tbuckley/cabot-search huggingface dataset:
Human megakaryocytes. II. Expression of platelet proteins in early marrow megakaryocytes.
Authors: E M Rabellino, R B Levene, L L Leung, R L Nachman
Journal: The Journal of Experimental Medicine (1981)

Analysis of various platelet proteins by immunofluorescence demonstrated that platelet glycoproteins Ib, IIb, and IIIa, as well as plasma factor VIII antigen (factor VIII:AGN), platelet factor 4, and fibronectin are present in the vast majority of morphologically recognizable megakaryocytes. In addition, a small number of lymphoid-like mononuclear marrow cells, representing approximately 1.4--2.9/10(4) marrow cells, was found to express the same platelet proteins. This population of early marrow megakaryocytes is analogous to small acetylcholinesterase-positive rat and mouse marrow cells. Fc receptors for IgG were expressed in all megakaryocytes and megakaryocyte precursors, whereas the Ia antigen was detected only on a proportion of mature megakaryocytes and not on only early or precursor megakaryocytes. Platelet glycoproteins Ib, IIb, and IIIa, as well as factor VIII:AGN, and platelet factor 4 were established as distinct markers for marrow megakaryocytes and may be helpful for identifying megakaryocytic cells as well as for monitoring events of megakaryocyte differentiation.
Non-publication of large randomized clinical trials: cross sectional analysis
Authors: C. W. Jones, L. Handler, K. E. Crowell, L. G. Keil, M. A. Weaver, T. F. Platts-Mills
Journal: BMJ (2013)

<b>Objective</b> To estimate the frequency with which results of large randomized clinical trials registered with ClinicalTrials.gov are not available to the public. <b>Design</b> Cross sectional analysis <b>Setting</b> Trials with at least 500 participants that were prospectively registered with ClinicalTrials.gov and completed prior to January 2009. <b>Data sources</b> PubMed, Google Scholar, and Embase were searched to identify published manuscripts containing trial results. The final literature search occurred in November 2012. Registry entries for unpublished trials were reviewed to determine whether results for these studies were available in the ClinicalTrials.gov results database. <b>Main outcome measures</b> The frequency of non-publication of trial results and, among unpublished studies, the frequency with which results are unavailable in the ClinicalTrials.gov database. <b>Results</b> Of 585 registered trials, 171 (29%) remained unpublished. These 171 unpublished trials had an estimated total enrollment of 299 763 study participants. The median time between study completion and the final literature search was 60 months for unpublished trials. Non-publication was more common among trials that received industry funding (150/468, 32%) than those that did not (21/117, 18%), P=0.003. Of the 171 unpublished trials, 133 (78%) had no results available in ClinicalTrials.gov. <b>Conclusions</b> Among this group of large clinical trials, non-publication of results was common and the availability of results in the ClinicalTrials.gov database was limited. A substantial number of study participants were exposed to the risks of trial participation without the societal benefits that accompany the dissemination of trial results.
“Veterinary” diagnosis of lead poisoning in pregnancy
Authors: Stergios K Doumouchtsis, Nigel S Martin, James B Robins
Journal: BMJ (2006)

A high index of suspicion is essential in cases at risk of lead exposure in pregnancy Lead exposure in pregnancy could potentially cause adverse outcomes, including premature labour, iron deficiency anaemia, and intrauterine growth restriction.This case of lead poisoning in a pregnant woman highlights the importance of early recognition and removal of lead sources in the prevention of maternal and perinatal morbidity.
Varicocele treatment in the light of evidence-based andrology
Authors: A. Kamischke
Journal: Human Reproduction Update (2001)

Treatment of varicoceles became the most common treatment for male infertility merely on an empirical basis. However, in the age of evidence-based medicine it is surprising that only a few, and mainly recent, randomized controlled clinical trials with relevant outcome parameters have been published to allow adequate judgement of treatment effectiveness. Moreover, difficulties in study design could also be detected in most of these high-quality studies. Despite these difficulties and in contrast to the majority of uncontrolled studies on varicocelectomy, meta-analysis of these randomized controlled clinical studies involving 385 patients showed no significant treatment benefit and questions the common practice of varicocelectomy. Even the high-quality studies show conflicting results and therefore the topic of varicocele treatment will remain controversial and further randomized clinical trials should readdress this issue. For the time being, intervention by surgical or angiographic occlusion of the spermatic vein cannot be recommended.
Influence of practice characteristics on injury risk in young athletes
Authors: A Frisch, A Urhausen, R Seil, T Windal, H Agostinis, J L Croisier, D Theisen
Journal: British Journal of Sports Medicine (2011)

