tbuckley/cabot-search huggingface dataset:
Predictive Value of the High-Sensitivity Troponin T Assay and the Simplified Pulmonary Embolism Severity Index in Hemodynamically Stable Patients With Acute Pulmonary Embolism
Authors: Mareike Lankeit, David Jiménez, Maciej Kostrubiec, Claudia Dellas, Gerd Hasenfuss, Piotr Pruszczyk, Stavros Konstantinides
Journal: Circulation (2011)

The new, high-sensitivity troponin T (hsTnT) assay may improve risk stratification of normotensive patients with acute pulmonary embolism (PE). We externally validated the prognostic value of hsTnT, and of the simplified Pulmonary Embolism Severity Index (sPESI), in a large multicenter cohort.We prospectively examined 526 normotensive patients with acute PE; of those, 31 (5.9%) had an adverse 30-day outcome. The predefined hsTnT cutoff value of 14 pg/mL was associated with a high prognostic sensitivity and negative predictive value, comparable to those of the sPESI. Both hsTnT ≥14 pg/mL (OR, 4.97 [95% CI, 1.71-14.43]; P=0.003) and sPESI ≥1 point(s) (OR, 9.51 [2.24-40.29]; P=0.002) emerged, besides renal insufficiency (OR, 2.97 [1.42-6.22]; P=0.004), as predictors of early death or complications; in a multivariable model, they remained independent predictors of outcome (P=0.044 and 0.012, respectively). A total of 127 patients (24.1%) were identified as low risk by a sPESI of 0 and hsTnT <14 pg/mL; none of them had an adverse 30-day outcome. During 6-month follow-up, 52 patients (9.9%) died. Kaplan-Meier analysis illustrated that patients with hsTnT ≥14 pg/mL (P=0.001) and those with sPESI ≥1 (P<0.001) had a decreased probability of 6-month survival. Patients with sPESI of 0 and hsTnT <14 pg/mL at baseline had a 42% reduction in the risk of dying (hazard ratio, 0.58 [0.01-0.42]; P=0.005).The hsTnT assay and the sPESI improve risk stratification of acute PE. Combination of both modalities may yield additive prognostic information and particularly identify possible candidates for out-of-hospital treatment.
Familial Recurrence of Autism Spectrum Disorder: Evaluating Genetic and Environmental Contributions
Authors: Neil Risch, Thomas J. Hoffmann, Meredith Anderson, Lisa A. Croen, Judith K. Grether, Gayle C. Windham
Journal: American Journal of Psychiatry (2014)

This study was designed to examine the pattern of familial recurrence of autism spectrum disorder (ASD) in terms of genetic and environmental contributions related to timing of birth.The authors linked California Department of Developmental Services records with state birth certificates to identify all siblings and half siblings of individuals affected with ASD born between 1990 and 2003. A total of 6,616 full siblings, 644 maternal half siblings, and 299 paternal half siblings born after ASD index cases were used to calculate recurrence risks. Control families, identified through matching to cases, were included for comparison (a total of 29,384 siblings).The overall sibling recurrence risk was 10.1%, compared with a prevalence of 0.52% in siblings of controls. The recurrence risk in second-born children was higher (11.5%) than in later-born siblings (7.3%); a similar pattern was observed for maternal half siblings (6.5% for second-born compared with 3.0% for later-born siblings; 4.8% overall). The recurrence risk was significantly higher for siblings who immediately followed the index case in birth order compared with those later in birth order. The recurrence risk for paternal half siblings (2.3%) was half the overall recurrence risk for maternal half siblings but was similar to that for later-born maternal half siblings. An exponential effect of short interbirth interval was observed, with the recurrence risk reaching 14.4% for an interbirth interval of 18 months or less, compared with 6.8% for an interval of 4 years or more. An identical phenomenon was observed in maternal half siblings.The results support genetic susceptibility in the familial recurrence of ASD along with factors related to timing of birth.
Medical Treatment of a Pacemaker Endocarditis due to Candida albicans and to Candida glabrata
Authors: P.-M. Roger, C. Boissy, M. Gari-Toussaint, R. Foucher, V. Mondain, F. Vandenbos, Y. Le Fichoux, J. Michiels, P. Dellamonica
Journal: Journal of Infection (2000)
POSTURE AND CENTRAL VENOUS PRESSURE MEASUREMENT IN CIRCULATORY VOLUME DEPLETION
Authors: RobertA. Scott, N. Beechey-Newman, S. Burgess, A. Harms, M. Muller, K. Delaney, S. Livingstone, C. Newstead, B. Smith, GuyA. Haywood, A.John Camm, P.G.F. Nixon
Journal: The Lancet (1989)
Endothelin-1 Inhibits the Epithelial Na+ Channel through βPix/14-3-3/Nedd4-2
Authors: Tengis S. Pavlov, Ahmed Chahdi, Daria V. Ilatovskaya, Vladislav Levchenko, Alain Vandewalle, Oleh Pochynyuk, Andrey Sorokin, Alexander Staruschenko
Journal: Journal of the American Society of Nephrology (2010)

