MiniBooNE and MicroBooNE Combined Fit to a 3+1 Sterile Neutrino Scenario.

This Letter presents the results from the MiniBooNE experiment within a full "3+1" scenario where one sterile neutrino is introduced to the three-active-neutrino picture. In addition to electron-neutrino appearance at short baselines, this scenario also allows for disappearance of the muon-neutrino and electron-neutrino fluxes in the Booster Neutrino Beam, which is shared by the MicroBooNE experiment. We present the 3+1 fit to the MiniBooNE electron-(anti)neutrino and muon-(anti)neutrino data alone and in combination with MicroBooNE electron-neutrino data. The best-fit parameters of the combined fit with the exclusive charged-current quasielastic analysis (inclusive analysis) are Δm^{2}=0.209 eV^{2}(0.033 eV^{2}), |U_{e4}|^{2}=0.016(0.500), |U_{µ4}|^{2}=0.500(0.500), and sin^{2}(2θ_{µe})=0.0316(1.0). Comparing the no-oscillation scenario to the 3+1 model, the data prefer the 3+1 model with a Δχ^{2}/d.o.f.=24.7/3(17.3/3), a 4.3σ(3.4σ) preference assuming the asymptotic approximation given by Wilks's theorem.

Ultra-deep next-generation sequencing of plasma cell-free DNA in patients with advanced lung cancers: results from the Actionable Genome Consortium.

BACKGROUND: Noninvasive genotyping using plasma cell-free DNA (cfDNA) has the potential to obviate the need for some invasive biopsies in cancer patients while also elucidating disease heterogeneity. We sought to develop an ultra-deep plasma next-generation sequencing (NGS) assay for patients with non-small-cell lung cancers (NSCLC) that could detect targetable oncogenic drivers and resistance mutations in patients where tissue biopsy failed to identify an actionable alteration. PATIENTS AND METHODS: Plasma was prospectively collected from patients with advanced, progressive NSCLC. We carried out ultra-deep NGS using cfDNA extracted from plasma and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50 000× raw target coverage filtering somatic mutations attributable to clonal hematopoiesis. Clinical sensitivity and specificity for plasma detection of known oncogenic drivers were calculated and compared with tissue genotyping results. Orthogonal ddPCR validation was carried out in a subset of cases. RESULTS: In 127 assessable patients, plasma NGS detected driver mutations with variant allele fractions ranging from 0.14% to 52%. Plasma ddPCR for EGFR or KRAS mutations revealed findings nearly identical to those of plasma NGS in 21 of 22 patients, with high concordance of variant allele fraction (r = 0.98). Blinded to tissue genotype, plasma NGS sensitivity for de novo plasma detection of known oncogenic drivers was 75% (68/91). Specificity of plasma NGS in those who were driver-negative by tissue NGS was 100% (19/19). In 17 patients with tumor tissue deemed insufficient for genotyping, plasma NGS identified four KRAS mutations. In 23 EGFR mutant cases with acquired resistance to targeted therapy, plasma NGS detected potential resistance mechanisms, including EGFR T790M and C797S mutations and ERBB2 amplification. CONCLUSIONS: Ultra-deep plasma NGS with clonal hematopoiesis filtering resulted in de novo detection of targetable oncogenic drivers and resistance mechanisms in patients with NSCLC, including when tissue biopsy was inadequate for genotyping.

Measurements of Nonsinglet Moments of the Nucleon Structure Functions and Comparison to Predictions from Lattice QCD for Q

We present extractions of the nucleon nonsinglet moments utilizing new precision data on the deuteron F_{2} structure function at large Bjorken-x determined via the Rosenbluth separation technique at Jefferson Lab Experimental Hall C. These new data are combined with a complementary set of data on the proton previously measured in Hall C at similar kinematics and world datasets on the proton and deuteron at lower x measured at SLAC and CERN. The new Jefferson Lab data provide coverage of the upper third of the x range, crucial for precision determination of the higher moments. In contrast to previous extractions, these moments have been corrected for nuclear effects in the deuteron using a new global fit to the deuteron and proton data. The obtained experimental moments represent an order of magnitude improvement in precision over previous extractions using high x data. Moreover, recent exciting developments in lattice QCD calculations provide a first ever comparison of these new experimental results with calculations of moments carried out at the physical pion mass, as well as a new approach that first calculates the quark distributions directly before determining moments.

Significant Excess of Electronlike Events in the MiniBooNE Short-Baseline Neutrino Experiment.

