tbuckley/cabot-search huggingface dataset:
A combinational approach to optimize biomarkers efficacy in identifying patients with sarcoidosis and monitoring respiratory functional worsening
Authors: Gregorino Paone, Gian Luca Di Tanna, Sandro Batzella, Francesco Belli, Salvatore D'Antonio, Mario Giuseppe Alma, Giovanni Schmid, Giovanni Puglisi, Annarita Vestri
Journal: European Respiratory Journal (2012)

Background Sarcoidosis is a multisystemic granulomatous disease of unknown aetiology which affects lungs and lymphatic system.Its diagnosis is established by histologic evidence of non-caseating granuloma and the clinical course is unpredictable.

Aims We aimed to investigate whether a panel of biomarkers combined together may help identify sarcoidosis and predict its functional worsening.

Methods We analyzed 30 subjects with sarcoidosis and 34 with IPF. Participants underwent PFTs, radiologic investigations, and fiberoptic bronchoscopy. We examined BALF cellular profiles and BALF and serum concentrations of ECP, MPO, tryptase, procollagenIII, sIL-2R, IL-6, and TNFα.

Results The linear predictor score,based on the combination of BALF lymphocytes, CD4, CD8,and ECP, correctly allocated 29 patients with sarcoidosis (97% of correct classification; 95% CI, 84.4%-99.8%) and 28 with IPF (82% correct classification; 95% CI, 68.8%-92.2%). The AUC was 0.93.

We also analyzed PFTs of participants with sarcoidosis during a 2-years follow-up period. At revaluation 76% of participants had stable disease, and 24% experienced a worsening of the respiratory function. The combination of BALF neutrophil percentage, ECP, and tryptase, yielded a 100% correct classification of patients (95% CI, 90.6%-100%); the AUC was 1. None of the markers analyzed as a single variable reached a similar allocation rate and a dissatisfying discrimination was obtained using markers from peripheral blood.

Conclusion This combinational method could be a valuable approach to optimize biomarkers performance in the effort to identify sarcoidosis and to predict its clinical course.
Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer.
Authors: A D Seidman, A Tiersten, C Hudis, M Gollub, S Barrett, T J Yao, J Lepore, T Gilewski, V Currie, J Crown
Journal: Journal of Clinical Oncology (1995)

