Discovery of a nitroaromatic nannocystin with potent in vivo anticancer activity against colorectal cancer by targeting AKT1.

The development of targeted chemotherapeutic agents against colorectal cancer (CRC), one of the most common cancers with a high mortality rate, is in a constant need. Nannocystins are a family of myxobacterial secondary metabolites featuring a 21-membered depsipeptide ring. The in vitro anti-CRC activity of natural and synthetic nannocystins was well documented, but little is known about their in vivo efficacy and if positive, the underlying mechanism of action. In this study we synthesized a nitroaromatic nannocystin through improved preparation of a key fragment, and characterized its in vitro activity and in vivo efficacy against CRC. We first described the total synthesis of compounds 2-4 featuring Heck macrocyclization to forge their 21-membered macrocycle. In a panel of 7 cancer cell lines from different tissues, compound 4 inhibited the cell viability with IC values of 1-6 nM. In particular, compound 4 (1, 2, 4 nM) inhibited the proliferation of CRC cell lines (HCT8, HCT116 and LoVo) in both concentration and time dependent manners. Furthermore, compound 4 concentration-dependently inhibited the colony formation and migration of CRC cell lines. Moreover, compound 4 induced cell cycle arrest at sub-G1 phase, apoptosis and cellular senescence in CRC cell lines. In three patient-derived CRC organoids, compound 4 inhibited the PDO with IC values of 3.68, 28.93 and 11.81 nM, respectively. In a patient-derived xenograft mouse model, injection of compound 4 (4, 8 mg/kg, i.p.) every other day for 12 times dose-dependently inhibited the tumor growth without significant change in body weight. We conducted RNA-sequencing, molecular docking and cellular thermal shift assay to elucidate the anti-CRC mechanisms of compound 4, and revealed that it exerted its anti-CRC effect at least in part by targeting AKT1.

Genome-wide DNA methylation analysis identifies potent CpG signature for temzolomide response in non-G-CIMP glioblastomas with unmethylated MGMT promoter: MGMT-dependent roles of GPR81.

PURPOSES: To identify potent DNA methylation candidates that could predict response to temozolomide (TMZ) in glioblastomas (GBMs) that do not have glioma-CpGs island methylator phenotype (G-CIMP) but have an unmethylated promoter of O-6-methylguanine-DNA methyltransferase (unMGMT). METHODS: The discovery-validation approach was planned incorporating a series of G-CIMP-/unMGMT GBM cohorts with DNA methylation microarray data and clinical information, to construct multi-CpG prediction models. Different bioinformatic and experimental analyses were performed for biological exploration. RESULTS: By analyzing discovery sets with radiotherapy (RT) plus TMZ versus RT alone, we identified a panel of 64 TMZ efficacy-related CpGs, from which a 10-CpG risk signature was further constructed. Both the 64-CpG panel and the 10-CpG risk signature were validated showing significant correlations with overall survival of G-CIMP-/unMGMT GBMs when treated with RT/TMZ, rather than RT alone. The 10-CpG risk signature was further observed for aiding TMZ choice by distinguishing differential outcomes to RT/TMZ versus RT within each risk subgroup. Functional studies on GPR81, the gene harboring one of the 10 CpGs, indicated its distinct impacts on TMZ resistance in GBM cells, which may be dependent on the status of MGMT expression. CONCLUSIONS: The 64 TMZ efficacy-related CpGs and in particular the 10-CpG risk signature may serve as promising predictive biomarker candidates for guiding optimal usage of TMZ in G-CIMP-/unMGMT GBMs.

Tyrosine metabolic reprogramming coordinated with the tricarboxylic acid cycle to drive glioma immune evasion by regulating PD-L1 expression.