Background Prior research has identified athlete-related risk factors associated with increased sports injury rate. Practice characteristics of young athletes have never been investigated in this respect. Objective To assess the injury problem in a multi-sport setting of young athletes and to determine practice-related risk factors. Design Prospective epidemiological study. Setting Follow-up of young athletes of a Luxembourgish sport school from September 2008 to July 2009 (42 weeks). Participants 190 athletes (14.9 ± 1.6 years) (65% boys) from 16 different sport disciplines. Assessment of risk factors Practice-related characteristics (context, volume, frequency and subjective intensity). Main outcome measurements Data pertaining to training and competition were recorded daily for each athlete. Standardised injury characteristics were registered. An injury was defined as an incident occurring during sport practice preventing the athlete to participate in at least one full training session or game. Results From the 190 athletes, 74% sustained at least one injury during the observation period. Injury rate was 1.65 injuries per athlete; injury incidence was 3.72 injuries/1000 h. The risk of injury was six times higher (CI95% (4.70–8.12)) in competition than in training (13.60 and 1.96 injuries/1000 h, respectively). Two thirds of the injuries were of intrinsic nature (27% progressive and 40% acute non-contact injuries). In team sports athletes having sustained at least one intrinsic injury had, compared to those with no intrinsic injury, a lower number of practice sessions per day (0.83 versus 0.89 sessions/day; p=0.023), a higher percentage of intense sessions (40 versus 30%; p=0.007), a higher number of intense sessions per day (0.33 versus 0.27 sessions/day; p=0.047) and a higher proportion of days with two intense sessions (5.7% versus 2.7%; p=0.007). Conclusion The relationship between practice characteristics and sports injuries should be further studied and might point to interesting prevention initiatives, provided that sports practice can be monitored.
Relaxed Negative Selection in Germinal Centers and Impaired Affinity Maturation in <i>bcl-x</i>L Transgenic Mice
Authors: Yoshimasa Takahashi, Douglas M. Cerasoli, Joseph M. Dal Porto, Michiko Shimoda, Robert Freund, Wei Fang, David G. Telander, Erika-Nell Malvey, Daniel L. Mueller, Timothy W. Behrens, Garnett Kelsoe
Journal: The Journal of Experimental Medicine (1999)

The role of apoptosis in affinity maturation was investigated by determining the affinity of (4-hydroxy-3-nitrophenyl)acetyl (NP)-specific antibody-forming cells (AFCs) and serum antibody in transgenic mice that overexpress a suppressor of apoptosis, Bcl-xL, in the B cell compartment. Although transgenic animals briefly expressed higher numbers of splenic AFCs after immunization, the bcl-xL transgene did not increase the number or size of germinal centers (GCs), alter the levels of serum antibody, or change the frequency of NP-specific, long-lived AFCs. Nonetheless, the bcl-xL transgene product, in addition to endogenous Bcl-xL, reduced apoptosis in GC B cells and resulted in the expansion of B lymphocytes bearing VDJ rearrangements that are usually rare in primary anti-NP responses. Long-lived AFCs bearing these noncanonical rearrangements were frequent in the bone marrow and secreted immunoglobulin G1 antibodies with low affinity for NP. The abundance of noncanonical cells lowered the average affinity of long-lived AFCs and serum antibody, demonstrating that Bcl-xL and apoptosis influence clonal selection/maintenance for affinity maturation.
Chemotherapy of advanced small-bowel adenocarcinoma: a multicenter AGEO study
Authors: A. Zaanan, L. Costes, M. Gauthier, D. Malka, C. Locher, E. Mitry, D. Tougeron, T. Lecomte, J.-M. Gornet, I. Sobhani, V. Moulin, P. Afchain, J. Taïeb, F. Bonnetain, T. Aparicio
Journal: Annals of Oncology (2010)
ΔNp63α-Mediated Activation of Bone Morphogenetic Protein Signaling Governs Stem Cell Activity and Plasticity in Normal and Malignant Mammary Epithelial Cells
Authors: Amanda L. Balboni, Justine A. Hutchinson, Andrew J. DeCastro, Pratima Cherukuri, Karen Liby, Michael B. Sporn, Gary N. Schwartz, Wendy A. Wells, Lorenzo F. Sempere, Paul B. Yu, James DiRenzo
Journal: Cancer Research (2012)

