Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor suppressor gene

Germline mutations of the LKB1 gene are responsible for Peutz-Jeghers syndrome (PJS), an autosomal dominant inherited disorder bestowing an increased risk of cancer. We have recently demonstrated that LKB1 inactivating mutations are not confined to PJS, but also appear in lung adenocarcinomas of sporadic origin, including primary tumors and lung cancer cell lines. To accurately determine the frequency of inactivating LKB1 gene mutations in lung tumors we have sequenced the complete coding region of LKB1 in 21 additional lung cancer cell lines. Here we describe the mutational status of LKB1 gene in 30 lung cancer cell lines from different histopathological types, including 11 lung adenocarcinomas (LADs) and 11 small cell lung cancers (SCLCs). LKB1 gene alterations were present in six (54%) of the LAD cell lines tested but in none of the other histological types. Similar to our previous observations in primary tumors, all point mutations were of the nonsense or frameshift type, leading to an abnormal, truncated protein. Moreover, 2 cell lines (A427 and H2126) harbored large gene deletions that spanned several exons. Hence, we have identified additional lung cancer cell lines carrying inactivating mutations of the LKB1 tumor suppressor gene, further attesting to the significance of this gene in the development of LADs and providing new natural LKB1 knockouts for studies of the biological function of the LKB1 protein

Anisotropy at the end of the cosmic ray spectrum?

The starburst galaxies M82 and NGC253 have been proposed as the primary sources of cosmic rays with energies above $10^{18.7}$ eV. For energies \agt 10^{20.3} eV the model predicts strong anisotropies. We calculate the probabilities that the latter can be due to chance occurrence. For the highest energy cosmic ray events in this energy region, we find that the observed directionality has less than 1% probability of occurring due to random fluctuations. Moreover, during the first 5 years of operation at Auger, the observation of even half the predicted anisotropy has a probability of less than $10^{-5}$ to occur by chance fluctuation. Thus, this model can be subject to test at very small cost to the Auger priors budget and, whatever the outcome of that test, valuable information on the Galactic magnetic field will be obtained.Comment: Final version to be published in Physical Review

A model based on the quantification of complement C4c, CYFRA 21-1 and CRP exhibits high specificity for the early diagnosis of lung cancer

Lung cancer screening detects early-stage cancers, but also a large number of benign nodules. Molecular markers can help in the lung cancer screening process by refining inclusion criteria or guiding the management of indeterminate pulmonary nodules. In this study, we developed a diagnostic model based on the quantification in plasma of complement-derived fragment C4c, cytokeratin fragment 21-1 (CYFRA 21-1) and C-reactive protein (CRP). The model was first validated in two independent cohorts, and showed a good diagnostic performance across a range of lung tumor types, emphasizing its high specificity and positive predictive value. We next tested its utility in two clinically relevant contexts: assessment of lung cancer risk and nodule malignancy. The scores derived from the model were associated with a significantly higher risk of having lung cancer in asymptomatic individuals enrolled in a computed tomography (CT)-screening program (OR = 1.89; 95% CI = 1.20–2.97). Our model also served to discriminate between benign and malignant pulmonary nodules (AUC: 0.86; 95% CI = 0.80–0.92) with very good specificity (92%). Moreover, the model performed better in combination with clinical factors, and may be used to reclassify patients with intermediate-risk indeterminate pulmonary nodules into patients who require a more aggressive work-up. In conclusion, we propose a new diagnostic biomarker panel that may dictate which incidental or screening-detected pulmonary nodules require a more active work-up

NUP98 is fused to HOXA9 in a variant complex t(7;11;13;17) in a patient with AML-M2

The t(7;11)(p15;p15.4) has been reported to fuse the NUP98 gene (11p15), a component of the nuclear pore complex, with the class-1 homeobox gene HOXA9 at 7p15. This translocation has been associated with myeloid leukemias, predominantly acute myeloid leukemia (AML) M2 subtype with trilineage myelodysplastic features, and with a poor prognosis. The derived fusion protein retains the FG repeat motif of NUP98 N-terminus and the homeodomain shared by the HOX genes, acting as an oncogenic transcription factor critical for leukemogenesis. We report here a new complex t(7;11)-variant, i.e., t(7;11;13;17)(p15;p15;p?;p1?2) in a patient with AML-M2 and poor prognosis. The NUP98-HOXA9 fusion transcript was detected by RT-PCR, suggesting its role in the malignant transformation as it has been postulated for other t(7;11)-associated leukemias. No other fusion transcripts involving the NUP98 or HOXA9 genes were present, although other mechanisms involving several genes on chromosomes 13 and 17 may also be involved. To our knowledge, this is the first t(7;11) variant involving NUP98 described in hematological malignancies

Non-collinear and asymmetric polar moments at back-gated SrTiO<inf>3</inf> interfaces

The mechanism of the gate-field-induced metal-to-insulator transition of the electrons at the interface of SrTiO3 with LaAlO3 or AlOx is of great current interest. Here, we show with infrared ellipsometry and confocal Raman spectroscopy that an important role is played by a polar lattice distortion that is non-collinear, highly asymmetric and hysteretic with respect to the gate field. The anomalous behavior and the large lateral component of the underlying local electric field is explained in terms of the interplay between the oxygen vacancies, that tend to migrate and form extended clusters at the antiferrodistortive domain boundaries, and the interfacial electrons, which get trapped/detrapped at the oxygen vacancy clusters under a positive/negative gate bias. Our findings open new perspectives for the defect engineering of lateral devices with strongly enhanced and hysteretic local electric fields that can be manipulated with various parameters, like strain, temperature, or photons.F.L. and C.B. acknowledge enlightening discussions with S. Das, J. Maier, R. Merkle, A. Dubroka, and B. I. Shklovskii. Work at the University of Fribourg was supported by the Schweizerische Nationalfonds (SNF) by Grant No. 200020-172611. M.B. acknowledges support from the ERC Advanced grant n° 833973 “FRESCO” and the QUANTERA project “QUANTOX”. G.H. acknowledges financial support from Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033) through the Severo Ochoa FUNFUTURE (CEX2019-000917-S) and Grant No. PID2020-118479RB-I00, and Generalitat de Catalunya (2017 400 SGR 1377).With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).Peer reviewe

Extended tachyon field, Chaplygin gas and solvable k-essence cosmologies

We investigate a flat Friedmann-Robertson-Walker spacetime filled with k-essence and find the set of functions F which generate three different families of extended tachyon fields and Chaplygin gases. They lead to accelerated and superaccelerated expanding scenarios. For any function F, we find the first integral of the k-field equation when the k-field is driven by an inverse square potential or by a constant one. In the former, we obtain the general solution of the coupled Einstein-k-field equations for a linear function F. This model shares the same kinematics of the background geometry with the ordinary scalar field one driven by an exponential potential. However, they are dynamically different. For a constant potential, we introduce a k-field model that exhibits a transition from a power-law phase to a de Sitter stage, inducing a modified Chaplygin gas.Comment: 24 pages, revised version accepted for publication in Phys. Rev.