bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two major gate-keepers in the self-renewal of neural stem cells: Erk1/2 and PLCγ1 in FGFR signaling
Authors: Lee Jin-A , Jang Deok-Jin , Kaang Bong-Kiun 
Published: June 2009

Abstract
Neural stem cells are undifferentiated precursor cells that proliferate, self-renew, and give rise to neuronal and glial lineages. Understanding the molecular mechanisms underlying their self-renewal is an important aspect in neural stem cell biology. The regulation mechanisms governing self-renewal of neural stem cells and the signaling pathways responsible for the proliferation and maintenance of adult stem cells remain largely unknown. In this issue of Molecular Brain [Ma DK et al. Molecular genetic analysis of FGFR1 signaling reveals distinct roles of MAPK and PLCγ1 activation for self-renewal of adult neural stem cells. Molecular Brain 2009, 2:16], characterized the different roles of MAPK and PLCγ1 in FGFR1 signaling in the self-renewal of neural stem cells. These novel findings provide insights into basic neural stem cell biology and clinical applications of potential stem-cell-based therapy.
Molecular genetic analysis of FGFR1 signalling reveals distinct roles of MAPK and PLCγ1 activation for self-renewal of adult neural stem cells
Authors: Ma Dengke K , Ponnusamy Karthikeyan , Song Mi-Ryoung , Ming Guo-li , Song Hongjun 
Published: June 2009

Abstract

Background
Neural stem cells (NSCs) are present in the adult mammalian brain and sustain life-long adult neurogenesis in the dentate gyrus of the hippocampus. In culture, fibroblast growth factor-2 (FGF-2) is sufficient to maintain the self-renewal of adult NSCs derived from the adult rat hippocampus. The underlying signalling mechanism is not fully understood.

Results
In the established adult rat NSC culture, FGF-2 promotes self-renewal by increasing proliferation and inhibiting spontaneous differentiation of adult NSCs, accompanied with activation of MAPK and PLC pathways. Using a molecular genetic approach, we demonstrate that activation of FGF receptor 1 (FGFR1), largely through two key cytoplasmic amino acid residues that are linked to MAPK and PLC activation, suffices to promote adult NSC self-renewal. The canonical MAPK, Erk1/2 activation, is both required and sufficient for the NSC expansion and anti-differentiation effects of FGF-2. In contrast, PLC activation is integral to the maintenance of adult NSC characteristics, including the full capacity for neuronal and oligodendroglial differentiation.

Conclusion
These studies reveal two amino acid residues in FGFR1 with linked downstream intracellular signal transduction pathways that are essential for maintaining adult NSC self-renewal. The findings provide novel insights into the molecular mechanism regulating adult NSC self-renewal, and pose implications for using these cells in potential therapeutic applications.
Tissue-specific variation in DNA methylation levels along human chromosome 1
Authors: De Bustos Cecilia , Ramos Edward , Young Janet M , Tran Robert K , Menzel Uwe , Langford Cordelia F , Eichler Evan E , Hsu Li , Henikoff Steve , Dumanski Jan P , Trask Barbara J 
Published: June 2009

Abstract

Background
DNA methylation is a major epigenetic modification important for regulating gene expression and suppressing spurious transcription. Most methods to scan the genome in different tissues for differentially methylated sites have focused on the methylation of CpGs in CpG islands, which are concentrations of CpGs often associated with gene promoters.

Results
Here, we use a methylation profiling strategy that is predominantly responsive to methylation differences outside of CpG islands. The method compares the yield from two samples of size-selected fragments generated by a methylation-sensitive restriction enzyme. We then profile nine different normal tissues from two human donors relative to spleen using a custom array of genomic clones covering the euchromatic portion of human chromosome 1 and representing 8% of the human genome. We observe gross regional differences in methylation states across chromosome 1 between tissues from the same individual, with the most striking differences detected in the comparison of cerebellum and spleen. Profiles of the same tissue from different donors are strikingly similar, as are the profiles of different lobes of the brain. Comparing our results with published gene expression levels, we find that clones exhibiting extreme ratios reflecting low relative methylation are statistically enriched for genes with high expression ratios, and vice versa, in most pairs of tissues examined.