PURPOSE To evaluate the efficacy and safety of paclitaxel administered by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. PATIENTS AND METHODS Forty-nine patients with metastatic breast cancer received paclitaxel via 3-hour intravenous infusion after standard premedication. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not used, and chemotherapy was cycled every 3 weeks. For 25 patients who received paclitaxel as initial therapy (group I), the starting dose was 250 mg/m2. Twenty-four patients who had received two or more prior regimens, including an anthracycline (group II), started at 175 mg/m2. Paclitaxel pharmacokinetics were evaluated in 23 patients in group I. RESULTS Grade 3 and 4 toxicities included (groups I/II) neutropenia (36%/33%), thrombocytopenia (0%/8%), anemia (0%/13%), neuropathy (8%/0%), arthralgia/myalgia (16%/4%), and mucositis (4%/4%). No significant hypersensitivity-type reactions or cardiac arrhythmias were seen. Six patients who received paclitaxel at &gt; or = 250 mg/m2 experienced transient photopsia, without apparent chronic neuro-ophthalmologic sequelae. The mean peak plasma paclitaxel concentration was 5.87 mumol/L (range, 1.99 to 7.89) for these patients, and 6.08 mumol/L (range, 0.81 to 13.81) for 17 of 19 patients who did not experience visual symptoms. In 25 assessable patients in group I at a median follow-up time of 12 months, one complete response (CR) and seven partial responses (PRs) have been observed, for a total response rate of 32% (95% confidence interval [CI], 15% to 53%). In group II, five PRs were noted in 24 assessable patients (20.8%; 95% CI, 7% to 42%). Median response durations were 7 months for group I and 4 months for group II. CONCLUSION Paclitaxel via 3-hour infusion, without prophylactic G-CSF, is active and safe as initial and subsequent therapy for metastatic breast cancer. The transient visual symptoms noted at higher doses seem unrelated to peak plasma paclitaxel concentration. Further studies that compare 3- and 24 hour (or other) infusion schedules are necessary to determine the optimal administration of paclitaxel in metastatic breast cancer.
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition
Authors: Nathalie Bergeron, Binh An P. Phan, Yunchen Ding, Aleyna Fong, Ronald M. Krauss
Journal: Circulation (2015)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the regulation of cholesterol homeostasis. By binding to hepatic low-density lipoprotein (LDL) receptors and promoting their lysosomal degradation, PCSK9 reduces LDL uptake, leading to an increase in LDL cholesterol concentrations. Gain-of-function mutations in PCSK9 associated with high LDL cholesterol and premature cardiovascular disease have been causally implicated in the pathophysiology of autosomal-dominant familial hypercholesterolemia. In contrast, the more commonly expressed loss-of-function mutations in PCSK9 are associated with reduced LDL cholesterol and cardiovascular disease risk. The development of therapeutic approaches that inhibit PCSK9 function has therefore attracted considerable attention from clinicians and the pharmaceutical industry for the management of hypercholesterolemia and its associated cardiovascular disease risk. This review summarizes the effects of PCSK9 on hepatic and intestinal lipid metabolism and the more recently explored functions of PCSK9 in extrahepatic tissues. Therapeutic approaches that prevent interaction of PCSK9 with hepatic LDL receptors (monoclonal antibodies, mimetic peptides), inhibit PCSK9 synthesis in the endoplasmic reticulum (antisense oligonucleotides, siRNAs), and interfere with PCSK9 function (small molecules) are also described. Finally, clinical trials testing the safety and efficacy of monoclonal antibodies to PCSK9 are reviewed. These have shown dose-dependent decreases in LDL cholesterol (44%-65%), apolipoprotein B (48%-59%), and lipoprotein(a) (27%-50%) without major adverse effects in various high-risk patient categories, including those with statin intolerance. Initial reports from 2 of these trials have indicated the expected reduction in cardiovascular events. Hence, inhibition of PCSK9 holds considerable promise as a therapeutic option for decreasing cardiovascular disease risk.
Aberrant expression of miR-9/9* in myeloid progenitors inhibits neutrophil differentiation by post-transcriptional regulation of ERG
Authors: K Nowek, S M Sun, L Bullinger, E M J Bindels, C Exalto, M K Dijkstra, K van Lom, H Döhner, S J Erkeland, B Löwenberg, M Jongen-Lavrencic
Journal: Leukemia (2015)
Effects of Hyperglycemia and Hyperthermia on the pH, Glycolysis, and Respiration of the Yoshida Sarcoma In Vivo&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J A Dickson, S K Calderwood
Journal: JNCI Journal of the National Cancer Institute (1979)

Tissue (extracellular) pH (pHe) and intracellular pH (pHi) were measured together in vivo in the solid Yoshida sarcoma and normal organs (liver, gastrocnemius muscle) of noninbred Wistar rats. pHe was monitored by insertion of a miniature capillary glass electrode, and pHi was measured indirectly by equilibrium partitioning of the weak organic acid 5,5-dimethyloxazolidine-2,4-dione across the cell membrane. Under normal conditions, tumor, liver, and gastrocnemius had a similar pHe of 7.05--7.30; tumor pHi was consistently higher (7.2) than that of the normal tissues (6.8--7.1). Curative hyperthermia (42 degrees C for 1 hr) did not significantly change tumor pHe or pHi. After ip glucose injection [6 g/kg body wt; blood glucose level greater than 400 mg/100 ml (22 mmoles/liter) for 4 hr], tumor pHe decreased markedly to 6.6 within 4 hours and did not return to normal for a further 12--14 hours, whereas tumor pHi was hardly affected. No marked change was noted in pHe or pHi of the normal organs following glucose loading of the host. In tumor slices removed from hyperglycemic hosts, marked reduction of both respiration and glycolysis was observed. Hyperglycemia (4 hr) plus hyperthermia at 40 degrees C (1 hr) had a synergistic inhibitory effect on metabolism that was equivalent to heat alone at 42 degrees C, and respiration and glycolysis almost ceased after 3--4 hours. However, tumor heating at 40 degrees C in hyperglycemic hosts was not equivalent to hyperthermia at 42 degrees C: With the former treatment, tumor regression did not occur, and animal survival did not differ from that of control untreated rats. The data do not support the postulate that the effects of heat on tumor cells are mediated via low pHi or that hyperglycemia leads to a lowered pHi which sensitizes the tumor to destruction at 40 degrees C instead of 42 degrees C.
Liver Necrosis and Lipid Peroxidation in the Rat as the Result of Paraquat and Diquat Administration
Authors: Raymond F. Burk, Richard A. Lawrence, James M. Lane
Journal: Journal of Clinical Investigation (1980)

