The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired ...resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.
We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).
In cohort A, median progression-free survival (PFS) was 2.1 and 1.3months for T790M-negative and T790M-positive patients, respectively (P=0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20–1.24). Median PFS was 2.1 and 1.3months for patients with a PD-L1 expression level of≥1% or<1%, respectively (P=0.084; hazard ratio of 0.37, 95% confidence interval of 0.10–1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of≥10% and≥50%. The proportion of tumors with a PD-L1 level of≥10% or≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden.
T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.
POU5F1B (POU domain class 5 transcription factor 1B), a processed pseudogene that is highly homologous to OCT4, was recently shown to be transcribed in cancer cells, but its clinical relevance and ...biological function have remained unclear. We now show that POU5F1B, which is located adjacent to MYC on human chromosome 8q24, is frequently amplified in gastric cancer (GC) cell lines. POU5F1B, but not OCT4, was also found to be expressed at a high level in GC cell lines and clinical specimens. In addition, the DNA copy number and mRNA abundance for POU5F1B showed a positive correlation in both cancer cell lines and GC specimens. Overexpression of POU5F1B in GC cells promoted colony formation in vitro as well as both tumorigenicity and tumor growth in vivo, and these effects were enhanced in the additional presence of MYC overexpression. Furthermore, knockdown of POU5F1B expression with a short hairpin RNA confirmed a role for the endogenous pseudogene in the promotion of cancer cell growth in vitro and tumor growth in vivo. POU5F1B overexpression induced upregulation of various growth factors in GC cells as well as exhibited mitogenic, angiogenic and antiapoptotic effects in GC xenografts. Finally, amplification of POU5F1B was detected in 17 (12%) of 145 cases of GC and was a significant predictor of poor prognosis in patients with stage IV disease. In conclusion, we found that the POU5F1B pseudogene is amplified and expressed at a high level in, as well as confers an aggressive phenotype on, GC, and that POU5F1B amplification is associated with a poor prognosis in GC patients.
Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although ...increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated.
In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore.
ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity.
Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection.
JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center).
Abstract
In recent years, there have been several ground surface collapses due to tunnel excavation in Japan. Although such accident is caused by ground loosening and tunnel face collapses due to ...excavation, there is no accepted theory for estimating the face stability because this phenomenon is quite complicated and highly influenced by the supports and lining types. Specifically, the loosened area is relatively large for the urban NATM method, which applied in a shallow sedimentary rock layer. Therefore, a method to quantitatively evaluate the tunnel face stability by this kind of mechanical property is essential. In this study, 2D tunnel pull-out test was conducted to observe the influence of frictional resistance on tunnel face failure and loosening area by changing the shear resistance angle using three particle sizes of dry silica sand and different variation of earth covering. The result demonstrated that failure region doesn’t reach the ground surface when the shear resistance angle is 46.4° and covering thickness to tunnel height ratio H/D is over 5 or the angle is 55.8° and H/D is over 3. This study considered that there is an arch effect depending on frictional resistance and earth coverings occurred. Furthermore, even with the same earth covering, the smaller the shear resistance is, the earlier the ground surface collapses. Therefore, it could be said that the higher the frictional resistance is, the later the collapse proceeds.
The prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing with the growing epidemics of obesity and diabetes. NAFLD encompasses a ...clinicopathologic spectrum of disease ranging from isolated hepatic steatosis to NASH, which is a more aggressive form of fatty liver disease, to cirrhosis and, finally, hepatocellular carcinoma (HCC). The exact mechanism behind the development of HCC in NASH remains unclear; however, it has been established that hepatic steatosis is the important risk factor in the development of HCC. Metformin has recently drawn attention because of its potential antitumor effect. Here, we investigated the effects of metformin on high-fat diet (HFD)-induced liver tumorigenesis, using a mouse model of NASH and liver tumor. Metformin prevented long-term HFD-induced liver tumorigenesis in C57Bl/6 mice. Of note, metformin failed to protect against liver tumorigenesis in mice that had already begun to develop NAFLD. Metformin improved short-term HFD-induced fat accumulation in the liver, associated with the suppression of adipose tissue inflammation. Collectively, these results suggest that metformin may prevent liver tumorigenesis via suppression of liver fat accumulation in the early stage, before the onset of NAFLD, which seems to be associated with a delay in the development of inflammation of the adipose tissue.