Conclusion
The varied patterns of methylation differences detected between tissues by our methylation profiling method reinforce the potential functional significance of regional differences in methylation levels outside of CpG islands.
Somatostatin and opioid receptors do not regulate proliferation or apoptosis of the human multiple myeloma U266 cells
Authors: Kerros Céline , Cavey Thibault , Sola Brigitte , Jauzac Philippe , Allouche Stéphane 
Published: June 2009

AbstractBackgroundopioid and somatostatin receptors (SSTRs) that can assemble as heterodimer were individually reported to modulate malignant cell proliferation and to favour apoptosis. Materials and methods: SSTRs and opioid receptors expression were examined by RT-PCR, western-blot and binding assays, cell proliferation was studied by XTT assay and propidium iodide (PI) staining and apoptosis by annexin V-PI labelling.Resultsalmost all human malignant haematological cell lines studied here expressed the five SSTRs. Further experiments were conducted on the human U266 multiple myeloma cells, which express also μ-opioid receptors (MOP-R). XTT assays and cell cycle studies provide no evidence for a significant effect upon opioid or somatostatin receptors stimulation. Furthermore, neither direct effect nor potentiation of the Fas-receptor pathway was detected on apoptosis after these treatments.Conclusionthese data suggest that SSTRs or opioid receptors expression is not a guaranty for an anti-tumoral action in U266 cell line.
Mechanical ventilation during experimental sepsis increases deposition of advanced glycation end products and myocardial inflammation
Authors: Kneyber Martin CJ , Gazendam Roel P , Niessen Hans WM , Kuiper Jan-Willem , Dos Santos Claudia C , Slutsky Arthur S , Plötz Frans B 
Published: June 2009

Abstract
Introduction
Increasing evidence links advanced glycation end products (AGE) including Nε-(carboxymethyl)lysine (CML) to the development of heart failure. Accumulation of AGE leads to myocardial inflammation, which is considered as one of the possible mechanisms underlying sepsis-induced cardiac dysfunction. We hypothesized that mechanical ventilation (MV) augmented sepsis-induced myocardial CML deposition and inflammation.

Methods
Sepsis was induced using a modified cecal ligation and perforation (CLP) technique in 36 male adult Sprague Dawley rats. Rats were randomized to four hours of MV with low tidal volume (LTV: 6 ml/kg, PEEP 5 cmH2O, n = 10) or high tidal volume (HTV: 15 ml/kg, PEEP 3 cmH2O, n = 10) 24 hours after the induction of sepsis. Eight rats served as septic, non-ventilated controls and eight as non-septic, non-ventilated controls. After 28 hours all rats were killed. The number of extravascular polymorphonuclear (PMN) leucocytes, macrophages, and lymphocytes was measured as the number of positive cells/mm2. The number of CML positive endothelial cells were semi-quantified based upon an intensity score. The CML intensity score was correlated with the number of inflammatory cells to study the association between CML depositions and inflammation.

Results
Gas exchange was comparable between the ventilated groups. Sepsis induced a significant increase in CML deposition in both ventricles that was significantly augmented by MV compared with non-ventilated septic controls (left ventricle 1.1 ± 1.0 vs 0.7 ± 0.1, P = 0.030; right ventricle 2.5 ± 0.5 vs 0.6 ± 0.1, P = 0.037), irrespective of ventilatory strategy. In the right ventricle there was a non-significant tendency towards increased CML deposition in the HTV group compared with septic, non-ventilated controls (1.0 ± 0.1 vs 0.7 ± 0.09, P = 0.07). Sepsis induced a significant increase in the number of macrophages and PMNs compared with non-ventilated septic controls that was augmented by MV, irrespective of ventilatory strategy. CML deposition was significantly correlated with the number of macrophages and PMNs in the heart.

Conclusions
Sepsis induces CML deposition in the heart with a predominant right ventricular inflammation that is significantly augmented by MV, irrespective of the ventilatory strategy.
Prospective Minimal Residual Disease Monitoring to Predict Relapse of Acute Promyelocytic Leukemia and to Direct Pre-Emptive Arsenic Trioxide Therapy
Authors: Grimwade David , Jovanovic Jelena V. , Hills Robert K. , Nugent Elizabeth A. , Patel Yashma , Flora Rajinder , Diverio Daniela , Jones Katy , Aslett Hannah , Batson Elaine , Rennie Kristian , Angell Roger , Clark Richard E. , Solomon Ellen , Lo-Coco Francesco , Wheatley Keith , Burnett Alan K. 
Published: June 2009