Paraquat and diquat facilitate formation of superoxide anion in biological systems, and lipid peroxidation has been postulated to be their mechanism of toxicity. Paraquat has been shown to be more toxic to selenium-deficient mice than to controls, presumably as the result of decreased activity of the selenoenzyme glutathione peroxidase. The present study was designed to measure lipid peroxidation and to assess toxicity in control and selenium-deficient rats given paraquat and diquat. Lipid peroxidation was measured by determining ethane production rates of intact animals; toxicity was assessed by survival and by histological and serum enzyme evidence of liver and kidney necrosis. Paraquat and diquat were both much more toxic to selenium-deficient rats than to control rats. Diquat (19.5 μmol/kg) caused rapid and massive liver and kidney necrosis and very high ethane production rates in selenium-deficient rats. The effect of paraquat (78 μmol/kg) was similar to that of diquat but was not as severe. Acutely lethal doses of paraquat (390 μmol/kg) and diquat (230 μmol/kg) in control rats caused very little ethane production and no evidence of liver necrosis. These findings suggest that paraquat and diquat exert their acute toxicity largely through lipid peroxidation in selenium-deficient rats. Selenium deficiency had no effect on superoxide dismutase activity in erythrocytes or in 105,000 g supernate of liver or kidney. Glutathione peroxidase, which represents the only well-characterized biochemical function of selenium in animals, was dissociated from the protective effect of selenium against diquat-induced lipid peroxidation and toxicity by a time-course study in which selenium-deficient rats were injected with 50 μg of selenium and later given diquat (19.5 μmol/kg). Within 10 h, the selenium injection provided significant protection against diquat-induced lipid peroxidation and mortality even though this treatment resulted in no rise in glutathione peroxidase activity of liver, kidney, lung, or plasma at 10 h. This suggests that a selenium-dependent factor in addition to glutathione peroxidase exists that protects against lipid peroxidation.
Use of Procalcitonin to Shorten Antibiotic Treatment Duration in Septic Patients
Authors: Vandack Nobre, Stephan Harbarth, Jean-Daniel Graf, Peter Rohner, Jérôme Pugin
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: The duration of antibiotic therapy in critically ill patients with sepsis can result in antibiotic overuse, increasing the risk of developing bacterial resistance.Objectives: To test the hypothesis that an algorithm based on serial measurements of procalcitonin (PCT) allows reduction in the duration of antibiotic therapy compared with empirical rules, and does not result in more adverse outcomes in patients with severe sepsis and septic shock.Methods: In patients randomly assigned to the intervention group, antibiotics were stopped when PCT levels had decreased 90% or more from the initial value (if clinicians agreed) but not before Day 3 (if baseline PCT levels were <1 μg/L) or Day 5 (if baseline PCT levels were ⩾1 μg/L). In control patients, clinicians decided on the duration of antibiotic therapy based on empirical rules.Measurements and Main Results: Patients assigned to the PCT group had 3.5-day shorter median duration of antibiotic therapy for the first episode of infection than control subjects (intention-to-treat, n = 79, P = 0.15). In patients in whom a decision could be taken based on serial PCT measurements, PCT guidance resulted in a 4-day reduction in the duration of antibiotic therapy (per protocol, n = 68, P = 0.003) and a smaller overall antibiotic exposure (P = 0.0002). A similar mortality and recurrence of the primary infection were observed in PCT and control groups. A 2-day shorter intensive care unit stay was also observed in patients assigned to the PCT group (P = 0.03).Conclusions: Our results suggest that a protocol based on serial PCT measurement allows reducing antibiotic treatment duration and exposure in patients with severe sepsis and septic shock without apparent harm.Clinical trial registered with www.clinicaltrials.gov (NCT 00250666).
Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis.
Authors: J B Sørensen, H H Hansen, M Hansen, P Dombernowsky
Journal: Journal of Clinical Oncology (1988)