Genetic analysis of TP63 indicates that ΔNp63 isoforms are required for preservation of regenerative stasis within diverse epithelial tissues. In squamous carcinomas, TP63 is commonly amplified, and ΔNp63α confers a potent survival advantage. Genome-wide occupancy studies show that ΔNp63 promotes bidirectional target gene regulation by binding more than 5,000 sites throughout the genome; however, the subset of targets mediating discreet activities of TP63 remains unclear. We report that ΔNp63α activates bone morphogenic proteins (BMP) signaling by inducing the expression of BMP7. Immunohistochemical analysis indicates that hyperactivation of BMP signaling is common in human breast cancers, most notably in the basal molecular subtype, as well as in several mouse models of breast cancer. Suppression of BMP signaling in vitro with LDN193189, a small-molecule inhibitor of BMP type I receptor kinases, represses clonogenicity and diminishes the cancer stem cell-enriched ALDH1(+) population. Importantly, LDN193189 blocks reconstitution of mixed ALDH1(+)/ALDH1(-) cultures indicating that BMP signaling may govern aspects of cellular plasticity within tumor hierarchies. These results show that BMP signaling enables reversion of committed populations to a stem-like state, potentially supporting progression and maintenance of tumorigenesis. Treatment of a mouse model of breast cancer with LDN193189 caused reduced expression of markers associated with epithelial-to-mesenchymal transition (EMT). Furthermore, in vivo limiting dilution analysis assays revealed that LDN193189 treatment suppressed tumor-initiating capacity and increased tumor latency. These studies support a model in which ΔNp63α-mediated activation of BMP signaling governs epithelial cell plasticity, EMT, and tumorigenicity during breast cancer initiation and progression.
Prostate Cancer Tumour Features on Template Prostate-mapping Biopsies: Implications for Focal Therapy
Authors: Paras B. Singh, Chukwuemeka Anele, Emma Dalton, Omar Barbouti, Daniel Stevens, Pratik Gurung, Manit Arya, Charles Jameson, Alex Freeman, Mark Emberton, Hashim U. Ahmed
Journal: European Urology (2013)

Focal therapy is being offered as a viable alternative for men with localised prostate cancer (PCa), but it is unclear which men may be suitable.To determine the proportion of men with localised PCa who are potentially suitable for focal therapy.Our institutional transperineal template prostate-mapping (TTPM) biopsy registry of 377 men from 2006 to 2010 identified 291 consecutive men with no prior treatment.TTPM biopsies using a 5-mm sampling frame.Suitability for focal therapy required the cancer to be (1) unifocal, (2) unilateral, (3) bilateral/bifocal with at least one neurovascular bundle avoided, or (4) bilateral/multifocal with one dominant index lesion and secondary lesions with Gleason ≤3 + 3 and cancer core involvement ≤3 mm. Binary logistic regression modelling was used to determine variables predictive for focal therapy suitability.The median age was 61 yr, and the median prostate-specific antigen was 6.8 ng/ml. The median total was 29 cores, with a median of 8 positive cores. Of 239 of 291 men with cancer, 29% (70 men), 60% (144 men), and 8% (20 men) had low-, intermediate-, and high-risk PCa, respectively. Ninety-two percent (220 men) were suitable for one form of focal therapy: hemiablation (22%, 53 men), unifocal ablation (31%, 73 men), bilateral/bifocal ablation (14%, 33 men), and index lesion ablation (26%, 61 men). Binary logistic regression modelling incorporating transrectal biopsy parameters showed no statistically significant predictive variable. When incorporating TTPM parameters, only T stage was a significant negative predictor for suitability (p=0.001) (odds ratio: 0.001 [95% confidence interval, 0.000-0.048]). Limitations of the study include potential selection bias caused by tertiary referral practise and lack of long-term results on focal therapy efficacy.Focal therapy requires an accurate tool to localise individual cancer lesions. When such a test, TTPM biopsy, was applied to men with low- and intermediate-risk PCa, most of the men were suitable for a tissue preservation strategy.
Integration of 3D digital mammography with tomosynthesis for population breast-cancer screening (STORM): a prospective comparison study
Authors: Stefano Ciatto, Nehmat Houssami, Daniela Bernardi, Francesca Caumo, Marco Pellegrini, Silvia Brunelli, Paola Tuttobene, Paola Bricolo, Carmine Fantò, Marvi Valentini, Stefania Montemezzi, Petra Macaskill
Journal: The Lancet Oncology (2013)
Exome Sequencing Identifies <i>SMAD3</i> Mutations as a Cause of Familial Thoracic Aortic Aneurysm and Dissection With Intracranial and Other Arterial Aneurysms
Authors: Ellen S. Regalado, Dong-chuan Guo, Carlos Villamizar, Nili Avidan, Dawna Gilchrist, Barbara McGillivray, Lorne Clarke, Francois Bernier, Regie L. Santos-Cortez, Suzanne M. Leal, Aida M. Bertoli-Avella, Jay Shendure, Mark J. Rieder, Deborah A. Nickerson, Dianna M. Milewicz
Journal: Circulation Research (2011)

Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) can be inherited in families in an autosomal dominant manner. As part of the spectrum of clinical heterogeneity of familial TAAD, we recently described families with multiple members that had TAAD and intracranial aneurysms or TAAD and intracranial and abdominal aortic aneurysms inherited in an autosomal dominant manner.To identify the causative mutation in a large family with autosomal dominant inheritance of TAAD with intracranial and abdominal aortic aneurysms by performing exome sequencing of 2 distantly related individuals with TAAD and identifying shared rare variants.A novel frame shift mutation, p. N218fs (c.652delA), was identified in the SMAD3 gene and segregated with the vascular diseases in this family with a logarithm of odds score of 2.52. Sequencing of 181 probands with familial TAAD identified 3 additional SMAD3 mutations in 4 families, p.R279K (c.836G>A), p.E239K (c.715G>A), and p.A112V (c.235C>T), resulting in a combined logarithm of odds score of 5.21. These 4 mutations were notably absent in 2300 control exomes. SMAD3 mutations were recently described in patients with aneurysms osteoarthritis syndrome and some of the features of this syndrome were identified in individuals in our cohort, but these features were notably absent in many SMAD3 mutation carriers.SMAD3 mutations are responsible for 2% of familial TAAD. Mutations are found in families with TAAD alone, along with families with TAAD, intracranial aneurysms, abdominal aortic and bilateral iliac aneurysms segregating in an autosomal dominant manner.
Deliberate self harm in adolescents: self report survey in schools in England
Authors: K. Hawton
Journal: BMJ (2002)

<h3>Abstract</h3> <b>Objective:</b> To determine the prevalence of deliberate self harm in adolescents and the factors associated with it. <b>Design:</b> Cross sectional survey using anonymous self report questionnaire. <b>Setting:</b> 41 schools in England. <b>Participants:</b> 6020 pupils aged 15 and 16 years. <b>Main outcome measure:</b> Deliberate self harm. <b>Results:</b> 398 (6.9%) participants reported an act of deliberate self harm in the previous year that met study criteria. Only 12.6% of episodes had resulted in presentation to hospital. Deliberate self harm was more common in females than it was in males (11.2% <i>v</i> 3.2%; odds ratio 3.9, 95% confidence interval 3.1 to 4.9). In females the factors included in a multivariate logistic regression for deliberate self harm were recent self harm by friends, self harm by family members, drug misuse, depression, anxiety, impulsivity, and low self esteem. In males the factors were suicidal behaviour in friends and family members, drug use, and low self esteem. <b>Conclusions:</b> Deliberate self harm is common in adolescents, especially females. School based mental health initiatives are needed. These could include approaches aimed at educating school pupils about mental health problems and screening for those at risk. <h3>What is already known on this topic</h3> Deliberate self harm is a common reason for presentation of adolescents to hospital Community studies from outside the United Kingdom have shown much greater prevalence of self harm in adolescents than hospital based studies <h3>What this study adds</h3> Deliberate self harm defined according to strict criteria is common in adolescents, especially females Associated factors include recent awareness of self harm in peers, self harm by family members, drug misuse, depression, anxiety, impulsivity, and low self esteem
Enhancing bone marrow regeneration by SALL4 protein
Authors: Wenbin Liao, Jerell R Aguila, Yixin Yao, Jianchang Yang, Gary Zieve, Yongping Jiang, Cecilia Avila, Lisa Senzel, Raymond Lai, Dazhong Xu, Wei Dai, Yupo Ma
Journal: Journal of Hematology & Oncology (2013)