Epithelial Na+ channels (ENaCs) mediate sodium reabsorption in the cortical collecting duct (CCD), but the regulatory pathways that modulate the activity of these channels are incompletely understood. Here, we observed that endothelin-1 (ET-1) attenuates ENaC activity acutely by reducing the channel's open probability and chronically by decreasing the number of channels in the plasma membrane. To investigate whether beta1Pix, a signaling protein activated by ET-1, mediates ENaC activity, we reconstituted ENaC in CHO cells with or without coexpressed beta1Pix and found that beta1Pix negatively regulates ENaC. Knockdown of betaPix in native principal cells abolished the ET-1-induced decrease in ENaC channel number. Furthermore, we found that betaPix does not decrease ENaC activity through its guanine nucleotide exchange factor (GEF) activity for Rac1 and Cdc42. Instead, coexpression of beta1Pix mutant constructs revealed that beta1Pix affects ENaC activity through binding 14-3-3 proteins. Coimmunoprecipitation experiments supported a physical interaction between beta1Pix and 14-3-3beta in cultured principal cells. Coexpression of 14-3-3beta increased ENaC activity in CHO cells, but concomitant expression of beta1Pix attenuated this increase. Recruitment of 14-3-3beta by beta1Pix impaired the interaction of 14-3-3beta with the ubiquitin ligase Nedd4-2, thereby promoting ubiquitination and degradation of ENaC. Taken together, these results suggest that the inhibitory effects of chronic ET-1 on ENaC result from betaPix interacting with the 14-3-3/Nedd4-2 pathway.
Does the Left Atrial Appendage Morphology Correlate With the Risk of Stroke in Patients With Atrial Fibrillation?
Authors: Luigi Di Biase, Pasquale Santangeli, Matteo Anselmino, Prasant Mohanty, Ilaria Salvetti, Sebastiano Gili, Rodney Horton, Javier E. Sanchez, Rong Bai, Sanghamitra Mohanty, Agnes Pump, Mauricio Cereceda Brantes, G. Joseph Gallinghouse, J. David Burkhardt, Federico Cesarani, Marco Scaglione, Andrea Natale, Fiorenzo Gaita
Journal: Journal of the American College of Cardiology (2012)
Lower Vital Capacity Is Associated With Diabetes but Not With Metabolic Syndrome in Nonobese Japanese Men
Authors: Kei Nakajima, Masafumi Saito
Journal: Diabetes Care (2009)

Oda and Kawai (1) have reported that lower vital capacity (VC) (VC ≤96%) is associated with diabetes but not with the metabolic syndrome (MetS) in nonobese Japanese men and that no significant association between low VC, diabetes, and MetS was found in nonobese women. However, the coexistence of type 2 diabetes and MetS is often observed even in nonobese people (2,3). Furthermore, because both are mostly due to insulin resistance, we wondered whether their involvement in a specific pathology can also occur in normal-weight people.