Purpose Molecular diagnostics and early assessment of treatment response that use methodologies capable of detecting submicroscopic disease can distinguish subgroups of patients with leukemia at differing relapse risk. Such information is being incorporated into risk-stratified protocols; however, there are few data concerning prospective use of sequential minimal residual disease (MRD) monitoring to identify more precisely those patients destined to experience relapse, which would allow more tailored therapies. Methods Real-time quantitative polymerase chain reaction (RQ-PCR) assays to detect leukemia-specific transcripts (ie, PML-RARA, RARA-PML) were used to prospectively analyze 6,727 serial blood and marrow samples from 406 patients with newly diagnosed acute promyelocytic leukemia (APL) who were receiving all-trans-retinoic acid and anthracycline-based chemotherapy. Results MRD monitoring according to the recommended schedule successfully identified the majority of patients subject to relapse and provided the most powerful predictor of relapse-free survival (RFS) in multivariable analysis (hazard ratio, 17.87; 95% CI, 6.88 to 46.41; P < .0001); MRD monitoring was far superior to presenting WBC (hazard ratio, 1.02; 95% CI, 1.00 to 1.03; P = .02), which is currently widely used to guide therapy. In patients who were predicted to experience relapse on the basis of MRD monitoring, early treatment intervention with arsenic trioxide prevented progression to overt relapse in the majority, and the RFS rate at 1 year from molecular relapse was 73%. By using this strategy, 3-year cumulative incidence of clinical relapse was only 5% in the Medical Research Council AML15 trial. Conclusion Rigorous sequential RQ-PCR monitoring provides the strongest predictor of RFS in APL and, when coupled with pre-emptive therapy, provides a valid strategy to reduce rates of clinical relapse. This provides a model for development of a more individualized approach to management of other molecularly defined subtypes of acute leukemia.
Primary Therapy of Waldenström Macroglobulinemia With Bortezomib, Dexamethasone, and Rituximab: WMCTG Clinical Trial 05-180
Authors: Treon Steven P. , Ioakimidis Leukothea , Soumerai Jacob D. , Patterson Christopher J. , Sheehy Patricia , Nelson Marybeth , Willen Michael , Matous Jeffrey , Mattern John , Diener Jakow G. , Keogh George P. , Myers Thomas J. , Boral Andy , Birner Ann , Esseltine Dixie L. , Ghobrial Irene M. 
Published: June 2009

Purpose We examined the activity of bortezomib, dexamethasone, and rituximab (BDR) in patients with symptomatic, untreated Waldenström macroglobulinemia (WM). Patients and Methods A cycle of therapy consisted of bortezomib 1.3 mg/m2 intravenously; dexamethasone 40 mg on days 1, 4, 8, and 11; and rituximab 375 mg/m2 on day 11. Patients received four consecutive cycles for induction therapy and then four more cycles, each given 3 months apart, for maintenance therapy. Twenty-three patients received a median of seven cycles of treatment. Results Median bone marrow disease involvement declined from 55% to 10% (P = .0004), serum immunoglobulin M levels declined from 4,830 to 1,115 mg/dL (P < .0001), and hematocrit increased from 29.8% to 38.2% (P = .0002) at best response. The overall response rates and major response rates were 96% and 83% with three complete responses, two near complete responses, three very good partial responses, 11 partial responses, and three minor responses. Responses occurred at a median of 1.4 months. With a median follow-up of 22.8 months, 18 of 23 patients remained free of disease progression. Peripheral neuropathy was the most common toxicity, and it resolved to grade ≤ 1 in 13 of 16 patients at a median of 6.0 months. Four of the first seven treated patients developed herpes zoster, resulting in the institution of prophylactic antiviral therapy. Conclusion The results demonstrate that BDR produces rapid and durable responses, along with high rates of response and complete remissions in WM. Herpes zoster prophylaxis is necessary with BDR, and reversible peripheral neuropathy was the most common toxicity leading to premature discontinuation of bortezomib in 61% of patients. Exploration of alternative schedules for bortezomib administration that includes weekly dosing should be pursued.
Protective effect of JBP485 on concanavalin A-induced liver injury in mice
Authors: Yang Tao , Wu Jingjing , Wang Changyuan , Liu Qi , Ma Xiaochi , Peng Jinyong , Kaku Taiichi , Liu Kexin 
Published: June 2009

