A search for mixing between active neutrinos and light sterile neutrinos has been performed by looking for muon neutrino disappearance in two detectors at baselines of 1.04 and 735 km, using a ...combined MINOS and MINOS+ exposure of 16.36×10^{20} protons on target. A simultaneous fit to the charged-current muon neutrino and neutral-current neutrino energy spectra in the two detectors yields no evidence for sterile neutrino mixing using a 3+1 model. The most stringent limit to date is set on the mixing parameter sin^{2}θ_{24} for most values of the sterile neutrino mass splitting Δm_{41}^{2}>10^{-4} eV^{2}.
Targeting HER2 with antibodies or small molecule inhibitors in HER2-positive breast cancer leads to improved survival, but resistance is a common clinical problem. To uncover novel mechanisms of ...resistance to anti-HER2 therapy in breast cancer, we performed a kinase open reading frame screen to identify genes that rescue HER2-amplified breast cancer cells from HER2 inhibition or suppression. In addition to multiple members of the MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) signaling pathways, we discovered that expression of the survival kinases PRKACA and PIM1 rescued cells from anti-HER2 therapy. Furthermore, we observed elevated PRKACA expression in trastuzumab-resistant breast cancer samples, indicating that this pathway is activated in breast cancers that are clinically resistant to trastuzumab-containing therapy. We found that neither PRKACA nor PIM1 restored MAPK or PI3K activation after lapatinib or trastuzumab treatment, but rather inactivated the pro-apoptotic protein BAD, the BCl-2-associated death promoter, thereby permitting survival signaling through BCL-XL. Pharmacological blockade of BCL-XL/BCL-2 partially abrogated the rescue effects conferred by PRKACA and PIM1, and sensitized cells to lapatinib treatment. These observations suggest that combined targeting of HER2 and the BCL-XL/BCL-2 anti-apoptotic pathway may increase responses to anti-HER2 therapy in breast cancer and decrease the emergence of resistant disease.
We report results of a search for oscillations involving a light sterile neutrino over distances of 1.04 and 735 km in a ν_{μ}-dominated beam with a peak energy of 3 GeV. The data, from an exposure ...of 10.56×10^{20} protons on target, are analyzed using a phenomenological model with one sterile neutrino. We constrain the mixing parameters θ_{24} and Δm_{41}^{2} and set limits on parameters of the four-dimensional Pontecorvo-Maki-Nakagawa-Sakata matrix, |U_{μ4}|^{2} and |U_{τ4}|^{2}, under the assumption that mixing between ν_{e} and ν_{s} is negligible (|U_{e4}|^{2}=0). No evidence for ν_{μ}→ν_{s} transitions is found and we set a world-leading limit on θ_{24} for values of Δm_{41}^{2}≲1 eV^{2}.
We report measurements of oscillation parameters from ν(μ) and ν(μ) disappearance using beam and atmospheric data from MINOS. The data comprise exposures of 10.71×10(20) protons on target in the ...ν(μ)-dominated beam, 3.36×10(20) protons on target in the ν(μ)-enhanced beam, and 37.88 kton yr of atmospheric neutrinos. Assuming identical ν and ν oscillation parameters, we measure |Δm2| = (2.41(-0.10)(+0.09))×10(-3) eV2 and sin2(2θ) = 0.950(-0.036)(+0.035). Allowing independent ν and ν oscillations, we measure antineutrino parameters of |Δm2| = (2.50(-0.25)(+0.23))×10(-3) eV2 and sin2(2θ) = 0.97(-0.08)(+0.03), with minimal change to the neutrino parameters.
We report the final measurement of the neutrino oscillation parameters Δm322 and sin2 θ23 using all data from the MINOS and MINOS+ experiments. These data were collected using a total exposure of ...23.76 × 1020 protons on target producing νμ and νμ beams and 60.75 kt yr exposure to atmospheric neutrinos. The measurement of the disappearance of νμ and the appearance of νe events between the Near and Far detectors yields ... and ... at 68% C.L. for normal (inverted) hierarchy. (ProQuest: ... denotes formulae omited.).
