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Patients with ALK gene rearrangements often manifest dramatic responses to crizotinib, an ALK inhibitor. Accurate identification of patients with ALK-positive non-small cell lung cancer (NSCLC) is essential for the clinical application of ALK-targeted therapy. However, assessing EML4-ALK rearrangement in NSCLC remains challenging in routine pathology practice. The aim of this study was to compare the diagnostic accuracy of FISH, immunohistochemistry (IHC), and real-time quantitative RT-PCR (QPCR) methodologies for detection of EML4-ALK rearrangement in NSCLC and to appraise immunohistochemistry as a pre-screening tool. In this study, a total of 473 paraffin-embedded NSCLC samples from surgical resections and biopsies were analyzed by IHC with ALK antibody. ALK rearrangement was further confirmed by FISH and QPCR. ALK protein expression was detected in twenty patients (20/473, 4.2%). Of the 20 ALK-positive cases by IHC, 15 cases were further confirmed as ALK rearrangement by FISH, and 5 cases were not interpretable. Also, we evaluated 13 out of the 20 IHC-positive tissues by QPCR in additional to FISH, and found that 9 cases were positive and 2 cases were equivocal, whereas 2 cases were negative although they were positive by both IHC and FISH. The ALK status was concordant in 5 out of 8 cases that were interpretable by three methods. Additionally, none of the 110 IHC-negative cases with adenocarcinoma histology showed ALK rearrangements by FISH. Histologically, almost all the ALK-rearranged cases were adenocarcinoma, except that one case was sarcomatoid carcinoma. A solid signet-ring cell pattern or mucinous cribriform pattern was presented at least focally in all ALK-positive tumors. In conclusion, our findings suggested that ALK rearrangement was associated with ALK protein expression. The conventional IHC assay is a valuable tool for the pre-screening of patients with ALK rearrangement in clinical practice and a combination of FISH and QPCR is required for further confirmation.

The title compound, C20H17N3O2S2, was synthesized by the reaction of 2-(1,5-diphenyl-1H-pyrazol-3-yloxy)acetic acid and thiazolidine-2-thione. The C-linked benzene ring, N-linked benzene ring and thiazolidine-2-thione ring are twisted 31.33 (2), 62.87 (1) and 82.71 (2)°, respectively, from the plane of the bridging 1H-pyrazole ring. The phenyl rings are oriented at a dihedral angle of 72.16 (2)°.

In the title compound, C13H9ClN2O4, the dihedral angle between the benzene rings is 79.5 (1)°. The mean plane of the carbamate group makes angles of 7.4 (2) and 73.6 (2)° with the mean planes of the two benzene rings. In the crystal, weak C—H...O interactions are observed between the molecules, connecting them into a two-dimensional network.

In the crystal structure of the title compound, C8H6Br2FNO, C—H...O and N—H...O hydrogen bonding results in six-membered rings and links the molecules into chains running parallel to the c axis. The dihedral angle between the fluorophenyl ring and the acetamide group is 29.5 (5)°.

In the title compound, C18H17ClO4, the dihedral angle between the mean planes of the benzene rings is 53.4 (1)°. Weak intermolecular C—H...O interactions are observed.

In the title compound, C12H9F3N2O2, the benzene ring is nearly perpendicular to the isoxazole ring, making a dihedral angle of 82.97 (2)°. In the crystal, molecules are linked by N—H...O hydrogen bonds into a supramolecular chain running along the c axis.

In the title compound, C16H24N2, the aliphatic amine substituent is rotated almost orthogonally [C—C—C—C torsion angle = 75.7 (3)°] out of the plane of the indole unit. The amine N atom has a pyramidal configuration deviating by 0.380 (3) Å from the plane of the adjacent C atoms. All of the aliphatic groups are in extended transoid conformations. In the crystal, molecules form chains along the a axis via N—H...N hydrogen bonds.

In the title compound, C24H30N6O5, the cyclohexyl ring adopts a chair conformation, while the remainder of the molecule adopts a U-shape. The dihedral angles between the pyridine ring and the pendant pyrimidine rings are 69.04 (12) and 75.99 (9)°. The two pyrimidine rings, however, are nearly parallel to one another, with a dihedral angle of 8.56 (15)° between them. They are also involved in an intramolecular π–π stacking interaction with a distance of 3.6627 (18) Å between the ring centroids. In the crystal, C—H...O contacts link the molecules into chains along the b axis.

