tbuckley/cabot-search huggingface dataset:
Randomized Controlled Trial of Cetuximab Plus Chemotherapy for Patients With <i>KRAS</i> Wild-Type Unresectable Colorectal Liver-Limited Metastases
Authors: Le-Chi Ye, Tian-Shu Liu, Li Ren, Ye Wei, De-Xiang Zhu, Sheng-Yong Zai, Qing-Hai Ye, Yiyi Yu, Bo Xu, Xin-Yu Qin, Jianmin Xu
Journal: Journal of Clinical Oncology (2013)

Purpose To assess the effects of cetuximab plus chemotherapy as first-line treatment for unresectable colorectal liver metastases (CLMs). Patients and Methods After resection of their primary tumors, patients with KRAS wild-type synchronous nonresectable liver-limited metastases from colorectal cancer were randomly assigned to receive chemotherapy (FOLFIRI [fluorouracil, leucovorin, and irinotecan] or mFOLFOX6 [modified fluorouracil, leucovorin, and oxaliplatin]) plus cetuximab (arm A) or chemotherapy alone (arm B). The primary end point was the rate of patients converted to resection for liver metastases. Secondary end points included tumor response and survival. Results The intent-to-treat population comprised 138 patients; 70 patients were randomly assigned to arm A and 68 to arm B. After a median of 25.0 months of follow-up, the 3-year overall survival (OS) rate and median survival time (MST) for all patients were 30% and 24.4 months, respectively. The R0 resection rates for liver metastases were 25.7% (18 of 70 patients) in arm A and 7.4% (five of 68 patients) in arm B, which were significantly different (P &lt; .01). Patients in arm A had improved objective response rates (57.1% v 29.4%; P &lt; .01), increased 3-year OS rate (41% v 18%; P = .013) and prolonged MST (30.9 v 21.0 months; P = .013) compared with those in arm B. In addition, in arm A, patients who had resection of liver metastases had a significantly improved MST (46.4 v 25.7 months; P &lt; .01) compared with those who did not undergo surgery. Conclusion For patients with initially unresectable KRAS wild-type CLMs, cetuximab combined with chemotherapy improved the resectability of liver metastases and improved response rates and survival compared with chemotherapy alone.
Targeting Src and Tubulin in Mucinous Ovarian Carcinoma
Authors: Tao Liu, Wei Hu, Heather J. Dalton, Hyun Jin Choi, Jie Huang, Yu Kang, Sunila Pradeep, Takahito Miyake, Jian H. Song, Yunfei Wen, Chunhua Lu, Chad V. Pecot, Justin Bottsford-Miller, Behrouz Zand, Nicholas B. Jennings, Cristina Ivan, Gary E. Gallick, Keith A. Baggerly, David G. Hangauer, Robert L. Coleman, Michael Frumovitz, Anil K. Sood
Journal: Clinical Cancer Research (2013)

Abstract Purpose: To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma. Experimental Design: The in vitro and in vivo effects and molecular mechanisms of KX-01, which inhibits Src pathway and tubulin polymerization, were examined in mucinous ovarian cancer models. Results: In vitro studies using RMUG-S and RMUG-L cell lines showed that KX-01 inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G2–M phase, and enhanced the cytotoxicity of oxaliplatin in the KX-01–sensitive cell line, RMUG-S. In vivo studies showed that KX-01 significantly decreased tumor burden in RMUG-S and RMUG-L mouse models relative to untreated controls, and the effects were greater when KX-01 was combined with oxaliplatin. KX-01 alone and in combination with oxaliplatin significantly inhibited tumor growth by reducing cell proliferation and inducing apoptosis in vivo. PTEN knock-in experiments in RMUG-L cells showed improved response to KX-01. Reverse phase protein array analysis showed that in addition to blocking downstream molecules of Src family kinases, KX-01 also activated acute stress-inducing molecules. Conclusion: Our results showed that targeting both the Src pathway and tubulin with KX-01 significantly inhibited tumor growth in preclinical mucinous ovarian cancer models, suggesting that this may be a promising therapeutic approach for patients with mucinous ovarian carcinoma. Clin Cancer Res; 19(23); 6532–43. ©2013 AACR.
Expression of Trefoil Factor Family Members Correlates with Patient Prognosis and Neoangiogenesis
Authors: Dipok Kumar Dhar, Timothy C. Wang, Hideki Tabara, Yasuhito Tonomoto, Riruke Maruyama, Mitsuo Tachibana, Hirofumi Kubota, Naofumi Nagasue
Journal: Clinical Cancer Research (2005)