The MiniBooNE experiment at Fermilab reports results from an analysis of ν_{e} appearance data from 12.84×10^{20} protons on target in neutrino mode, an increase of approximately a factor of 2 over previously reported results. A ν_{e} charged-current quasielastic event excess of 381.2±85.2 events (4.5σ) is observed in the energy range 200

First Measurement of Monoenergetic Muon Neutrino Charged Current Interactions.

We report the first measurement of monoenergetic muon neutrino charged current interactions. MiniBooNE has isolated 236 MeV muon neutrino events originating from charged kaon decay at rest (K^{+}→µ^{+}ν_{µ}) at the NuMI beamline absorber. These signal ν_{µ}-carbon events are distinguished from primarily pion decay in flight ν_{µ} and ν[over ¯]_{µ} backgrounds produced at the target station and decay pipe using their arrival time and reconstructed muon energy. The significance of the signal observation is at the 3.9σ level. The muon kinetic energy, neutrino-nucleus energy transfer (ω=E_{ν}-E_{µ}), and total cross section for these events are extracted. This result is the first known-energy, weak-interaction-only probe of the nucleus to yield a measurement of ω using neutrinos, a quantity thus far only accessible through electron scattering.

Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer.

Background: Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. Patients and methods: Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer. Results: In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germline BRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100 mg b.i.d.). The MTD was determined to be BKM120 50 mg q.d. and olaparib 300 mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAm and gBRCA wild-type (gBRCAwt) patients. Conclusions: BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone.

Dark Matter Search in a Proton Beam Dump with MiniBooNE.

The MiniBooNE-DM Collaboration searched for vector-boson mediated production of dark matter using the Fermilab 8-GeV Booster proton beam in a dedicated run with 1.86×10^{20} protons delivered to a steel beam dump. The MiniBooNE detector, 490 m downstream, is sensitive to dark matter via elastic scattering with nucleons in the detector mineral oil. Analysis methods developed for previous MiniBooNE scattering results were employed, and several constraining data sets were simultaneously analyzed to minimize systematic errors from neutrino flux and interaction rates. No excess of events over background was observed, leading to a 90% confidence limit on the dark matter cross section parameter, Y=ε^{2}α_{D}(m_{χ}/m_{V})^{4}≲10^{-8}, for α_{D}=0.5 and for dark matter masses of 0.01

Utility of a molecular prescreening program in advanced colorectal cancer for enrollment on biomarker-selected clinical trials.

BACKGROUND: Incorporation of multiple enrichment biomarkers into prospective clinical trials is an active area of investigation, but the factors that determine clinical trial enrollment following a molecular prescreening program have not been assessed. PATIENTS AND METHODS: Patients with 5-fluorouracil-refractory metastatic colorectal cancer at the MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion phase I or II clinical trials with a therapy targeted to an aberration detected in the patient, based on testing by immunohistochemistry, targeted gene sequencing panels, and CpG island methylation phenotype assays. RESULTS: Between August 2010 and December 2013, 484 patients were enrolled, 458 (95%) had a biomarker result, and 157 (32%) were enrolled on a clinical trial (92 on biomarker-selected and 65 on nonbiomarker selected). Of the 458 patients with a biomarker result, enrollment on biomarker-selected clinical trials was ninefold higher for predefined ATTACC-companion clinical trials as opposed to nonpredefined biomarker-selected clinical trials, 17.9% versus 2%, P < 0.001. Factors that correlated positively with trial enrollment in multivariate analysis were higher performance status, older age, lack of standard of care therapy, established patient at MD Anderson, and the presence of an eligible biomarker for an ATTACC-companion study. Early molecular screening did result in a higher rate of patients with remaining standard of care therapy enrolling on ATTACC-companion clinical trials, 45.1%, in contrast to nonpredefined clinical trials, 22.7%; odds ratio 3.1, P = 0.002. CONCLUSIONS: Though early molecular prescreening for predefined clinical trials resulted in an increase rate of trial enrollment of nonrefractory patients, the majority of patients enrolled on clinical trials were refractory to standard of care therapy. Within molecular prescreening programs, tailoring screening for preidentified and open clinical trials, temporally linking screening to treatment and optimizing both patient and physician engagement are efforts likely to improve enrollment on biomarker-selected clinical trials. CLINICAL TRIALS NUMBER: The study NCT number is NCT01196130.

Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol.

