G2 checkpoint abrogators as anticancer drugs

Many conventional anticancer treatments kill cells irrespective of whether they are normal or cancerous, so patients suffer from adverse side effects due to the loss of healthy cells. Anticancer insights derived from cell cycle research has given birth to the idea of cell cycle G2 checkpoint abrogation as a cancer cell specific therapy, based on the discovery that many cancer cells have a defective G1 checkpoint resulting in a dependence on the G2 checkpoint during cell replication. Damaged DNA in humans is detected by sensor proteins (such as hHUS1, hRAD1, hRAD9, hRAD17, and hRAD26) that transmit a signal via ATR to CHK1, or by another sensor complex (that may include gammaH2AX, 53BP1, BRCA1, NBS1, hMRE11, and hRAD50), the signal of which is relayed by ATM to CHK2. Most of the damage signals originated by the sensor complexes for the G2 checkpoint are conducted to CDC25C, the activity of which is modulated by 14-3-3. There are also less extensively explored pathways involving p53, p38, PCNA, HDAC, PP2A, PLK1, WEE1, CDC25B, and CDC25A. This review will examine the available inhibitors of CHK1 (Staurosporin, UCN-01, Go6976, SB-218078, ICP-1, and CEP-3891), both CHK1 and CHK2 (TAT-S216A and debromohymenialdisine), CHK2 (CEP-6367), WEE1 (PD0166285), and PP2A (okadaic acid and fostriecin), as well as the unknown checkpoint inhibitors 13-hydroxy-15-ozoapathin and the isogranulatimides. Among these targets, CHK1 seems to be the most suitable target for therapeutic G2 abrogation to date, although an unexplored target such as 14-3-3 or the strategy of targeting multiple proteins at once may be of interest in the future.     

Primary hepatic neuroendocrine carcinoma with a cholangiocellular carcinoma component in one nodule

Primary neuroendocrine carcinomas (NECs) in the liver are very rare; however, several reports have described cases of a primary hepatic NEC combined with a hepatocellular carcinoma (HCC). We present the first report of a primary hepatic NEC with a cholangiocellular carcinoma (CCC) component in one nodule in a patient with a metachronous liver HCC. A 73-year old man who had received partial hepatectomy surgery because of a primary HCC and a primary CCC two years prior was diagnosed with a primary hepatic NEC after surgical treatment. Histological analysis of the resected tumor revealed that the tumor consisted of a predominant NEC area with a partial CCC component in one nodule and that the NEC cells were negative for markers of pancreatic NEC. Neoplastic cells in both the NEC and CCC component focally expressed CD44, a representative marker for cancer-initiating cells, and the CD44-positive cells in the NEC component were seen in the vicinity of those in the CCC component of one nodule. This case report provides suggestive information for the origin of primary hepatic NECs.     

Prognostic Impact of Tumor Mutation Burden in Patients With Completely Resected Non–Small Cell Lung Cancer: Brief Report

Introduction

Tumor mutation burden (TMB) is thought to be associated with the amount of neoantigen in the tumor and to have an important role in predicting the effect of immune checkpoint inhibitors. However, the relevance of TMB to prognosis is not yet fully understood. In this study, we investigated the clinical significance of TMB in patients with NSCLC and examined the relationship between TMB and prognosis.

Improvement of ischemic damage in gerbil hippocampal neurons by procaine

Acute cerebral ischemia induces membrane depolarization in the neuron, thereby incurring the simultaneous influx of various ions such as Na⁺ and Ca²⁺. Since procaine possesses the ability to inhibit the release of Ca²⁺ from intracellular Ca²⁺ stores to the cytosol as well as the ability to block Na⁺ channels, the effects of procaine on ischemia were investigated in the present study in gerbils both in vivo and in vitro. The histologic outcome was evaluated 7 days after 3 min of transient forebrain ischemia by assessing delayed neuronal death in hippocampal CA1 pyramidal cells in animals administered procaine (0.2, 0.4, or 2 μmol) intracerebroventricularly 10 min before ischemia and in animals given saline. The changes in the direct-current potential shift in the hippocampal CA1 area were measured using an identical animal model. A hypoxia-induced intracellular Ca²⁺ increase was evaluated by in vitro microfluorometry in gerbil hippocampal slices, and the effects of procaine (10, 50, and 100 μmol/l) on the Ca²⁺ accumulation were examined. Additionally, the effect of procaine (100 μmol/l) in a Ca²⁺-free condition was investigated. The histologic outcome was improved and the onset of the ischemia-induced membrane depolarization was prolonged by the preischemic administration of procaine. The increase in the intracellular concentration of Ca²⁺ induced by the in vitro hypoxia was suppressed by the perfusion of procaine-containing mediums (50 and 100 μmol/l), regarding both the initiation and the extent of the increase. A hypoxia-induced intracellular Ca²⁺ elevation in the Ca²⁺-free condition was observed, and the perfusion with procaine (100 μmol/l) inhibited this elevation. Procaine helps protect neurons from ischemia by suppressing the direct-current potential shift and by inhibiting the release of Ca²⁺ from the intracellular Ca²⁺ stores, as well as by inhibiting the influx of Ca²⁺ from the extracellular space.     

