tbuckley/cabot-search huggingface dataset:
Predicting cisplatin-induced ototoxicity in testicular germ cell cancer.
Authors: J. G. Monzon, L. Brunham, C. K. Kollmannsberger, N. Murray, A. J. Attwell, C. Ross, T. Wong, B. Carleton, M. Hayden, K. A. Gelmon
Journal: Journal of Clinical Oncology (2010)

9061 Background: Testicular germ cell cancer (TC) is the most common cancer in 20-40 year old men. As the cure rate exceeds 90%, treatment related long-term toxicity becomes a priority. Cisplatin, the main agent used in the management of TC, can cause severe bilateral hearing loss in 10-25% of patients (pts) exposed to standard doses and up to 50% of pts receiving high doses. Recently, our group reported specific genetic variants in the thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT) genes that are predictive for cisplatin induced hearing loss in children (Ross, Nat Gen, 2009). Increasing number of risk alleles predicted for earlier onset, more frequent and more severe cisplatin-induced hearing loss. We hypothesize that the same genetic variants will predict for severe hearing loss in an adult population of cisplatin treated TC pts, a group with few competing causes for deafness. Methods: We initiated a case control study in TC pts who had received cisplatin from 1998-2010 in British Columbia. After informed consent, DNA is obtained from saliva. Genotyping for the risk alleles will be performed as previously described. A hearing test is obtained anytime after the 2nd cycle of cisplatin. Pts with sensorineural hearing impairment of >25db at frequencies >4 kHz are deemed affected while those with normal hearing are designated as controls. Results: 86 consenting pts have provided DNA samples and recruitment continues to an estimated 150 samples to ensure adequate power. To date, 46 pts have completed hearing tests with 36 (78.3%) pts having normal and/or unilateral hearing loss and 10 pts (21.7%) having bilateral impairment. The ototoxicity cases tend to be older compared to controls, but balanced in terms of stage, number of cycles and total dose of cisplatin. Genotyping will be performed on all samples by March and the results available by June 2010. Conclusions: We have demonstrated in children that genetic variants in the COMT and TPMT genes predict for cisplatin ototoxicity. This is the first study to address whether the same alleles are of importance in an adult population of TC pts. Identifying pts with a higher risk of cisplatin ototoxicity based on genotype will improve risk/benefit counseling and treatment options. No significant financial relationships to disclose.
Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation as a Reward Signal In Vivo
Authors: Taku Nagai, Shinichi Nakamuta, Keisuke Kuroda, Sakura Nakauchi, Tomoki Nishioka, Tetsuya Takano, Xinjian Zhang, Daisuke Tsuboi, Yasuhiro Funahashi, Takashi Nakano, Junichiro Yoshimoto, Kenta Kobayashi, Motokazu Uchigashima, Masahiko Watanabe, Masami Miura, Akinori Nishi, Kazuto Kobayashi, Kiyofumi Yamada, Mutsuki Amano, Kozo Kaibuchi
Journal: Neuron (2016)
Abstract 13864: Functional Characterization of Cardiac Ion Channel Gene Variants in Lone Atrial Fibrillation
Authors: Kenshi Hayashi, Satoyuki Tani, Li Liu, Hidekazu Ino, Noboru Fujino, Tetsuo Konno, Akihiko Hodatsu, Toyonobu Tsuda, Akihiro Inazu, Haruhiro Higashida, Masa-aki Kawashiri, Masakazu Yamagishi
Journal: Circulation (2012)

Background: Mutations in multiple genes were implicated in lone atrial fibrillation (AF) in which abnormally-functioning mutants may cause ectopic activity or action potential duration shortening. However, few data exist regarding functional characterization of these mutations to identify a causal relationship between a gene variant and occurrence of AF. Objective: We sought to determine the frequency of potassium and sodium channel gene mutations in patients with lone AF and characterized the electrophysiological properties of the detected mutations. Methods: We studied 82 patients with lone AF whose onset was 47±11 years old (60 men, mean age 56 years). There were 22 (27%) with familial AF and 51 (62%) with paroxysmal AF. In these patients, we screened for variants in all exons of KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2 KCNA5, SCN5A, SCN1B, SCN2B, SCN3B, and SCN4B. The potassium and sodium currents were analyzed using whole-cell patch clamp technique. Results: We identified 2 mutations in KCNH2 (T436M and T89...
Association of neuropathic limb pain in multiple sclerosis with cognition, behaviour, and measures of brain structure: a case-control MRI neuroimaging study
Authors: Peter Foley, Cyril Pernet, Maria Valdes-Hernandez, Ramune Margeviciute, Neil Roberts, Yazhuo Kong, Robin Sellar, Lesley Colvin, Christopher Weir, Thomas Bak, Siddharthan Chandran, Irene Tracey, Marie Fallon
Journal: The Lancet (2016)
Schistosomiasis in Malawi [letter]
Authors: Pugh Rn
Journal: BMJ (1993)