Therefore, we reanalyzed the data from our ongoing cross-sectional study (4) to evaluate the associations between impaired …
Osteosarcoma of the Pelvis: Experience of the Cooperative Osteosarcoma Study Group
Authors: Toshifumi Ozaki, Silke Flege, Matthias Kevric, Norbert Lindner, Rainer Maas, Günter Delling, Rudolf Schwarz, Arthur R. von Hochstetter, Mechthild Salzer-Kuntschik, Wolfgang E. Berdel, Heribert Jürgens, G. Ulrich Exner, Peter Reichardt, Regine Mayer-Steinacker, Volker Ewerbeck, Rainer Kotz, Winfried Winkelmann, Stefan S. Bielack
Journal: Journal of Clinical Oncology (2003)

To define patients and tumor characteristics as well as therapy results, patients with pelvic osteosarcoma who were registered in the Cooperative Osteosarcoma Study Group (COSS) were analyzed.Sixty-seven patients with a high-grade pelvic osteosarcoma were eligible for this analysis. Fifteen patients had primary metastases. All patients received chemotherapy according to COSS protocols. Thirty-eight patients underwent limb-sparing surgery, 12 patients underwent hemipelvectomy, and 17 patients did not undergo definitive surgery. Eleven patients received irradiation to the primary tumor site: four postoperatively and seven as the only form of local therapy.Local failure occurred in 47 of all 67 patients (70%) and in 31 of 50 patients (62%) who underwent definitive surgery. Five-year overall survival (OS) and progression-free survival rates were 27% and 19%, respectively. Large tumor size (P =.0137), primary metastases (P =.0001), and no or intralesional surgery (P <.0001) were poor prognostic factors. In 30 patients with no or intralesional surgery, 11 patients with radiotherapy had better OS than 19 patients without radiotherapy (P =.0033). Among the variables, primary metastasis, large tumor, no or intralesional surgery, no radiotherapy, existence of primary metastasis (relative risk [RR] = 3.456; P =.0009), surgical margin (intralesional or no surgical excision; RR = 5.619; P <.0001), and no radiotherapy (RR = 4.196; P =.0059) were independent poor prognostic factors.An operative approach with wide or marginal margins improves local control and OS. If the surgical margin is intralesional or excision is impossible, additional radiotherapy has a positive influence on prognosis.
Multiple Mutations and Bypass Mechanisms Can Contribute to Development of Acquired Resistance to MET Inhibitors
Authors: Jie Qi, Michele A. McTigue, Andrew Rogers, Eugene Lifshits, James G. Christensen, Pasi A. Jänne, Jeffrey A. Engelman
Journal: Cancer Research (2011)

Therapies targeting receptor tyrosine kinases have shown efficacy in molecularly defined subsets of cancers. Unfortunately, cancers invariably develop resistance, and overcoming or preventing resistance will ultimately be key to unleashing their full therapeutic potential. In this study, we examined how cancers become resistant to MET inhibitors, a class of drugs currently under clinical development. We utilized the highly sensitive gastric carcinoma cell line, SNU638, and two related MET inhibitors PHA-665752 and PF-2341066. To our surprise, we observed at least two mechanisms of resistance that arose simultaneously. Both resulted in maintenance of downstream PI3K (phosphoinositide 3-kinase)-AKT and MEK (MAP/ERK kinase)-ERK signaling in the presence of inhibitor. One mechanism, observed by modeling resistance both in vitro and in vivo, involved the acquisition of a mutation in the MET activation loop (Y1230). Structural analysis indicates that this mutation destabilizes the autoinhibitory conformation of MET and abrogates an important aromatic stacking interaction with the inhibitor. The other cause of resistance was activation of the epidermal growth factor receptor (EGFR) pathway due to increased expression of transforming growth factor α. Activation of EGFR bypassed the need for MET signaling to activate downstream signaling in these cells. This resistance could be overcome by combined EGFR and MET inhibition. Thus, therapeutic strategies that combine MET inhibitors capable of inhibiting Y1230 mutant MET in combination with anti-EGFR-based therapies may enhance clinical benefit for patients with MET-addicted cancers. Importantly, these results also underscore the notion that a single cancer can simultaneously develop resistance induced by several mechanisms and highlight the daunting challenges associated with preventing or overcoming resistance.
Concordance of Survival in Family Members With Prostate Cancer
Authors: Kari Hemminki, Jianguang Ji, Asta Försti, Jan Sundquist, Per Lenner
Journal: Journal of Clinical Oncology (2008)