Due to the existence of the blood-brain barrier in glioma, traditional drug therapy has a poor therapeutic outcome. Emerging immunotherapy has been shown to have satisfactory therapeutic effects in solid tumors, and it is clinically instructive to explore the possibility of immunotherapy in glioma. We performed a retrospective analysis of RNA-seq data and clinical information in 1027 glioma patients, utilizing machine learning to explore the relationship between tyrosine metabolizing enzymes and clinical characteristics. In addition, we also assessed the role of tyrosine metabolizing enzymes in the immune microenvironment including immune infiltration and immune evasion. Highly expressed tyrosine metabolizing enzymes 4-hydroxyphenylpyruvate dioxygenase, homogentisate 1,2-dioxygenase, and fumarylacetoacetate hydrolase not only promote the malignant phenotype of glioma but are also closely related to poor prognosis. The expression of tyrosine metabolizing enzymes could distinguish the malignancy degree of glioma. More importantly, tyrosine metabolizing enzymes regulate the adaptive immune process in glioma. Mechanistically, multiple metabolic enzymes remodel fumarate metabolism, promote α-ketoglutarate production, induce programmed death-ligand 1 expression, and help glioma evade immune surveillance. Our data suggest that the metabolic subclass driven by tyrosine metabolism provides promising targets for the immunotherapy of glioma.

New Insights into TRP Ion Channels in Stem Cells.

Transient receptor potential (TRP) ion channels are cationic permeable proteins located on the plasma membrane. TRPs are cellular sensors for perceiving diverse physical and/or chemical stimuli; thus, serving various critical physiological functions, including chemo-sensation, hearing, homeostasis, mechano-sensation, pain, taste, thermoregulation, vision, and even carcinogenesis. Dysregulated TRPs are found to be linked to many human hereditary diseases. Recent studies indicate that TRP ion channels are not only involved in sensory functions but are also implicated in regulating the biological characteristics of stem cells. In the present review, we summarize the expressions and functions of TRP ion channels in stem cells, including cancer stem cells. It offers an overview of the current understanding of TRP ion channels in stem cells.

Low Serum 25-Hydroxyvitamin D Levels Are Associated With Hyperandrogenemia in Polycystic Ovary Syndrome: A Cross-Sectional Study.

Background: Increasing evidence suggests a link between vitamin D and polycystic ovary syndrome (PCOS). However, whether vitamin D is related to hyperandrogenemia in PCOS is still inconclusive. The aim of our study is to elucidate the relationship between vitamin D and hyperandrogenemia in women with PCOS in China. Methods: This is a cross-sectional study including 625 Chinese women with PCOS and 217 controls from January 2016 to June 2020. The anthropometric and biochemical parameters related to 25(OH)D, sex steroids, glucose and lipid profiles were measured. Results: Serum 25(OH)D levels were lower in women with PCOS than controls (33.99 ± 15.05 vs 36.58 ± 16.49 nmol/L, P = 0.034), especially lower in hyperandrogenic women with PCOS (32.79 ± 14.24 vs 36.21 ± 16.27 nmol/L, P = 0.007). Higher 25(OH)D levels were independently associated with lower risks of hyperandrogenemia after adjusting demographic, metabolic and hormonal confounders (OR = 0.982, 95% CI: 0.969 - 0.995, P = 0.006). Consistent results were observed in subgroup analyses. Among PCOS women with vitamin D deficiency, females with age ≥ 26 years had lower risks of hyperandrogenemia (OR = 0.611, 95% CI = 0.389 - 0.958, P = 0.032), while overweight patients had higher risks of hyperandrogenemia (OR = 2.202, 95% CI = 1.130 - 4.293, P = 0.020) after adjusting multiple confounders. Conclusions: Our study reported lower vitamin D levels in Chinese women with PCOS, especially in those with hyperandrogenemia. An independent negative correlation between 25(OH)D and hyperandrogenemia was noted in PCOS. For PCOS women with vitamin D deficiency, females that have higher BMI with age < 26 years may be prioritized for hyperandrogenemia assessment.

A non-small cell lung cancer (NSCLC) patient with leptomeningeal metastasis harboring rare epidermal growth factor receptor (EGFR) mutations G719S and L861Q benefited from doubling dosage of osimertinib: a case report.