A consecutive group of 259 patients with inoperable adenocarcinoma of the lung (ACL) were observed to define risk groups for and frequency of brain metastases together with prognosis. All patients received chemotherapy in a three-armed randomized trial. Brain metastases were diagnosed in 25 patients before protocol entry and in 37 during treatment. Brain autopsy was performed in 87 patients and was positive in 38 (44%). Eleven of these (29%) were not diagnosed clinically. Patients younger than 60 years had a somewhat higher overall frequency of brain metastases than older patients. Patients with initial performance status above 60% and patients responding to chemotherapy had higher risk for developing brain metastasis during treatment than other patients, probably because of the increasing cumulated risk for this complication with prolonged survival. Median survival after onset of brain metastases was 73 days and survival was significantly shorter for these patients than for patients without this complication at days 0, 90, 180, and 365 after protocol entry. Thus, brain metastases is a frequent complication in ACL and the frequency increases with prolonged survival. Survival after development of brain metastases is short and it is questionable whether the inclusion of this subgroup of ACL patients into experimental cytostatic treatments is justified.
Hydrogel Templates for Rapid Manufacturing of Bioactive Fibers and 3D Constructs
Authors: Ali Tamayol, Alireza Hassani Najafabadi, Bahar Aliakbarian, Elmira Arab‐Tehrany, Mohsen Akbari, Nasim Annabi, David Juncker, Ali Khademhosseini
Journal: Advanced Healthcare Materials (2015)

Hydrogel templates are formed to entrap various pre-polymers prior to their crosslinking process. Upon the completion of the crosslinking process, an independent polymer network with the same fiber geometry is formed. The hydrogel template can be removed if necessary. As the proof-of-principle, fibers from various polymers are fabricated. The fabricated hybrid polymeric fibers are bioactive and can be bioprinted or assembled using textile processes. The approach can be used for creating complex 3D constructs for various applications. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Phylogenetic analysis of the 90 kD heat shock family of protein sequences and an examination of the relationship among animals, plants, and fungi species.
Authors: R S Gupta
Journal: Molecular Biology and Evolution (1995)

The heat shock protein (Hsp) sequences, because of their ubiquity and high degree of conservation, provide useful models for phylogenetic analysis. In this paper I have carried out a global alignment of all available sequences (a total of 31) for the 90-kD heat shock protein (Hsp90) family. The minimum amino acid identity that is seen between presently known Hsp90 homologs is about 40% over the entire length, indicating that it is a highly conserved protein. Based on the alignment, a number of signature sequences that either are distinctive of the Hsp90 family or that distinguish between the cytosolic and the endoplasmic reticular forms of Hsp90 have been identified. Detailed phylogenetic analyses based on Hsp90 sequences reported here strongly indicate that the cytosolic and the endoplasmic reticulum (ER) resident forms of Hsp90 constitute paralogous gene families which arose by a gene duplication event that took place very early in the evolution of eukaryotic cells. A minimum of two additional gene duplication events, which took place at a later time, are required to explain the presence of two different forms of Hsp90 that are found in fungi and vertebrate species. In a consensus neighbor-joining bootstrap tree based on Hsp90 sequences, plants and animals species grouped together 989 times of 1,000 (a highly significant score), indicating a closer relationship between them as compared to fungi. A closer affiliation of plant and animal species was also observed in the maximum-parsimony tree, although the relationship was not significantly supported by this method. A survey of the recent literature on this subject indicates that depending on the protein sequence and the methods of phylogenetic analysis, the animal species are indicated as closer relatives to either plants or fungi with significant statistical support for both topologies. Thus the relationship among the animal, plant, and fungi kingdoms remains an unresolved issue at the present time.
Early introduction of non invasive ventilation (NIV) in patients with systemic lupus erythematosus (SLE) and diaphragmatic weakness
Authors: Ziaudeen Ansari, Pooja Sharma, Susil Herath, Mike Lang, Amina Mohamed, Nazim Nathani
Journal: European Respiratory Journal (2014)