AbstractObjectivesCyclo-trans-4-L-hydroxyprolyl-L-serine (JBP485) was first isolated from Laennec (hydrolysate of human placenta). We thought it valuable to clarify the antihepatitis molecular mechanism of JBP485 to develop a new oral anti-hepatitis drug.MethodsWe investigated the hepatoprotective effect of JBP485 on immune-mediated, concanavalin A (Con A)-induced liver injury in mice. Mice were administered JBP485 before and after injection of Con A (10 mg/kg). Eight hours after Con A, the cytosolic enzyme activity (alanine aminotransferase, lactate dehydrogenase) in serum, and the enzyme activity or concentration (superoxide dismutase, maleic dialdehyde, myeloperoxidase, nitric oxide) in liver homogenate were determined. The liver slices were investigated to observe changes in histology. The effect of JBP485 on level of tumour necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1) in liver were detected by immunohistochemistry. Hepatocyte DNA fragmentation was assayed by agarose gel electrophoresis and the transcription of the genes bax and bcl-2 in hepatocytes was determined by reverse transcription-polymerase chain reaction.Key findingsCon A increased the cytosolic and liver homogenate enzyme activity, and the concentrations of ICAM-1 and TNF-α, which were significantly inhibited by JBP485 administration. Also, the increase in DNA fragmentation and decrease in bcl-2/bax mRNA induced by Con A administration were significantly inhibited by JBP485.ConclusionsThese results indicated that immune-mediated liver damage can be prevented by JBP485, and that this is mainly associated with immunomodulatory effects on T cells and adhesion molecules, antioxidation, and inhibition of apoptosis.
Synergistic action of statins and nitrogen-containing bisphosphonates in the development of rhabdomyolysis in L6 rat skeletal myoblasts
Authors: Matzno Sumio , Nishiguchi Tomoko , Akiyoshi Takeshi , Anami Setsuko , Nakabayashi Toshikatsu , Matsuyama Kenji 
Published: June 2009

Abstract

Objectives
Nitrogen-containing bisphosphonates, which are widely used to treat osteoporosis, act as inhibitors of farnesyl pyrophosphate synthase, one of the key enzymes of the mevalonate pathway, and thus may have the potential to enhance the effect of statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase). In this study, we evaluated the synergistic effect of two nitrogen-containing bisphosphonates, alendronate and risedronate, in statin-induced apoptosis in rat skeletal L6 myoblasts.

Methods
L6 rat myoblasts were differentiated with drugs. DNA fragmentation was measured and small GTPase was detected by immunoblotting.

Key findings
Alendronate and risedronate caused dose-dependent apoptosis of L6 myoblasts. Risedronate induced detachment of rho GTPase from the cell membrane, followed by activation of the caspase-8-related cascade. Risedronate-induced apoptosis was synergistically enhanced with atorvastatin and significantly reduced by addition of geranylgeraniol. By contrast, alendronate did not reduce membrane GTPases and the apoptosis was caspase independent.

Conclusions
These results suggest that risedronate-induced apoptosis is related to geranylgeranyl pyrophosphate depletion followed by rho detachment, whereas alendronate affects are independent of rho. Our results suggest a risk of synergistic action between nitrogen-containing bisphosphonates and statins in the development of rhabdomyolysis when treating osteoporosis in women with hyperlipidaemia.
Protective effects of water-soluble low-molecular-weight β-(1,3-1,6)D-glucan purified from Aureobasidium pullulans GM-NH-1A1 against UFT toxicity in mice
Authors: Kimura Yoshiyuki , Sumiyoshi Maho , Suzuki Toshio 
Published: June 2009

Abstract

Objectives
5-Fluorouracil and its derivatives are widely used in the treatment of a variety of tumours. However, their use is associated with gastrointestinal toxicity, myelotoxicity and immune toxicity. In this study, we examined the protective effects of low-molecular-weight β-glucan isolated from Aureobasidium pullulans GM-NH-1A1 against toxicity of UFT (combination of tegafur (1-(2-tetrahydrofuryl)-5-fluorouracil) and uracil) in mice bearing colon 26 tumours.

Methods
UFT was administered orally at 50 mg/kg once daily for 14 days alone or with orally administered low-molecular-weight β-glucan, 25, 50 and 100 mg/kg twice daily.

Key findings
Tumour growth was inhibited equally in all treatment groups. Onset of diarrhoea, which started on day 9 of UFT administration, was delayed by concomitant administration of the β-glucan (50 and 100 mg/kg twice daily). Histological analysis showed that damage to small-intestine villi by UFT was inhibited by the orally administered β-glucan.

