bluuebunny/crossref_metadata_2025 huggingface dataset:
Virtual Sectioning and Haptic Exploration of Volumetric Shapes in the Absence of Visual Feedback
Authors: Evreinova Tatiana V. , Evreinov Grigori , Raisamo Roope
Published: July 2013

The reduced behavior for exploration of volumetric data based on the virtual sectioning concept was compared with the free scanning at the use of the StickGrip linkage-free haptic device. Profiles of the virtual surface were simulated through the penholder displacements in relation to the pen tip of the stylus. One or two geometric shapes (cylinder, trapezoidal prism, ball, and torus) or their halves and the ripple surface were explored in the absence of visual feedback. In the free scanning, the person physically moved the stylus. In the parallel scanning, cross-sectional profiles were generated automatically starting from the location indicated by the stylus. Analysis of the performance of 18 subjects demonstrated that the new haptic visualization and exploration technique allowed to create accurate mental images, to recognize and identify virtual shapes. The mean number of errors was about 2.5% in the free scanning mode and 1.9% and 1.5% in the parallel scanning mode at the playback velocity of 28 mm/s and 42 mm/s, respectively. All participants agreed that the haptic visualization of the 3D virtual surface presented as the cross-sectional slices of the workspace was robust and easy to use. The method was developed for visualization of spatially distributed data collected by sensors.
Dynamics of a Multigroup SIR Epidemic Model with Nonlinear Incidence and Stochastic Perturbation
Authors: Lin Yuguo , Jiang Daqing
Published: July 2013

We introduce stochasticity into a multigroup SIR model with nonlinear incidence. We prove that when the intensity of white noise is small, the solution of stochastic system converges weakly to a singular measure (i.e., a distribution) ifℛ0≤1and there exists an invariant distribution which is ergodic ifℛ0>1. This is the same situation as the corresponding deterministic case. When the intensity of white noise is large, white noise controls this system. This means that the disease will extinct exponentially regardless of the magnitude ofℛ0.
Same-Day CD4 Testing to Improve Uptake of HIV Care and Treatment in South Africa: Point-of-Care Is Not Enough
Authors: Larson Bruce A. , Schnippel Kathryn , Brennan Alana , Long Lawrence , Xulu Thembi , Maotoe Thapelo , Rosen Sydney , Sanne Ian , Fox Matthew P.
Published: July 2013

Background. We evaluated whether a pilot program providing point-of-care (POC), but not rapid, CD4 testing (BD FACSCount) immediately after testing HIV-positive improved retention in care.Methods. We conducted a retrospective record review at the Themba Lethu Clinic in Johannesburg, South Africa. We compared all walk-in patients testing HIV-positive during February, July 2010 (pilot POC period) to patients testing positive during January 2008–February 2009 (baseline period). The outcome for those with a≤250cells/mm3when testing HIV-positive was initiating ART<16weeks after HIV testing.Results. 771 patients had CD4 results from the day of HIV testing (421 pilots, 350 baselines). ART initiation within 16 weeks was 49% in the pilot period and 46% in the baseline period. While all 421 patients during the pilot period should have been offered the POC test, patient records indicate that only 73% of them were actually offered it, and among these patients only 63% accepted the offer.Conclusions. Offering CD4 testing using a point-of-care, but not rapid, technology and without other health system changes had minor impacts on the uptake of HIV care and treatment. Point-of-care technologies alone may not be enough to improve linkage to care and treatment after HIV testing.
Feasibility and Acceptability of a Real-Time Adherence Device among HIV-Positive IDU Patients in China
Authors: Bachman DeSilva Mary , Gifford Allen L. , Keyi Xu , Li Zhong , Feng Cheng , Brooks Mohamad , Harrold Mark , Yueying Hu , Gill Christopher J. , Wubin Xie , Vian Taryn , Haberer Jessica , Bangsberg David , Sabin Lora
Published: July 2013

We collected data on feasibility and acceptability of a real-time web-linked adherence monitoring container among HIV-positive injection drug users (IDU) in China. “Wisepill” uses wireless technology to track on-time medication dosing. Ten patients on antiretroviral therapy (ART) at the Guangxi CDC HIV clinic in Nanning, China, used Wisepill for one ART medication for one month. We monitored device use and adherence and explored acceptability of the device among patients. Mean adherence was 89.2% (SD 10.6%). Half of the subjects reported a positive overall experience with Wisepill. Seven said that it was inconvenient, supported by comments that it was large and conspicuous. Five worried about disclosure of HIV status due to the device; no disclosures were reported. Twelve signal lapses occurred (5.4% of prescribed doses), of which one was due to technical reasons, nine to behavioral reasons (both intentional and unintentional), and two to unclear reasons. Although the technical components must be monitored carefully, and acceptability to patients presents challenges which warrant further exploration, the Wisepill device has potential for adherence interventions that deliver rapid adherence-support behavioral feedback directly to patients, including IDU. The use of wireless technology appears uniquely promising for providing time-sensitive communication on patient behavior that can be harnessed to maximize the benefits of HIV treatment.
Survivin-3B Potentiates Immune Escape in Cancer but Also Inhibits the Toxicity of Cancer Chemotherapy
Authors: Végran Frédérique , Mary Romain , Gibeaud Anne , Mirjolet Céline , Collin Bertrand , Oudot Alexandra , Charon-Barra Céline , Arnould Laurent , Lizard-Nacol Sarab , Boidot Romain
Published: July 2013

