tbuckley/cabot-search huggingface dataset:
High-Dose Samarium-153 Ethylene Diamine Tetramethylene Phosphonate: Low Toxicity of Skeletal Irradiation in Patients With Osteosarcoma and Bone Metastases
Authors: Peter M. Anderson, Gregory A. Wiseman, Angela Dispenzieri, Carola A.S. Arndt, Lynn C. Hartmann, William A. Smithson, Brian P. Mullan, Oyvind S. Bruland
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Samarium-153 ethylene diamine tetramethylene phosphonate (153Sm-EDTMP), a bone-seeking radiopharmaceutical, provides therapeutic irradiation to osteoblastic bone metastases. Because the dose-limiting toxicity of 153Sm-EDTMP is thrombocytopenia, a dose-escalation trial using peripheral-blood progenitor cells (PBPCs) or marrow support was conducted to treat metastatic bone cancer. PATIENTS AND METHODS: Patients with locally recurrent or metastatic osteosarcoma or skeletal metastases avid on bone scan were treated with 1, 3, 4.5, 6, 12, 19, or 30 mCi/kg of 153Sm-EDTMP. RESULTS: Thirty patients were treated with 153Sm-EDTMP. Transient symptoms of hypocalcemia were seen at 30 mCi/kg. Estimates of radioisotope bound to bone surfaces and marrow radiation dose were linear with injected amount of 153Sm-EDTMP. Cytopenias also occurred in all subjects and were dose-related. At day +13 after 153Sm-EDTMP, residual whole-body radioactivity was 1% to 65% of whole-body radioactivity considered safe for PBPC infusion, 3.6 mCi. After PBPC or marrow infusion on day +14 after 153Sm-EDTMP, recovery of hematopoiesis was problematic in two patients at the 30 mCi/kg dose infused with less than 2 × 106 CD34+/kg on day +14, but not in other patients. Reduction or elimination of opiates for pain was seen in all patients. Patients had no adverse changes in appetite or performance status. CONCLUSION: 153Sm-EDTMP with PBPC support can provide bone-specific therapeutic irradiation (estimates of 39 to 241 Gy). Hematologic toxicity at 30 mCi 153Sm-EDTMP/kg requires PBPC grafts with more than 2 × 106 CD34+/kg to overcome myeloablative effects of skeletal irradiation. Nonhematologic side effects are minimal.
No-Flow Ischemia Inhibits Insulin Signaling in Heart by Decreasing Intracellular pH
Authors: Christophe Beauloye, Luc Bertrand, Ulrike Krause, Anne-Sophie Marsin, Tom Dresselaers, Florent Vanstapel, Jean-Louis Vanoverschelde, Louis Hue
Journal: Circulation Research (2001)

Abstract —Glucose-insulin-potassium solutions exert beneficial effects on the ischemic heart by reducing infarct size and mortality and improving postischemic left ventricular function. Insulin could be the critical protective component of this mixture, although the insulin response of the ischemic and postischemic myocardium has not been systematically investigated. The aim of this work was to study the insulin response during ischemia by analyzing insulin signaling. This was evaluated by measuring changes in activity and/or phosphorylation state of insulin signaling elements in isolated perfused rat hearts submitted to no-flow ischemia. Intracellular pH (pH i ) was measured by NMR. No-flow ischemia antagonized insulin signaling including insulin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase, protein kinase B, p70 ribosomal S6 kinase, and glycogen synthase kinase-3. These changes were concomitant with intracellular acidosis. Perfusing hearts with ouabain and amiloride in normoxic conditions decreased pH i and insulin signaling, whereas perfusing at pH 8.2 counteracted the drop in pH i and the inhibition of insulin signaling by ischemia. Incubation of cardiomyocytes in normoxic conditions, but at pH values below 6.75, mimicked the effect of ischemia and also inhibited insulin-stimulated glucose uptake. Finally, the in vitro insulin receptor tyrosine kinase activity was progressively inhibited at pH values below physiological pH i , being abolished at pH 6.0. Therefore, ischemic acidosis decreases kinase activity and tyrosine phosphorylation of the insulin receptor thereby preventing activation of the downstream components of the signaling pathway. We conclude that severe ischemia inhibits insulin signaling by decreasing pH i .
NJML+: An Extension of the NJML Method to Handle Protein Sequence Data and Computer Software Implementation
Authors: Satoshi Ota, Wen-Hsiung Li
Journal: Molecular Biology and Evolution (2001)