The long baseline between Earth and the Sun makes solar neutrinos an excellent test beam for exploring possible neutrino decay. The signature of such decay would be an energy-dependent distortion of ...the traditional survival probability which can be fit for using well-developed and high-precision analysis methods. Here a model including neutrino decay is fit to all three phases of B8 solar neutrino data taken by the Sudbury Neutrino Observatory (SNO). This fit constrains the lifetime of neutrino mass state ν2 to be >8.08×10−5 s/eV at 90% confidence. An analysis combining this SNO result with those from other solar neutrino experiments results in a combined limit for the lifetime of mass state ν2 of >1.92×10−3 s/eV at 90% confidence.
Activating mutations in the RAS family or BRAF frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the RAS-RAF-MEK-ERK MAPK pathway is ...commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. To identify breast cancer oncogenes that activate the MAPK pathway, we screened a library of human kinases for their ability to induce anchorage-independent growth in a derivative of immortalized human mammary epithelial cells (HMLE). We identified p21-activated kinase 1 (PAK1) as a kinase that permitted HMLE cells to form anchorage-independent colonies. PAK1 is amplified in several human cancer types, including 30--33% of breast tumor samples and cancer cell lines. The kinase activity of PAK1 is necessary for PAK1-induced transformation. Moreover, we show that PAK1 simultaneously activates MAPK and MET signaling; the latter via inhibition of merlin. Disruption of these activities inhibits PAK1-driven anchorage-independent growth. These observations establish PAK1 amplification as an alternative mechanism for MAPK activation in human breast cancer and credential PAK1 as a breast cancer oncogene that coordinately regulates multiple signaling pathways, the cooperation of which leads to malignant transformation.
Searches for a light sterile neutrino have been performed independently by the MINOS and the Daya Bay experiments using the muon (anti)neutrino and electron antineutrino disappearance channels, ...respectively. In this Letter, results from both experiments are combined with those from the Bugey-3 reactor neutrino experiment to constrain oscillations into light sterile neutrinos. The three experiments are sensitive to complementary regions of parameter space, enabling the combined analysis to probe regions allowed by the Liquid Scintillator Neutrino Detector (LSND) and MiniBooNE experiments in a minimally extended four-neutrino flavor framework. Stringent limits on sin^{2}2θ_{μe} are set over 6 orders of magnitude in the sterile mass-squared splitting Δm_{41}^{2}. The sterile-neutrino mixing phase space allowed by the LSND and MiniBooNE experiments is excluded for Δm_{41}^{2}<0.8 eV^{2} at 95% CL_{s}.
The practice of medicine has many expected and accepted challenges, but all physicians experience some patients as difficult to a degree that transcends these expectations. Physician-experienced ...difficulty is associated with a syndrome of three characteristics: patient psychopathology, abrasive interpersonal styles, and multiple physical symptoms.
To assess the roles played by the number of physical symptoms and by specific symptoms in determining whether physician-experienced difficulty occurs.
New analyses of epidemiologic survey data from the Primary Care Evaluation of Mental Disorders (PRIME-MD) 1000 Study.
Four primary care clinics.
627 ambulatory patients seen by 27 physicians.
Physician-experienced difficulty was measured by using the 10-item Difficult Doctor Patient Relationship Questionnaire (DDPRQ-10); patient-reported physical symptoms and physician-assessed psychopathology and somatoform symptoms were evaluated by using the PRIME-MD; and physical illnesses were measured by using a physician questionnaire.
The number of physical symptoms and the number of somatoform symptoms correlated with difficulty (r = 0.39 and r = 0.37, respectively; P < 0.001), and the correlations remained significant after adjustment for physical and mental disorders (r = 0.20 for both correlations; P < 0.001). Difficult patients were more likely to have each of 16 physical symptoms; the odds of being difficult were greater for patients with 1 of 5 particular symptoms (stomach pain, fainting, loose stools/diarrhea, palpitations, and sleep problems), even after adjustment for physical and mental disorders. All 10 items on the DDPRQ-10 were influenced by physical symptoms, particularly those items that asked about physician frustration and whether patients were manipulative and time consuming.
The association between physical symptoms and difficulty is due in part to the association between physical symptoms and mental disorders, but symptoms also contribute independently to difficulty. The independent component of symptom-associated difficulty may be due to 1) differences between patient and physician in expectations about treatment and 2) the part that symptoms play in conferring the "sick role" on a patient.
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