Purpose Several earlier studies have assessed survival in prostate cancer based on familial risk of this disease. As a novel concept, we posit that factors governing survival in prostate cancer are likely to be different from those governing risk of prostate cancer. To prove this, we searched for familial clustering of survival (ie, concordance of survival among family members). Patients and Methods We used the nationwide Swedish Family-Cancer Database to estimate hazard rates (HRs) for cause-specific and overall survival in invasive prostate cancer. HRs show the probability of death in the study group compared with the reference group. The study covered 610 sons of affected fathers with median follow-up times for survival ranging from 34 to 76 months. Results When the survival in sons was analyzed according to the fathers' length of survival, there was a concordance of prognosis; the HR was 0.62 for sons whose fathers had survived longer than 59 months, compared with sons whose fathers had survived fewer than 24 months (P for trend, .02). On a continuous scale, the sons' survival increased almost linearly with the fathers' survival time. When the analysis was reversed and HRs were derived for fathers, the concordance of good and poor survival remained. Conclusion The results are consistent in showing that both good and poor survival in prostate cancer aggregate in families. Genetic factors are likely to contribute to the results, which provide the first challenging population-level evidence on heritability in prognosis of prostate cancer.
Extensive Chordate and Annelid Macrosynteny Reveals Ancestral Homeobox Gene Organization
Authors: J. H. L. Hui, C. McDougall, A. S. Monteiro, P. W. H. Holland, D. Arendt, G. Balavoine, D. E. K. Ferrier
Journal: Molecular Biology and Evolution (2011)

Genes with the homeobox motif are crucial in developmental biology and widely implicated in the evolution of development. The Antennapedia (ANTP)-class is one of the two major classes of animal homeobox genes, and includes the Hox genes, renowned for their role in patterning the anterior–posterior axis of animals. The origin and evolution of the ANTP-class genes are a matter of some debate. A principal guiding hypothesis has been the existence of an ancient gene Mega-cluster deep in animal ancestry. This hypothesis was largely established from linkage data from chordates, and the Mega-cluster hypothesis remains to be seriously tested in protostomes. We have thus mapped ANTP-class homeobox genes to the chromosome level in a lophotrochozoan protostome. Our comparison of gene organization in Platynereis dumerilii and chordates indicates that the Mega-cluster, if it did exist, had already been broken up onto four chromosomes by the time of the protostome–deuterostome ancestor (PDA). These results not only elucidate an aspect of the genome organization of the PDA but also reveal high levels of macrosynteny between P. dumerilii and chordates. This implies a very low rate of interchromosomal genome rearrangement in the lineages leading to P. dumerilii and the chordate ancestor since the time of the PDA.
High Blood Glucose Concentration Is a Risk Factor for Mortality in Middle-Aged Nondiabetic Men: 20-year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study
Authors: Beverley Balkau, Martin Shipley, R John Jarrett, Kalevi Pyörälä, Marja Pyörälä, Anne Forhan, Eveline Eschwège
Journal: Diabetes Care (1998)