While the maximum-likelihood (ML) method of tree reconstruction is statistically rigorous, it is extremely time-consuming for reconstructing large trees. We previously developed a hybrid method (NJML) that combines the neighbor-joining (NJ) and ML methods and thus is much faster than the ML method and improves the performance of NJ. However, we considered only nucleotide sequence data, so NJML is not suitable for handling amino acid sequence data, which requires even more computer time. NJML+ is an implementation of a further improved method for practical data analyses (including protein sequence data). Our extensive simulations using nucleotide and amino acid sequences showed that NJML+ gave good results in tree reconstruction. Indeed, NJML+ showed substantial improvements over existing methods in terms of both computational times and efficiencies, especially for amino acid sequence data. We also developed a "user-friendly" interface for the NJML+ program, including a simple tree viewer.
Cardiovascular disease risk factors in patients with hidradenitis suppurativa: a systematic review and meta-analysis of observational studies
Authors: T. Tzellos, C.C. Zouboulis, W. Gulliver, A.D. Cohen, P. Wolkenstein, G.B.E. Jemec
Journal: British Journal of Dermatology (2015)

Hidradenitis suppurativa (HS) is a chronic, inflammatory, debilitating skin disease. The aim of the study was to systematically review the literature and critically answer the question: In patients with HS, do cardiovascular risk factors appear at a significantly higher rate compared with controls? The main search was conducted in Medline, Embase and the Cochrane Central Register. Studies eligible for inclusion were of case-control, cross-sectional and cohort design, and included comparison of any cardiovascular risk factor(s) in patients with HS with those of control groups. An I(2) value > 50% was considered to show substantial heterogeneity. In this case, DerSimonian and Laird random-effect models were considered to compute pooled odds ratios (OR). Otherwise, a fixed-effects model was suitable. Nine studies, with 6174 patients with HS and 24 993 controls, were included. Significant association of HS with obesity [OR 3·45, 95% confidence interval (CI) 2·20-5·38, P < 0·001], central obesity (OR 2·97, 95% CI 1·41-6·25, P = 0·004), active smoking (OR 4·34, 95% CI 2·48-7·60, P < 0·001), history of smoking (OR 6·34, 95% CI 2·41-16·68, P < 0·001), hypertriglyceridemia (OR 1·67, 95% CI 1·14-2·47, P = 0·009), low high-density lipoprotein (HDL) (OR 2·48, 95% CI 1·49-4·16, P < 0·001), diabetes (OR 2·85, 95% CI 1·34-6·08, P = 0·007) and metabolic syndrome (OR 2·22, 95% CI 1·62-3·06, P < 0·001) was detected. Associations were significant both in population and hospital patients with HS, with hospital HS groups having uniformly higher ORs than the population HS groups. Causality could not be assessed. Heterogeneity was substantial in all analyses. This systematic review indicated that cardiovascular risk factors appear at a significantly higher rate in patients with HS compared with controls. The need for screening of patients with HS for modifiable cardiovascular risks is emphasized.
The Role of Radiation Therapy in Endometrial Cancer
Authors: J. Frank Wilson
Journal: JAMA (1980)

RECENT emergence of adenocarcinoma of the uterine corpus as the most common invasive gynecologic malignant neoplasm in the United States is attributable to several concurrent factors. Earlier detection of carcinomas of the uterine cervix, still in noninvasive stages, through widespread cytologic screening, is chief among these, but it also may be attributed to an absolute increase in the incidence of endometrial cancer noted during the past decade.<sup>1</sup>Despite observations that these neoplasms may be undergoing transition to greater virulency, more than three fourths of patients continue to present with an early clinical stage of disease. Good results in treating these stages have been reported often but are not sufficiently satisfactory to justify the often complacent attitude of some therapists. In our aging population, with its reduced parity levels, and potential exposure to known or suspected carcinogens, it is essential to optimize available therapy. The challenge presented by this increasingly
CCR5 Antagonist Blocks Metastasis of Basal Breast Cancer Cells
Authors: Marco Velasco-Velázquez, Xuanmao Jiao, Marisol De La Fuente, Timothy G. Pestell, Adam Ertel, Michael P. Lisanti, Richard G. Pestell
Journal: Cancer Research (2012)