Dysregulation in patterns of alternative RNA splicing in cancer cells is emerging as a significant factor in cancer pathophysiology. In this study, we investigated the little known alternative splice isoform survivin-3B (S-3B) that is overexpressed in a tumor-specific manner. Ectopic overexpression of S-3B drove tumorigenesis by facilitating immune escape in a manner associated with resistance to immune cell toxicity. This resistance was mediated by interaction of S-3B with procaspase-8, inhibiting death-inducing signaling complex formation in response to Fas/Fas ligand interaction. We found that S-3B overexpression also mediated resistance to cancer chemotherapy, in this case through interactions with procaspase-6. S-3B binding to procaspase-6 inhibited its activation despite mitochondrial depolarization and caspase-3 activation. When combined with chemotherapy, S-3B targeting in vivo elicited a nearly eradication of tumors. Mechanistic investigations identified a previously unrecognized 7-amino acid region as responsible for the procancerous properties of survivin proteins. Taken together, our results defined S-3B as an important functional actor in tumor formation and treatment resistance. Cancer Res; 73(17); 5391–401. ©2013 AACR.
Estrogen Receptor α Regulates ATM Expression through miRNAs in Breast Cancer
Authors: Guo Xiaojing , Yang Chunying , Qian Xiaolong , Lei Ting , Li Yaqing , Shen Haifa , Fu Li , Xu Bo
Published: July 2013

Purpose: Estrogen receptor α (ERα) is an essential element regulating mammary gland development and it contributes to breast cancer development and progression. Most of the ER-negative breast cancers display more aggressive clinical behaviors and are resistant to antiestrogen therapies. In addition, many ER-negative tumors show insensitivity to many chemotherapeutic drugs and radiotherapy, although mechanisms underlying this phenotype are less clear.

Experimental Design: We conducted immunohistochemistry on 296 cases of breast cancer tissues using a variety of antibodies. On the basis of the clinical data, we conducted siRNA knockdown to study the role of ERα on ATM expression in breast cancer cell lines. Furthermore, we used antisense oligonucleotides against micro RNAs (miRNA) or miRNA overexpression plasmids to study the role of miR-18a and -106a on ATM expression. Finally we used in situ hybridization to assess miR-18a and -106a expression in breast cancer tissues.

Results: We found that in ER-negative breast cancer tissues, expression of the ATM kinase, a critical DNA damage-response protein, is aberrantly upregulated. We also found that the locoregional recurrence rate after radiotherapy positively correlates with ATM expression. On the cellular level, we showed that ERα, but not ERβ, negatively regulates ATM expression. Furthermore, we identified that ERα activates miR-18a and -106a to downregulate ATM expression. We also showed that miR-18a and -106a were significantly underexpressed in ER-negative breast cancer tissues.

Conclusions: We reveal a novel mechanism involving ERα and miR-18a and -106a regulation of ATM in breast cancer. Clin Cancer Res; 19(18); 4994–5002. ©2013 AACR.
The Translocation t(4;14) Can Be Present Only in Minor Subclones in Multiple Myeloma
Authors: Hébraud Benjamin , Caillot Denis , Corre Jill , Marit Gérald , Hulin Cyrille , Leleu Xavier , Lodé Laurence , Wetterwald Marc , Dib Mamoun , Rodon Philippe , Voillat Laurent , Royer Bruno , Voog Eric , Fitoussi Olivier , Stoppa Anne-Marie , Garderet Laurent , Kolb Brigitte , Maigre Michel , Boullanger Nadine , Allangba Olivier , Karlin Lionel , Daguindau Nicolas , Legros Laurence , Sohn Claudine , Joubert Marie-Véronique , Lenain Pascal , Facon Thierry , Attal Michel , Moreau Philippe , Avet-Loiseau Hervé
Published: July 2013

Purpose: Although the translocation t(4;14) is supposed to be a primary event in multiple myeloma, we have been surprised to observe that in large relapse series of patients, the t(4;14) can be observed only in subpopulations of plasma cells, in contrast to what is seen at diagnosis. This observation raised the question of possible subclones harboring the translocation that would be observable only at the time of relapse.

Experimental Design: To address this issue, we analyzed by FISH a cohort of 306 patients for whom we had at least two samples obtained at different disease phases.

Results: We observed a “gain” of the t(4;14) in 14 patients, and conversely, a “loss” of the translocation in 11 patients. Two hypotheses were raised: either an acquisition of the translocation during evolution or the existence of small t(4;14)-positive subclones at the time of diagnosis. To address this question, we had the opportunity to analyze two patients at the time of diagnosis by RT-PCR (reverse transcription-polymerase chain reaction) to look for the chimeric Eμ-MMSET transcript, and one patient positive at diagnosis, but negative at relapse. The samples were positive, supporting the second hypothesis. Furthermore, the IGH sequences of two patients who “lose” the t(4;14) were identical at diagnosis and relapse, confirming the existence of a common ancestral clone.

Conclusion: Thus, the conclusion of this study is that the t(4;14) is not a primary event in multiple myeloma and that it can be present in silent subclones at diagnosis, but also at relapse. Clin Cancer Res; 19(17); 4634–7. ©2013 AACR.
IL-17A Stimulates the Progression of Giant Cell Tumors of Bone
Authors: Xu Meng , Song Zhi-Gang , Xu Cheng-Xiong , Rong Guang-Hua , Fan Ke-Xing , Chen Ji-Ying , Zhang Wei , Jia Jin-Peng , Han Gang , Wang Wei , Chai Wei , Liang Wen-Tao , Bi Wen-Zhi , Wang Yan
Published: July 2013

Purpose: Giant cell tumors of bone (GCTB) exhibit aggressive bone lytic behavior. Studies have shown that interleukin 17A (IL-17A) is involved pathologic bone resorption in various skeletal disorders. Thus, we have investigated the role of IL-17A in GCTBs.

Experimental Design: We evaluated the progression of GCTBs using Campanacci grading and Enneking staging systems in 74 patients with GCTB. The expression of IL-17A and the IL-17A receptor A (IL-17RA) was assessed in GCTB tissues and in both multinucleated giant cells (MNGC) and stromal cells cultured in vitro using immunostaining and reverse transcription PCR (RT-PCR). The effects of IL-17A on the osteolytic activity of the MNGCs and the proliferation of the stromal cells were investigated using the “pit” formation and MTT assays, respectively. The effects of IL-17A on the expression of proosteolytic factors were examined in primary cultured MNGCs and stromal cells using RT-PCR, Western blotting, and gene expression microarrays.

