioritize in vivo. To confirm the translatability of these findings, we designed a pilot in vivo study using DFAM-68555. Mice were randomized to receive vehicle, venetoclax + HMA, or venetoclax + AZD5153 when peripheral blood disease reached ~5% (hCD45+hCD33+ cells by flow cytometry). After two weeks of dosing, animals were sacrificed to evaluate disease burden in bone marrow (sternum), spleen, and peripheral blood. The model remained insensitive to venetoclax + HMA in vivo. The combination of AZD5153 with venetoclax decreased disease burden in blood and spleen compared to vehicle (30% and 42% hCD45+CD33+ cells by flow cytometry vs 70% and 95%, respectively) with similar efficacy seen by immunohistochemistry in the bone. Finally, we screened these venetoclax combinations in additional aggressive AML PDX models which were resistant or only partially responsive to venetoclax in vivo. Addition of AZD2811NP and AZD5991 to venetoclax was more effective than venetoclax alone and venetoclax + HMA in the bone marrow. The most active combination varied from model to model. Efficacy screening in additional models is ongoing to further build ex vivo to in vivo translation and prioritize development of specific combinations. Also ongoing is genomic and transcriptomic profiling of these PDXs to identify potential predictive biomarkers of combination activity. In summary, we developed an ex vivo screening platform to test clinically actionable combinations for activity in clinically relevant models. Using this platform and subsequent in vivo efficacy, we identified venetoclax combinations across multiple mechanisms (pro-apoptotic, cell cycle regulation, transcriptional regulation, DNA damage response) with activity in venetoclax-insensitive models. These results suggest potential therapeutic options to explore clinically for AML patients. Disclosures Andersen: AstraZeneca: Employment. Christie:AstraZeneca: Employment. Rosen:Astrazeneca: Employment. Maratea:AstraZeneca: Employment. Hattersley:AstraZeneca: Employment. Travers:AstraZeneca: Employment. Cidado:AstraZeneca: Employment. Pulukuri:AstraZeneca: Employment. Saeh:AstraZeneca: Employment. Clark:AstraZeneca: Employment, Equity Ownership. Reimer:AstraZeneca: Employment. Mettetal:AstraZeneca: Employment.

3085 Background: BRD4 is a bromodomain and extraterminal (BET) protein that regulates oncogenic programs by modifying gene transcription and additional mechanisms. AZD5153 is a novel, reversible BRD4 inhibitor with bivalent mechanism of action and enhanced antitumor activity in preclinical models. This phase 1, multicenter, dose escalation study (NCT03205176) assesses AZD5153’s safety, pharmacokinetics (PK), and pharmacodynamics (PD). We report here preliminary, unvalidated data from AZD5153 monotherapy in pts with RR solid tumor, including lymphoma. Methods: Adult pts received oral AZD5153 QD/BID to determine the MTD. During dose escalation, a continual reassessment model was used to estimate toxicity and all final decisions were made by the Safety Review Committee. PK and PD were characterized using standard methods. Results: As of 1 Nov 2018, 28 pts (78.6% female, median age 66.5 y) were treated in 7 cohorts: 2 mg QD (3 pts), 5 mg QD (3 pts), 10 mg QD (3 pts), 10 mg BID (5 pts), 15 mg BID (4 pts), 20 mg BID (7 pts), and 30 mg QD (3 pts). Treatment was ongoing in 8 pts at data cut-off. Safety findings showed 50% of pts experienced treatment-related AEs. 25% of pts experienced treatment-related Grade ≥3 AEs, which were thrombocytopenia and fatigue (7.1% each), and anemia, diarrhea, and platelet count decreased (3.6% each). SAEs were observed in 25% of pts; none of the SAEs was attributable to AZD5153 alone. Dose-limiting toxicities of thrombocytopenia (1 pt) and diarrhea with herpetic rash leading to discontinuation (1 pt) occurred at 20 mg BID. 53.6% of pts discontinued due to disease progression. Total median treatment duration was 1.3 mo (range up to 8.9 mos). Dose proportional increase in Cmax and AUC were observed across the dose range tested. Tmax ranged from 0.5 to 3 h and t1/2 was 6 h. Dose-dependent changes in expression of target genes (eg, HEXIM1, HIST2H2BF, CD274, and CCR2) and platelet counts were observed in the peripheral blood. Conclusions: AZD5153 monotherapy is safe and tolerated at doses up to 30 mg QD and 15 mg BID. Linear increase in PK was observed. Additional safety and efficacy updates will be reported at the annual meeting. Clinical trial information: NCT03205176.

Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency.

BACKGROUND: Concern for respiratory decompensation after immunization in premature infants, particularly those with bronchopulmonary dysplasia (BPD), may lead to delayed and altered immunization schedules. METHODS: A retrospective cohort of premature infants at RESULTS: Of 403 infants admitted to the NICU and immunized, 240 met the study criteria. Of those infants, 172 had a diagnosis of BPD. There was no difference in the primary outcome of respiratory decompensation after immunization between groups (P = .65). There was also no significant difference in apnea, bradycardia, and desaturation events between groups (P = .51). CONCLUSIONS: In this cohort, respiratory decompensation requiring clinical intervention after immunization of preterm infants both with and without BPD was uncommon and not significantly different between groups. Consideration for immunization of this vulnerable population should not be delayed out of concern for clinical deterioration.

The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting of BRD4 bromodomains by small molecule inhibitors has proven to be an effective means to disrupt aberrant transcriptional programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, and orally available BET/BRD4 bromodomain inhibitor possessing a bivalent binding mode. Unlike previously described monovalent inhibitors, AZD5153 ligates two bromodomains in BRD4 simultaneously. The enhanced avidity afforded through bivalent binding translates into increased cellular and antitumor activity in preclinical hematologic tumor models. In vivo administration of AZD5153 led to tumor stasis or regression in multiple xenograft models of acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma. The relationship between AZD5153 exposure and efficacy suggests that prolonged BRD4 target coverage is a primary efficacy driver. AZD5153 treatment markedly affects transcriptional programs of MYC, E2F, and mTOR. Of note, mTOR pathway modulation is associated with cell line sensitivity to AZD5153. Transcriptional modulation of MYC and HEXIM1 was confirmed in AZD5153-treated human whole blood, thus supporting their use as clinical pharmacodynamic biomarkers. This study establishes AZD5153 as a highly potent, orally available BET/BRD4 inhibitor and provides a rationale for clinical development in hematologic malignancies. Mol Cancer Ther; 15(11); 2563–74. ©2016 AACR.

// Ryan E. Henry 1,* , Evan R. Barry 1,* , Lillian Castriotta 1 , Brendon Ladd 1 , Aleksandra Markovets 1 , Garry Beran 2 , Yongxin Ren 3 , Feng Zhou 3 , Ammar Adam 1 , Michael Zinda 1 , Corinne Reimer 1 , Weiguo Qing 3 , Weiguo Su 3 , Edwin Clark 1 , Celina M. D’Cruz 1 and Alwin G. Schuller 1 1 AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Waltham, MA, USA 2 AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Alderley Park, UK 3 Hutchison Medi Pharma Ltd, Zhangjiang Hi-Tech Park, Shanghai, China * These authors have contributed equally to this work Correspondence to: Alwin G. Schuller, email: // Celina M. D’Cruz, email: // Keywords : MET, MYC, NSCLC, acquired resistance, savolitinib Received : January 14, 2016 Accepted : July 13, 2016 Published : July 26, 2016 Abstract Lung cancer is the most common cause of cancer death globally with a significant, unmet need for more efficacious treatments. The receptor tyrosine kinase MET has been implicated as an oncogene in numerous cancer subtypes, including non-small cell lung cancer (NSCLC). Here we explore the therapeutic potential of savolitinib (volitinib, AZD6094, HMPL-504), a potent and selective MET inhibitor, in NSCLC. In vitro , savolitinib inhibits MET phosphorylation with nanomolar potency, which correlates with blockade of PI3K/AKT and MAPK signaling as well as MYC down-regulation. In vivo , savolitinib causes inhibition of these pathways and significantly decreases growth of MET-dependent xenografts. To understand resistance mechanisms, we generated savolitinib resistance in MET -amplified NSCLC cell lines and analyzed individual clones. We found that upregulation of MYC and constitutive mTOR pathway activation is a conserved feature of resistant clones that can be overcome by knockdown of MYC or dual mTORC1/2 inhibition. Lastly, we demonstrate that mechanisms of resistance are heterogeneous, arising via a switch to EGFR dependence or by a requirement for PIM signaling. This work demonstrates the efficacy of savolitinib in NSCLC and characterizes acquired resistance, identifying both known and novel mechanisms that may inform combination strategies in the clinic.