Trefoil factor family (TFF) peptides are thought to contribute to epithelial protection and restitution by virtue of their protease-resistant nature and their strong affinity for mucins. However, they are often overexpressed in tumors, where they seem to be negative prognostic factors, possibly contributing to tumor spread, although the precise mechanisms have not been defined.Tissue sections from 111 patients with curatively resected advanced gastric carcinoma were immunohistochemically stained for TFF2, ITF (TFF3), and CD34. Microvessel density was expressed as number and area of microvessels. Results were correlated with clinicopathological characteristics and patient survival.Forty-nine (44.1%) and 41 (36.9%) tumors were immunohistochemically positive for TFF3 and TFF2, respectively. Among the various clinicopathologic variables, overexpression of TFF3 had a significant correlation with patient age only. In addition, a significantly higher prevalence of positive TFF2 staining was detected in large, diffuse tumors and in tumors with lymph node metastasis. The number of microvessels had a significant correlation with both TFF3 and TFF2 staining, whereas the area of microvessels had a significant correlation only with TFF3 staining. Both TFF3 and TFF2 were independent predictors of a worse disease-free survival. TFF3 had a gender-specific negative survival advantage, with a 91.3% disease-free survival in female patients with TFF3-negative advanced gastric carcinoma.Induction of increased tumor vascularity might be one of the mechanisms by which TFFs confer metastatic phenotype and frequent disease recurrence in gastric carcinomas. Female patients with TFF3-negative advanced gastric carcinoma have comparable survival as that reported for patients with early gastric carcinoma.
Quantitative magnetic resonance imaging of hepatic steatosis: Validation in ex vivo human livers
Authors: Peter Bannas, Harald Kramer, Diego Hernando, Rashmi Agni, Ashley M. Cunningham, Rakesh Mandal, Utaroh Motosugi, Samir D. Sharma, Alejandro Munoz del Rio, Luis Fernandez, Scott B. Reeder
Journal: Hepatology (2015)

Emerging magnetic resonance imaging (MRI) biomarkers of hepatic steatosis have demonstrated tremendous promise for accurate quantification of hepatic triglyceride concentration. These methods quantify the proton density fat‐fraction (PDFF), which reflects the concentration of triglycerides in tissue. Previous in vivo studies have compared MRI‐PDFF with histologic steatosis grading for assessment of hepatic steatosis. However, the correlation of MRI‐PDFF with the underlying hepatic triglyceride content remained unknown. The aim of this ex vivo study was to validate the accuracy of MRI‐PDFF as an imaging biomarker of hepatic steatosis. Using ex vivo human livers, we compared MRI‐PDFF with magnetic resonance spectroscopy‐PDFF (MRS‐PDFF), biochemical triglyceride extraction, and histology as three independent reference standards. A secondary aim was to compare the precision of MRI‐PDFF relative to biopsy for the quantification of hepatic steatosis. MRI‐PDFF was prospectively performed at 1.5 Tesla in 13 explanted human livers. We performed colocalized paired evaluation of liver fat content in all nine Couinaud segments using single‐voxel MRS‐PDFF (n = 117) and tissue wedges for biochemical triglyceride extraction (n = 117), and five core biopsies performed in each segment for histologic grading (n = 585). Accuracy of MRI‐PDFF was assessed through linear regression with MRS‐PDFF, triglyceride extraction, and histology. Intraobserver agreement, interobserver agreement, and repeatability of MRI‐PDFF and histologic grading were assessed through Bland‐Altman analyses. MRI‐PDFF showed an excellent correlation with MRS‐PDFF ( r = 0.984, confidence interval 0.978‐0.989) and strong correlation with histology ( r = 0.850, confidence interval 0.791‐0.894) and triglyceride extraction ( r = 0.871, confidence interval 0.818‐0.909). Intraobserver agreement, interobserver agreement, and repeatability showed a significantly smaller variance for MRI‐PDFF than for histologic steatosis grading (all P &lt; 0.001). Conclusion : MRI‐PDFF is an accurate, precise, and reader‐independent noninvasive imaging biomarker of liver triglyceride content, capable of steatosis quantification over the entire liver. (H epatology 2015;62:1444–1455)
Hamstring strain injuries: are we heading in the right direction?
Authors: Jurdan Mendiguchia, Eduard Alentorn-Geli, Matt Brughelli
Journal: British Journal of Sports Medicine (2011)

