Human lung adenocarcinoma, the most prevalent form of lung cancer, is characterized by many molecular abnormalities. K-ras mutations are associated with the initiation of lung adenocarcinomas, but ...K-ras-independent mechanisms may also initiate lung tumors. Here, we find that the runt-related transcription factor Runx3 is essential for normal murine lung development and is a tumor suppressor that prevents lung adenocarcinoma. Runx3-/- mice, which die soon after birth, exhibit alveolar hyperplasia. Importantly, Runx3-/- bronchioli exhibit impaired differentiation, as evidenced by the accumulation of epithelial cells containing specific markers for both alveolar (that is SP-B) and bronchiolar (that is CC10) lineages. Runx3-/- epithelial cells also express Bmi1, which supports self-renewal of stem cells. Lung adenomas spontaneously develop in aging Runx3+/- mice ( approximately 18 months after birth) and invariably exhibit reduced levels of Runx3. As K-ras mutations are very rare in these adenomas, Runx3+/- mice provide an animal model for lung tumorigenesis that recapitulates the preneoplastic stage of human lung adenocarcinoma development, which is independent of K-Ras mutation. We conclude that Runx3 is essential for lung epithelial cell differentiation, and that downregulation of Runx3 is causally linked to the preneoplastic stage of lung adenocarcinoma.
Uncovering the mechanisms that govern the maintenance of stem-like cancer cells is critical for developing therapeutic strategies for targeting these cells. Constitutive activation of c-Jun ...N-terminal kinase (JNK) has been reported in gliomas and correlates with histological grade. Here, we found that JNK signaling is crucial for the maintenance of 'stemness' in glioma cells. Sphere-cultured glioma cells showed more phosphorylation of JNK compared with serum-containing monolayer cultures. Importantly, blockade of JNK signaling with SP600125 or small interfering RNAs targeting JNK1 or JNK2 significantly reduced the CD133(+)/Nestin(+) population and suppressed sphere formation, colony formation in soft agar, and expression of stem cell markers in sphere-cultured glioma cells. Intriguingly, sphere-cultured glioma cells exhibited enhanced expression of Notch-2, but not Notch-1, -3 or -4, and JNK inhibition almost completely abrogated this increase. Blocking the phosphoinoside 3-kinase (PI3K)/Akt pathway with LY294002 or si-Akt also suppressed the self-renewal of sphere-cultured glioma cells. PI3K, but not Akt, had a role as an upstream kinase in JNK1/2 activation. In addition, treatment with si-JNK greatly increased etoposide- and ionizing radiation (IR)-induced cell death in glioma spheres. Consistent with glioma cell lines, glioma stem-like cells isolated from primary patient glioma cells also had a higher activity of JNK and Notch-2 expression. Importantly, inhibition of JNK2 led to a decrease of Notch-2 expression and suppressed the CD133(+)/Nestin(+) cell population in patient-derived primary glioma cells. Finally, downregulation of JNK2 almost completely suppressed intracranial tumor formation by glioma cells in nude mice. Taken together, these data demonstrate that JNK signaling is crucial for the maintenance of self-renewal and tumorigenicity of glioma stem-like cells and drug/IR resistance, and can be considered a promising target for eliminating stem-like cancer cells in gliomas.
Sensory information is essential for the precise control of movement. Patients with Parkinson's disease (PD) have higher-order sensory dysfunctions including prolonged temporal discrimination ...threshold (TDT). However, the impact of prolonged TDT on parkinsonian motor deficits is uncertain.
This study includes 33 PD patients and 24 healthy controls. TDT values were measured in the index finger. Using coin rotation task (CRT), dexterous finger movement was assessed. Using an inertial sensor, the speed, amplitude, and frequency of finger tapping were measured. The impact of prolonged index finger TDT on two different finger movements was analyzed using the general estimating equation.
Compared to healthy controls, TDT was prolonged in the PD patients. There was no impact of TDT on mean values or decrement for amplitude and speed, as well as mean values, decrement and variability of tapping frequency. However, prolonged TDT had a significant impact on the variability in amplitude (B = 436.905 × 10-4, Wald χ2 = 9.140, p = 0.014) and speed (B = 425.655 × 10-4, Wald χ2 = 9.876, p = 0.014) of finger tapping. There was a marginal correlation between TDT and CRT. In addition, CRT correlated with variability in amplitude and speed of finger tapping.