Mcl-1, a member of the Bcl/Mcl family, is a key protein involved in evasion of apoptosis in a wide variety of tumors. Its amplification and overexpression have also been implicated in innate and acquired resistance to anticancer drugs. Mcl-1 is capable of preventing induction of apoptosis, both by binding and inactivating the pro-apoptotic executioner Bcl-2 protein, Bak, as well as by sequestering other pro-apoptotic BH3-only proteins such as Bim and Noxa. AZD5991 is a rationally designed macrocycle with sub-nanomolar affinity for Mcl-1. It demonstrates all the hallmarks of a true Mcl-1 inhibitor: 1. potent, selective, and rapid apoptosis in Mcl-1-dependent cell lines (e.g., GI50 as low as 10 nM in multiple myeloma cell lines); 2. loss of activity upon overexpression of Bcl-xL or siRNA-mediated knockout of Bak; 3. Mcl-1:Bak complex disruption as demonstrated by co-immunoprecipitation. AZD5991 is active in vivo, with complete (100%) tumor regression demonstrated in several mouse xenograft models after a single tolerated dose. We have also demonstrated synergistic in vivo efficacy in combination with standard-of-care agents. Analysis of ex vivo activity in primary samples from leukemia patients indicates that a high percentage of leukemia patients should respond to drug treatment, which supports our plan for a phase I trial of AZD5991 in patients with hematologic cancers. Citation Format: Alexander W. Hird, J. Paul Secrist, Ammar Adam, Matthew A. Belmonte, Eric Gangl, Frank Gibbons, David Hargreaves, Jeffrey W. Johannes, Stephen L. Kazmirski, Jason G. Kettle, Stephen E. Kurtz, Michelle L. Lamb, Martin J. Packer, Bo Peng, Craig R. Stewart, Jeffrey W. Tyner, Wenzhan Yang, Qing Ye, XiaoLan Zheng, Edwin A. Clark. AZD5991: A potent and selective macrocyclic inhibitor of Mcl-1 for treatment of hematologic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT01-02. doi:10.1158/1538-7445.AM2017-DDT01-02

The knot coloring polynomial defined by Eisermann for a finite pointed group is generalized to an infinite pointed group as the longitudinal mapping invariant of a knot. In turn, this can be thought of as a generalization of the quandle 2-cocycle invariant for finite quandles. If the group is a topological group, then this invariant can be thought of as a topological generalization of the 2-cocycle invariant. The longitudinal mapping invariant is based on a meridian–longitude pair in the knot group. We also give an interpretation of the invariant in terms of quandle colorings of a 1-tangle for generalized Alexander quandles without use of a meridian–longitude pair in the knot group. The invariant values are concretely evaluated for the torus knots [Formula: see text], their mirror images, and the figure eight knot for the group SU(2).

Mcl-1 is a member of the Bcl/Mcl family of proteins that promotes cell survival by preventing induction of apoptosis in a broad range of cancers. High expression of Mcl-1 has been linked to tumor development and resistance to anticancer therapies, underscoring the potential of Mcl-1 inhibitors as anticancer drugs. We have previously shown that AZD5991, a rationally designed macrocycle with sub-nanomolar affinity for Mcl-1 and high selectivity, induces rapid and irreversible commitment to apoptosis in Mcl-1-dependent cancer cells in a manner dependent on proapoptotic BAK. Here, we demonstrate that AZD5991 exhibits cytotoxic activity (GI50 Citation Format: Adriana E. Tron, Matthew A. Belmonte, Steven Criscione, Edwin A. Clark, Eric Gangl, Francis D. Gibbons, Jeffrey W. Tyner, Stephen E. Kurtz, Qing Ye, Alexander W. Hird, Alwin Schuller, J. Paul Secrist. Selective Mcl-1 inhibition by AZD5991 induces on-target cell death and achieves antitumor activity in multiple myeloma and acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 302.