BACKGROUND: Next-generation sequencing in cancer research may reveal germline variants of clinical significance. We report patient preferences for return of results and the prevalence of incidental pathogenic germline variants (PGVs). PATIENTS AND METHODS: Targeted exome sequencing of 202 genes was carried out in 1000 advanced cancers using tumor and normal DNA in a research laboratory. Pathogenic variants in 18 genes, recommended for return by The American College of Medical Genetics and Genomics, as well as PALB2, were considered actionable. Patient preferences of return of incidental germline results were collected. Return of results was initiated with genetic counseling and repeat CLIA testing. RESULTS: Of the 1000 patients who underwent sequencing, 43 had likely PGVs: APC (1), BRCA1 (11), BRCA2 (10), TP53 (10), MSH2 (1), MSH6 (4), PALB2 (2), PTEN (2), TSC2 (1), and RB1 (1). Twenty (47%) of 43 variants were previously known based on clinical genetic testing. Of the 1167 patients who consented for a germline testing protocol, 1157 (99%) desired to be informed of incidental results. Twenty-three previously unrecognized mutations identified in the research environment were confirmed with an orthogonal CLIA platform. All patients approached decided to proceed with formal genetic counseling; in all cases where formal genetic testing was carried out, the germline variant of concern validated with clinical genetic testing. CONCLUSIONS: In this series, 2.3% patients had previously unrecognized pathogenic germline mutations in 19 cancer-related genes. Thus, genomic sequencing must be accompanied by a plan for return of germline results, in partnership with genetic counseling.

Open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with triple receptor-negative breast cancer†.

BACKGROUND: Everolimus synergistically enhances taxane-induced cytotoxicity in breast cancer cells in vitro and in vivo in addition to demonstrating a direct antiproliferative activity. We aim to determine pharmacodynamics changes and response of adding everolimus to standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Phase II study in patients with primary TNBC randomized to T-FEC (paclitaxel 80 mg/m(2) i.v. weekly for 12 weeks, followed by 5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2) every 3 weeks for four cycles) versus TR-FEC (paclitaxel 80 mg/m(2) i.v. and everolimus 30 mg PO weekly for 12 weeks, followed by FEC). Tumor samples were collected to assess molecular changes in the PI3K/AKT/mTOR pathway, at baseline, 48 h, 12 weeks, and at surgery by reverse phase protein arrays (RPPA). Clinical end points included 12-week clinical response rate (12-week RR), pathological complete response (pCR), and toxicity. RESULTS: Sixty-two patients were registered, and 50 were randomized, 27 received T-FEC, and 23 received TR-FEC. Median age was 48 (range 31-75). There was downregulation of the mTOR pathway at 48 h in the TR-FEC arm. Twelve-week RR by ultrasound were 29.6% versus 47.8%, (P = 0.075), and pCR were 25.9% versus 30.4% (P = 0.76) for T-FEC and TR-FEC, respectively. mTOR downregulation at 48 h did not correlate with 12-week RR in the TR-FEC group (P = 0.58). Main NCI grade 3/4 toxicities included anemia, neutropenia, rash/desquamation, and vomiting in both arms. There was one case of grade 3 pneumonitis in the TR-FEC arm. No grade 3/4 stomatitis occurred. CONCLUSION: The addition of everolimus to paclitaxel was well tolerated. Everolimus downregulated mTOR signaling but downregulation of mTOR at 48 h did not correlate with 12-week RR in the TR-FEC group. CLINICAL TRIAL NUMBER: NCT00499603.

Functional proteomics characterization of residual triple-negative breast cancer after standard neoadjuvant chemotherapy.

BACKGROUND: In this study, we used functional proteomics to determine the molecular characteristics of residual triple receptor-negative breast cancer (TNBC) patients after neoadjuvant systemic chemotherapy (NCT) and their relationship with patient outcomes in order to identify potential targets for therapy. PATIENTS AND METHODS: Protein was extracted from 54 residual TNBCs, and 76 proteins related to breast cancer signaling were measured by reverse phase protein arrays (RPPAs). Univariable and multivariable Cox proportional hazard models were fitted for each protein. Survival outcomes were estimated by the Kaplan-Meier product limit method. Training and cross validation were carried out. The coefficients estimated from the multivariable Cox model were used to calculate a risk score (RS) for each sample. RESULTS: Multivariable analysis using the top 25 proteins from univariable analysis at a false discovery rate (FDR) of 0.3 showed that AKT, IGFBP2, LKB1, S6 and Stathmin were predictors of recurrence-free survival (RFS). The cross-validation model was reproducible. The RS model calculated based on the multivariable analysis was -1.1086 × AKT + 0.2501 × IGFBP2 - 0.6745 × LKB1+1.0692 × S6 + 1.4086 × stathmin with a corresponding area under the curve, AUC = 0.856. The RS was an independent predictor of RFS (HR = 3.28, 95%CI = 2.07-5.20, P < 0.001). CONCLUSIONS: We found a five-protein model that independently predicted RFS risk in patients with residual TNBC disease. The PI3 K pathway may represent potential therapeutic targets in this resistant disease.