In PD, cutaneous temporal discriminative sensory dysfunction appears to be related to increased variabilities in the speed and amplitude of fast repetitive finger movements and disturbed finger dexterity.
On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G_{target} of 1.5. This is the first laboratory demonstration of exceeding ..."scientific breakeven" (or G_{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result.
Background
This study aimed to investigate whether radiofrequency ablation (RFA) is an alternative to surgical resection for hepatocellular carcinoma (HCC) within the context of current guidelines.
...Methods
This retrospective study included patients with normal portal pressure and serum bilirubin level who initially underwent liver resection or RFA for a single HCC of maximum size 3 cm. Between‐group differences in cumulative rates of survival and recurrence specific for HCC were analysed in the entire cohort and in a propensity score‐matched cohort.
Results
A total of 604 patients were enrolled, 273 in the liver resection group and 331 in the RFA group. The 5‐ and 10‐year HCC‐specific survival rates for the resection and RFA groups were 87·6 versus 82·1 per cent and 59·0 versus 61·2 per cent respectively (P = 0·214), whereas overall 5‐ and 10‐year recurrence‐free survival rates for the corresponding groups were 60·6 versus 39·4 per cent and 37·5 versus 25·1 per cent respectively (P < 0·001). In the propensity score‐matched cohort (152 pairs), there were no differences in HCC‐specific survival (hazard ratio (HR) 1·03 for RFA versus resection; P = 0·899), whereas recurrence‐free survival again differed between the treatment groups (HR 1·75; P < 0·001). RFA was independently associated with poorer outcomes in terms of treatment‐site recurrence‐free survival (adjusted HR 1·66; P = 0·026), but not non‐treatment‐site recurrence‐free survival (adjusted HR 1·15; P = 0·354).
Conclusion
Although RFA carries a higher risk of treatment‐site recurrence than hepatic resection, it provides comparable overall survival in patients with a single small HCC without portal hypertension or a raised bilirubin level.
Good alternative in small hepatocellular carcinoma
Static strain in complex oxide heterostructures has been extensively used to engineer electronic and magnetic properties at equilibrium. In the same spirit, deformations of the crystal lattice with ...light may be used to achieve functional control across heterointerfaces dynamically. Here, by exciting large-amplitude infrared-active vibrations in a LaAlO3 substrate we induce magnetic order melting in a NdNiO3 film across a heterointerface. Femtosecond resonant soft X-ray diffraction is used to determine the spatiotemporal evolution of the magnetic disordering. We observe a magnetic melt front that propagates from the substrate interface into the film, at a speed that suggests electronically driven motion. Light control and ultrafast phase front propagation at heterointerfaces may lead to new opportunities in optomagnetism, for example by driving domain wall motion to transport information across suitably designed devices.
We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC).
The ...PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected toin vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling.
The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations ofFGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib.
FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.
Abstract
Superconductivity in the cuprates is found to be intertwined with charge and spin density waves. Determining the interactions between the different types of order is crucial for ...understanding these important materials. Here, we elucidate the role of the charge density wave (CDW) in the prototypical cuprate La
1.885
Sr
0.115
CuO
4
, by studying the effects of large magnetic fields (
H
) up to 24 Tesla. At low temperatures (
T
), the observed CDW peaks reveal two distinct regions in the material: a majority phase with short-range CDW coexisting with superconductivity, and a minority phase with longer-range CDW coexisting with static spin density wave (SDW). With increasing magnetic field, the CDW first grows smoothly in a manner similar to the SDW. However, at high fields we discover a sudden increase in the CDW amplitude upon entering the vortex-liquid state. Our results signify strong coupling of the CDW to mobile superconducting vortices and link enhanced CDW amplitude with local superconducting pairing across the
H
−
T
phase diagram.
We report charge transfer and built-in electric fields across the epitaxial SrNb_{x}Ti_{1-x}O_{3-δ}/Si(001) interface. Electrical transport measurements indicate the formation of a hole gas in the Si ...and the presence of built-in fields. Hard x-ray photoelectron measurements reveal pronounced asymmetries in core-level spectra that arise from these built-in fields. Theoretical analysis of core-level spectra enables built-in fields and the resulting band bending to be spatially mapped across the heterojunction. The demonstration of tunable charge transfer, built-in fields, and the spatial mapping of the latter, lays the groundwork for the development of electrically coupled, functional heterojunctions.
PDF