Apoptosis is a normal cellular process that is regulated by the dynamic interaction of pro- and anti-apoptotic proteins of the B-cell lymphoma 2 (Bcl-2) family. Cancers, however, have evolved mechanisms to hijack this process and tip the balance in favor of anti-apoptotic proteins, conferring a survival advantage for tumor cells as well as a means of resistance to anti-cancer therapies. Indeed, the Bcl-2 family are some of the most frequently amplified genes and over-expressed proteins across various tumor types. As a result, tumor cells can become addicted to Bcl-2 family members and, hence, vulnerable to targeted BH3 mimetics. Clinical validation of this concept has been demonstrated by venetoclax with its approval for treatment of R/R CLL patients with 17p deletion. Given the great potential that directly targeting the apoptotic machinery holds in treating cancer, developing BH3 mimetics is an attractive proposition. To that end, we have developed a potent small molecule, AZD4320,1 that has nanomolar affinity for Bcl-2 and Bcl-xL, similar to navitoclax, but has physicochemical properties suitable for IV administration. This will help mitigate toxicities observed with oral administration of navitoclax (e.g. allow recovery of platelets), thus improving therapeutic index. AZD4320 also displays the hallmarks of a bona fide BH3 mimetic, most notably the ability to disrupt the complex formation of Bcl-2 with BH3-only proteins and the necessity for intact BAK and BAX to propagate the apoptotic cascade. A kinetic study was also conducted to explore apoptosis induction in the Bcl-2-addicted B-ALL cell line, RS4;11, which revealed both a dose- and time-dependent increase in cleaved caspase-3 (CC3) and corresponding reduction in cell viability. In an expanded panel of human cancer cell lines, AZD4320 rapidly induced CC3 (6h) and loss of viability (24h) in a diverse set of hematological lines with a median EC50 of 182nM. Solid tumor cell lines, however, were much less responsive (median EC50 >30μM). A comparison to venetoclax from the same cell line panel screen revealed that many more hematological tumor cell lines were sensitive to AZD4320, highlighting the utility and promise of a dual Bcl-2/xL inhibitor. Furthermore, in a venetoclax-resistant derived ABC-DLBCL cell line, AZD4320 was equally potent when compared to the parental cell line whereas venetoclax exhibited a >20-fold reduction in activity. Lastly, for in vivo efficacy studies with RS4;11 xenograft tumors, regressions with corresponding induction of CC3 were observed following a single dose of AZD4320. Together, these results highlight the therapeutic potential of a dual Bcl-2/xL inhibitor to be used as a foundation therapy across a broad range of hematological tumor types as well as combat resistance to other BH3 mimetics and targeted therapies. 1Hennessy, E; et al. ACS National Meeting 24 (2015). Citation Format: Justin Cidado, J Paul Secrist, Francis D. Gibbons, Edward J. Hennessy, Stephanos Ioannidis, Edwin A. Clark. AZD4320 is a potent, dual Bcl-2/xLinhibitor that rapidly induces apoptosis in preclinical hematologic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 311.

For a permutation f of an n-dimensional vector space V over a finite field of order q we let k-affinity(f) denote the number of k-flats X of V such that f(X) is also a k-flat. By k-spectrum(n,q) we mean the set of integers k-affinity(f) where f runs through all permutations of V. The problem of the complete determination of k-spectrum(n,q) seems very difficult except for small or special values of the parameters. However, we are able to establish that k-spectrum(n,q) contains 0 in the following cases: (i) q>2 and 02. The maximum of k-affinity(f) is, of course, obtained when f is any semi-affine mapping. We conjecture that the next to largest value of k-affinity(f) is when f is a transposition and we are able to prove this when q=2, k=2, n>2 and when q>2, k=1, n>1., Comment: 25 pages