Acute hamstring injuries are the most prevalent muscle injuries reported in sport. Despite a thorough and concentrated effort to prevent and rehabilitate hamstring injuries, injury occurrence and re-injury rates have not improved over the last three decades. This failure is most likely due to the following: (1) a lack of studies with high level of evidence into the identification and prevention of hamstring injuries and (2) a reductionist approach of the current literature. The objectives of this article are to review and critique the current literature regarding isolated risk factors, and introduce a new concept for a more comprehensive scientific understanding of how multiple risk factors contribute to hamstring strain injury. The authors hope that this new conceptual model can serve as a foundation for future evidence-based research and aid in the development of new prevention methods to decrease the high incidence of this type of injury.
Epidemiology of sarcoidosis in the Isle of Man--2: Evidence for space-time clustering.
Authors: S E Hills, S A Parkes, S B Baker
Journal: Thorax (1987)

The case-control test for space-time clustering developed by Pike and Smith was applied to 96 cases of sarcoidosis diagnosed in the Isle of Man from 1962 to 1983. There were significantly more links between cases separated by time intervals of less than 10 years and distances of less than 100 metres than between the others. Analysis of the type of links indicated that clusters consisted of pairs whose contact was by place of residence or work. More linked cases were diagnosed less than three years apart than would be expected by chance. These findings lend support to the idea that sarcoidosis is a communicable disease.
Diabetes-Related Symptom Distress in Association With Glucose Metabolism and Comorbidity
Authors: Marcel C. Adriaanse, Frans Pouwer, Jacqueline M. Dekker, Giel Nijpels, Coen D. Stehouwer, Robert J. Heine, Frank J. Snoek
Journal: Diabetes Care (2008)

OBJECTIVE—The purpose of this study was to determine the associations between diabetes-related symptom distress, glucose metabolism status, and comorbidities of type 2 diabetes. RESEARCH DESIGN AND METHODS—This was a cross-sectional sample of 281 individuals with normal glucose metabolism (NGM), 181 individuals with impaired glucose metabolism (IGM), and 107 subjects with type 2 diabetes. We used the revised type 2 Diabetes Symptom Checklist (DSC-R) to assess diabetes-related symptom distress. RESULTS—The total symptom distress score (range 0–100) was relatively low for diabetic subjects (mean ± SD 8.4 ± 9.4), although it was significantly different from that for subjects with IGM (6.5 ± 7.1) and NGM (6.1 ± 7.9) (F = 3.1, 2 d.f., P = 0.046). Ischemic heart disease was associated with elevated DSC-R scores on three subscales, whereas depression showed higher symptom distress levels across all DSC-R domains. CONCLUSIONS—Worsening glucose metabolism is associated with increasing diabetes-related symptom distress. This relationship is attenuated by ischemic heart disease and particularly by depression.
A 3-year longitudinal study of sleep disordered breathing in the elderly
Authors: Emilia Sforza, Maylis Gauthier, Emilie Crawford-Achour, Vincent Pichot, Delphine Maudoux, Jean Claude Barthélémy, Frédéric Roche
Journal: European Respiratory Journal (2012)

Limited and controversial data exist on the natural evolution of sleep disordered breathing (SDB) in untreated individuals. This study examines the evolution of SDB over a 3-yr period in a community-based sample of elderly subjects. From the initial cohort of 854 healthy subjects aged mean± sd 68.4±0.8 yrs, 519 untreated subjects accepted clinical and instrumental follow-up 3.6±1.6 yrs later. SDB was defined as a respiratory disturbance index (RDI) &gt;15 events·h −1 . At baseline, 202 (39%) subjects had an RDI ≤15 events·h −1 and 317 (61%) had an RDI &gt;15 events·h −1 . 3 yrs later, 280 (54%) subjects were non-SDB and 239 (46%) had SDB. Between evaluations, the RDI decreased from 22.3±16.2 to 16.4±13.0 events·h −1 , with a greater decrease in the number of cases with an RDI &gt;30 events·h −1 that in those with RDI ≥30 events·h −1 . In the non-SDB group, 81% had a stable RDI and 19% increased their RDI by a mean of 13.7 events·h −1 . In the SDB group, the RDI decreased to values ≤15 events·h −1 in 36.6% of cases, 63.4% still having SDB. The RDI changes did not depend on weight changes. In healthy elderly subjects, the prevalence and severity of SDB did not show a tendency toward natural worsening, some cases having improvement or a remission independent of weight changes. These findings also suggest that in the elderly, natural SDB progression is still hypothetical.
ADAPT, a Novel Scaffold Protein-Based Probe for Radionuclide Imaging of Molecular Targets That Are Expressed in Disseminated Cancers
Authors: Javad Garousi, Sarah Lindbo, Johan Nilvebrant, Mikael Åstrand, Jos Buijs, Mattias Sandström, Hadis Honarvar, Anna Orlova, Vladimir Tolmachev, Sophia Hober
Journal: Cancer Research (2015)