To assess the association between high but nondiabetic blood glucose levels and the risk of death from all causes, coronary heart disease (CHD), cardiovascular disease, and neoplasms.We studied the 20-year mortality of non-diabetic, working men, age 44-55 years, in three European cohorts known as the Whitehall Study (n = 10,025), the Paris Prospective Study (n = 6,629), and the Helsinki Policeman Study (n = 631). These men were identified by their 2-h glucose levels following an oral glucose tolerance test and by the absence of a prior diagnosis of diabetes. As the protocol for the oral glucose tolerance test and methods for measuring glucose differed between studies, mortality was analyzed according to the percentiles of the 2-h and fasting glucose distributions, using the Cox's proportional hazards model.Men in the upper 20% of the 2-h glucose distributions and those in the upper 2.5% for fasting glucose had a significantly higher risk of all-cause mortality in comparison with men in the lower 80% of these distributions, with age-adjusted hazard ratios of 1.6 (95% CI 1.4-1.9) and 2.0 (1.6-2.6) for the upper 2.5%. For death from cardiovascular and CHD, men in the upper 2.5% of the 2-h and fasting glucose distributions were at higher risk, with age-adjusted hazard ratios for CHD of 1.8 (1.4-2.4) and 2.7 (1.7-4.4), respectively.If early intervention aimed at lowering blood glucose concentrations can be shown to reduce mortality, it may be justified to lower the levels of both 2-h and fasting glucose, which define diabetes.
Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial
Authors: Jason R Westin, Fuliang Chu, Min Zhang, Luis E Fayad, Larry W Kwak, Nathan Fowler, Jorge Romaguera, Fredrick Hagemeister, Michelle Fanale, Felipe Samaniego, Lei Feng, Veerabhadran Baladandayuthapani, Zhiqiang Wang, Wencai Ma, Yanli Gao, Michael Wallace, Luis M Vence, Laszlo Radvanyi, Tariq Muzzafar, Rinat Rotem-Yehudar, R Eric Davis, Sattva S Neelapu
Journal: The Lancet Oncology (2013)
Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and -independent apoptosis
Authors: Kenji Ishitsuka, Teru Hideshima, Makoto Hamasaki, Noopur Raje, Shaji Kumar, Hiromasa Hideshima, Norihiko Shiraishi, Hiroshi Yasui, Aldo M. Roccaro, Paul Richardson, Klaus Podar, Steven Le Gouill, Dharminder Chauhan, Kazuo Tamura, Jack Arbiser, Kenneth C. Anderson
Journal: Blood (2005)
DEMONSTRATION OF PASSIVE IMMUNITY IN EXPERIMENTAL MONKEY MALARIA
Authors: L. T. Coggeshall, H. W. Kumm
Journal: The Journal of Experimental Medicine (1937)

A Plasmodium knowlesi infection in rhesus monkeys is almost invariably fatal. This infection, however, may be made chronic by the early administration of antimalarial drugs. The animals then will harbor a chronic infection for an indefinite period. The serum taken from monkeys with chronic infection and injected into those suffering from an acute attack was found to have a definite depressing effect upon the course of the experimental disease. In some instances death was prevented and the acute infection changed into a chronic form; in others, the course of the experimental disease was prolonged. In a similar manner the serum from monkeys harboring a chronic Plasmodium inui infection, when injected into monkeys suffering from an acute attack due to this parasite, was found to be effective in reducing the intensity of the primary infection. The data presented indicate that protective antibodies are produced in the serum of monkeys during experimental malaria infection.
Setting Clock Speed in Mammals: The CK1ɛ tau Mutation in Mice Accelerates Circadian Pacemakers by Selectively Destabilizing PERIOD Proteins
Authors: Qing-Jun Meng, Larisa Logunova, Elizabeth S. Maywood, Monica Gallego, Jake Lebiecki, Timothy M. Brown, Martin Sládek, Andrei S. Semikhodskii, Nicholas R.J. Glossop, Hugh D. Piggins, Johanna E. Chesham, David A. Bechtold, Seung-Hee Yoo, Joseph S. Takahashi, David M. Virshup, Raymond P. Boot-Handford, Michael H. Hastings, Andrew S.I. Loudon
Journal: Neuron (2008)
p27Kip1 in Stage III Colon Cancer: Implications for Outcome following Adjuvant Chemotherapy in Cancer and Leukemia Group B Protocol 89803
Authors: Monica M. Bertagnolli, Robert S. Warren, Donna Niedzwiecki, Elke Mueller, Carolyn C. Compton, Mark Redston, Margaret Hall, Hejin P. Hahn, Scott D. Jewell, Robert J. Mayer, Richard M. Goldberg, Leonard B. Saltz, Massimo Loda
Journal: Clinical Cancer Research (2009)

