Dual Inhibition of PI3K/AKT and MEK/ERK Pathways Induces Synergistic Antitumor Effects in Diffuse Intrinsic Pontine Glioma Cells

Diffuse intrinsic pontine glioma (DIPG) is a devastating disease with an extremely poor prognosis. Recent studies have shown that platelet-derived growth factor receptor (PDGFR) and its downstream effector pathway, PI3K/AKT/mTOR, are frequently amplified in DIPG, and potential therapies targeting this pathway have emerged. However, the addition of targeted single agents has not been found to improve clinical outcomes in DIPG, and targeting this pathway alone has produced insufficient clinical responses in multiple malignancies investigated, including lung, endometrial, and bladder cancers. Acquired resistance also seems inevitable. Activation of the Ras/Raf/MEK/ERK pathway, which shares many nodes of cross talk with the PI3K/AKT pathway, has been implicated in the development of resistance. In the present study, perifosine, a PI3K/AKT pathway inhibitor, and trametinib, a MEK inhibitor, were combined, and their therapeutic efficacy on DIPG cells was assessed. Growth delay assays were performed with each drug individually or in combination. Here, we show that dual inhibition of PI3K/AKT and MEK/ERK pathways synergistically reduced cell viability. We also reveal that trametinib induced AKT phosphorylation in DIPG cells that could not be effectively attenuated by the addition of perifosine, likely due to the activation of other compensatory mechanisms. The synergistic reduction in cell viability was through the pronounced induction of apoptosis, with some effect from cell cycle arrest. We conclude that the concurrent inhibition of the PI3K/AKT and MEK/ERK pathways may be a potential therapeutic strategy for DIPG.     

The Effect of Adding Neoadjuvant Chemotherapy to Concurrent Chemoradiotherapy in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma and Undetectable Pretreatment Epstein-Barr Virus DNA

PURPOSE: To assess the effect of adding neoadjuvant chemotherapy (NACT) to concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and undetectable pretreatment Epstein-Barr virus (pEBV) DNA. MATERIALS AND METHODS: We enrolled 639 NPC patients with stage II to IVB and undetectable pEBV DNA to receive CCRT with or without NACT. Radiotherapy was 2.0 to 2.27 Gy per fraction with five daily fractions per week for 6 to 7 weeks to the primary tumor and 62 to 70 Gy to the involved neck area. NACT was cisplatin (80-100 mg/m² day 1) and 5-fluorouracil (800-1000 mg/m², 120-hour continuous intravenous infusion) every 3 weeks for two or three cycles. CCRT was cisplatin (80-100 mg/m² day 1) every 3 weeks for three cycles. RESULTS: For all patients, the 5-year overall survival (OS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS) rates were 91.9%, 92.2%, 95.0%, and 86.4%, respectively. There was no significant difference in OS (5-year OS 90.8% [NACT + CCRT group] vs 92.7% [CCRT alone]; hazard ratio [HR] 1.24; P = .486), LRFS (HR 1.13, 95% confidence interval [CI] 0.59-2.14, P = .715), DMFS (HR 0.78, 95% CI 0.34-1.78, P = .554), or PFS (HR 1.21, 95% CI 0.75-1.95, P = .472). CONCLUSION: CCRT with or without NACT produced a good treatment outcome in patients with locoregionally advanced NPC and undetectable pEBV DNA, but NACT before CCRT did not significantly improve survival rates.     

Impact of Serum Apolipoprotein A-I on Prognosis and Bevacizumab Efficacy in Patients with Metastatic Colorectal Cancer: a Propensity Score-Matched Analysis

PURPOSE: We aimed to investigate the role of apolipoprotein A-I (ApoA-I) as a predictor of prognosis and treatment efficacy of bevacizumab in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy with or without bevacizumab. METHODS: We conducted a retrospective study on consecutive patients who were diagnosed with mCRC at Sun Yat-sen University Cancer Center. According to their pretreatment ApoA-I level, patients were divided into low– and high–ApoA-I groups. Propensity score-matched method was performed to balance baseline characteristics between two groups. Based on whether they accepted bevacizumab as a first-line therapy, patients were further divided into the chemo + bevacizumab group and the chemo group. Overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier method, log-rank test, and Cox regression. RESULTS: The optimal cutoff value for the ApoA-I level was determined to be 1.105 g/l. In the propensity-matched cohort of 508 patients, low ApoA-I was significantly associated with inferior OS (P < .001) and PFS (P < .001) than high ApoA-I. Multivariate analysis showed that ApoA-I level was an independent prognostic maker of OS (P < .001) and PFS (P = .001). PFS (P < .001) in either the high– or low–ApoA-I groups could be extended significantly after the administration of bevacizumab, and patients with a high ApoA-I level also had a better OS in the chemo + bevacizumab group than the chemo group (P = .049). CONCLUSIONS: Patients with a low ApoA-I level have poor prognoses, and they did not display an OS benefit from bevacizumab.     