Abstract Small engineered scaffold proteins have attracted attention as probes for radionuclide-based molecular imaging. One class of these imaging probes, termed ABD-Derived Affinity Proteins (ADAPT), has been created using the albumin-binding domain (ABD) of streptococcal protein G as a stable protein scaffold. In this study, we report the development of a clinical lead probe termed ADAPT6 that binds HER2, an oncoprotein overexpressed in many breast cancers that serves as a theranostic biomarker for several approved targeting therapies. Surface-exposed amino acids of ABD were randomized to create a combinatorial library enabling selection of high-affinity binders to various proteins. Furthermore, ABD was engineered to enable rapid purification, to eradicate its binding to albumin, and to enable rapid blood clearance. Incorporation of a unique cysteine allowed site-specific conjugation to a maleimido derivative of a DOTA chelator, enabling radionuclide labeling, 111In for SPECT imaging and 68Ga for PET imaging. Pharmacologic studies in mice demonstrated that the fully engineered molecule 111In/68Ga-DOTA-(HE)3-ADAPT6 was specifically bound and taken up by HER2-expressing tumors, with a high tumor-to-normal tissue ratio in xenograft models of human cancer. Unbound tracer underwent rapid renal clearance followed by high renal reabsorption. HER2-expressing xenografts were visualized by gamma-camera or PET at 1 hour after infusion. PET experiments demonstrated feasibility for discrimination of xenografts with high or low HER2 expression. Our results offer a preclinical proof of concept for the use of ADAPT probes for noninvasive in vivo imaging. Cancer Res; 75(20); 4364–71. ©2015 AACR.
Prognostic significance of an apoptotic index and apoptosis/proliferation ratio for patients with high-grade astrocytomas
Authors: Hiroko Kuriyama, Kathleen R. Lamborn, Judith R. O'Fallon, N. Iturria, Thomas Sebo, Paul L. Schaefer, Bernd W. Scheithauer, Jan C. Buckner, Nagato Kuriyama, Robert B. Jenkins, Mark A. Israel
Journal: Neuro-Oncology (2002)

We evaluated the association of spontaneous apoptosis and an apoptosis/proliferation index with survival to determine the potential of such measures to serve as predictive markers for patients with glioblastoma multiforme (GBM). We examined the extent of spontaneous apoptosis in tumors from newly diagnosed patients, 75 with GBM and 21 with anaplastic astrocytoma, who were entered on treatment protocols of the North Central Cancer Treatment Group. In the group of GBM patients, those with a higher apoptotic index tended to live longer (P = 0.04; Cox proportional hazards model including performance score, age, and extent of resection in a multivariate model). We found that the apoptotic index values for anaplastic astrocytoma patients tended to be lower than those in the GBM patients, although with small sample sizes, the result was not statistically significant (P = 0.1). We also examined expression of the Ki-67 cell proliferation antigen immunohistochemically using the MIB-1 monoclonal antibody. Ki-67 expression did not provide additional information regarding the survival of patients with GBM. In this group of GBM patients, those patients with higher apoptotic index/proliferation ratios had a better prognosis than did those with a low ratio (P < 0.021, same model as above). These findings suggest that both apoptosis and a cell death/cell proliferation ratio are associated with patient survival, and they may be useful for either the clinical evaluation of patients with GBM or the stratification of patients for treatment evaluation.
Managing chronic diseases
Authors: Peter Cox
Journal: BMJ (2005)