Leptomeningeal metastasis (LM) is a rare but lethal complication of advanced non-small cell lung cancer (NSCLC) that has a devastating impact on patient survival and quality of life. Osimertinib, an irreversible tyrosine kinase inhibitor, is approved as a therapy for advanced NSCLC with epidermal growth factor receptor (EGFR) mutation. However, the efficacy and optimal dosage of osimertinib in the treatment of NSCLC patients with LM who harbor uncommon EGFR mutations have yet to be fully investigated. Herein, we report a case of an advanced NSCLC patient with LM carrying EGFR G719S and L861Q, who was successfully treated by osimertinib at 160 mg. The patient initially presented with clear cell renal carcinoma and renal metastatic adenocarcinoma, and underwent right nephrectomy. At 2 months after nephrectomy, he developed a disturbance of consciousness and was subsequently diagnosed with NSCLC with LM by meningeal biopsy pathology and cerebrospinal fluid (CSF) cytology. Next-generation sequencing detected the rare EGFR mutations G719S and L861R in the meningeal biopsy tissues. The patient was then administered osimertinib at 80 mg quaque die (QD); after 1 month of treatment, his symptoms were alleviated. However, two months later, he experienced epileptic episode. Subsequently, the osimertinib dosage was doubled to 160 mg QD. After 1 month of treatment, the patient achieved central nervous system (CNS) response, and at the time of this manuscript's submission, he had maintained stable disease (SD) for more than 1 year. To our knowledge, this study provides the first clinical evidence that the administration of osimertinib at 160 mg once daily can achieve an encouraging, durable response in an NSCLC patient with LM carrying EGFR G719S and L861Q.

Broadening the role of osteocalcin in the hypothalamic-pituitary-gonadal axis.

Bone is emerging as a versatile endocrine organ and its interactions with apparently unrelated organs are being more widely recognized. Osteocalcin (OCN), a polypeptide hormone secreted by osteoblasts, has been found to exert multiple endocrine functions through its metabolically active form, uncarboxylated OCN (uOCN). Mounting evidence has shown that following its binding to G-protein coupled receptor 6a (Gprc6a) in the peripheral tissues, uOCN acts on pancreatic ß cells to increase insulin secretion, and on muscle and white adipose tissue to promote glucose and lipid metabolism. More strikingly, researchers have found a surprising role of uOCN in testicular function to facilitating testosterone biosynthesis and regulating male fertility via a pancreas-bone-gonadal axis. However, the detailed functional mechanisms of uOCN on the hypothalamic-pituitary-gonadal axis or the pancreas-bone-gonadal axis are not fully understood. Besides highlighting the regulatory mechanisms of uOCN in the hypothalamus and pituitary, we also discuss its role in male as well as female fertility and its potential clinical implications in some reproductive endocrine diseases and pubertal developmental disorders.

Differential expression of genes associated with hypoxia pathway on bone marrow stem cells in osteoporosis patients with different bone mass index.

BACKGROUND: This study aimed to assess gene expression changes associated with hypoxia pathway on bone marrow stem cells (BMSCs) and explore effects of bone mass index (BMI) on hypoxia pathway of osteoporosis (OP) patients. METHODS: Human BMSCs were isolated from bone marrow. Subjects were divided into healthy control group and OP group which was further divided into BMI <25 OP subgroup and BMI ≥25 OP subgroup. RESULTS: The genes downregulated in OP patients were involved in hypoxia pathway. Furthermore, those genes were even downregulated in OP patients BMI ≥25 subgroup than OP patients BMI <25 subgroup. The genes were expressed in response to decreased oxygen levels, and their functions are related to photoperiodism, positive regulation of myoblast differentiation, and entrainment of circadian clock by gene ontology (GO) analysis. CONCLUSIONS: The expression of genes associated with hypoxia pathway on BMSCs in OP patients are lower than healthy subjects, and the expression of genes related to carbohydrate metabolism are lower in overweight OP patients than in normal weight OP patients. These results need further research.