A reply is offered to the opinion that swimming in Lake Malawi carries the danger of contracting schistosomiasis. No doubt the cleared white palm-lined beaches fronting hotels and weekend chalets are safe for bathing. The lake with the occasional squall high waves and strong currents with its lack of suitable vegetation is no habitat for the vector snail species; the wave action is hostile to any fragile cercariae that may be found and the lake itself presents a massive dilutional factor. Overland visitors to Africa should be aware that inland pools and streams pose the greatest threat. The nearer they are to endemic village areas the greater the risk and degree of exposure to cercariae. The lake is the least likely place to acquire schistosomiasis. However the tourist should beware the cheaper accommodations that border fishing communities around vegetated areas of calm bays lagoons and river inlets. This type of accommodation these parts of the lake may present a risk to the bather. Malawis tourist trade deserves protection from generalized criticism on health grounds of one of its prime assets. The risk to the informed traveller of contracting schistosomiasis in Lake Malawi may exist but this risk should be put into perspective.
Abstract 19251: Identification of Conducting Channels by Delayed Enhanced Cardiac Magnetic Resonance Imaging
Authors: Olurotimi Mesubi, Jean Jeudy, Kelechi Ego-Osuala, Jim Purtilo, Dawn Ament, Martine Etienne-Mesubi, Vincent See, Anastasios Saliaris, Stephen Shorofsky, Timm-Michael Dickfeld
Journal: Circulation (2012)

Objective: Delayed enhanced cardiac magnetic resonance imaging (DE-CMRI) is able to define a heterogeneous zone of fibrotic tissue and surviving myocytes, known as ‘gray zone’ (GZ). Studies suggest that the GZ is related to ventricular tachycardia (VT) slow conducting channels (CC). There are established algorithms for GZ characterization. We evaluated the correlation of DE-CMRI defined CC and VT electroanatomic maps (EAM). Methods: Preprocedural DE-CMRI for scar evaluation and electrophysiology study were done in 14 male patients with ischemic (10) and non-ischemic (4) cardiomyopathy and VT. GZ was assessed on contiguous two-dimensional (2D) short axis DE-CMRI slices and reconstructed three-dimensional (3D) models. The reconstructed scar models were integrated in a clinical mapping system and compared to EAM. GZ were defined based on previously described signal intensity (SI) thresholds; full-width half maximum (FWHM), n-standard deviation (NSD) using 2-3SD thresholds and ‘Roes’ (≥ 35% - 50% of peak SI as GZ, and &gt; 50% of peak SI as core). Results: CMRI and scar detection was possible in all patients including 64% of the patients with ICDs. Software analysis allowed detection and reconstruction of scar core and GZ on all 2D- and 3D-CMRI image series. Scar core and GZ were detected with all 3 algorithms. There was more scar core by NSD (NSD vs. Roes vs FWHM, 27±11g vs. 17±8g vs 17±8g, p &lt; 0.01 ) but more GZ by FWHM (NSD vs. Roes vs. FWHM, 5±2g vs. 8±3g vs 12±7g, p &lt; 0.01 ). CC were detected by CMRI in 50% (NSD), 64% (Roes) and 64% (FWHM) of patients. Compared to 12 CC seen on EAM, there were 17 CC seen by FWHM and Roes and 11 CC by the NSD method. There were 14 successful ablation sites in 12 patients with 2 (14%) located in EAM defined CC compared with 18% (FWHM and Roes) and 9% (NSD) in CMRI defined CC. Above 80% of the ablation sites were located in GZ areas on DE-CMRI for all algorithms (91%, 82% and 91% for NSD, Roes and FWHM). Conclusion: CMRI defined GZ/channels can be detected by established algorithms and compared with EAM. The FWHM has the highest GZ mass and FWHM/Roes visualize more CC. More than 80% of successful ablation sites are located in direct vicinity of the GZ. This may enable a more refined analysis of the MRI scar substrate with important features for the successful ablation sites.
Progressive Chromosome Changes Associated with Different Sites of One Ovarian Carcinoma2, 3
Authors: Christine J. Kusyk, Jan C. Seski, William V. Medli, Creighton L. Edwards
Journal: JNCI Journal of the National Cancer Institute (1981)