Downregulation of SIRT2 Inhibits Invasion of Hepatocellular Carcinoma by Inhibiting Energy Metabolism

Hepatocellular carcinoma (HCC) is one of the most common neoplasms, and metastasis is the most important feature for HCC-related deaths. Mounting evidence implies the dynamic regulatory role of SIRT2, a histone deacetylase, in cancer cells. Unfortunately, the role of SIRT2 and the antitumor activity of its inhibition are not known in HCC. The present study aims to evaluate the biological function of SIRT2 in HCC and identify the target of SIRT2 as well as evaluate its therapeutic efficacy. We found that SIRT2 was upregulated in HCC tissues compared to adjacent normal tissues, and this was correlated with reduced patient survival. Although CCK8 and colony-formation assays showed that SIRT2 inhibiton marginally promotes proliferation in HCC cell lines, SIRT2 knockdown decreased the invasion of HCC cells. We demonstrated that downregulation of SIRT2 could inhibit its downstream target phosphoenolpyruvate carboxykinase 1 and glutaminase, which is related to mitochondrial metabolism and the E-Cadherin pathway. These results demonstrate, for the first time that downregulation of SIRT2 decreases migration as well as invasion in human HCC cells, indicating that inhibiting SIRT2 may be an effective therapeutic strategy for treating HCC.     

Coiled-coil binding of the leucine zipper domains of APOL1 is necessary for the open cation channel conformation

Apolipoprotein L-I (APOL1) is a channel-forming effector of innate immunity. The common human APOL1 variant G0 provides protection against infection with certain Trypanosoma and Leishmania parasite species, but it cannot protect against the trypanosomes responsible for human African trypanosomiasis. Human APOL1 variants G1 and G2 protect against human-infective trypanosomes but also confer a higher risk of developing chronic kidney disease. Trypanosome-killing activity is dependent on the ability of APOL1 to insert into membranes at acidic pH and form pH-gated cation channels. We previously mapped the channel’s pore-lining region to the C-terminal domain (residues 332–398) and identified a membrane-insertion domain (MID, residues 177–228) that facilitates acidic pH-dependent membrane insertion. In this article, we further investigate structural determinants of cation channel formation by APOL1. Using a combination of site-directed mutagenesis and targeted chemical modification, our data indicate that the C-terminal heptad-repeat sequence (residues 368–395) is a bona fide leucine zipper domain (ZIP) that is required for cation channel formation as well as lysis of trypanosomes and mammalian cells. Using protein-wide cysteine-scanning mutagenesis, coupled with the substituted cysteine accessibility method, we determined that, in the open channel state, both the N-terminal domain and the C-terminal ZIP domain are exposed on the intralumenal/extracellular side of the membrane and provide evidence that each APOL1 monomer contributes four transmembrane domains to the open cation channel conformation. Based on these data, we propose an oligomeric topology model in which the open APOL1 cation channel is assembled from the coiled-coil association of C-terminal ZIP domains.     

东欧黄土-古土壤剖面的孢粉和气候地层学记录及其与ESR测年的海相地层对比

记述东欧平原黄土－古土壤剖面多重年代地层的划分结果,评估黄土地区更新世主要的古地理事件的对比,建立东欧平原黄土－古土壤发育时期的17个期－9个间冰期和8个冰期,间冰期内次一级单元是吸热凉温阶（endothermal coolings)（冷时段,cold speels),干热阶,湿热阶（thermoxerotic and thermohygrotic stges)和间冰期中次级气候韵律,以及冰期内的冰阶（Stadials),间冰阶（Interstadials),中间阶（interphasials),湿冷阶（cryohygrotic),干冷阶（Cryoxerotic stages) 和冰期中的次级气候韵律,其中吸热凉温阶占据了间冰期的大部分。东欧平面黄土－古土壤形成时期的环境和植被演化由以下剖面的孢粉资料构成：上Oka(Likhvin-Chekalin section),上Don(Strelitsa Section),中Kuma(Otkaznoe,setion),中Dniester(Molodova section,Ketrosy section)和中Desna (Arapovichi section),根据孢粉－气候地层研究获得的原始资料,本文重建了欧亚大陆北部60万年以来的古气候事件,古基岩沉积,冰川,冰缘,外冰缘带沉积,并进行了周期的确定和远距离对比,在综合年代地层柱上的古环境事件及其相应的带和年代地层的对比,是依据亚化石化的软体动物外壳的电子自旋共振分析结果,已知的间冰期集中在58万年,40万年,31万年,22万年及14．5－7万年之间,这些孢粉序列,电子自旋共振测年的气候温暖事件及其他文献记载 的古环境事件的对比关系都标注在上部11个氧同位素阶段里。     