The roles of the chemokine CCL5 and its receptor CCR5 in breast cancer progression remain unclear. Here, we conducted microarray analysis on 2,254 human breast cancer specimens and found increased expression of CCL5 and its receptor CCR5, but not CCR3, in the basal and HER-2 genetic subtypes. The subpopulation of human breast cancer cell lines found to express CCR5 displayed a functional response to CCL5. In addition, oncogene transformation induced CCR5 expression, and the subpopulation of cells that expressed functional CCR5 also displayed increased invasiveness. The CCR5 antagonists maraviroc or vicriviroc, developed to block CCR5 HIV coreceptor function, reduced in vitro invasion of basal breast cancer cells without affecting cell proliferation or viability, and maraviroc decreased pulmonary metastasis in a preclinical mouse model of breast cancer. Taken together, our findings provide evidence for the key role of CCL5/CCR5 in the invasiveness of basal breast cancer cells and suggest that CCR5 antagonists may be used as an adjuvant therapy to reduce the risk of metastasis in patients with the basal breast cancer subtype.
Harming through Protection?
Authors: Mary Ann Baily
Journal: New England Journal of Medicine (2008)

About 80,000 catheter-related bloodstream infections occur in U.S. intensive care units (ICUs) each year, causing as many as 28,000 deaths and costing the health care system as much as $2.3 billion. If there were procedures that could prevent these infections, wouldn't we encourage hospitals to introduce them? And wouldn't we encourage the development, testing, and dissemination of strategies that would get clinicians to use them? Apparently not, judging from the experience of Peter Pronovost and other Johns Hopkins investigators who helped 103 ICUs in 67 Michigan hospitals carry out a highly successful infection-control effort,1 only to run into major problems . . .
Critics call for "misleading" consultation on shared decision making to be withdrawn
Authors: A. O'Dowd
Journal: BMJ (2012)

Several health policy experts and organisations in England are calling on the government to drop or at least rebrand a recent consultation, which they say is “misleading and damaging.”

The government has been accused of blurring the lines between two different concepts—shared decision making for patients and choice of providers—in its consultation Liberating the NHS: No Decision About Me, Without Me , published on 23 May.1

The document says the Department of Health is consulting further on detailed proposals to implement its commitment to giving patients more say and choice over their care and treatment.

However, it has already provoked angry responses from many quarters because critics believe that the document is masquerading as something else.

A joint letter signed by various organisations is due to be sent to …
A comparison of stool fluid and stool dialysate obtained in vivo
Authors: M. J. Tarlow, H. Thom
Journal: Gut (1974)

Stool fluid has been obtained for analysis by homogenization and high speed centrifugation of fresh stool. This fluid, from two healthy individuals with soft stools has been compared with stool dialysate obtained <i>in vivo</i> by retrieval of swallowed dialysis bags from their stools. Stool fluid was more acid, with a higher osmolality, an increased concentration of organic anions, sugar and ammonia, and a lower bicarbonate concentration than dialysate <i>in vivo.</i> It is suggested that in the individuals studied, dialysate <i>in vivo</i> may not be in equilibrium with the stool fluid surrounding it, and may not represent a true dialysate of faecal water.
Preferential Killing of Breast Tumor Initiating Cells by <i>N,N</i>-Diethyl-2-[4-(Phenylmethyl)Phenoxy]Ethanamine/Tesmilifene
Authors: Tao Deng, Jeff C. Liu, Kathleen I. Pritchard, Andrea Eisen, Eldad Zacksenhaus
Journal: Clinical Cancer Research (2008)

Abstract Purpose: N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE; tesmilifene) is thought to potentiate the antineoplastic effect of cytotoxic drugs. In a phase III randomized trial for metastatic breast cancer using doxorubicin with or without DPPE, addition of the latter resulted in a significant improvement in overall survival and a trend toward a difference in progression-free survival but, paradoxically, no difference in objective tumor response. Here we tested the hypothesis that DPPE targets breast tumor-initiating cells (TICs). Experimental Design: Human breast TICs from pleural effusions were identified as CD44+:CD24−/low cells by flow cytometry and functionally by their ability to form nonadherent spheres in culture. Mouse mammary TICs from two different models of breast cancer were identified as cells capable of initiating spheres in culture and secondary tumors following transplantation into the mammary gland of syngeneic mice. Results: We show that at physiologically attainable concentrations, treatment with DPPE alone reduced tumorsphere formation and viability of CD44+:CD24−/low breast cancer cells. The kinetics of killing varied for the different breast tumor cells and required continuous exposure to the drug. Whereas doxorubicin killed CD44+:CD24−/low and CD44−:CD24+ cells equally well, DPPE induced apoptosis preferentially in CD44+:CD24−/low cells. Treatment of Her2/Neu+ mammary tumor cells with DPPE in vitro efficiently killed TICs, as determined by flow cytometry and transplantation assays; DPPE further cooperated with doxorubicin to completely eradicate tumorigenic cells. Conclusions: Our results show that continuous treatment with DPPE alone directly targets breast TICs, and provide rationale to test for cooperation between DPPE and known drugs with efficacy toward breast cancer subtypes.
Social Support, Psychological Distress, and Natural Killer Cell Activity in Ovarian Cancer
Authors: Susan K. Lutgendorf, Anil K. Sood, Barrie Anderson, Stephanie McGinn, Heena Maiseri, Minh Dao, Joel I. Sorosky, Koen De Geest, Justine Ritchie, David M. Lubaroff
Journal: Journal of Clinical Oncology (2005)