The browning of white adipose tissue and body weight loss in primary hyperparathyroidism.

BACKGROUND: Parathyroid hormone related protein (PTHrP) triggers white adipose tissue (WAT) browning and cachexia in lung cancer mouse models. It remains unknown whether excessive PTH secretion affects WAT browning and to what extent it contributes to body weight change in primary hyperparathyroidism (PHPT). METHODS: Using the adeno-associated virus injection, Pth gene over-expressed mice mimicking PHPT were firstly established to observe their WAT browning and body weight alteration. The association between PTH and body weight was investigated in 496 PHPT patients. The adipose browning activities of 20 PHPT and 60 control subjects were measured with PET/CT scanning. FINDINGS: Elevated plasma PTH triggered adipose tissue browning, leading to increased energy expenditure, reduced fat content, and finally decreased body weight in PHPT mice. Higher circulating PTH levels were associated with lower body weight (ß = -0.048, P = .0003) independent of renal function, serum calcium, phosphorus,and albumin levels in PHPT patients. PHPT patients exhibited both higher prevalence of detectable brown/beige adipose tissue (20% vs 3.3%, P = .03) and increased browning activities (SUV in cervical adipose was 0.77 vs 0.49,P = .02) compared with control subjects. INTERPRETATION: Elevated serum PTH drove WAT browning program, which contributed in part to body weight loss in both PHPT mice and patients. These results give insights into the novel pathological effect of PTH and are of importance in understanding the metabolic changes of PHPT. FUND: This research is supported by the National Key Research and Development Program of China and National Natural Science Foundation of China.

Smart MMP2-Responsive Nanoprobe for Activatable Fluorescence Imaging-Guided Local Triple-Combination Therapies with Single Light.

Elaborately designed stimuli-responsive smart systems simultaneously enabling activatable imaging and selective treatment are highly desirable for precise diagnosis and therapy of cancer. Herein, such a smart theranostic nanoprobe composed of hollow gold nanospheres (HAuNs), photosensitizer (PS), matrix metalloproteinase 2 (MMP2) substrate peptide, and model drug doxorubicin (DOX) was designed. In the design, HAuNs served as the acceptor of Förster resonance energy transfer (FRET), photothermal therapy (PTT) reagent, and nanocarrier. The fluorescence and 1O2 generation of PS were inhibited by HAuNs through FRET effect, avoiding phototoxicity to normal tissues during circulation. Meanwhile, owing to the MMP2-triggered peptide cleavage, the PS could be efficiently activated in a tumor for selective fluorescence imaging and photodynamic therapy (PDT). The recovered fluorescence could be applied for detecting MMP2, locating tumor in vivo, and further guiding the local triple-combination therapies including PDT, PTT, and chemotherapy. The synergistic treatments of activated PDT, PTT, and controlled DOX release were achieved with single light, which provided the best therapeutic effects with enhanced stability and remarkably reduced nonspecific toxicity of PS and anticancer drug. This study helps to design novel stimuli-responsive systems for precise molecular sensing and site-specific cancer treatment.

Advanced glycation end products induce the apoptosis of and inflammation in mouse podocytes through CXCL9-mediated JAK2/STAT3 pathway activation.