There are two independent molecules in the asymmetric unit of the title compound, C15H10ClNO2, which differ in the dihedral angles between the mean planes of the phenyl ring and the 4-chloroindoline-2,3-dione ring system [59.48 (9) and 79.0 (1)°]. In the crystal, molecules are linked through C—H...O hydrogen bonds, forming polymeric chains in [100].

Leukemia initiating cells (LIC) contribute to therapeutic resistance through acquisition of mutations in signaling pathways, such as NOTCH1, that promote self-renewal and survival within supportive niches. Activating mutations in NOTCH1 occur commonly in T cell acute lymphoblastic leukemia (T-ALL) and have been implicated in therapeutic resistance. However, the cell type and context specific consequences of NOTCH1 activation, its role in human LIC regeneration, and sensitivity to NOTCH1 inhibition in hematopoietic microenvironments had not been elucidated.We established humanized bioluminescent T-ALL LIC mouse models transplanted with pediatric T-ALL samples that were sequenced for NOTCH1 and other common T-ALL mutations. In this study, CD34(+) cells from NOTCH1(Mutated) T-ALL samples had higher leukemic engraftment and serial transplantation capacity than NOTCH1(Wild-type) CD34(+) cells in hematopoietic niches, suggesting that self-renewing LIC were enriched within the NOTCH1(Mutated) CD34(+) fraction. Humanized NOTCH1 monoclonal antibody treatment reduced LIC survival and self-renewal in NOTCH1(Mutated) T-ALL LIC-engrafted mice and resulted in depletion of CD34(+)CD2(+)CD7(+) cells that harbor serial transplantation capacity.These results reveal a functional hierarchy within the LIC population based on NOTCH1 activation, which renders LIC susceptible to targeted NOTCH1 inhibition and highlights the utility of NOTCH1 antibody targeting as a key component of malignant stem cell eradication strategies.

In the title compound, C11H8ClN3O4, the dihedral angle between benzene and isoxazole rings is 9.92 (1) °. The nitro group is almost coplanar with the benzene ring with an O—N—C—C torsion angle of 8.4 (3)°. The molecular conformation is stabilized by an intramolecular N—H...O hydrogen bond, closing a six-membered ring.

There are two molecules with similar configurations in the asymmetric unit of the title compound, C9H7N5, which are linked by intermolecular N—H...N hydrogen bonds into chains with graph-set motif C22(8) along the b axis. The indole core has the expected planar geometry in the two molecules, with a maximum deviation of 0.008 (8) Å from the least-squares plane defined by the nine constituent atoms, and the dihedral angles between the indole and tetrazole rings are similar [42.4 (2) and 42.7 (2)°].

In the title compound, C17H21ClN4O, the benzene ring is oriented at dihedral angles of 1.59 (3) and 1.27 (3)° with respect to the pyrimidine and pyrazole rings, while the dihedral angle between the pyrimidine and pyrazole rings is 0.83 (3)°. An intramolecular N—H...O hydrogen bond results in the formation of a planar (r.m.s. deviation 0.004 Å) six-membered ring.

In the molecule of the title compound, C9H8ClNO4, an intramolecular C—H...O interaction results in the formation of a near-planar (r.m.s. deviation 0.002 Å) five-membered ring, which is oriented at a dihedral angle of 4.07 (4)° with respect to the adjacent aromatic ring. In the crystal structure, intermolecular C—H...O interactions link the molecules into a two-dimensional network.

The asymmetric unit of the title compound, C14H13NO3, contains two crystallographically independent molecules, in which the aromatic rings are oriented at dihedral angles of 75.64 (3) and 83.14 (3)°. An N—H...O hydrogen bond links the two molecules. Weak intramolecular C—H...O interactions are observed in the two molecules. In the crystal structure, intermolecular N—H...O and C—H...O interactions link the molecules into a two-dimensional network.