We present a set of 26 finite quandles that distinguish (up to reversal and mirror image) by number of colorings, all of the 2977 prime oriented knots with up to 12 crossings. We also show that 1058 of these knots can be distinguished from their mirror images by the number of colorings by quandles from a certain set of 23 finite quandles. We study the colorings of these 2977 knots by all of the 431 connected quandles of order at most 35 found by L. Vendramin. Among other things, we collect information about quandles that have the same number of colorings for all of the 2977 knots. For example, we prove that if $Q$ is a simple quandle of prime power order then $Q$ and the dual quandle $Q^*$ of $Q$ have the same number of colorings for all knots and conjecture that this holds for all Alexander quandles $Q$. We study a knot invariant based on a quandle homomorphism $f:Q_1\to Q_0$. We also apply the quandle colorings we have computed to obtain some new results for the bridge index, the Nakanishi index, the tunnel number, and the unknotting number. In an appendix we discuss various properties of the quandles in Vendramin's list. Links to the data computed and various programs in C, GAP and Maple are provided., A newer version of arXiv:1312.3307, Typos fixed

We prove that certain functions involving the gamma and q-gamma function are monotone. We also prove that (xmψ(x))(m+1) is completely monotonic. We conjecture that -(xmψ(m)(x))(m) is completely monotonic for m ≥ 2; and we prove it, with help from Maple, for 2 ≤ m ≤ 16. We give a very useful Maple procedure to verify this for higher values of m. A stronger result is also formulated where we conjecture that the power series coefficients of a certain function are all positive.

We explore a knot invariant derived from colorings of corresponding [Formula: see text]-tangles with arbitrary connected quandles. When the quandle is an abelian extension of a certain type the invariant is equivalent to the quandle [Formula: see text]-cocycle invariant. We construct many such abelian extensions using generalized Alexander quandles without explicitly finding [Formula: see text]-cocycles. This permits the construction of many [Formula: see text]-cocycle invariants without exhibiting explicit [Formula: see text]-cocycles. We show that for connected generalized Alexander quandles the invariant is equivalent to Eisermann’s knot coloring polynomial. Computations using this technique show that the [Formula: see text]-cocycle invariant distinguishes all of the oriented prime knots up to 11 crossings and most oriented prime knots with 12 crossings including classification by symmetry: mirror images, reversals, and reversed mirrors.

436 Background: Savolitinib (HMPL504/Volitinib, AZD6094) is a potent, selective MET inhibitor (IC50 of 4nM). MET and its ligand, HGF, are known to play an important role in the molecular events underlying oncogenesis in PRCC, a disease without a clear standard of care and marked by alterations of chromosome 7 (containing both MET and HGF genes) in a majority of patients as well as gene amplification or MET kinase domain mutations (Albiges et al. 2014, Linehan et al., 2015). Methods: This study evaluates savolitinib in PRCC patients dosed at 600mg daily until disease progression. ORR is the primary endpoint. PFS & DoR are secondary endpoints. PRO & HRQoL questionnaires are exploratory endpoints. Eligibility includes naive and previously treated metastatic PRCC, ECOG PS 0 or 1. Archival tumor was used to centrally confirm PRCC pathology post hoc and to determine MET status using Next Generation Sequencing (Foundation Medicine Inc, USA). Results: As of 27 June 2016, 109 pts were dosed. Best response was PR n=8, SD n=43, PD n=48 and 10 patients were not evaluable for response. 44 pts are MET-driven (MET/HGF gene copy number gain or kinase domain mutations), 46 pts were MET-negative, 19 pts are status unknown. MET-driven pts included Papillary Type I & II histologies. All 8 responders were in the MET-driven group, 18% RR in this subset. Median PFS in the MET-driven group was 6.2 months (95% CI: 4.1–7.0) vs. 1.4 months (95% CI: 1.4–2.7) in the MET-negative group (p = 0.002). Overall 10/109 pts had AEs leading to discontinuation. 23/109 pts had ≥ Grade 3 toxicity related to savolitinib. The most common AEs (all grades) includes: nausea (39%), fatigue (27%), edema (18%), and abnormal LFTs (17%). One death from hepatic encephalopathy was considered related to savolitinib. PRO & HRQoL data was not statistically analysed, descriptive data support main efficacy findings. Conclusions: In the largest biomarker-profiled trial dedicated to PRCC, savolitinib was generally well tolerated with anti-tumor activity in MET-driven patients. These findings warrant further clinical investigation of savolitinib in MET-driven PRCC. Clinical trial information: NCT02127710.

We reviewed cases of mastitis in infants treated at Children's Healthcare of Atlanta from 2005 to 2011. Among infants with breast cultures, Staphylococcus aureus was the most common cause. No infant with a positive breast culture had a concordant positive culture elsewhere. Our findings argue that urine, blood and spinal fluid cultures are unnecessary in well-appearing afebrile infants with mastitis.