The fundamental insight into Brownian motion by Einstein is that all substances exhibit continual fluctuations due to thermal agitation balancing with the frictional resistance. However, even at ...thermal equilibrium, biological activity can give rise to non-equilibrium fluctuations that cause "active diffusion" in living cells. Because of the non-stationary and non-equilibrium nature of such fluctuations, mean square displacement analysis, relevant only to a steady-state ensemble, may not be the most suitable choice as it depends on the choice of the ensemble; hence, a new analytical method for describing active diffusion is desired. Here we discuss the stochastic energetics of a thermally fluctuating single active diffusion trajectory driven by non-thermal random forces. Heat dissipation, usually difficult to measure, can be estimated from the active diffusion trajectory; guidelines on the analysis such as criteria for the time resolution and driving force intensity are shown by a statistical test. This leads to the concept of an "instantaneous diffusion coefficient" connected to heat dissipation that may be used to analyse the activity and molecular transport mechanisms of living systems.
ALK-positive large B-cell lymphoma is a rare subtype of lymphoma, and most cases follow an aggressive clinical course with a poor prognosis. We examined an ALK-positive large B-cell lymphoma case ...showing an anti-ALK immunohistochemistry pattern distinct from those of 2 known ALK fusions, CLTC-ALK and NPM-ALK, for the presence of a novel ALK fusion; this led to the identification of SQSTM1-ALK. SQSTM1 is an ubiquitin binding protein that is associated with oxidative stress, cell signaling, and autophagy. We showed transforming activities of SQSTM1-ALK with a focus formation assay and an in vivo tumorigenicity assay using 3T3 fibroblasts infected with a recombinant retrovirus encoding SQSTM1-ALK. ALK-inhibitor therapies are promising for treating ALK-positive large B-cell lymphoma, especially for refractory cases. SQSTM1-ALK may be a rare fusion, but our data provide novel biological insights and serve as a key for the accurate diagnosis of this rare lymphoma.
Aims/hypothesis
We investigated changes in the expression of genes involved in beta cell function and proliferation in mouse islets stimulated with glucokinase activator (GKA) in order to elucidate ...the mechanisms by which GKA stimulates beta cell function and proliferation.
Methods
Islets isolated from mice were used to investigate changes in the expression of genes related to beta cell function and proliferation stimulated by GKA. In addition,
Irs2
knockout (
Irs2
−/−
) mice on a high-fat diet or a high-fat diet containing GKA were used to investigate the effects of GKA on beta cell proliferation in vivo.
Results
In wild-type mice,
Irs2
and
Pdx1
expression was increased by GKA. In
Irs2
−/−
mice, GKA administration increased the glucose-stimulated secretion of insulin and
Pdx1
expression, but not beta cell proliferation. It was particularly noteworthy that oxidative stress inhibited the upregulation of the
Irs2
and
Pdx1
genes induced by GKA. Moreover, whereas neither GKA alone nor exendin-4 alone upregulated the expression of
Irs2
and
Pdx1
in the islets of
db
/
db
mice, prior administration of exendin-4 to the mice caused GKA to increase the expression of these genes.
Conclusions/interpretation
GKA-stimulated IRS2 production affected beta cell proliferation but not beta cell function. Oxidative stress diminished the effects of GKA on the changes in expression of genes involved in beta cell function and proliferation. A combination of GKA and an incretin-related agent might therefore be effective in therapy.
The detection of ALK rearrangements is mainly performed using fluorescence in-situ hybridization (FISH). However, such analyses can yield false-positive and false-negative results. Other ALK ...diagnostic techniques have been developed, including immunohistochemistry (IHC) for the detection of the chimeric ALK protein and a reverse transcriptase-polymerase chain reaction analysis to search for the presence of abnormal fusion transcript. Some studies have reported significant clinical improvement after treatment with crizotinib in patients with tumors that were designated as ALK-negative by FISH but were found to be ALK-positive by IHC. In the present study, we identified an ALK R1192G mutation in an NSCLC clinical sample with ALK IHC-positive/FISH-negative findings and showed that this mutation was an oncogenic activating mutation. In addition, ALK inhibitors were likely to be effective against NSCLC cells carrying this mutation. To the best of our knowledge, this is the first study to show that a clinical sample with ALK IHC-positive/FISH-negative findings has an ALK activating mutation. Although this patient has not been treated with any ALK inhibitors because of no recurrence, ALK inhibitors can be effective against such NSCLC cells. To ensure that candidates for treatment with ALK inhibitors are not missed, further comprehensive analyses, such as next generation sequencing, should be introduced into clinical practice.
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