Diabetic nephropathy (DN) is a serious and one of the most common microvascular complications of diabetes. There is accumulating evidence to indicate that advanced glycation end products (AGEs), senescent macroprotein derivatives formed at an accelerated rate under conditions of diabetes, play a role in DN. In this study, we found that the serum and urine levels of C-X-C motif chemokine ligand 9 (CXCL9) were significantly elevated in patients with DN compared with healthy controls. Based on an in vitro model of mouse podocyte injury, AGEs decreased the proliferation of podocytes and increased the expression of CXCL9 and C-X-C motif chemokine receptor 3 (CXCR3), and promoted the activation of signal transducer and activator of transcription 3 (STAT3). The knockdown of CXCL9 by the transfection of mouse podoyctes with specific siRNA significantly increased the proliferation and decreased the apoptosis of the podoyctes. Moreover, the levels of inflammatory factors, such as tumor necrosis factor (TNF)­α and interleukin (IL)­6 were also decreased in the podoyctes transfected with siRNA-CXCL9, accompanied by the increased expression of nephrin and podocin, and decreased levels of Bax/Bcl-2 and activated caspase-3. The knockdown of CXCL9 also led to the inactivation of the Janus kinase 2 (JAK2)/STAT3 pathway. Importantly, the use of the JAK2 inhibitor, AG490, and valsartan (angiotensin II receptor antagonist) attenuated the injury induced to mouse podoyctes by AGEs. On the whole, and to the best of our knowledge, this study demonstrates for the first time that AGEs exert pro-apoptotic and pro-inflammatory effects in mouse podoyctes through the CXCL9-mediated activation of the JAK2/STAT3 pathway. Thus, our data provide a potential therapeutic target for DN.

A core-shell metal-organic-framework (MOF)-based smart nanocomposite for efficient NIR/H2O2-responsive photodynamic therapy against hypoxic tumor cells.

Core-shell MOF-based smart nanocomposite UCNPs/MB@ZIF-8@catalase (UCNPs = upconversion nanoparticles; MB = methylene blue; ZIF = zeolitic imidazolate framework) has been constructed for bio-imaging and efficient NIR/H2O2-responsive photodynamic therapy against hypoxic tumor cells. The nanoporous MOF shell can prevent aggregation of photosensitizers and serve as an efficient self-sufficient oxygen gas acceptor.

Additive Neuroprotective Effect of Borneol with Mesenchymal Stem Cells on Ischemic Stroke in Mice.

Intravenous stem cell transplantation initiates neuroprotection related to the secretion of trophic factor. Borneol, a potential herbal neuroprotective agent, is a penetration enhancer. Here, we aimed to investigate whether they have additive neuroprotective effect on cerebral ischemia. Borneol was given to mice by gavage 3 days before middle cerebral artery occlusion (MCAO) induction until the day when the mice were sacrificed. Mesenchymal stem cells (MSCs) were intravenously injected at 24 h after MCAO induction. Neurological deficits, infarct volume, cell death, and neurogenesis were evaluated. Combined use of MSCs and borneol could more effectively reduce infarction volume and cell apoptosis, enhance neurogenesis, and improve the functional recovery than that of MSCs alone. The findings showed that combined use of borneol and stem cells provided additive neuroprotective effect on cerebral ischemia. However, the supposed effect of borneol on the improved MSC penetration still needs further direct evidence.

ACVR1-Fc suppresses BMP signaling and chondro-osseous differentiation in an in vitro model of Fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease of heterotopic endochondral ossification (HEO), and currently no effective therapies are available for this disease. A recurrent causative heterozygous mutation (c.617 G>A; R206H) for FOP was identified in activin receptor type IA (ACVR1), a bone morphogenetic protein (BMP) type I receptor. This mutation aberrantly activates the BMP-Smad1/5/8 signaling pathway and leads to HEO in FOP patients. Here we report development of a soluble recombinant ACVR1-Fc fusion protein by combining the extracellular domain of human wild type ACVR1 and the Fc portion of human immunoglobulin gamma 1 (IgG1). The ACVR1-Fc fusion protein significantly down-regulated the dysregulated BMP signaling caused by the FOP ACVR1 mutation and effectively suppressed chondro-osseous differentiation in a previously described cellular FOP model, human umbilical vein endothelial cells (HUVECs) that were infected with adenovirus-ACVR1R206H (HUVECR206H). This ACVR1-Fc fusion protein holds great promise for prevention and treatment of HEO in FOP and related diseases.

Magnetic Properties Controlled by Interstitial or Interlayer Cations in Iron Chalcogenides.