Hematopoietic stem cells (HSCs) are widely used in transplantation therapy to treat a variety of blood diseases. The success of hematopoietic recovery is of high importance and closely related to the patient’s morbidity and mortality after Hematopoietic stem cell transplantation (HSCT). We have previously shown that SALL4 is a potent stimulator for the expansion of human hematopoietic stem/progenitor cells in vitro. In these studies, we demonstrated that systemic administration with TAT-SALL4B resulted in expediting auto-reconstitution and inducing a 30-fold expansion of endogenous HSCs/HPCs in mice exposed to a high dose of irradiation. Most importantly, TAT-SALL4B treatment markedly prevented death in mice receiving lethal irradiation. Our studies also showed that TAT-SALL4B treatment was able to enhance both the short-term and long-term engraftment of human cord blood (CB) cells in NOD/SCID mice and the mechanism was likely related to the in vivo expansion of donor cells in a recipient. This robust expansion was required for the association of SALL4B with DNA methyltransferase complex, an epigenetic regulator critical in maintaining HSC pools and in normal lineage progression. Our results may provide a useful strategy to enhance hematopoietic recovery and reconstitution in cord blood transplantation with a recombinant TAT-SALL4B fusion protein.
Association Between Circulating Tumor Cells and Prognosis in Patients With Stage III Melanoma With Sentinel Lymph Node Metastasis in a Phase III International Multicenter Trial
Authors: Sojun Hoshimoto, Tatsushi Shingai, Donald L. Morton, Christine Kuo, Mark B. Faries, Kelly Chong, David Elashoff, He-Jing Wang, Robert M. Elashoff, Dave S.B. Hoon
Journal: Journal of Clinical Oncology (2012)

The outcomes of patients with melanoma who have sentinel lymph node (SLN) metastases can be highly variable, which has precluded establishment of consensus regarding treatment of the group. The detection of high-risk patients from this clinical setting may be helpful for determination of both prognosis and management. We report the utility of multimarker reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) detection of circulating tumor cells (CTCs) in patients with melanoma diagnosed with SLN metastases in a phase III, international, multicenter clinical trial.
Inversion variants in the human genome: role in disease and genome architecture
Authors: Lars Feuk
Journal: Genome Medicine (2010)

Significant advances have been made over the past 5 years in mapping and characterizing structural variation in the human genome. Despite this progress, our understanding of inversion variants is still very restricted. While unbalanced variants such as copy number variations can be mapped using array-based approaches, strategies for characterization of inversion variants have been limited and underdeveloped. Traditional cytogenetic approaches have long been able to identify microscopic inversion events, but discovery of submicroscopic events has remained elusive and largely ignored. With the advent of paired-end sequencing approaches, it is now possible to map inversions across the human genome. Based on the paired-end sequencing studies published to date, it is now feasible to make a first map of inversions across the human genome and to use this map to explore the characteristics and distribution of this form of variation. The current map of inversions indicates that many remain to be identified, especially in the smaller size ranges. This review provides an overview of the current knowledge about human inversions and their contribution to human phenotypes. Further characterization of inversions should be considered as an important step towards a deeper understanding of human variation and genome dynamics.
Fluctuating and Diffusion-Limited Hypoxia in Hypoxia-Induced Metastasis
Authors: Einar K. Rofstad, Kanthi Galappathi, Berit Mathiesen, Else-Beate M. Ruud
Journal: Clinical Cancer Research (2007)

Most tumors develop regions with hypoxic cells during growth, owing to permanent limitations in oxygen diffusion (chronic or diffusion-limited hypoxia) and/or transient limitations in blood perfusion (acute or fluctuating hypoxia). The aim of this study was to investigate the relative significance of chronic and acute hypoxia in the development of metastatic disease.D-12 and R-18 human melanoma xenografts were used as models of human cancer. D-12 tumors metastasize to the lungs, whereas R-18 tumors develop lymph node metastases. Fraction of radiobiologically hypoxic cells (HF(Rad)) was measured in individual primary tumors by using a radiobiological assay based on the paired survival curve method. Fraction of immunohistochemically hypoxic cells (HF(Imm)) was assessed in the same tumors by using a pimonidazole-based immunohistochemical assay optimized with respect to achieving selective staining of chronically hypoxic cells. HF(Imm) and the difference between HF(Rad) and HF(Imm), HF(Rad) - HF(Imm), were verified to be adequate variables for fraction of chronically hypoxic cells and fraction of acutely hypoxic cells, respectively.Chronic as well as acute hypoxia were found to promote spontaneous metastasis of D-12 and R-18 tumors. Acute hypoxia influenced metastasis to a greater extent than chronic hypoxia, partly because the fraction of acutely hypoxic cells was larger than the fraction of chronically hypoxic cells in most tumors and partly because acutely hypoxic cells showed a higher metastatic potential than chronically hypoxic cells.It may be beneficial to focus on fluctuating hypoxia rather than diffusion-limited hypoxia when searching for hypoxia-related prognostic variables and predictive assays.