Results: In GCTBs, we detected abundant levels of IL-17A, which were associated with tumor extension and grade. IL-17A is predominantly produced by MNGCs, whereas IL-17RA is expressed by both MNGCs and stromal cells in GCTBs. In the MNGCs, the IL-17A increased the mRNA expression of IL-17A and proosteolytic enzymes, and also enhanced osteolytic ability. In the stromal cells, the IL-17A stimulated cellular proliferation and the expression of proosteolytic factors, including RANKL through myc and STAT3, respectively. In addition, IL-17A stimulated in vivo tumor growth and the extent of angiogenesis in GCTBs.

Conclusion: IL-17A stimulates the progression of GCTBs and might represent a useful candidate marker for progression and as a therapeutic target for GCTBs. Clin Cancer Res; 19(17); 4697–705. ©2013 AACR.
RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer
Authors: Ataie-Kachoie Parvin , Badar Samina , Morris David L. , Pourgholami Mohammad H.
Published: July 2013

Substantial evidence supports the critical role of NF-κB in ovarian cancer. Minocycline, a tetracycline, has been shown to exhibit beneficial effects in this malignancy through regulation of a cohort of genes that overlap significantly with the NF-κB transcriptome. Here, it was examined whether or not the molecular mechanism could be attributed to modulation of NF-κB signaling using a combination of in vitro and in vivo models. Minocycline suppressed constitutive NF-κB activation in OVCAR-3 and SKOV-3 ovarian carcinoma cells and was correlated with attenuation of IκBα kinase (IKK) activation, IκBα phosphorylation and degradation, and p65 phosphorylation and nuclear translocation. The inhibition of IKK was found to be associated with suppression of TGF-β-activated-kinase-1 (TAK1) activation and its dissociation from TAK1-binding-protein-1 (TAB1), an indispensable functional mediator between TGF-β and TAK1. Further studies demonstrated that minocycline downregulated TGF-β1 expression. Enforced TGF-β1 expression induced NF-κB activity, and minocycline rescued this effect. Consistent with this finding, TGF-β1 knockdown suppressed NF-κB activation and abrogated the inhibitory effect of minocycline on this transcription factor. These results suggest that the minocycline-induced suppression of NF-κB activity is mediated, in part, through inhibition of TGF-β1. Furthermore, the influence of minocycline on NF-κB pathway activation was examined in female nude mice harboring intraperitoneal OVCAR-3 tumors. Both acute and chronic administration of minocycline led to suppression of p65 phosphorylation and nuclear translocation accompanied by downregulation of NF-κB activity and endogenous protein levels of its target gene products. These data reveal the therapeutic potential of minocycline as an agent targeting the pro-oncogenic TGF-β—NF-κB axis in ovarian cancer.

Implications: This preclinical study lends support to the notion that ovarian cancer management would benefit from administration of minocycline. Mol Cancer Res; 11(10); 1279–91. ©2013 AACR.
Oral Administration of a Gemini Vitamin D Analog, a Synthetic Triterpenoid and the Combination Prevents Mammary Tumorigenesis Driven by ErbB2 Overexpression
Authors: So Jae Young , Wahler Joseph E. , Yoon Taesook , Smolarek Amanda K. , Lin Yong , Shih Weichung Joe , Maehr Hubert , Uskokovic Milan , Liby Karen T. , Sporn Michael B. , Suh Nanjoo
Published: July 2013

HER2 (or ErbB2), a member of ErbB receptor tyrosine kinases, is overexpressed in approximately 20% of human breast cancer, and the ErbB2 signaling pathway is a critical therapeutic target for ErbB2-overexpressing breast cancer. We investigated the inhibitory effects of the Gemini vitamin D analog BXL0124, the synthetic triterpenoid CDDO-Im and the combination on the tumorigenesis of ErbB2-overexpressing breast cancer. MMTV-ErbB2/neu transgenic mice were treated with BXL0124, CDDO-Im, or the combination from three months of age until the end of the experiment. Formation and growth of MMTV-ErbB2/neu mammary tumors were monitored every week, and all three treatments delayed the development of mammary tumors without significant toxicity. Decreased activation of ErbB2 as well as other ErbB receptors, ErbB1 and ErbB3, in MMTV-ErbB2/neu mammary tumors was shown by all treatments. Protein levels of downstream targets of the ErbB2 signaling pathway, including activated-Erk1/2, activated-Akt, c-Myc, CycD1, and Bcl2, were repressed by all three treatments, with the combination treatment exhibiting the strongest effects. To investigate therapeutic efficacy, the combination of BXL0124 and CDDO-Im was given to MMTV-ErbB2/neu mice after mammary tumors were established between 23 and 30 weeks of age. Short-term treatment with the combination did not show effects on tumor growth nor the ErbB2 signaling pathway. The present study shows BXL0124, CDDO-Im, and the combination as potential agents for prevention, but not treatment, against the tumorigenesis of ErbB2-overexpressing breast cancer. Cancer Prev Res; 6(9); 959–70. ©2013 AACR.
Evaluation of a Novel Endobronchial Ultrasound-Guided Lymph Node Forceps in Enlarged Mediastinal Lymph Nodes
Authors: Darwiche Kaid , Freitag Lutz , Nair Arun , Neumann Christiane , Karpf-Wissel Ruediger , Welter Stefan , Wohlschlaeger Jeremias , Theegarten Dirk
Published: July 2013