Managing chronic diseases Palliative care spectrum starts early onEditor-Palliative care does not start when a patient is dying. 1 A whole spectrum of palliation begins from the day of diagnosis of a potentially terminal disease, such as soft tissue sarcoma.Palliation, in the sense of needing to absorb what this means for the patient, becomes even then a medical imperative.The "How long have I got, Doc?" question may not be articulated, but it will be there and needs an empathetic response.Curative treatment is sought, but-with sarcoma-lung metastases signal the end of that phase and the beginning of palliative treatment.The doctor and the patient know the dragon can be disabled but never slain.Palliation is then partnership, working to decide what may be gained at what cost.(This may apply during curative treatment: to take chemotherapy drugs now "just in case," or to keep them for later?)Palliative treatment can be long (in sarcoma up to 20 years or more), or it can be brief.Its ending is not solely a medical judgment.Doctors may decide they can do no more, but active patients use online support groups, seeking new treatment options across the world.Patients may decide to end palliative treatment.Grown weary of painful chemotherapy offering diminishing returns, they may prefer a shorter but better life.Making that choice together is an aspect of palliation.When death is near, palliative care becomes terminal care.If throughout doctors and patients have aligned their understanding of the disease, and have taken decisions jointly, have explored the holistic meaning of disease in life and death, the palliative spectrum may offer healing if not cure.If, however, being palliative begins only when the patient is dying doctors cannot then meet patients, where they are most needed, in the ground of their being and their not being.
Tumour necrosis factor (TNF)-blocking agents in juvenile psoriatic arthritis: are they effective?
Authors: M. H. Otten, F. H. M. Prince, R. ten Cate, M. A. J. van Rossum, M. Twilt, E. P. A. H. Hoppenreijs, Y. Koopman-Keemink, A. P. Oranje, F. B. de Waard-van der Spek, S. L. Gorter, W. Armbrust, K. M. Dolman, N. M. Wulffraat, L. W. A. van Suijlekom-Smit
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objectives</h3> To evaluate the effectiveness of tumour necrosis factor (TNF) blockers in juvenile psoriatic arthritis (JPsA). <h3>Methods</h3> The study was a prospective ongoing multicentre, observational study of all Dutch juvenile idiopathic arthritis (JIA) patients using biologicals. The response of arthritis was assessed by American College of Rheumatology (ACR) paediatric response and Wallace inactive disease criteria. The response of psoriatic skin lesions was scored by a 5-point scale. <h3>Results</h3> Eighteen JPsA patients (72% female, median age onset 11.1 (range 3.3–14.6) years, 50% psoriatic skin lesions, 39% nail pitting, 22% dactylitis) were studied. The median follow-up time since starting anti-TNFα was 26 (range 3–62) months. Seventeen patients started on etanercept and one started on adalimumab. After 3 months of treatment 83% of the patients achieved ACR30 response, increasing to 100% after 15 months. Inactive disease reached in 67% after 39 months. There was no discontinuation because of inefficacy. Six patients discontinued treatment after a good clinical response. However, five patients flared and restarted treatment, all with a good response. During treatment four patients (two JPsA and two JIA patients with other subtypes) developed de novo psoriasis. In four of the nine patients the pre-existing psoriatic skin lesions improved. <h3>Conclusion</h3> Anti-TNFα therapy in JPsA seems effective in treating arthritis. However, in most patients the arthritis flared up after treatment discontinuation, emphasising the need to investigate optimal therapy duration. The psoriatic skin lesions did not respond well and four patients developed de novo psoriasis.
Targets for therapy in sarcomeric cardiomyopathies
Authors: J. C. Tardiff, L. Carrier, D. M. Bers, C. Poggesi, C. Ferrantini, R. Coppini, L. S. Maier, H. Ashrafian, S. Huke, J. van der Velden
Journal: Cardiovascular Research (2015)

To date, no compounds or interventions exist that treat or prevent sarcomeric cardiomyopathies. Established therapies currently improve the outcome, but novel therapies may be able to more fundamentally affect the disease process and course. Investigations of the pathomechanisms are generating molecular insights that can be useful for the design of novel specific drugs suitable for clinical use. As perturbations in the heart are stage-specific, proper timing of drug treatment is essential to prevent initiation and progression of cardiac disease in mutation carrier individuals. In this review, we emphasize potential novel therapies which may prevent, delay, or even reverse hypertrophic cardiomyopathy caused by sarcomeric gene mutations. These include corrections of genetic defects, altered sarcomere function, perturbations in intracellular ion homeostasis, and impaired myocardial energetics.
ngLOC: an n-gram-based Bayesian method for estimating the subcellular proteomes of eukaryotes
Authors: Brian R King, Chittibabu Guda
Journal: Genome biology (2007)

Abstract We present a method called ngLOC, an n -gram-based Bayesian classifier that predicts the localization of a protein sequence over ten distinct subcellular organelles. A tenfold cross-validation result shows an accuracy of 89% for sequences localized to a single organelle, and 82% for those localized to multiple organelles. An enhanced version of ngLOC was developed to estimate the subcellular proteomes of eight eukaryotic organisms: yeast, nematode, fruitfly, mosquito, zebrafish, chicken, mouse, and human.