In the molecule of the title compound, C9H9N3O2, the indazole ring system is almost planar [maximum deviation = 0.019 (3) Å for the C atom bearing the nitro group]. In the crystal structure, intermolecular C—H...O interactions link the molecules into centrosymmetric dimers, forming R22(18) ring motifs. Aromatic π–π contacts between indazole rings [centroid–centroid distances = 3.632 (1) and 3.705 (1) Å] may further stabilize the structure.

In the crystal structure of the title compound, C7H10N2O2S, a benzoic acid derivative, intermolecular N—H...O interactions link the molecules into a three-dimensional network.

The asymmetric unit of the title compound, C14H13NO2, contains two crystallographically independent molecules, in which the aromatic rings are oriented at dihedral angles of 59.01 (3) and 56.98 (3)°. In the crystal structure, intermolecular N—H...O hydrogen bonds link the molecules into chains.

In the molecule of the title compound, C9H8BrNO4, the acetate group is close to planar [maximum deviation = 0.042 (3) Å] and is oriented at a dihedral angle of 73.24 (3)° with respect to the aromatic ring. In the crystal structure, intermolecular C—H...O interactions link the molecules into a three-dimensional network, forming R22(10) ring motifs.

The molecule of the title compound, C4H2Cl2N2, is almost planar [maximum deviation = 0.013 (3) Å for a Cl atom]. In the crystal structure, intermolecular C—H...N interactions link the molecules into chains.

In the molecule of the title compound, C9H8ClNO4, the nearly planar acetate moiety [maximum deviation = 0.015 (3) Å for an O atom] is oriented with respect to the plane of the aromatic ring at a dihedral angle of 73.03 (3)°. In the crystal structure, intermolecular C—H...O interactions link molecules into a network. π–π contacts between benzene rings [centroid–centroid distance = 4.000 (1) Å] may further stabilize the structure.

The molecule of the title compound, C8H10N2O2, is nearly planar [maximum deviation of 0.163 (3) Å for one of the O atoms of the NO2 group]. In the crystal structure, weak intermolecular N—H...N and C—H...O hydrogen bonds link the molecules into chains, forming R22(10) ring motifs.

In the molecule of the title complex, [Ni(C30H29N3O5)], the Ni atom is coordinated in a distorted square-planar geometry by three N and one O atoms. The aromatic rings are oriented at dihedral angles of 29.01 (3), 79.73 (3) and 83.37 (3)°. The remaining rings adopt envelope conformations with the C and N atoms at the flap positions. In the crystal structure, intermolecular O—H...O hydrogen bonds link the molecules into chains along the b axis. There is also a weak C—H...π interaction.

In the molecule of the title compound, C6H8N2, the methyl C and amine N atoms are 0.021 (2) and 0.058 (2) Å from the pyridine ring plane. In the crystal structure, intermolecular N—H...N hydrogen bonds link the molecules.

A novel approach is proposed for the efficient estimation of the two-dimensional (2-D) direction-of-arrival (DOA) of signals impinging on two orthogonal uniform linear arrays (ULAs). By partitioning the cross-correlation matrix (CCM) between two ULAs data into a great deal of submatrices and making use of the submatrices and the symmetric subarrays, an extended correlation matrix is constructed, and then uses the modified ESPRIT approach to extract out the so-called Kronecker Steering Vectors (KSVs) of which each is the Kronecker product of the elevation and azimuth angle with a one-to-one relationship. Upon that the proposed method yields the estimate of the 2-D DOA efficiently without requiring the additionally computational burden to remove the pair-matching problem. Furthermore, the main idea of the matrix partition and stacking is to much-enhanced subspace estimate. So based on the use of the concept, the proposed method's performance is better than the existing similar approaches. Meanwhile, unlike the traditional subspace methods, it is shown that the proposed can resolve the same uncorrelated sources as the number of subarray sensor through a delicate partition-and-stacking process. Simulation results demonstrate that the proposed method is superior to the existing techniques in both DOA estimation and the detection capability of sources.

In the title compound C21H21P, the P atom is situated on a crystallographic threefold rotatory-inversion axis, resulting in threefold rotation symmetry of the title compound. The dihedral angles between the symmetry-related benzene rings are 87.40 (18)°.