Background: Endobronchial ultrasound-transbronchial nee dle aspiration (EBUS-TBNA) is a useful technique for cytological assessment of enlarged mediastinal lymph nodes with a high diagnostic yield for lung cancer. However, the small sample volume can be problematic in diagnosing benign diseases and for molecular analysis of malignant tumours. Objectives: The aim of the study was to evaluate a novel lymph node forceps for EBUS-guided lymph node biopsy (EBUS-transbronchial forceps biopsy; EBUS-TBFB) in malignant and benign conditions concerning safety, feasibility, and diagnostic yield. Methods: Patients with enlarged mediastinal or hilar lymph nodes were included. EBUS-TBNA was performed followed by EBUS-guided TBFB with the lymph node forceps. Three biopsy specimens were obtained. The diagnostic yields of EBUS-TBFB, EBUS-TBNA, and the combination of both sampling techniques were compared. Complications were systematically recorded. Results: Fifty-five patients with enlarged mediastinal nodes were enrolled into this study. Specimens adequate for histological analysis were obtained in all but one case using EBUS-TBFB. EBUS-TBFB increased the diagnostic yield of EBUS-TBNA from 64 to 93% in benign conditions. The overall diagnostic yield was higher compared to EBUS-TBNA alone. EGFR mutation analysis could be achieved in the forceps biopsy samples as needed. No complications were observed. Conclusions: EBUS-TBFB with a novel lymph node forceps is safe and provides adequate histological specimens of enlarged mediastinal lymph nodes. EBUS-TBFB increases the diagnostic yield in benign conditions and may add value in molecular analysis of non-small cell lung cancer.
Metoprolol-Mediated Amelioration of Sympathetic Nerve Sprouting after Myocardial Infarction
Authors: Wang Ye , Liu Ju , Suo Fei , Hu He-Sheng , Xue Mei , Cheng Wen-Juan , Xuan Yong-Li , Yan Su-Hua
Published: July 2013

Objectives: Systemic or local inflammation causes cardiac nerve sprouting and consequent arrhythmia. Metoprolol can prevent sympathetic nerve remodeling after myocardial infarction (MI), but the underlying mechanism is unclear. In this study, we evaluated the role of metoprolol in ameliorating sympathetic sprouting. Methods: Rabbits underwent ligation of the coronary artery for MI. MI rabbits received metoprolol or saline for 7 days. Immunohistochemistry was used to measure cardiac nerve sprouting and sympathetic innervations. Nuclear factor-κB (NF-κB) DNA binding activity was analyzed by electrophoretic mobility shift assay. The protein levels of NF-κB p65, inhibitor κBa (IκBa) and nerve growth factor (NGF) were detected by Western blot analysis. The mRNA levels of NGF, interleukin-1ß (IL-1ß) and tumor necrosis factor-a (TNF-a) were examined by quantitative real-time PCR. Results: MI rabbits showed nerve sprouting and sympathetic hyperinnervation. In MI rabbits, as compared with saline treatment, metoprolol reduced NF-κB DNA binding activity and NF-κB p65 level, and increased IκBa level. Moreover, metoprolol downregulated IL-1ß, TNF-a and NGF levels, and reduced the density of sympathetic nerve fibers. Conclusions: Metoprolol ameliorates sympathetic nerve sprouting in rabbits after MI and is associated in part with inhibiting NF-κB activity.
Chicken MDA5 Senses Short Double-Stranded RNA with Implications for Antiviral Response against Avian Influenza Viruses in Chicken
Authors: Hayashi Tsuyoshi , Watanabe Chiaki , Suzuki Yasushi , Tanikawa Taichiro , Uchida Yuko , Saito Takehiko
Published: July 2013

Mammalian melanoma differentiation-associated gene-5 (MDA5) and retinoic acid-inducible gene-I (RIG-I) selectively sense double-stranded RNA (dsRNA) according to length, as well as various RNA viruses to induce an antiviral response. RIG-I, which plays a predominant role in the induction of antiviral responses against influenza virus infection, has been considered to be lacking in chicken, putting the function of chicken MDA5 (chMDA5) under the spotlight. Here, we show that chMDA5, unlike mammalian MDA5, preferentially senses shorter dsRNA synthetic analogues, poly(I:C), in chicken DF-1 fibroblasts. A requirement for caspase activation and recruitment domains for chMDA5-mediated chicken interferon beta (chIFNβ) induction and its interaction with mitochondrial antiviral signaling proteins were demonstrated. We also found that chMDA5 is involved in chIFNβ induction against avian influenza virus infection. Our findings imply that chMDA5 compensates in part the function of RIG-I in chicken, and highlights the importance of chMDA5 in the innate immune response in chicken.
Endothelial Cell Activation and Proliferation Modulate NKG2D Activity by Regulating MICA Expression and Shedding
Authors: Chauveau Annabelle , Tonnerre Pierre , Pabois Angélique , Gavlovsky Pierre-Jean , Chatelais Mathais , Coupel Stéphanie , Charreau Béatrice
Published: July 2013

MICA are major histocompatibility complex class I-related molecules, expressed by endothelial cells (ECs), that may be targets for alloantibodies and NKG2D-expressing natural killer (NK) and T effector cells in organ allografts. This study shows that basal levels of MICA expressed on vascular ECs is sufficient to functionally modulate the expression and activity of the immunoreceptor NKG2D in allogeneic NK cells. We found that MICA expression is differentially regulated at the EC surface in response to cytokines. TNFa upregulates MICA while IFNγ significantly decreases MICA at the EC surface. Both cytokines induce the release of soluble MICA by ECs. Modulation of NKG2D correlates with the MICA level on the EC surface. Glycosylation and metalloproteinase activities account for major post-transcriptional mechanisms controlling MICA level and the function in ECs. Our results indicate that, in addition to the NFγB pathway, the mitogen-activated protein kinase pathways JNK, ERK1/2 and p38 are key signaling pathways in the control of MICA by the cytokines. Finally, we show that EC proliferation mediated by FGF-2 or wound healing increases the MICA level. Together, our data suggest that inflammation and proliferation regulate endothelial MICA expression and shedding, enabling ECs to modulate NKG2D activity on effector NK and T cells, and provide further evidence of a role for ECs in immunoregulation.
Treatment of a Patient with Multiple Cutaneous Piloleiomyoma-Related Pain with a Local Injection of Triamcinolone Acetonide
Authors: Liu Chao , Tang Zhi-Hui , Bei Hong , Zeng Hai-Yan
Published: July 2013