Detritivores in Kenyan highland streams: more evidence for the paucity of shredders in the tropics?

1. The relationship between coarse particulate organic matter (CPOM) standing stock and benthic macroinvertebrate assemblages in Kenyan highland streams was determined by sampling seven sites on three rivers (2000–2700 m a.s.l.). Taxa recorded were allocated to functional feeding groups using published literature, mouthpart analysis and examination of gut contents. Patterns were compared with five structurally similar streams in three areas of Europe (south-west France, south-east England, north-east England).
2. Number of individuals and proportion of detritivores in Kenyan streams were equivalent to, or greater than, those in European sites. Shredders were, however, almost completely absent from Kenyan sites, despite high standing stocks of CPOM. Shredders were abundant in all European sites.
3. The phenomenon of low shredder abundance has been observed in other tropical streams in south-east Asia and Central and South America but, in contrast to these regions, the African rivers studied were devoid of shrimps or fish which may occupy the shredding niche elsewhere.
4. These preliminary data suggest that shredder-mediated detritus processing, which is a key functional component of streams in the North Temperate Zone, does not operate in East African streams. There are three possible reasons for this. The first is that tropical African rivers are functionally different to those in temperate regions. This could be because of enhanced microbial activity replacing shredder activity at high temperatures. Alternatively, it could be a result of low palatability of detrital inputs from dominant riparian trees in the region. The second and third are methodological: that our allocation to functional feeding groups is incorrect, and that our sampling methods missed a potentially key shredding taxon – the freshwater crab Potamonautes sp.     

The Relationship of Rapid Weight Gain in Infancy to Obesity and Skeletal Maturity in Childhood

Objective: Children with birth weight appropriate for gestational age (AGA) who also demonstrate rapid weight gain in infancy have a greater risk of being overweight or obese during childhood. A concurrent advancement in skeletal maturity would account for their greater size and would, therefore, not necessarily pose a threat of greater risk during adolescence and early adulthood. This study aims to determine whether children with rapid weight gain during infancy have advanced skeletal maturity during childhood. Research Methods and Procedures: One hundred and ninety‐three African children (boys = 108; girls = 85) of normal birth weight and gestational age were assessed from birth to 9 years. Body composition was assessed at 9 years of age by whole‐body DXA, and skeletal maturity was assessed using the Tanner‐Whitehouse II technique. Rapid weight gain in infancy was defined as a +0.67 change in weight‐for‐age Z‐score between birth and 2 years. Results: Rapid weight gain was experienced by over 20% of the sample. Children with rapid weight gain were significantly lighter at birth and significantly taller, heavier, and fatter throughout childhood. Chronological age and Tanner‐Whitehouse II technique skeletal ages at 9 years were not significantly different between groups or between sexes within groups. Discussion: Because AGA children with rapid weight gain have a greater risk of overweight and obesity but are not advanced in skeletal maturity, later adolescent adjustments toward average weight and fatness values are unlikely. The identification and monitoring of such children is of importance in reducing their risk of morbidity.     

不同水分处理对耐旱性不同小麦品种旗叶衰老的影响

在防雨池栽条件下,研究了不同土壤水分处理对不同耐旱性小麦品种旗叶衰老的影响。结果表明,开花后小麦旗叶叶绿素含量、iPAs含量和光合速率均随土壤水分含量降低而降低,而MDA和ABA含量升高,旗叶衰老进程加快,产量降低。旱地品种菜农8834比水浇地品种鲁麦7号上述指标随土壤水分含量降低而下降或升高的幅度小,这是旱地小麦品种莱农8834在水分亏缺条件下产量较高的内在生理基础。