Better understanding of the underlying biology of primary central nervous system lymphomas (PCNSL) is critical for the development of early detection strategies, molecular markers, and new ...therapeutics. This study aimed to define genes associated with survival of patients with PCNSL.
Expression profiling was conducted on 32 PCNSLs. A gene classifier was developed using the random survival forests model. On the basis of this, prognosis prediction score (PPS) using immunohistochemical analysis is also developed and validated in another data set with 43 PCNSLs.
We identified 23 genes in which expressions were strongly and consistently related to patient survival. A PPS was developed for overall survival (OS) using a univariate Cox model. Survival analyses using the selected 23-gene classifiers revealed a prognostic value for high-dose methotrexate (HD-MTX) and HD-MTX-containing polychemotherapy regimen-treated patients. Patients predicted to have good outcomes by the PPS showed significantly longer survival than those with poor predicted outcomes (P < 0.0001). PPS using immunohistochemical analysis is also significant in test (P = 0.0004) and validation data set (P = 0.0281). The gene-based predictor was an independent prognostic factor in a multivariate model that included clinical risk stratification (P < 0.0001). Among the genes, BRCA1 protein expressions were most strongly associated with patient survival.
We have identified gene expression signatures that can accurately predict survival in patients with PCNSL. These predictive genes should be useful as molecular biomarkers and they could provide novel targets for therapeutic interventions.
New findings
What is the central question of this study?
Measurement of ventilation (as well as simultaneous recording of ventilation and pulmonary gas exchange) in exercising mice has not been ...studied thoroughly. We evaluated ventilation in association with metabolic changes during constant‐load exercise in mice and examined the role of D
1
receptors in addition to the D
2
receptors previously studied. This reliable method can be used in gene‐manipulated mice.
What is the main finding and its importance?
We showed that the D
1
receptors participate in resting ventilation and exercise hyperpnoea in parallel with metabolic changes during the steady state in mice. The metabolic control of D
1
receptors was important for maintenance of the steady state.
Previously, we undertook simultaneous recording of ventilation and pulmonary gas exchange in mice and revealed that dopamine D
2
receptors participate in exercise hyperpnoea via behavioural control of ventilation with unchanged pulmonary gas exchange. Here, we examined the hypothesis that D
1
receptors also contribute to exercise hyperpnoea using a D
1
receptor antagonist (SCH 23390; SCH) that crosses the blood–brain barrier, with the same recording technique and protocol as in the previous study. The respiratory responses of mice injected with saline or SCH (50 μg (kg body weight)
−1
,
i.p.
) were compared during constant‐load exercise at 6 m min
−1
. Each mouse was set in an airtight treadmill chamber equipped with a differential pressure transducer and open‐circuit system with a mass spectrometer. At rest, SCH‐injected mice had significantly reduced respiratory frequency, minute ventilation and pulmonary gas exchange compared with saline‐injected mice. Ventilation during hyperoxic gas inhalation and hypercapnic ventilatory responses between groups were similar. Abrupt increases and sequential declines to the steady‐state level were produced by treadmill exercise in both groups of mice. Treatment with SCH lowered the increased levels of respiratory frequency, tidal volume and minute ventilation during the steady state, as well as reducing the O
2
uptake, CO
2
output and body temperature throughout treadmill exercise. These data suggest that D
1
receptors contribute to a resting ventilation level and exercise hyperpnoea during the steady state in parallel with metabolic changes. Notably, the metabolic control of D
1
receptors was important for maintenance of the steady state, and D
1
receptors in hypothalamic nuclei could be involved in this modulation.
Dysfunction of the p53 network is a major cause of cancer development, and selective elimination of p53-inactivated cancer cells therefore represents an ideal therapeutic strategy. In this study, we ...performed a microRNA target screen that identified NEK9 (NIMA-related kinase 9) as a crucial regulator of cell-cycle progression in p53-inactivated cancer cells. NEK9 depletion selectively inhibited proliferation in p53-deficient cancer cells both in vitro and in vivo. The resultant cell-cycle arrest occurred predominantly in G1 phase, and exhibited senescence-like features. Furthermore, NEK9 repression affected expression of a broad range of genes encoding cell-cycle regulators and factors involved in mRNA processing, suggesting a novel role for NEK9 in p53-deficient cells. Lung adenocarcinoma patients with positive staining for NEK9 and mutant p53 proteins exhibited significantly poorer prognoses, suggesting that expression of both proteins promotes tumor growth. Our findings demonstrate that a novel NEK9 network regulates the growth of cancer cells lacking functional p53.
Graphical abstract Highlights ► We measured ventilation during constant-load exercise on a treadmill in mice. ► Exercise hyperpnoea started before locomotion actually began. ► Ventilation peaked ...during the early phase of exercise and then decreased. ► Ventilatory increase at exercise onset occurred independently of limb movements. ► Hyperpnoea at exercise onset showed plasticity but was attenuated by experience.
Objective: To report a case of ruptured anterior cerebral artery dissection treated with stent-assisted coil embolization with overlapping stents.Case Presentation: A 51-year-old woman developed ...subarachnoid hemorrhage the day after transient left hemiparesis. Angiography revealed a ruptured anterior cerebral artery dissecting aneurysm. We conducted stent-assisted coil embolization with the overlapping stent technique on the day after the hemorrhage. She recovered steadily without rebleeding. Six months after embolization, no recurrence was found on angiography.Conclusion: Although an acceptable result was achieved in this case, the safety and efficacy of this procedure are unconfirmed. A larger number of cases should be accumulated.