Background: Multiple cutaneous piloleiomyomas are rare, frequently painful and difficult-to-treat benign tumours originating in the arrectores pilorum muscles of the hair follicles. Objective: The aim of this study was to determine the efficacy of a local injection of triamcinolone acetonide in relieving cutaneous piloleiomyoma-related pain. Methods: A patient with multiple painful piloleiomyomas was treated with weekly local injections of triamcinolone acetonide into the nodules and papules for 3 weeks. Results: The patient's nodules and papules became smaller, and the pain disappeared. At 1-year follow-up, there were no side effects, pain recurrence or significant enlargement of any of the injected lesions. Conclusion: Our study demonstrates that local injection of triamcinolone acetonide may be a promising new treatment option for multiple painful cutaneous piloleiomyomas.
Propensity-Based Matching between Esophagogastric Cancer Patients Who Had Surgery and Who Declined Surgery after Preoperative Chemoradiation
Authors: Taketa Takashi , Xiao Lianchun , Sudo Kazuki , Suzuki Akihiro , Wadhwa Roopma , Blum Mariela A. , Lee Jeffrey H. , Weston Brian , Bhutani Manoop S. , Skinner Heath , Komaki Ritsuko , Maru Dipen M. , Rice David C. , Swisher Stephen G. , Hofstetter Wayne L. , Ajani Jaffer A.
Published: July 2013

Background: Trimodality therapy (TMT; chemoradiation plus surgery) has level-1 evidence for survival advantage for TMT-eligible esophagogastric cancer patients. Some patients, however, decline surgery after preoperative chemoradiation. The question of which patient should have esophagectomy and which one should not is unlikely to be answered by a prospective comparison; therefore, we matched the clinical covariates of several patients who had surgery with those who declined surgery (DS). Methods: Between 2002 and 2011, we identified 623 patients in our databases. Of 623 patients, 244 patients had TMT and 61 TMT-eligible patients were in the DS group. Using the propensity-score method, we matched 16 covariates between 36 DS patients and 36 TMT patients. Results: Baseline characteristics between the two groups were balanced (p = NS). The median overall survival times were: 57.9 months (95% CI: 27.7 to not applicable, NA) for the DS group and 50.8 months (95% CI: 30.7 to NA) for the TMT group (p = 0.28). The median relapse-free survival times were: 18.5 (95% CI: 11.5-30.4) for the DS group and 26.5 months (95% CI: 15.5-NA) for the TMT group (p = 0.45). Eleven (31%) of 36 patients in the DS group had salvage surgery. Conclusions: Our results are intriguing but skewed by the patients who had salvage surgery in the DS group. Until highly reliable predictive models are developed for esophageal preservation, TMT must be encouraged for all TMT-eligible gastroesophageal cancer patients.
Anti-Aquaporin-4 Antibody Positivity in Neuromyelitis Optica Is Associated with Lesion Activity
Authors: Liu Yaou , Han Yue , Duan Yunyun , Huang Jing , Ren Zhuoqiong , Butzkueven Helmut , Li Kuncheng
Published: July 2013

Aims: To assess the demographic, clinical and spinal cord MRI characteristics of clinically definite neuromyelitis optica (NMO) patients for association with anti-aquaporin-4 (AQP4) antibody positivity in Chinese patients. Methods: We recruited 72 consecutive patients with NMO. The clinical assessments, sera and spinal MRI scans were obtained within 1 week after the onset of symptoms of acute myelitis. The statistical significance of potential differences in demographic, clinical and spinal MRI lesion characteristics between the two groups (anti-AQP4 antibody positive vs. negative) was determined using the two-sample t test or Fisher's exact test. Results: Forty-nine patients (49/72, 68.1%) were anti-AQP4 antibody positive and 23 patients (23/72, 31.9%) were anti-AQP4 antibody negative. The only characteristic that was significantly different between the groups was the presence of an enhancing spinal cord lesion (p < 0.001). Conclusion: We found a strong association between serum anti-AQP4 antibody positivity and lesional gadolinium enhancement in patients with clinically definite NMO. These findings support prior evidence that anti-AQP4 antibody could be pathogenic in NMO lesion development.
Association of Angiotensinogen Gene Polymorphisms and Angiogenic Factors with Preeclampsia in Chinese Women
Authors: Song Chengwen , Xie Shouzhen , Wang Jing , Lian Junhong , Diao Bo , Tang Ying
Published: July 2013

Objective: To investigate the association of angiotensinogen (AGT) gene polymorphisms and angiogenic factors with preeclampsia (PE) in Chinese women. Methods: A study on Chinese women was performed. Detection of the M235T polymorphism of AGT gene was carried out by PCR. Using a χ2 test, genotype and allele frequencies were compared in all groups. Maternal serum levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt1) at gestation were compared between 92 women with PE and 100 controls by ELISA. Results: Compared to the controls, the AGT homozygous of TT genotype in PE occurred significantly more frequently and the T allele was observed to occur more frequently than the M allele (p < 0.05). sFlt1 was present in high quantities in the serum of women with PE and was associated with low levels of free VEGF and PlGF (p < 0.05). Plasma sFlt1 levels are higher in PE patients with TT heterozygotes compared with MM homozygotes, but PIGF is lower (p < 0.05). Plasma VEGF concentrations showed no significant difference. Conclusions: Our study showed that AGT M235T polymorphism is associated with PE in Chinese women. Furthermore, the gene polymorphism of the components of the renin-angiotensin system may contribute to the concentration alterations of sFlt1, VEGF, and PlGF in maternal serum, which causes disordered vasculogenesis contributing to PE.
Axillary Lymph Node Status in Early-Stage Breast Cancer Patients with Sentinel Node Micrometastases (0.2-2 mm)
Authors: Bargehr Johannes , Edlinger Michael , Hubalek Michael , Marth Christian , Reitsamer Roland
Published: July 2013