Let V be an n-dimensional vector space over a field F. We attempt to determine the least positive integer γ=(k, n, F) for which there exists a family U1 U2 ,⋯,Uγ of k-dimensional subspaces of V such that for every (n−k)-dimensional subspace W of V there is an ie{1,2,⋯,γ} satisfying Ui ⨷W=V. We find upper and lower bounds for γ{k, n, F). In a few special cases we find exact values.

Alterations in the MET oncogene occurs across a broad range of tumor indications. Amplification or mutations in MET lead to increased activity of downstream pathways including PI3K and MAPK, eventually resulting in tumor formation. Several small molecule inhibitors are currently in clinical trials, including the selective inhibitor Savolitinib (HMP-504, Volitinib, AZD6094), which shows single digit nanomolar activity in MET-amplified cell lines. Newly emerging data suggest mutations in MET causing complete skipping of Exon 14 occur in approximately 4% of non-small cell lung cancer (NSCLC), and are more rare in other indications [1, 2]. MET exon 14 skipping mutations were shown to be mutually exclusive from EGFRm, ALK and KRAS and can occur in the context of MET gene amplification [3]. Exon 14 harbors the CBL binding site (Y1003), which is critical for receptor degradation after binding of its ligand, HGF, and suppression of downstream signaling events. Clinical trial results with less potent, pan RTK inhibitors Crizotinib (31nM GI50 vs 3nM for Savolitinib) and Cabozantinib show promising early results, but fall short in long term responses. Therefore, better therapies targeting MET are needed. Human cell line models with Exon 14 deletions are rare. Therefore, we used engineered cell lines to test the effect of Savolitinib on these mutations. To do this, we expressed MET-Y1003F mutants in NIH-3T3 and HEK293T cells. We found that Savolitinib potently inhibited phospho-MET in both models expressing this mutant (100% phospho-MET inhibition). In addition, we tested whether or not Savolitinib could inhibit HGF-dependent signaling and growth of a NSCLC cell line, NCI-H596. In the presence of FBS (10%), Savolitinib had no effect on the growth rate of these cells, however was highly efficient at blocking HGF-dependent growth in the absence of FBS. To test the effect of this mutation in the background of amplification, we also tested the gastric cancer cell line Hs746T, which harbors exon 14 skipping in addition to MET amplification. Savolitinib was highly efficacious at blocking the growth of this cell line. Future studies are aimed at looking at the in vivo effect of Savolitinib targeting exon 14 mutants. These data provide a platform of evidence for using Savolitinib to target exon 14 mutant MET in patients. 1. Paik, P.K., et al., Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov, 2015. 5(8): p. 842-9. 2. Frampton, G.M., et al., Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov, 2015. 5(8): p. 850-9. 3. Cancer Genome Atlas Research, N., Comprehensive molecular profiling of lung adenocarcinoma. Nature, 2014. 511(7511): p. 543-50. Citation Format: Evan Barry, Elizabeth Maloney, Ryan Henry, Alexandra Borodovsky, Edwin Clark, Melanie Frigault, Michael Zinda, Celina D’Cruz. Targeting MET Exon 14 mutations with the selective small molecule inhibitor Savolitinib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1150.