By applying density functional theory calculations to iron chalcogenides, we find that magnetic order in Fe1+yTe and magnetic instability at (π, π) in KyFe2Se2 are controlled by interstitial and interlayer cations, respectively. While in Fe1+yTe, magnetic phase transitions occur among collinear, exotic bicollinear and plaquette-ordered antiferronmagnetic states when the height of interstitial irons measured from iron plane or the concentration of interstitial irons is varied, the magnetic instability at (π, π) which is believed to be responsible for the Cooper pairing in iron pnictides is significantly enhanced when y is much smaller than 1 in KyFe2Se2. Our results indicate that, similar to iron pnictides, itinerant electrons play important roles in iron chalcogenides, even though the fluctuating local moments become larger.

Adipocytes exert lipotoxic effects on osteoblast through activating hypoxia signaling pathway in vitro.

This study aimed to investigate the effect of adipocytes on osteoblastic bone formation in vitro. The differentiated and undifferentiated 3T3-L1 cells were co-cultured with primary calvarial osteoblasts. At 48 h, proliferated osteoblasts decreased significantly after co-culture with differentiated preadipocytes as compared to those co-cultured with undifferentiated preadipocytes; at 7 days, the expressions of bone formation-related genes decreased in osteoblasts co-cultured with differentiated preadipocytes; at 14 days, osteoblasts mineralization also decreased significantly after co-culture with differentiated preadipocytes. To further determine whether the decreased proliferation and mineralization were related to the hypoxia signaling pathway, the expressions of hypoxia related-genes were detected. Results showed the expressions of these genes significantly increased after co-culture with differentiated preadipocytes. NF-κB and IL-6 expressions were also up-regulated in osteoblasts co-cultured with differentiated preadipocytes. Osteoblasts from Hif1α(f/f) mice showed increased proliferation and mineralization after co-culture with adipocytes transfected with adenoviral-cre, accompanied by up-regulated expressions of bone formation-related genes and down-regulated expressions of NF-κB and IL-6. These results demonstrated that adipocytes exert a negative effect on the proliferation and mineralization of osteoblasts via up-regulating the expressions of hypoxia-related genes, and NF-κB and IL-6 may impair the osteoblastic bone formation.

Primary cN0 lip squamous cell carcinoma and elective neck dissection: Systematic review and meta-analysis.

BACKGROUND: Management of clinically negative lymph nodes (cN0) in primary lip squamous cell carcinoma (SCC) has always been a controversial topic. METHODS: A systematic review of English-language electronic databases using Medline, Embase, Cochrane library, Google Scholar, SCI, and specific journals on the subject matter was done. Only the studies mentioning primary nonmetastatic lip SCC with cN0 neck treated by surgery only and having at least 2 years of follow-up data were selected. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews and meta-analysis was followed. RESULTS: The pooled estimate of occult metastasis in neck dissected specimen was 0.17 (95% confidence interval [CI], 0.10-0.28) and that of delayed nodal metastasis in patients without neck dissection was 0.08 (95% CI, 0.01-0.18). CONCLUSION: The results do not prove sufficient to justify elective treatment of the neck in primary cN0 lip SCC and close observation would be a viable option in such cases. © 2014 Wiley Periodicals, Inc. Head Neck 37: 1392-1400, 2015.

Mitochondrial translocation of cofilin is required for allyl isothiocyanate-mediated cell death via ROCK1/PTEN/PI3K signaling pathway.

BACKGROUND: Cofilin is a member of the actin depolymerizing factor (ADF)/cofilin family, which regulates actin dynamics. Increasing evidence suggests that mitochondrial translocation of cofilin appears necessary for the regulation of apoptosis. RESULTS: We report that allyl isothiocyanate (AITC) potently induces mitochondria injury and apoptosis. These events were accompanied by a loss of polymerized filamentous actin (F-actin) and increase in unpolymerized globular actin (G-actin). AITC also induces dephosphorylation of cofilin through activation of PP1 and PP2A. Only dephosphorylated cofilin binds to G-actin and translocates to mitochondria during AITC-mediated apoptosis. Mechanistic study revealed that interruption of ROCK1/PTEN/PI3K signaling pathway plays a critical role in AITC-mediated dephosphorylation and mitochondrial translocation of cofilin and apoptosis. Our in vivo study also showed that AITC-mediated inhibition of tumor growth of mouse leukemia xenograft model is in association with dephosphorylation of cofilin. CONCLUSIONS: These findings support a model in which induction of apoptosis by AITC stems primarily from activation of ROCK1 and PTEN, and inactivation of PI3K, leading in turn to activation of PP1 and PP2A, resulting in dephosphorylation of cofilin, which binds to G-actin and translocates to mitochondria, culminating in the dysfunction of mitochondria, release of cytochrome c and apoptosis.