Functional proteomics characterization of residual breast cancer after neoadjuvant systemic chemotherapy.

BACKGROUND: The purpose of this study was to determine the functional proteomic characteristics of residual breast cancer and hormone receptor (HR)-positive breast cancer after neoadjuvant systemic chemotherapy, and their relationship with patient outcomes. METHODS: Reverse phase protein arrays of 76 proteins were carried out. A boosting approach in conjunction with a Cox proportional hazard model defined relapse predictors. A risk score (RS) was calculated with the sum of the coefficients from the final model. Survival outcomes and associations of the RS with relapse were estimated. An independent test set was used to validate the results. RESULTS: Test (n = 99) and validation sets (n = 79) were comparable. CoxBoost revealed a three-biomarker (CHK1pS345, Caveolin1, and RAB25) and a two-biomarker (CD31 and Cyclin E1) model that correlated with recurrence-free survival (RFS) in all residual breast cancers and in HR-positive disease, respectively. Unsupervised clustering split patients into high- and low risk of relapse groups with different 3-year RFS (P ≤ 0.001 both). RS was a substantial predictor of RFS (P = 0.0008 and 0.0083) after adjustment for other substantial characteristics. Similar results were found in validation sets. CONCLUSIONS: We found models that independently predicted RFS in all residual breast cancer and in residual HR-positive disease that may represent potential targets of therapy in this resistant disease.

Improved search for ν¯(µ)→ν¯(e) oscillations in the MiniBooNE experiment.

The MiniBooNE experiment at Fermilab reports results from an analysis of ν[over ¯](e) appearance data from 11.27×10(20) protons on target in the antineutrino mode, an increase of approximately a factor of 2 over the previously reported results. An event excess of 78.4±28.5 events (2.8σ) is observed in the energy range 200

PIK3CA is implicated as an oncogene in ovarian cancer.

Ovarian cancer is the leading cause of death from gynecological malignancy and the fourth leading cause of cancer death among American women, yet little is known about its molecular aetiology. Studies using comparative genomic hybridization (CGH) have revealed several regions of recurrent, abnormal, DNA sequence copy number that may encode genes involved in the genesis or progression of the disease. One region at 3q26 found to be increased in copy number in approximately 40% of ovarian and others cancers contains PIK3CA, which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3-kinase). The association between PIK3CA copy number and PI3-kinase activity makes PIK3CA a candidate oncogene because a broad range of cancer-related functions have been associated with PI3-kinase mediated signalling. These include proliferation, glucose transport and catabolism, cell adhesion, apoptosis, RAS signalling and oncogenic transformation. In addition, downstream effectors of PI3-kinase, AKT1 and AKT2, have been found to be amplified or activated in human tumours, including ovarian cancer. We show here that PIK3CA is frequently increased in copy number in ovarian cancers, that the increased copy number is associated with increased PIK3CA transcription, p110alpha protein expression and PI3-kinase activity and that treatment with the PI3-kinase inhibitor LY294002 decreases proliferation and increases apoptosis. Our observations suggest PIK3CA is an oncogene that has an important role in ovarian cancer.

A network-based, integrative study to identify core biological pathways that drive breast cancer clinical subtypes.

BACKGROUND: The rapid collection of diverse genome-scale data raises the urgent need to integrate and utilise these resources for biological discovery or biomedical applications. For example, diverse transcriptomic and gene copy number variation data are currently collected for various cancers, but relatively few current methods are capable to utilise the emerging information. METHODS: We developed and tested a data-integration method to identify gene networks that drive the biology of breast cancer clinical subtypes. The method simultaneously overlays gene expression and gene copy number data on protein-protein interaction, transcriptional-regulatory and signalling networks by identifying coincident genomic and transcriptional disturbances in local network neighborhoods. RESULTS: We identified distinct driver-networks for each of the three common clinical breast cancer subtypes: oestrogen receptor (ER)+, human epidermal growth factor receptor 2 (HER2)+, and triple receptor-negative breast cancers (TNBC) from patient and cell line data sets. Driver-networks inferred from independent datasets were significantly reproducible. We also confirmed the functional relevance of a subset of randomly selected driver-network members for TNBC in gene knockdown experiments in vitro. We found that TNBC driver-network members genes have increased functional specificity to TNBC cell lines and higher functional sensitivity compared with genes selected by differential expression alone. CONCLUSION: Clinical subtype-specific driver-networks identified through data integration are reproducible and functionally important.

Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.

BACKGROUND: Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH). METHODS: Ovarian tumours from two independent data sets were characterised for defects in BRCA1, BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines. RESULTS: Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10(-11)). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10(-5) and 10(-29)), and identified breast and pancreatic cell lines with BRCA defects. CONCLUSION: The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers.

Identification of the tyrosine phosphatase PTP1C as a B cell antigen receptor-associated protein involved in the regulation of B cell signaling.

Recent data implicating loss of PTP1C tyrosine phosphatase activity in the genesis of the multiple hemopoietic cell defects found in systemic autoimmune/immunodeficient motheaten (me) and viable motheaten (mev) mice suggest that PTP1C plays an important role in modulating intracellular signaling events regulating cell activation and differentiation. To begin elucidating the role for this cytosolic phosphatase in lymphoid cell signal transduction, we have examined early signaling events and mitogenic responses induced by B cell antigen receptor (BCR) ligation in me and mev splenic B cells and in CD5+ CH12 lymphoma cells, which represent the lymphoid population amplified in motheaten mice. Despite their lack of functional PTP1C, me and mev B cells proliferated normally in response to LPS. However, compared with wild-type B cells, cells from the mutant mice were hyperresponsive to normally submitogenic concentrations of F(ab')2 anti-Ig antibody, and they exhibited reduced susceptibility to the inhibitory effects of Fc gamma IIRB cross-linking on BCR-induced proliferation. Additional studies of unstimulated CH12 and wild-type splenic B cells revealed the constitutive association of PTP1C with the resting BCR complex, as evidenced by coprecipitation of PTP1C protein and phosphatase activity with BCR components and the depletion of BCR-associated tyrosine phosphatase activity by anti-PTP1C antibodies. These results suggest a role for PTP1C in regulating the tyrosine phosphorylation state of the resting BCR complex components, a hypothesis supported by the observation that PTP1C specifically induces dephosphorylation of a 35-kD BCR-associated protein likely representing Ig-alpha. In contrast, whereas membrane Ig cross-linking was associated with an increase in the tyrosine phosphorylation of PTP1C and an approximately 140-kD coprecipitated protein, PTP1C was no longer detected in the BCR complex after receptor engagement, suggesting that PTP1C dissociates from the activated receptor complex. Together these results suggest a critical role for PTP1C in modulating BCR signaling capacity, and they indicate that the PTP1C influence on B cell signaling is likely to be realized in both resting and activated cells.

Requirement of Lyn and Syk tyrosine kinases for the prevention of apoptosis by cytokines in human eosinophils.

In allergic diseases, the cytokines interleukin (IL)5 and granulocyte/macrophage colony-stimulating factor (GM-CSF) are upregulated and have been proposed to cause blood and tissue eosinophilia by inhibition of eosinophil apoptosis. We demonstrate herein, in freshly isolated human eosinophils, that the IL-3/IL-5/GM-CSF receptor beta subunit interacts with cytoplasmic tyrosine kinases to induce phosphorylation of several cellular substrates, including the beta subunit itself. The Lyn and Syk intracellular tyrosine kinases constitutively associate at a low level with the IL-3/IL-5/GM-CSF receptor beta subunit in human eosinophils. Stimulation with GM-CSF or IL-5 results in a rapid and transient increase in the amount of Lyn and Syk associated with the IL-3/IL-5/GM-CSF receptor beta subunit. Lyn is required for optimal tyrosine phosphorylation and activation of Syk. In contrast, Syk is not required for optimal tyrosine phosphorylation and activation of Lyn. These data suggest that Lyn is proximal to Syk in a tyrosine kinase cascade that transduces IL-3, IL-5, or GM-CSF signals. Compatible with this model, both Lyn and Syk are essential for the activation of the antiapoptotic pathway(s) induced through the IL-3/IL-5/GM-CSF receptor beta subunit in human eosinophils.