bluuebunny/crossref_metadata_2025_split huggingface dataset:
COX-2 and PPAR-γ Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells
Authors: Ramer Robert , Heinemann Katharina , Merkord Jutta , Rohde Helga , Salamon Achim , Linnebacher Michael , Hinz Burkhard 
Published: December 2012

Abstract
The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 and PPAR-γ in cannabidiol's proapoptotic and tumor-regressive action. In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. Apoptotic cell death by cannabidiol was suppressed by NS-398 (COX-2 inhibitor), GW9662 (PPAR-γ antagonist), and siRNA targeting COX-2 and PPAR-γ. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-γ mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-γ mRNA when compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2–dependent prostaglandins (PG) among which PGD2 and 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) caused a translocation of PPAR-γ to the nucleus and induced a PPAR-γ–dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-γ in tumor tissue and tumor regression that was reversible by GW9662. Together, our data show a novel proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2 and PPAR-γ and a subsequent nuclear translocation of PPAR-γ by COX-2–dependent PGs. Mol Cancer Ther; 12(1); 69–82. ©2012 AACR.
Activating HER2 Mutations in HER2 Gene Amplification Negative Breast Cancer
Authors: Bose Ron , Kavuri Shyam M. , Searleman Adam C. , Shen Wei , Shen Dong , Koboldt Daniel C. , Monsey John , Goel Nicholas , Aronson Adam B. , Li Shunqiang , Ma Cynthia X. , Ding Li , Mardis Elaine R. , Ellis Matthew J. 
Published: December 2012

Abstract
Data from 8 breast cancer genome-sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized 13 HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755–759, which is homologous to EGF receptor (EGFR) exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings show that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment.
Significance: We show that the majority of HER2 somatic mutations in breast cancer patients are activating mutations that likely drive tumorigenesis. Several patients had mutations that are resistant to the reversible HER2 inhibitor lapatinib, but are sensitive to the irreversible HER2 inhibitor, neratinib. Our results suggest that patients with HER2 mutation–positive breast cancers could benefit from existing HER2-targeted drugs. Cancer Discov; 3(2); 224–37. ©2013 AACR.
See related commentary by Weigelt and Reis-Filho, p. 145
This article is highlighted in the In This Issue feature, p. 125
Vascular Smooth Muscle Cell Sirtuin 1 Protects Against DNA Damage and Inhibits Atherosclerosis
Authors: Gorenne Isabelle , Kumar Sheetal , Gray Kelly , Figg Nichola , Yu Haixiang , Mercer John , Bennett Martin 
Published: December 2012

Background—
Vascular smooth muscle cells (VSMCs) in human atherosclerosis manifest extensive DNA damage and activation of the DNA damage response, a pathway that coordinates cell cycle arrest and DNA repair, or can trigger apoptosis or cell senescence. Sirtuin 1 deacetylase (SIRT1) regulates cell ageing and energy metabolism and regulates the DNA damage response through multiple targets. However, the direct role of SIRT1 in atherosclerosis and how SIRT1 in VSMCs might regulate atherosclerosis are unknown.

Methods and Results—

SIRT1 expression was reduced in human atherosclerotic plaques and VSMCs both derived from plaques and undergoing replicative senescence. SIRT1 inhibition reduced DNA repair and induced apoptosis, in part, through reduced activation of the repair protein Nijmegen Breakage Syndrome-1 but not p53. Fat feeding reduced SIRT1 and induced DNA damage in VSMCs. VSMCs from mice expressing inactive truncated SIRT1 (Δex4) showed increased oxidized low-density lipoprotein–induced DNA damage and senescence. ApoE
−/−
mice expressing SIRT1
Δex4
only in smooth muscle cells demonstrated increased DNA damage response activation and apoptosis, increased atherosclerosis, reduced relative fibrous cap thickness, and medial degeneration.