Background: Omission of axillary lymph node dissection (ALND) is increasingly becoming the new standard of care for patients with sentinel lymph node micrometastases (SNMMs). However, a formidable proportion of patients is afflicted with non-sentinel node (NSN) macrometastatic tumor burden. Methods: Over 1 decade 5,000 patients underwent sentinel node biopsies (SNB) at 2 certified breast cancer centers in Austria. All available cases of SNMM during this time period were reviewed. Clinical, tumor and lymph node parameters were analyzed using univariate and multivariate analysis to retrieve predictors for further NSN involvement. Results: We identified 216 patients with SNMMs, of whom 181 subsequently underwent ALND. Of the latter patients, 16% (n = 29/181) presented with NSN axillary metastases. ALND revealed NSN macrometastases in 10.5% (n = 19/181) of all the investigated patients, and 66% of the NSN-positive patients (n = 19/29). In 28% (n = 8/29) of the NSN-positive patients, more than 1 macrometastasis was detected. The number of removed sentinel nodes was found to be a significant predictor (p = 0.007) for NSN involvement. Conclusion: In this retrospective investigation of breast cancer patients with SNMMs, a substantial proportion exhibited involvement of NSNs. Macrometastases accounted for the largest fraction of NSN tumor burden. Refraining from ALND in the face of SNMMs may entail substantial micro- and macrometastatic tumor burden in the remaining axillary lymph node basin.
High Population Frequencies of APOL1 Risk Variants Are Associated with Increased Prevalence of Non-Diabetic Chronic Kidney Disease in the Igbo People from South-Eastern Nigeria
Authors: Ulasi Ifeoma I. , Tzur Shay , Wasser Walter G. , Shemer Revital , Kruzel Etty , Feigin Elena , Ijoma Chinwuba K. , Onodugo Obinna D. , Okoye Julius U. , Arodiwe Ejikeme B. , Ifebunandu Ngozi A. , Chukwuka Chinwe J. , Onyedum Cajetan C. , Ijoma Uchenna N. , Nna Emmanuel , Onuigbo Macaulay , Rosset Saharon , Skorecki Karl
Published: July 2013

Background: Continental Africa is facing an epidemic of chronic kidney disease (CKD). APOL1 risk variants have been shown to be strongly associated with an increased risk for non-diabetic kidney disease including HIV nephropathy, primary non-monogenic focal and segmental glomerulosclerosis, and hypertension-attributed nephropathy among African ancestry populations in the USA. The world's highest frequencies of APOL1 risk alleles have been reported in West African nations, overlapping regions with a high incidence of CKD and hypertension. One such region is south-eastern Nigeria, and therefore we sought to quantify the association of APOL1 risk alleles with CKD in this region. Methods: APOL1 risk variants were genotyped in a case-control sample set consisting of non-diabetic, CKD patients (n = 44) and control individuals (n = 43) from Enugu and Abakaliki, Nigeria. Results: We found a high frequency of two APOL1 risk alleles in the general population of Igbo people of south-eastern Nigeria (23.3%). The two APOL1 risk allele frequency in the CKD patient group was 66%. Logistic regression analysis under a recessive inheritance model showed a strong and significant association of APOL1 two-risk alleles with CKD, yielding an odds ratio of 6.4 (unadjusted p = 1.2E-4); following correction for age, gender, HIV and BMI, the odds ratio was 4.8 (adjusted p = 5.1E-03). Conclusion: APOL1 risk variants are common in the Igbo population of south-eastern Nigeria, and are also highly associated with non-diabetic CKD in this area. APOL1 may explain the increased prevalence of CKD in this region.
Long-Term Remodeling of Rat Pial Microcirculation after Transient Middle Cerebral Artery Occlusion and Reperfusion
Authors: Lapi D. , Vagnani S. , Sapio D. , Mastantuono T. , Sabatino L. , Paterni M. , Colantuoni A.
Published: July 2013

Objective: The aim of this study was to assess the in vivo structural and functional remodeling of pial arteriolar networks in the ischemic area of rats submitted to transient middle cerebral artery occlusion (MCAO) and different time intervals of reperfusion. Methods and Results: Two closed cranial windows were implanted above the left and right parietal cortex to observe pial microcirculation by fluorescence microscopy. The geometric characteristics of pial arteriolar networks, permeability increase, leukocyte adhesion and capillary density were analyzed after 1 h or 1, 7, 14 or 28 days of reperfusion. MCAO and 1-hour reperfusion caused marked microvascular changes in pial networks. The necrotic core was devoid of vessels, while the penumbra area presented a few arterioles, capillaries and venules with severe neuronal damage. Penumbra microvascular permeability and leukocyte adhesion were pronounced. At 7 days of reperfusion, new pial arterioles were organized in anastomotic vessels, overlapping the ischemic core and in penetrating pial arterioles. Vascular remodeling caused different arteriolar rearrangement up to 28 days of reperfusion and animals gradually regained their motor and sensory functions. Conclusions: Transient MCAO-induced pial-network remodeling is characterized by arteriolar anastomotic arcades. Remodeling mechanisms appear to be accompanied by an increased expression of nitric oxide synthases.
Nuclear Expression of Glioma-Associated Oncogene Homolog 1 and Nuclear Factor-κB Is Associated with a Poor Prognosis of Pancreatic Cancer
Authors: Yang Shih-Hung , Hsu Chih-Hung , Lee Jen-Chieh , Tien Yu-Wen , Kuo Sung-Hsin , Cheng Ann-Lii
Published: July 2013