Psychosocial stress has been related to impaired immunity in cancer patients. However, the extent to which these relationships exist in immune cells in the tumor microenvironment in humans has not been explored. We examined relationships among distress, social support, and natural killer (NK) cell activity in ovarian cancer patients in peripheral-blood mononuclear cells (PBMC), ascitic fluid, and tumor-infiltrating lymphocytes (TIL).Patients awaiting surgery for a pelvic mass suspected of being ovarian cancer completed psychological questionnaires and gave a presurgical sample of peripheral blood. Samples of tumor and ascites were taken during surgery, lymphocytes were then isolated, and NK cytotoxicity and percentage were determined. The final sample, which was confirmed by surgical diagnosis, included 42 patients with epithelial ovarian cancer and 23 patients with benign masses.Peripheral NK cell activity was significantly lower among ovarian cancer patients than in patients with benign masses. Among ovarian cancer patients, NK cytotoxicity in TIL was significantly lower than in PBMC or ascitic fluid. Social support was related to higher NK cytotoxicity in PBMC and TIL, adjusting for stage. Distress was related to lower NK cytotoxicity in TIL. A multivariate model indicated independent associations of both distress and social support with NK cell activity in TIL.Psychosocial factors, such as social support and distress, are associated with changes in the cellular immune response, not only in peripheral blood, but also at the tumor level. These relationships were more robust in TIL. These findings support the presence of stress influences in the tumor microenvironment.
Immunotherapy for Alzheimer’s disease: hoops and hurdles
Authors: Cynthia A Lemere
Journal: Molecular Neurodegeneration (2013)

Alzheimer's disease (AD) is the most common form of dementia, afflicting more than 30 million people worldwide. Currently, there is no cure or way to prevent this devastating disease. Extracellular plaques, containing various forms of amyloid-β protein (Aβ), and intracellular neurofibrillary tangles (NFTs), composed of hyper-phosphorylated tau protein, are two major pathological hallmarks of the AD brain. Aggregation, deposition, and N-terminal modification of Aβ protein and tau phosphorylation and aggregation are thought to precede the onset of cognitive decline, which is better correlated with tangle formation and neuron loss. Active and passive vaccines against various forms of Aβ have shown promise in pre-clinical animal models. However, translating these results safely and effectively into humans has been challenging. Recent clinical trials showed little or no cognitive efficacy, possibly due to the fact that the aforementioned neurodegenerative processes most likely pre-existed in the patients well before the start of immunotherapy. Efforts are now underway to treat individuals at risk for AD prior to or in the earliest stages of cognitive decline with the hope of preventing or delaying the onset of the disease. In addition, efforts to immunize against tau and other AD-related targets are underway.
Platelet Adhesion Via Glycoprotein IIb Integrin Is Critical for Atheroprogression and Focal Cerebral Ischemia
Authors: Steffen Massberg, Katrin Schürzinger, Michael Lorenz, Ildiko Konrad, Christian Schulz, Nikolaus Plesnila, Elisabeth Kennerknecht, Martina Rudelius, Susanne Sauer, Siegmund Braun, Elisabeth Kremmer, Nikla R. Emambokus, Jon Frampton, Meinrad Gawaz
Journal: Circulation (2005)