Conclusions—
SIRT1 is reduced in human atherosclerosis and is a critical regulator of the DNA damage response and survival in VSMCs. VSMC SIRT1 protects against DNA damage, medial degeneration, and atherosclerosis.
Symptomatic Improvement Reported After Receiving Reiki at a Cancer Infusion Center
Authors: Marcus Dawn A. , Blazek-O'Neill Betsy , Kopar Jennifer L. 
Published: December 2012

Objective: To evaluate patient-perceived benefits from receiving Reiki at a cancer infusion center. Methods: During a 6-month period, adults at a university hospital receiving Reiki through volunteer services were invited to complete a survey asking about perceived changes after Reiki. Changes in pain, mood, distress, sleep, and appetite were rated on a 5-point scale from no benefit to great benefit. Surveys were distributed after completing treatment and were returned in postage-paid envelops. Results: A total of 145 surveys were completed (34.5% response rate), with 47 participants seen in the cancer infusion center and 98 in other areas of the hospital. Reiki was rated as a positive experience by 94% at the cancer center and 93% of others, with 92% at the cancer center and 86% of others interested in receiving additional Reiki sessions. Symptomatic improvement was similar for people at the cancer center and others, respectively, with much to great improvement for 89% and 86% for relaxation, 75% and 75% for anxiety/worry, 81% and 78% for improved mood, 43% and 35% for improved sleep, 45% and 49% for reduced pain, 38% and 43% for reduced isolation/loneliness, 75% and 63% for improved attitude, and 30% and 30% for improved appetite. Response was unaffected by previous exposure to Reiki, massage, or other touch therapy. Conclusion: Reiki results in a broad range of symptomatic benefits, including improvements in common cancer-related symptoms.
A computational pipeline for the development of multi-marker bio-signature panels and ensemble classifiers
Authors: Günther Oliver P , Chen Virginia , Freue Gabriela Cohen , Balshaw Robert F , Tebbutt Scott J , Hollander Zsuzsanna , Takhar Mandeep , McMaster W Robert , McManus Bruce M , Keown Paul A , Ng Raymond T 
Published: December 2012

Abstract

Background
Biomarker panels derived separately from genomic and proteomic data and with a variety of computational methods have demonstrated promising classification performance in various diseases. An open question is how to create effective proteo-genomic panels. The framework of ensemble classifiers has been applied successfully in various analytical domains to combine classifiers so that the performance of the ensemble exceeds the performance of individual classifiers. Using blood-based diagnosis of acute renal allograft rejection as a case study, we address the following question in this paper: Can acute rejection classification performance be improved by combining individual genomic and proteomic classifiers in an ensemble?

Results
The first part of the paper presents a computational biomarker development pipeline for genomic and proteomic data. The pipeline begins with data acquisition (e.g., from bio-samples to microarray data), quality control, statistical analysis and mining of the data, and finally various forms of validation. The pipeline ensures that the various classifiers to be combined later in an ensemble are diverse and adequate for clinical use. Five mRNA genomic and five proteomic classifiers were developed independently using single time-point blood samples from 11 acute-rejection and 22 non-rejection renal transplant patients. The second part of the paper examines five ensembles ranging in size from two to 10 individual classifiers. Performance of ensembles is characterized by area under the curve (AUC), sensitivity, and specificity, as derived from the probability of acute rejection for individual classifiers in the ensemble in combination with one of two aggregation methods: (1) Average Probability or (2) Vote Threshold. One ensemble demonstrated superior performance and was able to improve sensitivity and AUC beyond the best values observed for any of the individual classifiers in the ensemble, while staying within the range of observed specificity. The Vote Threshold aggregation method achieved improved sensitivity for all 5 ensembles, but typically at the cost of decreased specificity.

Conclusion
Proteo-genomic biomarker ensemble classifiers show promise in the diagnosis of acute renal allograft rejection and can improve classification performance beyond that of individual genomic or proteomic classifiers alone. Validation of our results in an international multicenter study is currently underway.
Induction of IFNα or IL-12 depends on differentiation of THP-1 cells in dengue infections without and with antibody enhancement
Authors: Chen Rong-Fu , Wang Lin , Cheng Jiin-Tsuey , Yang Kuender D 
Published: December 2012

Abstract

Background
Appropriate induction of the early Th1 cytokine IL-12 is a critical defense directed against viral infection. We have previously shown that different viruses elicited either IL-12 or IFNα dependent Th1 reactions. Using dengue-2 virus, we sought to explore how dengue-2 induced IL-12 or IFNα expression by monocytic and its derived dendritic cells.