Conclusions
Oral administration of low-molecular-weight β-glucan prevents gastrointestinal mucositis associated with UFT therapy without interfering with its anti-tumour activity.
Effect of hesperidin on the oral pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats
Authors: Cho Young-Ah , Choi Dong-Hyun , Choi Jun-Shik 
Published: June 2009

AbstractObjectivesThis study was to investigate the effect of hesperidin, an antioxidant, on the bioavailability and pharmacokinetics of diltiazem and its active major metabolite, desacetyldiltiazem, in rats.MethodsA single dose of diltiazem was administered orally (15 mg/kg) in the presence or absence of hesperidin (1, 5 or 15 mg/kg), which was administered 30 min before diltiazem.Key findingsCompared with the control group (given diltiazem alone), hesperidin (5 or 15 mg/kg) significantly altered the pharmacokinetic parameters of diltiazem, except for 1 mg/kg hesperidin. The area under the plasma concentration-time curve from time 0 h to infinity (AUC0-∞) was significantly (5 mg/kg, P &lt; 0.05; 15 mg/kg, P &lt; 0.01) increased by 48.9–65.3% and the peak plasma concentration (Cmax) was significantly (P &lt; 0.05) increased by 46.7–62.4% in the presence of hesperidin (5 or 15 mg/kg). Consequently, the absolute bioavailability (F) of diltiazem with hesperidin was significantly (5 mg/kg, P &lt; 0.05; 15 mg/kg, P &lt; 0.01) higher than that in the control group. Hesperidin (5 or 15 mg/kg) significantly (P &lt; 0.05) increased the AUC0-∞ and 15 mg/kg of hesperidin significantly (P &lt; 0.05) increased the Cmax of desacetyldiltiazem. However, the metabolite-parent ratio (MR) of desacetyldiltiazem was not significantly changed in the presence of hesperidin.ConclusionsHesperidin significantly enhanced the oral bioavailability of diltiazem in rats. It might be considered that hesperidin increased the intestinal absorption and reduced the first-pass metabolism of diltiazem in the intestine and in the liver via an inhibition of cytochrome P450 3A or P-glycoprotein.
Predictors of STDs Among Asian and Pacific Islander Young Adults
Authors: Hahm Hyeouk Chris , Lee Jieha , Ozonoff Al , Amodeo Maryann 
Published: June 2009

CONTEXT:  Limited information is available on factors associated with STDs among Asian and Pacific Islander young adults. Such information is vital to developing effective interventions to reduce STDs within this group. METHODS:  Data were derived from the National Longitudinal Study of Adolescent Health, Wave 3; the sample consisted of 605 female and 578 male Asian and Pacific Islander young adults. Logistic regression analysis was used to assess factors associated with ever having had an STD. RESULTS:  Thirteen percent of females and 4% of males had ever had an STD. Among those who had had an STD, 75% were female, 9% had ever been paid for sex, 31% had had sex before age 15 and 55% had had multiple sex partners in the previous 12 months. Being female (odds ratio, 4.1), being Indian (compared with being Filipino; 4.8), having ever been paid money for sex (4.7) and having had more than one sex partner in the past 12 months (2.5) were associated with increased odds of having had an STD diagnosis. The more respondents believed that STDs were responsive to treatment, the greater their odds of having had an STD (2.3); the more they believed that STDs had negative consequences for a relationship, the lower their odds of having had an STD (0.7). CONCLUSIONS:  Asian and Pacific Islander women and Indians are priority groups for both research and clinical attention; prevention efforts to reduce STDs should be tailored to these groups. Clinicians working with Asians and Pacific Islanders need to focus on clients’ number of sexual partners and health‐related beliefs.
Timing of Sexual Debut and Initiation of Postsecondary Education by Early Adulthood
Authors: Spriggs Aubrey L , Halpern Carolyn Tucker 
Published: June 2009

CONTEXT:  Although sexual debut has been negatively associated with adolescent educational performance and aspirations, it is not clear whether such relationships continue beyond adolescence. METHODS:  Initiation of postsecondary education by young adulthood was assessed among 3,965 participants in the National Longitudinal Study of Adolescent Health who had not experienced sexual intercourse at baseline. Associations between age at sexual debut and educational progress were examined in bivariate and multivariable Poisson regression analyses. RESULTS:  Most respondents experienced sexual debut during adolescence: 15% before age 16 (early) and 53% at ages 16–18 (typical). Sixty‐five percent of respondents initiated postsecondary education by early adulthood; however, the proportion was significantly lower among those who had had an early (49%) or typical sexual debut (63%) than among those who debuted late (78%). In unadjusted analyses, early and typical debut were associated with a reduced likelihood of initiation of postsecondary education for both females (relative risk ratios, 0.6 and 0.8, respectively) and males (0.7 and 0.8). However, in adjusted analyses, the associations were attenuated for females (0.8 and 0.9) and were at best marginally significant for males. Childbearing was a significant mediator of this relationship. CONCLUSIONS:  Adolescent sexual debut appears to be modestly negatively associated with early adult postsecondary education initiation, particularly for females. Targeting mediators of the sexual debut–education relationship, such as early childbearing, could lead to effective interventions.