Objective: We investigated the association of the hedgehog pathway with nuclear factor (NF)-κB and clinical outcomes in pancreatic cancer patients. Methods: We analyzed tissue samples for the expression of NF-κB (RelA/p65), sonic hedgehog (Shh) and glioma-associated oncogene homolog 1 (Gli1) by immunohistochemistry and investigated their expression in association with clinical outcomes. Results: Eighty-one patients with pancreatic cancer were investigated. Expression of Shh and nuclear expression of Gli1 and NF-κB were found in 63 of 66 (96%), 28 of 68 (41%) and 22 of 68 cases (32%), respectively. Nuclear Gli1 expression was closely associated with nuclear expression of NF-κB (p < 0.001). Patients with nuclear Gli1 had significantly worse prognoses than those without (median survival 7.9 vs. 13.9 months; p = 0.009). Similarly, patients with nuclear expression of NF-κB had shorter overall survival than those with negative or cytoplasmic expression of NF-κB (median survival 5.5 vs. 13.9 months; p < 0.001). Shh expression had no prognostic significance. In the multivariate analysis, NF-κB nuclear expression was closely associated with unfavorable overall survival (p = 0.02). Conclusion: Our results indicate that nuclear expression of Gli1 or NF-κB is a strong predictor of poor prognosis in pancreatic cancer. Additional investigation of the biologic significance of this association is warranted.
From Acute Pancreatitis to Stage IV Pancreatic Cancer in 12 Weeks
Authors: Enweluzo Chijioke , Enweluzo Chijioke , Dutta Simanta , Aziz Fahad , Lenfest Stephen
Published: July 2013

Pancreatic cancer is well known to be an aggressive and highly malignant condition with varied ways of presentation. Pancreatic cystic neoplasms are very uncommon causes of pancreatic malignancy and can often be ignored or missed, especially in the early stages. We present the case of a 49-year-old Caucasian male with no past medical history presenting to an outside facility with sudden epigastric pain that was eventually diagnosed as acute pancreatitis. On transfer to our facility, he was eventually found to have metastatic malignant mucinous cystic pancreatic neoplasm. Barely 12 weeks after his initial presentation and following an aggressive hospital course, he passed away.
Jmjd3 Controls Mesodermal and Cardiovascular Differentiation of Embryonic Stem Cells
Authors: Ohtani Kisho , Zhao Cong , Dobreva Gergana , Manavski Yosif , Kluge Britta , Braun Thomas , Rieger Michael A. , Zeiher Andreas M. , Dimmeler Stefanie
Published: July 2013

Rationale:

The developmental role of the H3K27 demethylases Jmjd3, especially its epigenetic regulation at target genes in response to upstream developmental signaling, is unclear.

Objective:

To determine the role of Jmjd3 during mesoderm and cardiovascular lineage commitment.

Methods and Results:

Ablation of Jmjd3 in mouse embryonic stem cells does not affect the maintenance of pluripotency and self-renewal but compromised mesoderm and subsequent endothelial and cardiac differentiation. Jmjd3 reduces H3K27me3 marks at the
Brachyury
promoter and facilitates the recruitment of β-catenin, which is critical for Wnt signal–induced mesoderm differentiation.

Conclusions:

These data demonstrate that Jmjd3 is required for mesoderm differentiation and cardiovascular lineage commitment.
Rosiglitazone and Outcomes for Patients With Diabetes Mellitus and Coronary Artery Disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial
Authors: Bach Richard G. , Brooks Maria Mori , Lombardero Manuel , Genuth Saul , Donner Thomas W. , Garber Alan , Kennedy Laurence , Monrad E. Scott , Pop-Busui Rodica , Kelsey Sheryl F. , Frye Robert L.
Published: July 2013

Background—

Rosiglitazone improves glycemic control for patients with type 2 diabetes mellitus, but there remains controversy regarding an observed association with cardiovascular hazard. The cardiovascular effects of rosiglitazone for patients with coronary artery disease remain unknown.

Methods and Results—

To examine any association between rosiglitazone use and cardiovascular events among patients with diabetes mellitus and coronary artery disease, we analyzed events among 2368 patients with type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Total mortality, composite death, myocardial infarction, and stroke, and the individual incidence of death, myocardial infarction, stroke, congestive heart failure, and fractures, were compared during 4.5 years of follow-up among patients treated with rosiglitazone versus patients not receiving a thiazolidinedione by use of Cox proportional hazards and Kaplan–Meier analyses that included propensity matching. After multivariable adjustment, among patients treated with rosiglitazone, mortality was similar (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.58–1.18), whereas there was a lower incidence of composite death, myocardial infarction, and stroke (HR, 0.72; 95% CI, 0.55–0.93) and stroke (HR, 0.36; 95% CI, 0.16–0.86) and a higher incidence of fractures (HR, 1.62; 95% CI, 1.05–2.51); the incidence of myocardial infarction (HR, 0.77; 95% CI, 0.54–1.10) and congestive heart failure (HR, 1.22; 95% CI, 0.84–1.82) did not differ significantly. Among propensity-matched patients, rates of major ischemic cardiovascular events and congestive heart failure were not significantly different.