Karyotype analyses were done on cells from the primary and metastatic sites, as well as on the ascitic fluid, from 1 patient with serous carcinoma of the ovary. An increase in the proportion of near-tetraploid cells occurred in the following order: cells from the primary site less than cells from the metastatic site less than cells from ascitic fluid. In addition, two new marker chromosomes appeared among the polyploid cells of ascitic fluid.
Imbalance Between Bone Morphogenetic Protein 2 and Noggin Induces Abnormal Osteogenic Differentiation of Mesenchymal Stem Cells in Ankylosing Spondylitis
Authors: Zhongyu Xie, Peng Wang, Yuxi Li, Wen Deng, Xin Zhang, Hongjun Su, Deng Li, Yanfeng Wu, Huiyong Shen
Journal: Arthritis & Rheumatology (2015)

To study the osteogenic differentiation capacity of bone marrow-derived mesenchymal stem cells (BM-MSCs) from patients with ankylosing spondylitis (AS) and to investigate the mechanisms of abnormal osteogenic differentiation of BM-MSCs in AS.BM-MSCs from healthy donors (HD-MSCs) and patients with AS (AS-MSCs) were cultured in osteogenic differentiation medium for 0-21 days, after which their osteogenic differentiation capacity was determined using alizarin red S and alkaline phosphatase assays. Gene expression levels of osteoblastic markers and related cytokines were detected by high-throughput quantitative reverse transcription-polymerase chain reaction. Enzyme-linked immunosorbent assay was performed to detect protein levels of bone morphogenetic protein 2 (BMP-2) and Noggin in the cell culture supernatant. The activation of Smad1/5/8 and MAPK signaling pathways was measured by Western blotting. The balance between BMP-2 and Noggin expression was regulated using lentiviruses encoding short hairpin RNA and exogenous Noggin, respectively, which enabled evaluation of how this balance affected osteogenic differentiation of AS-MSCs.AS-MSCs outperformed HD-MSCs in osteogenic differentiation capacity. During osteogenic differentiation, AS-MSCs secreted more BMP-2 but less Noggin, accompanied by an overactivation of Smad1/5/8 and ERK-1/2. When the Noggin concentration was increased or BMP-2 expression was inhibited, the abnormal osteogenic differentiation of AS-MSCs was rectified. In addition, the balance between BMP-2 and Noggin secretion was restored.The results of this study demonstrate that an imbalance between BMP-2 and Noggin secretion induces abnormal osteogenic differentiation of AS-MSCs. These findings reveal a mechanism of pathologic osteogenesis in AS and provide a new perspective on inhibiting pathologic osteogenesis by regulating the balance between BMP-2 and Noggin.
Surfactant protein D is critical for local immunomodulation in the distal lung
Authors: Michael Beers, Deepika Jain, Fabian Blank, Yaniv Tomer, Christophe von Garnier
Journal: European Respiratory Journal (2011)

Surfactant Protein D (SP-D) is a multifunctional product of lung epithelia that modulates pulmonary host defense. SP-D deficient mice (SP-DKO) develop a progressive baseline phenotype of pulmonary inflammation, enhanced oxidative-nitrative stress, and lung remodeling punctuated by a morphologically heterogeneous population of mononuclear alveolar cells and poor clearance of pathogens. To further define the role of SP-D as a local modulator of this immune cell population, bronchoalveolar lavage (BAL) cells recovered from SP-DKO and C57/BL6 controls (WT) were characterized using FACS, qRT-PCR, and functional assays. By FACS, over 95% of BAL cells from WT mice consisted of a morphologically homogeneous population (FSC/SSC) with an expression profile of F4/80+, CD11c+, Dectin-1+, CD45+, CD3-, LY6G- consistent with alveolar macrophages. In contrast, SP-DKO BAL cells exhibited a dispersed FSC/SSC profile which separated into 2 major populations: Approximately 50% were F4/80+, CD11c+, Dectin-1+, CD45+ while a second group was F4/80-,CD11c-,CD45-,PECAM-, and c-Kit-. Less than 10% of the second population expressed CD3, Ly6G or CD11b. By qRT-PCR, when normalized to F4/80, BAL cells from SPDKO expressed greater amounts of iNOS and Cox2. Functionally F4/80+ SP-DKO cells internalized significantly less zymosan particulate than F4/80+ WT cells. SPDKO BAL cells in culture were hyporesponsive to stimulation by LPS and zymosan. In vivo, SP-DKO mice produced less TNF-α in response to intratracheal zymosan or LPS. These data are supportive of a critical role for SP-D in modulation of the local immune response in the lung through effects on antigen-presenting cell differentiation, composition, and function.
Does repeat usage of bevacizumab in patients with progressive recurrent ovarian cancer offer a survival advantage?
Authors: D. L. Richardson, F. J. Backes, L. G. Seamon, L. G. Seamon, J. D. Hurt, D. E. Cohn, J. M. Fowler, L. J. Copeland, D. M. O'Malley
Journal: Journal of Clinical Oncology (2009)