Methods
We employed human monocytic cell line, THP-1, to investigate whether differentiation of monocytic cells is involved in the switch between IFNα and IL-12 induction. Flow cytometry, RT-PCR and ELISA were respectively used to determine cell differentiation, IL-12 and IFNα mRNA expression and protein production.

Results
THP-1, expressing CD123, which is a plasmacytoid dendritic cell marker, but not CD14, CD11b or CD11c revealed IFNα mRNA expression while stimulated by dengue-2. In contrast, PMA-induced THP-1 differentiation toward monocytic cells expressed CD11b+, and CD14+, but not CD123, and revealed exclusively IL-12 expression while stimulated by dengue-2. Further studies showed that CD123+ expressing THP-1 cells elicited higher IFNα expression in dose and time dependent induction after infection, and PMA-induced monocytic differentiation of THP-1 cells revealed IL-12 expression. Antibody-dependent enhancement of DEN-2 infection significantly suppressed the DEN-2 induced IL-12 p40 expression in monocytic differentiated THP-1 cells.

Conclusions
Clarification and modulation of the early Th1 reaction in different monocytic cells may change or prevent complication from dengue infection.
In-vitro characterization of novel and functional regulatory SNPs in the promoter region of IL2 and IL2R alpha in a Gabonese population
Authors: Huang Xiangsheng , Kühne Vera , Kun Jürgen F J , Soboslay Peter T , Lell Bertrand , TP Velavan 
Published: December 2012

AbstractBackgroundThe selection pressure imposed by the parasite has a functional consequence on the immune genes, leading to altered immune function in which regulatory T cells (Tregs) induced by parasites during infectious challenges modulate or thwart T effector cell mechanism.MethodsWe identified and investigated regulatory polymorphisms in the immune geneIL2and its receptorIL2R alpha(also known asCD25) in Gabonese individuals exposed to plentiful parasitic infections.ResultsWe identified two reported variants each forIL2and its receptorIL2R alpha gene loci.Also identified were two novel variants, -83 /-84CTdeletions (ss410961576)forIL2and -409C/T(ss410961577)forIL2R alpha. We further validated all identified promoter variants for their allelic gene expression using transient transfection assays. Three promoter variants of theIL2locus revealed no significant expression of the reporter gene. The identified novel variant (ss410961577C/T) of theIL2R alpharevealed a significant higher expression of the reporter gene in comparison to the major allele (P<0.05). In addition, thers12722616C/Tvariant of theIL2R alphalocus altered the transcription factor binding site TBP (TATA box binding protein) and C/EBP beta (CCAAT/enhancer binding protein beta) that are believed to regulate the Treg function.ConclusionsThe identification and validation of such regulatory polymorphisms in the immune genes may provide a basis for future studies on parasite susceptibility in a population where T cell functions are compromised.
Impact of stem cell marker expression on recurrence of TACE-treated hepatocellular carcinoma post liver transplantation
Authors: Zeng Zhen , Ren Jinyu , O’Neil Maura , Zhao Jie , Bridges Brian , Cox Josiah , Abdulkarim Bashar , Schmitt Timothy M , Kumer Sean C , Weinman Steven A 
Published: December 2012

Abstract

Abstract

Background
Liver transplantation is the most effective therapy for cirrhosis-associated hepatocellular carcinoma (HCC) but its utility is limited by post-transplant tumor recurrence. Use of the Milan, size-based criteria, has reduced recurrence rate to less than 10% but many patients remain ineligible. Reduction of tumor size with local therapies has been used to “downstage” patients to allow them to qualify for transplantation, but the optimal criteria to predict tumor recurrence in these latter patients has not been established. The existence of a progenitor cell population, sometimes called cancer stem cells (CSCs), has been proposed to be one mechanism accounting for the chemotherapy resistance and recurrence of hepatocellular carcinoma. The aim of this study was to determine if transcatheter arterial chemoemolization (TACE) treated tumors have increased CSC marker expression and whether these markers could be used to predict tumor recurrence.

Methods
Formalin fixed specimens were obtained from 39 HCC liver explants (23 with no treatment and 16 after TACE). Immunohistochemical staining was performed for EpCAM, CD44, CD90, and CD133. Staining for each marker was scored 0–3 by evaluating the number and intensity of positive tumor cells in 5 hpf of tumor in each specimen.