Conclusions—

Among patients with type 2 diabetes mellitus and coronary artery disease in the BARI 2D trial, neither on-treatment nor propensity-matched analysis supported an association of rosiglitazone treatment with an increase in major ischemic cardiovascular events.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00006305.
Childhood Blood Pressure Trends and Risk Factors for High Blood Pressure
Authors: Rosner Bernard , Cook Nancy R. , Daniels Stephen , Falkner Bonita
Published: July 2013

The obesity epidemic in children makes it plausible that prevalence rates of elevated blood pressure (BP) are increasing over time. Yet, previous literature is inconsistent because of small sample sizes. Also, it is unclear whether adjusting for risk factors can explain longitudinal trends in prevalence of elevated BP. Thus, we analyzed a population-based sample of 3248 children in National Health and Nutrition Examination Survey (NHANES) III (1988–1994) and 8388 children in continuous NHANES (1999–2008), aged 8 to 17 years. Our main outcome measure was elevated BP (systolic BP or diastolic BP ≥90th percentile or systolic BP/diastolic BP ≥120/80 mm Hg). We found that the prevalence of elevated BP increased from NHANES III to NHANES 1999–2008 (Boys: 15.8% to 19.2%,
P
=0.057; Girls: 8.2% to 12.6%,
P
=0.007). Body mass index (Q4 versus Q1; odds ratio=2.00;
P
<0.001), waist circumference (Q4 versus Q1; odds ratio=2.14;
P
<0.001), and sodium (Na) intake (≥3450 mg versus <2300 mg/2000 calories; odds ratio=1.36;
P
=0.024) were independently associated with prevalence of elevated BP. Also, mean systolic BP, but not diastolic BP, was associated with increased Na intake in children (quintile 5 [Q5] versus quintile 1 [Q1] of Na intake; β=1.25±0.58;
P
=0.034). In conclusion, we demonstrate an association between high Na intake and elevated BP in children. After adjustment for age, sex, race/ethnicity, body mass index, waist circumference, and sodium intake, odds ratio for elevated BP in NHANES 1999–2008 versus NHANES III=1.27,
P
=0.069.
Coronary Vasomotor Response to Intracoronary Acetylcholine Injection, Clinical Features, and Long‐term Prognosis in 873 Consecutive Patients With Coronary Spasm: Analysis of a Single‐Center Study Over 20 Years
Authors: Sato Koji , Kaikita Koichi , Nakayama Naoki , Horio Eiji , Yoshimura Hiromi , Ono Takamichi , Ohba Keisuke , Tsujita Kenichi , Kojima Sunao , Tayama Shinji , Hokimoto Seiji , Matsui Kunihiko , Sugiyama Seigo , Yamabe Hiroshige , Ogawa Hisao
Published: July 2013

Background

The aim of this study was to elucidate the correlation between angiographic coronary vasomotor responses to intracoronary acetylcholine (
AC
h) injection, clinical features, and long‐term prognosis in patients with vasospastic angina (
VSA
).

Methods and Results

This is a retrospective, observational, single‐center study of 1877 consecutive patients who underwent
AC
h‐provocation test between January 1991 and December 2010.
AC
h‐provoked coronary spasm was observed in 873 of 1637 patients included in the present analysis.
AC
h‐positive patients were more likely to be older male smokers with dyslipidemia, to have a family history of ischemic heart disease, and to have a comorbidity of coronary epicardial stenosis than were
AC
h‐negative patients.
AC
h‐positive patients were divided into 2 groups: those with focal (total or subtotal obstruction, n=511) and those with diffuse (severe diffuse vasoconstriction, n=362) spasm patterns. Multivariable logistic regression analysis identified female sex and low comorbidity of coronary epicardial stenosis to correlate with the
AC
h‐provoked diffuse spasm pattern in patients with
VSA
.
K
aplan–
M
eier survival curve indicated better 5‐year survival rates free from major adverse cardiovascular events in patients with diffuse spasm pattern compared with those with focal spasm pattern (
P
=0.019). Multivariable Cox hazard regression analysis identified diffuse spasm pattern as a negative predictor of major adverse cardiovascular events in patients with
VSA
.

Conclusions

AC
h‐induced diffuse coronary spasm was frequently observed in female
VSA
patients free of severe coronary epicardial stenosis and was associated with better prognosis than focal spasm. These results suggest the need to identify the
AC
h‐provoked coronary spasm subtypes in patients with
VSA
.
Going beyond Inferior Prefrontal Involvement in Semantic Control: Evidence for the Additional Contribution of Dorsal Angular Gyrus and Posterior Middle Temporal Cortex
Authors: Noonan Krist A. , Jefferies Elizabeth , Visser Maya , Lambon Ralph Matthew A.
Published: July 2013

Semantic cognition requires a combination of semantic representations and executive control processes to direct activation in a task- and time-appropriate fashion [Jefferies, E., & Lambon Ralph, M. A. Semantic impairment in stroke aphasia versus semantic dementia: A case-series comparison. Brain, 129, 2132–2147, 2006]. We undertook a formal meta-analysis to investigate which regions within the large-scale semantic network are specifically associated with the executive component of semantic cognition. Previous studies have described in detail the role of left ventral pFC in semantic regulation. We examined 53 studies that contrasted semantic tasks with high > low executive requirements to determine whether cortical regions beyond the left pFC show the same response profile to executive semantic demands. Our findings revealed that right pFC, posterior middle temporal gyrus (pMTG) and dorsal angular gyrus (bordering intraparietal sulcus) were also consistently recruited by executively demanding semantic tasks, demonstrating patterns of activation that were highly similar to the left ventral pFC. These regions overlap with the lesions in aphasic patients who exhibit multimodal semantic impairment because of impaired regulatory control (semantic aphasia)—providing important convergence between functional neuroimaging and neuropsychological studies of semantic cognition. Activation in dorsal angular gyrus and left ventral pFC was consistent across all types of executive semantic manipulation, regardless of whether the task was receptive or expressive, whereas pMTG activation was only observed for manipulation of control demands within receptive tasks. Second, we contrasted executively demanding tasks tapping semantics and phonology. Our findings revealed substantial overlap between the two sets of contrasts within left ventral pFC, suggesting this region underpins domain-general control mechanisms. In contrast, we observed relative specialization for semantic control within pMTG as well as the most ventral aspects of left pFC (BA 47), consistent with our proposal of a distributed network underpinning semantic control.