Background : Respiratory failure and domiciliary NIV requirement is not well defined in patient with SLE and respiratory muscle weakness. Patients with SLE can develop ventilatory failure from muscle weakness due to a combination of myopathy and vasculitis induced neuromuscular compromise.  Our NIV service caters to a national referral Centre for lupus. We have come across 6 SLE patients within last 4 years who presented with respiratory compromise. The predominant cause of respiratory compromise seemed to be significant and progressive diaphragmatic weakness.  Case 1: 31 years female who had diaphragmatic weakness, which was diagnosed at early stage and substantially reversed with early aggressive immunosuppression and currently stable on NIV.  Case 2: 41 years female developed respiratory sepsis within one month of NIV introduction and has required longterm tracheostomy and remains ventilated.  Case 3: 46 years female succumbed to global and progressive respiratory weakness while on NIV and died.  Case 4: 79 years male with neuromuscular weakness died within few days of initiating NIV.  Case 5: 46 years female on NIV for last 24 months doing well with stable lung function.  Case 6: 67 years male on NIV for 31 months doing well with stable lung function.  Conclusion; SLE related diaphragmatic myopathy seems to have a reversible component and needs to be aggressively managed. NIV is effective in managing ventilatory impairment in shrinking lungs. Respiratory and rheumatology pathway needs to be developed with a low threshold in investigating and managing lupus patients with early signs of respiratory impairment.
Effect of Presymptomatic Body Mass Index and Consumption of Fat and Alcohol on Amyotrophic Lateral Sclerosis
Authors: Mark H. B. Huisman, Meinie Seelen, Perry T. C. van Doormaal, Sonja W. de Jong, Jeanne H. M. de Vries, Anneke J. van der Kooi, Marianne de Visser, H. Jurgen Schelhaas, Leonard H. van den Berg, Jan H. Veldink
Journal: JAMA Neurology (2015)

Because dietary intake may influence pathophysiologic mechanisms in sporadic amyotrophic lateral sclerosis (ALS), the association between premorbid dietary intake and the risk of sporadic ALS will provide insight into which mechanisms are possibly involved in ALS pathophogenesis.To systematically determine the association between premorbid dietary intake and the risk of sporadic ALS.A population-based case-control study was conducted in a general community setting in the Netherlands from January 1, 2006, to September 30, 2011. Analysis was conducted April 1, 2013, to November 15, 2014. All patients with a new diagnosis of possible, probable (laboratory supported), or definite ALS according to the revised El Escorial criteria were included and multiple sources were used to ensure complete case ascertainment. Of 986 eligible patients, 674 gave informed consent and returned a complete questionnaire; 2093 controls randomly selected from the general practitioners' registers and frequency matched to the patients for sex and age were included.We studied the premorbid intake of nutrients in association with the risk of ALS by using a 199-item food frequency questionnaire adjusted for confounding factors and corrected for multiple comparisons while minimizing recall bias.Presymptomatic total daily energy intake in patients, reported as mean (SD), was significantly higher compared with controls (2258 [730] vs 2119 [619] kcal/day; P < .01), and presymptomatic body mass index (calculated as weight in kilograms divided by height in meters squared) was significantly lower in patients (25.7 [4.0] vs 26.0 [3.7]; P = .02). With values reported as odds ratio (95% CI), higher premorbid intake of total fat (1.14; 1.07-1.23; P < .001), saturated fat (1.43; 1.25-1.64; P < .001), trans-fatty acids (1.03; 1.01-1.05; P < .001), and cholesterol (1.08; 1.05-1.12; P < .001) was associated with an increased risk of ALS; higher intake of alcohol (0.91; 0.84-0.99; P = .03) was associated with a decreased risk of ALS. These associations were independent of total energy intake, age, sex, body mass index, educational level, smoking, and lifetime physical activity. No significant associations between dietary intake and survival were found.The combination of independent positive associations of a low premorbid body mass index and a high fat intake together with prior evidence from ALS mouse models transgenic for SOD1 and earlier reports on premorbid body mass index support a role for increased resting energy expenditure before clinical onset of ALS.