We isolated a cDNA encoding a novel heterogeneous nuclear ribonucleoprotein (hnRNP)like protein on DNA affinity screening of a K562 cDNA expression library with an oligodeoxynucleotide (JKT41) ...derived from intron 9 of the human myeloperoxidase gene. The cDNA has a 1,305 bp sequence that encodes a polypeptide of 301 amino acid residues. The protein, named JKTBP, contains two repeats of a putative RNA binding domain (RBD), each composed of canonical RNP-2 and RNP-1 motifs, and a glycine- and tyrosine-rich carboxyl terminus. The sequences of these two repeats are highly homologous with those of the 2×RBD-Gly rich group of hnRNPs. Northern blotting showed that two mRNAs of approximately 1.4 and 2.8 kb were present in most cultured cells examined. The recombinant protein expressed in Escherichia coli interacted with the double-stranded form of JKT41 as well as with its single-stranded form. This interaction was competitively inhibited by the same unlabeled JKT41 and to nearly the same extent by unrelated oligonucleotides. Moreover, the recombinant protein interacted with poly(G) and poly(A), but not with poly(U) or poly(C). Transient expression of the protein in SKM-1 cells repressed the expression of chloramphenicol acetyltransferase reporter genes located downstream of the intron 9 element of JKT41 or intron 7 element of FERE27. The implications of the protein in the biogenesis of mRNA are discussed.
New findings * times What is the central question of this study? Measurement of ventilation (as well as simultaneous recording of ventilation and pulmonary gas exchange) in exercising mice has not ...been studied thoroughly. We evaluated ventilation in association with metabolic changes during constant-load exercise in mice and examined the role of D sub(1) receptors in addition to the D sub(2) receptors previously studied. This reliable method can be used in gene-manipulated mice. * times What is the main finding and its importance? We showed that the D sub(1) receptors participate in resting ventilation and exercise hyperpnoea in parallel with metabolic changes during the steady state in mice. The metabolic control of D sub(1) receptors was important for maintenance of the steady state. Previously, we undertook simultaneous recording of ventilation and pulmonary gas exchange in mice and revealed that dopamine D sub(2) receptors participate in exercise hyperpnoea via behavioural control of ventilation with unchanged pulmonary gas exchange. Here, we examined the hypothesis that D sub(1) receptors also contribute to exercise hyperpnoea using a D sub(1) receptor antagonist (SCH 23390; SCH) that crosses the blood-brain barrier, with the same recording technique and protocol as in the previous study. The respiratory responses of mice injected with saline or SCH (50 mu g (kg body weight) super(-1), i.p.) were compared during constant-load exercise at 6 m min super(-1). Each mouse was set in an airtight treadmill chamber equipped with a differential pressure transducer and open-circuit system with a mass spectrometer. At rest, SCH-injected mice had significantly reduced respiratory frequency, minute ventilation and pulmonary gas exchange compared with saline-injected mice. Ventilation during hyperoxic gas inhalation and hypercapnic ventilatory responses between groups were similar. Abrupt increases and sequential declines to the steady-state level were produced by treadmill exercise in both groups of mice. Treatment with SCH lowered the increased levels of respiratory frequency, tidal volume and minute ventilation during the steady state, as well as reducing the O sub(2) uptake, CO sub(2) output and body temperature throughout treadmill exercise. These data suggest that D sub(1) receptors contribute to a resting ventilation level and exercise hyperpnoea during the steady state in parallel with metabolic changes. Notably, the metabolic control of D sub(1) receptors was important for maintenance of the steady state, and D sub(1) receptors in hypothalamic nuclei could be involved in this modulation.
Noninvasive detection of early stage cancers with accurate prediction of tumor tissue-of-origin could improve patient prognosis. Because miRNA profiles differ between organs, circulating miRNomics ...represent a promising method for early detection of cancers, but this has not been shown conclusively.
A serum miRNA profile (miRNomes)-based classifier was evaluated for its ability to discriminate cancer types using advanced machine learning. The training set comprised 7931 serum samples from patients with 13 types of solid cancers and 5013 noncancer samples. The validation set consisted of 1990 cancer and 1256 noncancer samples. The contribution of each miRNA to the cancer-type classification was evaluated, and those with a high contribution were identified.
Cancer type was predicted with an accuracy of 0.88 (95% confidence interval CI = 0.87 to 0.90) in all stages and an accuracy of 0.90 (95% CI = 0.88 to 0.91) in resectable stages (stages 0-II). The F1 score for the discrimination of the 13 cancer types was 0.93. Optimal classification performance was achieved with at least 100 miRNAs that contributed the strongest to accurate prediction of cancer type. Assessment of tissue expression patterns of these miRNAs suggested that miRNAs secreted from the tumor environment could be used to establish cancer type-specific serum miRNomes.
This study demonstrates that large-scale serum miRNomics in combination with machine learning could lead to the development of a blood-based cancer classification system. Further investigations of the regulating mechanisms of the miRNAs that contributed strongly to accurate prediction of cancer type could pave the way for the clinical use of circulating miRNA diagnostics.
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