Medical Treatment of Mesothelioma: Anything New?

In the present report, we review the current standard and investigational treatments of malignant pleural mesothelioma (MPM). Several studies have reported the use of gemcitabine and cisplatin as an induction chemotherapy in combination with extrapleural pneumonectomy (EPP) and thoracic radiation in a combined-modality approach for resectable MPM. Since the combination of cisplatin with pemetrexed was applied as the standard first-line regimen for unresectable MPM, the combination as an induction chemotherapy regimen has been proven effective in phase 2 trials. In addition, intensity-modulated radiation therapy and proton therapy have been introduced as new radiation methods into the combined modality. Hyperthermic intraoperative chemotherapy following EPP appears effective with acceptable toxicity. In addition, clinical studies that include molecular targeting agents, immunotherapy, and gene therapy have all been conducted. Thus, although there are numerous hopeful treatments for MPM, the benefits of these regimens remain to be proven in a randomized clinical setting.     

Development of a New Benzophenone–Diketopiperazine-Type Potent Antimicrotubule Agent Possessing a 2-Pyridine Structure

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Disruptive neuronal development by acrylamide in the hippocampal dentate hilus after developmental exposure in rats

To examine whether developmental exposure to acrylamide (AA) impairs neuronal development, pregnant Sprague–Dawley rats were treated with AA at 0, 25, 50 or 100 ppm in drinking water from gestational day 6 until weaning on postnatal day 21. Offspring were immunohistochemically examined at the end of exposure. We investigated the expression of Reelin (a molecule regulating neuronal migration and positioning) in the hilus of the hippocampal dentate gyrus. As a positive control for direct exposure, AA (50 mg/kg body weight) was administered to pups by intraperitoneal injection 3 times per week during the lactation period. As well as pups directly injected with AA, maternally exposed offspring decreased body weight at 100 ppm; increased dose-dependently the number of Reelin-immunoreactive cells (from 25 ppm AA) and glutamic acid decarboxylase 67-immunoreactive cells (from 50 ppm AA), confirming an increase in γ-aminobutyric acid-ergic interneurons. We also noted decreased apoptosis in the neuroblast-producing subgranular zone of the dentate gyrus of maternally exposed pups at 100 ppm, as well as in directly AA-injected pups. These results suggest that a compensatory regulatory mechanism exists to correct impaired neurogenesis and mismigration caused by maternal exposure to AA during neuronal development. The lowest-observed-adverse-effect level of AA was determined to be 25 ppm (3.72 mg/kg body weight/day).     

The effect of dopamine depletion on the H2O2 production in the rat striatum following transient middle cerebral artery occlusion

The changes in the extracellular concentrations of rat striatal H₂O₂, dopamine (DA) and its metabolites during middle cerebral artery (MCA) occlusion and reperfusion were simultaneously examined by microdialysis, and the relationship between the ischemia-induced release of DA and the generation of H₂O₂ was estimated by assessing the effect of the lesion of the substantia nigra (SN). In the rats without SN lesions, a significant increase in the striatal H₂O₂ level was observed during the ischemia and reperfusion phases. In the rats with SN lesions, the ischemia-induced H₂O₂ production was not attenuated. These results suggest that DA is not an important source of H₂O₂ in cerebral ischemia and reperfusion.     

Second-phase validation study of short time exposure test for assessment of eye irritation potency of chemicals

A Short Time Exposure (STE) test is a cytotoxicity test that uses SIRC cells (rabbit corneal cell line) to assess eye irritation potency following a 5-min chemical exposure. This second-phase validation study assessed the predictive capacity of the STE test using 40 coded test substances at three laboratories. A Validation Management Team (VMT) then evaluated the predictivity of the STE test for United Nation (UN) Globally Harmonized System (GHS) categories using 63 test substances including the results of the first-phase validation study.The STE test can assess not only the severe or corrosive ocular irritants (corresponding to the UN GHS Category 1) but also non-irritant (corresponding to UN GHS Non Category) from other toxicity classes, especially for limited types of test substances. The predictivity by STE test, however, was insufficient for identification of UN GHS categories (Category 1, Category 2, or Non Category).These results suggest that the STE test can be recommended as an initial step in a top-down approach to identification of severe irritants and test substances that require classification for eye irritation (UN GHS Category 1) as well as an initial step in a bottom-up approach to identification of test substances that do not require classification for eye irritation (UN GHS Non Category) from other toxicity classes, especially for limited types of test substances. On the other hand, the STE test is not considered adequate for the identification of mild or moderate irritants (i.e., UN GHS Categories 2A and 2B) and severe irritants (UN GHS Category 1).