In retrospective studies, loss of p27(Kip1) (p27), a cyclin-dependent kinase inhibitor, has been associated with poor prognosis following colorectal cancer treatment. In a prospective study, we validated this relationship in patients enrolled on a trial of adjuvant chemotherapy for stage III colon cancer.Cancer and Leukemia Group B protocol 89803 randomized 1,264 stage III colon cancer patients to receive weekly bolus 5-fluorouracil/leucovorin or weekly bolus irinotecan, 5-fluorouracil, and leucovorin (IFL). The primary endpoint was overall survival (OS); disease-free survival was a secondary endpoint. Expression of p27 and DNA mismatch repair proteins were determined by immunohistochemistry in primary tumor and normal tissue from paraffin blocks. Data were analyzed using log-rank test.Of 601 tumors analyzed, 207 (34.4%) showed p27 loss, 377 (62.8%) retained p27, and 17 (2.8%) were indeterminate. Patients with p27-negative tumors showed reduced OS [5-year OS 66%: 95% confidence interval (95% CI), 0.59-0.72 versus 75%: 95% CI, 0.70-0.79; log-rank P = 0.021]. This relationship was not influenced by treatment arm. Combination of p27 status with mismatch repair status, however, identified a small subset of patients that may benefit from IFL (n = 36; 5-year disease-free survival 81%: 95% CI, 0.64-0.98 versus 47%: 95% CI, 0.21-0.72; log-rank P = 0.042; 5-year OS 81%: 95% CI, 0.64-0.98 versus 60%: 95% CI, 0.35-0.85; log-rank P = 0.128).Loss of p27 is associated with reduced survival in stage III colon cancer but by itself does not indicate a significant difference in outcome between patients treated IFL or 5-fluorouracil/leucovorin.
ALTERATION IN THE COLLAGEN CONTENT OF THE HUMAN UTERUS DURING PREGNANCY AND POST PARTUM INVOLUTION
Authors: Thomas G. Morrione, Sam Seifter
Journal: The Journal of Experimental Medicine (1962)

Quantitative collagen determinations demonstrate an increase of approximately 800 per cent in the collagen content of the human uterus at term as compared with the non-pregnant state. Following parturition, there is a rapid resorption of collagen. The amount of collagen which disappears from the post partum uterus is approximately 53 gm. By the 8th day post partum, the human uterus has lost approximately 72 per cent of the total collagen which was present at term. The slopes of curves depicting alterations in collagen content of the uterus of the rat and human are virtually identical, despite the marked differences in the length of the gestational periods of the two species. The alterations in the collagen content of the human uterus during pregnancy and involution closely follow changes in total uterine weight. There is a slight decrease in per cent collagen content of the uterus during pregnancy, and an increase in the water content of the post partum uterus. Approximately 97 per cent of the collagen which is present in the human uterus at term is of the so called "insoluble" type. The physiological resorbability of uterine collagen, as evidenced by its post partum dissolution, cannot therefore be correlated with its in vitro solubility characteristics. No collagenase was demonstrable in the myometrium of post partum uteri. A 2 day post partum uterus was found to contain an enzyme which slowly degraded gelatin at pH 3.85 but was virtually inactive at pH 7,0. There is an increase in myometrial prolidase activity of approximately 75 per cent, commencing 2 days post partum. Prolidase activity remains elevated until the 8th day post partum, and subsequently falls to almost normal levels by the 5th post partum week. During the process of involution, the post partum uterus shows histological evidence of edema and partial destruction of its reticular framework.