The platelet glycoprotein (GP) IIb/IIIa integrin binds to fibrinogen and thereby mediates platelet aggregation. Here, we addressed the role of GP IIb for platelet adhesion and determined the relevance of platelet GP IIb for the processes of atherosclerosis and cerebral ischemia-reperfusion (I/R) injury.GP IIb(-/-) mice were generated and bred with ApoE(-/-) animals to create GP IIb(-/-)ApoE(-/-) mice. Platelet adhesion to the mechanically injured or atherosclerotic vessel wall was monitored by in vivo video fluorescence microscopy. In the presence of GP IIb, vascular injury and early atherosclerosis induced platelet adhesion in the carotid artery (CA). In contrast, platelet adhesion was significantly reduced in the absence of GP IIb integrin (P<0.05). To address the contribution of platelet GP IIb to atheroprogression, we determined atherosclerotic lesion formation in the CA and aortic arch (AA) of GP IIb(+/+)ApoE(-/-) or GP IIb(-/-)ApoE(-/-) mice. Interestingly, the absence of GP IIb attenuated lesion formation in CA and AA, indicating that platelets, via GP IIb, contribute substantially to atherosclerosis. Next, we assessed the implication of GP IIb for cerebral I/R injury. We observed that after occlusion of the middle cerebral artery, the cerebral infarct size was drastically reduced in mice lacking GP IIb compared with wild-types.These findings show for the first time in vivo that GP IIb not only mediates platelet aggregation but also triggers platelet adhesion to exposed extracellular matrices and dysfunctional endothelial cells. In a process strictly involving GP IIb, platelets, which are among the first blood cells to arrive at the scene of endothelial dysfunction, contribute essentially to atherosclerosis and cerebral I/R injury.
Outcome of Diabetic Foot Osteomyelitis Treated Nonsurgically
Authors: Eric Senneville, Audrey Lombart, Eric Beltrand, Michel Valette, Laurence Legout, Marie Cazaubiel, Yazdan Yazdanpanah, Pierre Fontaine
Journal: Diabetes Care (2008)

The purpose of this article was to identify criteria predictive of remission in nonsurgical treatment of diabetic foot osteomyelitis.Diabetic patients who were initially treated without orthopedic surgery for osteomyelitis of the toe or metatarsal head of a nonischemic foot between June 2002 and June 2003 in nine French diabetic foot centers were identified, and their medical records were reviewed. Remission was defined as the absence of any sign of infection at the initial or contiguous site assessed at least 1 year after the end of treatment. A total of 24 demographic, clinical, and therapeutic variables including bone versus swab culture-based antibiotic therapy were analyzed.Fifty consecutive patients aged 62.2 +/- 11.1 years (mean +/- SD) with diabetes duration of 16 +/- 10.9 years were included. The mean duration of antibiotic treatment was 11.5 +/- 4.21 weeks. Bone biopsy was routinely available in four of the nine centers. Overall patient management was similar in the different centers except for the use of rifampin, which was recorded more frequently in patients from centers in which a bone biopsy was available. At the end of a 12.8-month posttreatment mean follow-up, 32 patients (64%) were in remission. Bone culture-based antibiotic therapy was the only variable associated with remission, as determined by both univariate (18 of 32 [56.3%] vs. 4 of 18 [22.2%], P = 0.02) and multivariate analyses (odds ratio 4.78 [95% CI 1.0-22.7], P = 0.04).Bone culture-based antibiotic therapy is a factor predictive of success in diabetic patients treated nonsurgically for osteomyelitis of the foot.
In Patients With Acute Myocardial Infarction, the Impact of Hyperglycemia as a Risk Factor for Mortality Is Not Homogeneous Across Age-Groups
Authors: José Carlos Nicolau, Carlos Vicente Serrano, Roberto Rocha Giraldez, Luciano Moreira Baracioli, Humberto Graner Moreira, Felipe Lima, Marcelo Franken, Roberto Kalil, José Antonio Franchini Ramires, Robert P. Giugliano
Journal: Diabetes Care (2011)

To assess the impact of hyperglycemia in different age-groups of patients with acute myocardial infarction (AMI).A total of 2,027 patients with AMI were categorized into one of five age-groups: <50 years (n = 301), ≥50 and <60 (n = 477), ≥60 and <70 (n = 545), ≥70 and <80 (n = 495), and ≥80 years (n = 209). Hyperglycemia was defined as initial glucose ≥115 mg/dL.The adjusted odds ratios for hyperglycemia predicting hospital mortality in groups 1-5 were, respectively, 7.57 (P = 0.004), 3.21 (P = 0.046), 3.50 (P = 0.003), 3.20 (P < 0.001), and 2.16 (P = 0.021). The adjusted P values for correlation between glucose level (as a continuous variable) and mortality were 0.007, <0.001, 0.043, <0.001, and 0.064. The areas under the ROC curves (AUCs) were 0.785, 0.709, 0.657, 0.648, and 0.613. The AUC in group 1 was significantly higher than those in groups 3-5.The impact of hyperglycemia as a risk factor for hospital mortality in AMI is more pronounced in younger patients.