e16510 Background: Many studies show bevacizumab (BEV) has activity in the treatment of recurrent ovarian cancer, especially when combined with cytotoxic chemotherapy. However, it is uncertain whether BEV should be continued if a patient progressives on treatment which includes BEV. Therefore, our objective is to compare response rates (RR), progression-free survival (PFS), and overall survival (OS) between patients who continued on BEV after progression on BEV (BPB) versus patients who were treated with cytotoxic chemotherapy without BEV (no BPB). Methods: All patients who received treatment with BEV (with or without cytotoxic chemotherapy) for recurrent ovarian cancer at a single institution were identified. Patients who received additional therapy after progression on BEV were included. Patients who were treated on GOG 218 or received first-line BEV or had their first BEV therapy discontinued due to side effects from BEV were excluded. RR were assessed using RECIST criteria, CA125 levels, or progressive disease symptoms. PFS was defined as the period from initiation of the treatment regimen until progression or date of last contact. OS was defined as the period from initiation of the second treatment regimen until death or date of last contact. Results: 35 patients met inclusion criteria. The median number of previous chemotherapy regimens was 4 (range 1–8). About 50% of the patients had a CR or PR prior to progressing on BEV. There were 27 patients in the BPB group, and 8 patients in the no BPB group. 13% (1/7) of patients responded to cytotoxic chemo after BEV, and 15% (4/27) of patients responded to repeat treatment with BEV, p = 1. The median PFS for patients in the no BPB group was 4.6 months (95% CI 1.6–5 mo), compared to 4.8 months (2.7–7.5 mo) for patients in the BPB group, p = 0.11. There was no difference in OS, 9.8 months (95% CI 2.73- ∞) versus 8.4 months (95% CI 5.8–15.6 months) p = 0.43 for patients in the no BPB group versus the BPB group. One patient in the BPB group died of a bowel perforation. Conclusions: We offer the first comparison of PFS and OS in patients treated with cytotoxic chemotherapy ± BEV after progression on BEV. After progressing on a BEV regimen, there was no difference in the PFS, OS or RR in those pts treated with or without BEV with an overall OS &lt; 1 year. [Table: see text]
Overexpression of PAK4 in hepatocellular carcinoma (HCC)
Authors: Hai-Tao Xu, Veronica Yl Leong, Irene Ol Ng, Yick Pang Ching
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

5133 

p21-activated protein kinases (PAKs) are activated by the small Rho family GTPases, Cdc42 and Rac1, in response to various extracellular signals and act in a variety of cellular processes including cell proliferation, morphology, motility, death and survival. PAK-4 is a newly identified Group II member of the PAK family. Like the Group I PAKs, PAK-4 contains an N-terminal p21 binding domain (PBD) and a C-terminal kinase domain, but lacks the auto-inhibitory domain (AID) which is present in Group I PAKs. Previous studies in fibroblasts have demonstrated that expression of activated form of PAK-4 promotes cell proliferation, anchorage-independent growth and cell migration, which are the characteristics of malignant tumors. Besides, PAK-4 was found to be frequently overexpressed in tumor cell lines. However, it is still not clear whether PAK-4 plays a role in the pathogenesis of human cancer. Here we report that PAK-4 is frequently over-expressed in hepatocellular carcinomas (HCCs), using real-time quantitative PCR and Western Blotting. To investigate the function of PAK-4 in the development of HCC, we established PAK-4 knocked-down stable cell lines, using vector-based siRNA approach. We report that knocking down of PAK-4 led to decrease in cell migration by trans-well assay. Morphological changes have also been observed after PAK-4 is knocked down. In summary these results incidated a possible tumorigenic effect of PAK-4 in HCC.Further studies are needed to address this issue and provide the molecular mechanism by which PAK-4 activity is regulated.
"We all have AIDS": case for reducing the cost of HIV drugs to zero Commentary: The reality of treating HIV and AIDS in poor countries Commentary: Most South Africans cannot afford anti-HIV drugs
Authors: Donald Berwick
Journal: BMJ (2002)