Bevacizumab rescue therapy extends the survival in patients with recurrent malignant glioma.

OBJECTIVE: We retrospectively studied the efficacy of bevacizumab as salvage therapy for recurrent malignant glioma with a focus on the overall survival (OS). METHODS: Patients who received a therapy other than surgery for recurrent malignant glioma were included. Efficacy was evaluated using MRI. Neurological function was evaluated using the Response Assessment in Neuro-Oncology (RANO). The survival rate was calculated using the Kaplan-Meier method. RESULTS: Fifty-one patients with recurrent glioma (31 grade III, 20 grade IV) were included. Among them, 22 subjects (43.1%) received bevacizumab. The median OS was 10.2 months (range, 1 to 27 months). Patients receiving bevacizumab had comparable OS (a median of 9.9 vs. 10.0 months) and similar 6-month survival rate (43% vs. 34%) to those who did not receive bevacizumab. A subgroup analysis failed to notice any significant difference in grade III glioma patients receiving bevacizumab vs. those who did not. The median survival was significantly longer at 8.9 months (range, 4 to 13 months) in grade IV glioma patients receiving bevacizumab than in those who did not (5.6 months, range, 2 to 7 months, P=0.042). The 6-month survival rate was higher (83%) in those who received bevacizumab than in those who did not (47%, P=0.046). No grade 3/4 adverse events were observed in any patient. CONCLUSIONS: Bevacizumab, as a rescue therapy, provides a survival benefit for recurrent grade IV glioma.

Colonization and plant growth promoting characterization of endophytic Pseudomonas chlororaphis strain Zong1 isolated from Sophora alopecuroides root nodules

The endophytic strain Zong1 isolated from root nodules of the legume Sophora alopecuroides was characterized by conducting physiological and biochemical tests employing gfp-marking, observing their plant growth promoting characteristics (PGPC) and detecting plant growth parameters of inoculation assays under greenhouse conditions. Results showed that strain Zong1 had an effective growth at 28 ºC after placed at 4-60 ºC for 15 min, had a wide range pH tolerance of 6.0-11.0 and salt tolerance up to 5% of NaCl. Zong1 was resistant to the following antibiotics (µg/mL): Phosphonomycin (100), Penicillin (100) and Ampicillin (100). It could grow in the medium supplemented with 1.2 mmol/L Cu, 0.1% (w/v) methylene blue and 0.1-0.2% (w/v) methyl red, respectively. Zong1 is closely related to Pseudomonas chlororaphis based on analysis the sequence of 16S rRNA gene. Its expression of the gfp gene indicated that strain Zong1 may colonize in root or root nodules and verified by microscopic observation. Furthermore, co-inoculation with Zong1 and SQ1 (Mesorhizobium sp.) showed significant effects compared to single inoculation for the following PGPC parameters: siderophore production, phosphate solubilization, organic acid production, IAA production and antifungal activity in vitro. These results suggest strains P. chlororaphi Zong1 and Mesorhizobium sp. SQ1 have better synergistic or addictive effect. It was noteworthy that each growth index of co-inoculated Zong1+SQ1 in growth assays under greenhouse conditions is higher than those of single inoculation, and showed a significant difference (p < 0.05) when compared to a negative control. Therefore, as an endophyte P. chlororaphis Zong1 may play important roles as a potential plantgrowth promoting agent.