Lung cancer is the most common cause of cancer death globally with a significant, unmet need for more efficacious treatments. Aberrant receptor tyrosine kinase (RTK) signaling is a well-documented driver of disease onset and progression in multiple cancer types, including non-small cell lung cancer (NSCLC), where the cMET RTK contributes to tumor progression, maintenance and resistance to targeted therapies. Here, we explore the therapeutic potential of the potent and selective cMET inhibitor savolitinib (volitinib, AZD6094, HMPL-504) in NSCLC and begin to elucidate mechanisms of acquired savolitinib resistance in preclinical models. Using in vitro proliferation assays and immunoblot analysis, we determine that savolitinib rapidly inhibits cMET auto-phosphorylation/activation and reduces the viability of NSCLC cell lines NCI-H1993 and EBC-1 with a GI50 of 4.20 nM and 2.14 nM, respectively. In vivo, once daily treatment of NCI-H1993 xenografts with 3.0 mg/kg savolitinib significantly slows tumor growth, whereas treatment of EBC-1 xenografts with 30.0 mg/kg results in tumor stasis. Importantly, we observe tumor regressions in a patient-derived xenograft model of a NSCLC lymph node metastasis, HLXF-036LN, dosed with savolitinib 50.0 mg/kg once daily. Pharmacodynamic analysis of in vitro and in vivo models shows that savolitinib sensitivity correlates with blockade of PI3K/AKT and MAPK signaling, and interestingly, with cMYC (MYC) protein down-regulation. To elucidate mechanisms of acquired resistance in NSCLC, we generated savolitinib resistance in vitro using the NCI-H1993 and EBC-1 cell lines and further sub-cloned resistant NCI-H1993 cells to study the heterogeneity of resistance mechanisms. Using small-molecule screening, phospho-protein arrays and interrogation of signaling pathway activity by immunoblot, we identify 1) deregulated mTORC1/2 signaling and 2) the uncoupling of MYC expression from cMET activation as commonly contributing to resistance in all clones tested. RNA interference (siRNA) and MYC over-expression experiments confirm the novel finding that sustained MYC expression can partially drive resistance to a tyrosine kinase inhibitor such as savolitinib. Additionally, we identify clone-specific resistance mechanisms arising via a previously-described switch to EGFR dependence or by our novel finding of a de novo requirement for PIM signaling. Taken together, this work demonstrates the preclinical efficacy of savolitinib in NSCLC and provides an initial characterization of potential resistance mechanisms, identifying core resistance targets and clone-specific vulnerabilities that could be exploited to counter acquired savolitinib resistance that may emerge in the clinic. Citation Format: Ryan E. Henry, Evan R. Barry, Brendon Ladd, Aleksandra Markovets, Garry J. Beran, Yongxin Ren, Feng Zhou, Lillian Castriotta, Ammar Adam, Weiguo Qing, Weiguo Su, Edwin Clark, Celina M. D'Cruz, Alwin Schuller. Acquired resistance to the cMET inhibitor savolitinib in lung cancer models through EGFR/mTOR/MYC deregulation and adoption of PIM signaling. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C22.

The k × n grid graph is the product Pk × Pn of a path of length k − 1 and a path of length n − 1. We prove here formulas found by E. O. Hare for the domination numbers of P5 × Pn and P6 × Pn. © 1993 John Wiley & Sons, Inc.

A subset S of an abelian group G is said to be sum-free if whenever a, b ∈ S, then a + b ∉ S. A maximal sum-free (msf) set S in G is a sum-free set which is not properly contained in another sum-free subset of G. We consider only the case where G is the vector space (V(n) of dimension n over GF(2). We are concerned with the problem of determining all msf sets in V(n). It is well known that if S is a msf set then |S| ⩽ 2n − 1. We prove that there are no msf sets S in V(n) with 5 × 2n − 4 < |S| < 2n − 1. (This bound is sharp at both ends.) Further, we construct msf sets S in V(n), n ⩾ 4, with |S| = 2n − s + 2s + t − 3 × 2t for 0 ⩽ t ⩽ n − 4 and 2 ⩽ s ⩽ [(n − t)2]. These methods suffice to construct msf sets of all possible cardinalities for n ⩽ 6. We also present some of the results of our computer searches for msf sets in V(n). Up to equivalence we found all msf-sets for n ⩽ 6. For n > 6 our searches used random sampling and, in this case, we find many more msf sets than our present methods of construction can account for.

A collection Q of linearly independent w-suhicfs of the n-dimensional vector space V(n) over GF(2) is a w-quilt if whenever X and Y are distinct elements of Q, then X is disjoint from the linear span of Y. The main problem is to determine the maximum possibility cardinality of a w-quilt in V(n) for fixed w and n. Here a graph T(Q) is associated with each quilt Q. The connected components of T(Q) are shown to be complete graphs and the structure of the subquilts corresponding to these components is completely determined. By use of Ramsey type arguments these results are shown to lead to new upper bounds on the cardinality of a w-quilt in V(n) where n = w + 2, a case of particular interest.