# "We all have AIDS": case for reducing the cost of HIV drugs to zero {#article-title-2} An editorial last year in the Washington Post challenged directors of drug companies to reduce the cost of HIV drugs in poor countries to zero. Here the reproduced editorial is accompanied by a discussion about why it was written and the response to it. We invited comment from one of the named directors and from a man with AIDS who refuses to take antiretroviral drugs until they are available to the public sector in South Africa Last year I wrote a guest editorial for the Washington Post in which I challenged the world's pharmaceutical companies to cut the cost of HIV drugs to zero in poor countries (see box on next page).1 Here I explain why I wrote it and describe some of the responses it provoked. #### Summary points Complex drug regimens, combined with social support, have been used to treat infectious diseases, even in conditions of extreme poverty The high costs of drugs can be used as an excuse for poor countries not to construct effective infrastructures for the care of patients with chronic infectious diseases Dramatic reductions in the costs of antituberculosis drugs catalysed worldwide action against multiresistant tuberculosis The boards and executives of drug companies could catalyse action against the AIDS epidemic by immediately reducing the costs of HIV drugs in poor countries to zero People living in poverty being denied access to modern health care is a form of violent, systematic social deprivation that we, as a civilised global community, ought not to accept. Even the poorest people in the poorest settings can, if they are allowed and assisted, be involved in improving their health and can benefit from the most advanced drugs. This philosophy of social justice drives the international health programme Partners in Health, which was founded by Paul Farmer and Jim Yong Kim. Partners … Correspondence to: Z Achmat
Effect of angio-echography with a second-generation contrast agent to assess tumor response to imatinib treatment in patients with advanced gastrointestinal stromal tumor (GIST): Comparison with computerized tomography (CT)
Authors: U. De Giorgi, C. Aliberti, G. Benea, B. Kopf, M. Marangolo
Journal: Journal of Clinical Oncology (2004)

4216 Background: GIST metastases are typically intra-abdominal and hypervascular. BR1 (Sonovue, Bracco, Milan, Italy) is a new blood pool second-generation contrast agent, which consists of stabilized microbubbles of a totally innocuous sulphur hexafluoride gas. We report preliminary results with angio-echography with BR1 (AE) to assess tumor response (TR) to imatinib treatment (IT) in patients (pts) with advanced GIST. Methods: Twelve consecutive pts with known advanced cKIT+ GIST were investigated prospectively. CT and AE were performed before IT and then at 1, 2, 4, 6, and then every 3 months during IT. A strict prospective evaluation with AE was performed in 2 pts at 1, 2, 4, 6, 8 weeks during IT. Results: At a median follow-up of 12 months (range 4–18), in the 11 evaluable pts CT documented TR in 5 (46%) pts and stable disease (SD) in 4 (36%) RECIST criteria), while AE showed early TR in all these 9 (82%) cases. The median time to TR by RECIST criteria at CT was 4 months (range 1–9), while TR was observed at the first AE, and after 2 weeks in the 2 cases receiving strict AE evaluation. During IT, in 1 case CT showed increase of liver metastases, but AE demonstrated TR with intra-tumoral edema. Compared with CT, AE better depicted liver subcentimetric metastases. No differences between CT and AE were seen in the evaluation of extra-hepatic metastases. Conclusions: In large studies, CT (RECIST criteria) showed TR (54%) or SD (34%) associated with IT, which correlated closely with a finding of ≥50% decrease in FDG uptake on PET scan in 89% of pts. In our study, AE improved the display of tumor vascularity as well as the accuracy in differentiating between SD and TR. The effective TR to IT in GISTs might be superior to that showed by CT only, according to RECIST criteria. The close relation between clinical outcome and the findings on AE indicates that such scanning might be an useful complement to standard anatomical imaging for monitoring the therapeutic effect of imatinib in pts with GIST. Large prospective studies are warranted. No significant financial relationships to disclose.
Device Closure of Patent Foramen Ovale After Stroke
Authors: David M. Kent, Issa J. Dahabreh, Robin Ruthazer, Anthony J. Furlan, Mark Reisman, John D. Carroll, Jeffrey L. Saver, Richard W. Smalling, Peter Jüni, Heinrich P. Mattle, Bernhard Meier, David E. Thaler
Journal: Journal of the American College of Cardiology (2016)