Results
TACE treated tumors displayed greater necrosis and fibrosis than non-TACE treated samples but there were no differences in morphology between the viable tumor cells of both groups. In TACE treated specimens, the staining of both EpCAM and CD133 was greater than in non-TACE specimens but CD44 and CD90 were the same. In the TACE group, the presence of high EpCAM staining was associated with tumor recurrence. Four of ten EpCAM high patients recurred while 0 of 6 EpCAM low patients recurred (P = 0.040). None of the other markers predicted recurrence.

Conclusion
High pre-transplant EpCAM staining predicted HCC recurrence. This suggests that the abundance of tumor cells with a CSC phenotype may be a critical factor in the likelihood of tumor recurrence in patients receiving liver transplantation after TACE.
A novel model-based approach for dose determination of glycopyrronium bromide in COPD
Authors: Arievich Helen , Overend Tim , Renard Didier , Gibbs Michael , Alagappan Vijay , Looby Michael , Banerji Donald 
Published: December 2012

Abstract

Background
Glycopyrronium bromide (NVA237) is an inhaled long-acting muscarinic antagonist in development for treatment of COPD. This study compared the efficacy and safety of once-daily (OD) and twice-daily (BID) glycopyrronium bromide regimens, using a novel model-based approach, in patients with moderate-to-severe COPD.

Methods
Double-blind, randomized, dose-finding trial with an eight-treatment, two-period, balanced incomplete block design. Patients (smoking history ≥10 pack-years, post-bronchodilator FEV1 ≥30% and <80% predicted, FEV1/FVC <0.7) were randomized to one of 16 independent sequences for 28 days. Primary endpoint: mean trough FEV1 at Day 28.

Results
385 patients (mean age 61.2 years; mean post-bronchodilator FEV1 53% predicted) were randomized; 88.6% completed. All OD and BID dosing regimens produced dose-dependent bronchodilation; at Day 28, increases in mean trough FEV1 versus placebo were statistically significant for all regimens, ranging from 51 mL (glycopyrronium bromide 12.5 μg OD) to 160 mL (glycopyrronium bromide 50 μg BID). Pharmacodynamic steady-state was reached by Day 7. There was a small separation (≤37 mL) between BID and OD dose–response curves for mean trough FEV1 at steady-state in favour of BID dosing. Over 24 hours, separation between OD and BID regimens was even smaller (FEV1 AUC0-24h maximum difference for equivalent daily dose regimens: 8 mL). Dose–response results for FEV1 at 12 hours, FEV1 AUC0-12h and FEV1 AUC0-4h at steady-state showed OD regimens provided greater improvement over placebo than BID regimens for total daily doses of 25 μg, 50 μg and 100 μg, while the reverse was true for OD versus BID regimens from 12–24 hours. The 12.5 μg BID dose produced a marginally higher improvement in trough FEV1 versus placebo than 50 μg OD, however, the response at 12 hours over placebo was suboptimal (74 mL). Glycopyrronium bromide was safe and well tolerated at all doses.

Conclusions
Glycopyrronium bromide 50 μg OD provides significant bronchodilation over a 24 hour period, and in terms of FEV1 AUC0-24h is not significantly different than the same total daily dose administered BID. Importantly, OD dosing may confer better patient adherence. The results are consistent with previous glycopyrronium bromide studies and support once-daily dosing of glycopyrronium bromide 50 μg in patients with moderate-to-severe COPD.

Trial registration
ClinicalTrials.gov: NCT01119950
Plasmodium vivax congenital malaria in an area of very low endemicity in Guatemala: implications for clinical and epidemiological surveillance in a malaria elimination context
Authors: Castellanos María Eugenia , Bardají Azucena , Menegon Michela , Mayor Alfredo , Desai Meghna , Severini Carlo , Menéndez Clara , Padilla Norma 
Published: December 2012