A combinatorial view of deadlock (as in Dijkstra's self-stabilizing systems) is presented which leads to precise lower bounds on the complexity of programs. Specifically, we consider a directed ring of k individual processors, each having n states, identical programs, and asynchronous activity. Our main theorem establishes the minimum size (i.e., complexity) of a program for which no global state is in deadlock.

A 1- blocking set in the projective space PG( m ,2), m ⩾2, is a set B of points such that any ( m −1)-flat meets B and no 1-flat is contained in B . A binary linear code is said to be uneven if it contains at least one codeword of odd weight. If B is a 1-blocking set in PG( r −1,2) and dim〈 B 〉= r −1 any matrix H whose columns are the vectors in B is a parity check matrix for an uneven binary code of length n =| B |, redundancy r , and minimum distance at least 4; Conversely, if B is the set of columns of the parity check matrix of such a code then it is a 1-blocking set. Using this and results on uneven binary codes of minimum distance 4, the author shows that there exists a 1-blocking set of cardinality n if and only if 5⩽ n ⩽5⋯2 m −3 .

Papillary renal cell carcinoma (PRCC) is the second most common cancer of the kidney and carries a poor prognosis for patients with non-localized disease. The central role of the hepatocyte growth factor (HGF) receptor MET in PRCC has been explored, demonstrating that MET aberrations, either through mutation, copy number gain, or trisomy of chromosome 7 (the location of MET and HGF) occur in the majority of PRCC cases. We sought to evaluate AZD6094 (HMPL-504), a potent and selective small molecule MET kinase inhibitor, in this disease setting. However, the development of effective therapies targeting MET and other targets in PRCC has been hampered in part by a lack of available preclinical models to test novel targeted therapies. Here we describe for the first time the pharmacodynamic (PD) response and anti-tumor activity of the selective MET inhibitor AZD6094 in two preclinical patient derived xenograft (PDX) models of PRCC (RCC-43b and RCC-47). Both PDX models have increased MET copy number of 8 and 9 copies by FISH in RCC-43b, and RCC-47 respectively, and robust MET protein staining by IHC. AZD6094 treatment resulted in dose dependent anti-tumor responses reaching ∼85% tumor growth inhibition (TGI) when dosed at 2.5 mg/kg daily (qd), stasis when dosed 10 mg/kg qd, and ∼20% regression when dosed at 25 mg/kg qd in the RCC-43b model and ∼63% TGI, ∼89% TGI, ∼64% regression, and ∼96% regression in the RCC-47 model when dosed 0.5, 2.5, 10, and 25 mg/kg qd respectively. The standard of care for RCC, sunitinib, showed no activity in RCC-43b when dosed at 10 mg/kg qd (∼10% TGI, p>0.05 vs vehicle) and ∼60% TGI when dosed at 80 mg/kg qd. Pharmacodynamic analysis of RCC-47 tumors revealed that two hours after an acute dose of AZD6094 pMET levels were reduced >95% at all dose levels tested (0.5 - 25 mg/kg). Eight hours after dosing, pMET levels returned to ∼50% in the 0.5 and 2.5 mg/kg dose groups whereas pMET was still inhibited >90% in the 10 and 25 mg/kg dose groups indicating that the duration of target inhibition was dose related. AZD6094 inhibited multiple signaling nodes including MAPK, PI3K, and EGFR. Finally, at doses that induced tumor regression, AZD6094 resulted in a dose and time dependent induction of cleaved PARP, a marker of cell death. The finding that lower, sub-optimal doses of AZD6094 showed return of pMET 8 hours after a single administration, raised the question whether splitting the dose over a longer duration would increase anti-tumor activity. Indeed, twice a day dosing (bid, 8;16 hours) of AZD6094 at 1.25 mg/kg was more efficacious than daily administration of 2.5 mg/kg resulting in 8% regression compared to 89% TGI (p Citation Format: Alwin Schuller, Evan Barry, Rhys Jones, Melanie Frigault, Garry Beran, Ryan Henry, David Linsenmayer, Maureen Hattersley, Aaron Smith, Joanne Wilson, Ammar Adam, Michael Zinda, Corinne Reimer, Stephen Fawell, Edwin Clark, Celina D'Cruz. Pharmacodynamic response and anti-tumor activity of the MET inhibitor AZD6094 in papillary renal cell carcinoma patient derived xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1477. doi:10.1158/1538-7445.AM2015-1477