Abstract
This is a report of the first Plasmodium vivax congenital malaria case in Guatemala and the first case in Latin America with genotypical, histological and clinical characterization. The findings show that maternal P. vivax infection still occurs in areas that are in the pathway towards malaria elimination, and can be associated with detrimental health effects for the neonate. It also highlights the need in very low transmission areas of not only maintaining, but increasing awareness of the problem and developing surveillance strategies, based on population risk, to detect the infection especially in this vulnerable group of the population.
Radiation treatment with volumetric modulated arc therapy of hepatocellular carcinoma patients. Early clinical outcome and toxicity profile from a retrospective analysis of 138 patients
Authors: Wang Po-Ming , Hsu Wei-Chung , Chung Na-Na , Chang Feng-Ling , Fogliata Antonella , Cozzi Luca 
Published: December 2012

Abstract

Background
To report early outcome and toxicity for inoperable patients with hepatocellular carcinoma (HCC) treated with volumetric modulated arc therapy (VMAT).

Methods
One hundred and thirty eight patients were retrospectively analysed. Dose prescription ranged from 45 to 66Gy with conventional fractionation regime. Based on AJCC staging, 88.4% presented stage III or IV. Two-thirds (69.6%) were Child-Pugh stage A, the remaining were stage B. According to Barcelona Clinic Liver Cancer staging, 72.5% of patients were classified as stage C.

Results
Median age was 66 years, median tumor volume was 516cm3 (28 to 3620cm3). The most patients (83%) were treated with 60Gy. Median follow-up time was 9 months. One-year overall survival rate was 45% (100% for AJCC stage I, 83% for stage II, 45% for stage III and 28% for stage IV), median survival was 10.3 months (95% C.I. 7.2-13.3). Local control was achieved in 94% (of 109 assessable patients), stable disease in 29%, partial response in 53%, complete response in 11%, and progression in 6%. Radiation-induced liver disease was observed in 34 patients (25%). Gastrointestinal grade 3 toxicity was modest with a total of 17 (12.3%) cases for all endpoints.

Conclusions
Clinical results could suggest to introduce VMAT as an appropriate technique for the patients with HCC.
Gabapentin reduces CX3CL1 signaling and blocks spinal microglial activation in monoarthritic rats
Authors: Yang Jia-Le , Xu Bo , Li Shuang-Shuang , Zhang Wei-Shi , Xu Hua , Deng Xiao-Ming , Zhang Yu-Qiu 
Published: December 2012

AbstractBackgroundSpinal glia, particularly microglia and astrocytes, are of the utmost importance in the development and maintenance of chronic pain. A recent study from our laboratory revealed that gabapentin, a recommended first-line treatment for multiple neuropathic conditions, could also efficiently antagonize thermal hyperalgesia evoked by complete Freund's adjuvant (CFA)-induced monoarthritis (MA). In the present study, we investigated whether the spinal glia are involved in the anti-hyperalgesic effect of gabapentin and how this event occurs.ResultsUnilateral intra-articular injection of CFA produced a robust activation of microglia and astrocytes. These cells exhibited large cell bodies, thick processes and increases in the ionized calcium binding adapter molecule 1 (Iba-1, a microglial marker) or the glia fibrillary acidic protein (GFAP, an astrocytic marker). These cells also displayed immunoreactive signals, and an upregulation of the voltage-gated calcium channels (VGCCs) α2/δ-1 subunit, CX3CL1 and CX3CR1 expression levels in the spinal cord. These changes were associated with the development of thermal hyperalgesia. Immunofluorescence staining showed that VGCC α2/δ-1 subunit, a proposed gabapentin target of action, was widely distributed in primary afferent fibers terminals and dorsal horn neurons. CX3CL1, a potential trigger to activate microglia, colocalized with VGCC α2/δ-1 subunits in the spinal dorsal horn. However, its receptor CX3CR1 was mainly expressed in the spinal microglia. Multiple intraperitoneal (i.p.) gabapentin injections (100 mg/kg, once daily for 4 days with the first injection 60 min before intra-articular CFA) suppressed the activation of spinal microglia, downregulated spinal VGCC α2/δ-1 subunits decreased CX3CL1 levels and blocked the development of thermal hyperalgesia in MA rats.ConclusionsHere we provide the first evidence that gabapentin diminishes CX3CL1 signaling and spinal microglia activation induced by joint inflammation. We also show that the VGCC α2/δ-1 subunits might be involved in these events.