tbuckley/cabot-search huggingface dataset:
The translational challenge in the development of new and effective therapies for endometriosis: a review of confidence from published preclinical efficacy studies
Authors: Nick Pullen, Claire L. Birch, Garry J. Douglas, Qasim Hussain, Ingrid Pruimboom-Brees, Rosalind J. Walley
Journal: Human Reproduction Update (2011)

Endometriosis is a benign gynaecological condition that presents symptoms of chronic pelvic pain and the ectopic growth of endometrial lesions at sites on the peritoneum. Few new approaches to the management of the disease symptoms and progression have emerged in decades. The cornerstone of developing new therapies is the confidence and translational value placed in the preclinical models used to assess efficacy of emerging approaches.We systematically reviewed preclinical efficacy data from rodent and non-human primates, evaluating the effects of an investigational agent or target reported in PubMed between 2000 and 2010. We evaluated the reports for which model and end-points had been used to determine efficacy, whether there was evidence of independent replication, whether techniques had been incorporated into the experimental design to eliminate potential bias and whether there was a confirmation of drug exposure or target engagement in the study.We identified 94 publications that met our criteria for review. Efficacy studies were conducted in a wider range of different models with no clear consensus on which model or end-point has the most translational value. The large majority of studies either did not report what measures were incorporated into the design to address potential bias or account for it or did not confirm whether the specified target was engaged.Greater scrutiny of the preclinical efficacy models, end-points and experimental designs is needed if the desire of translating novel treatment approaches is to be realized for women with endometriosis.
Pulmonary artery occlusion by tuberculous mediastinal lymphadenopathy
Authors: W. M. Drake, S. L. Elkin, A. al-Kutoubi, D. M. Mitchell, R. J. Shaw
Journal: Thorax (1997)

Two cases of tuberculous mediastinal lymphadenopathy are presented in which the clinical features mimicked those of pulmonary embolism, causing striking abnormalities on radionuclide scintigraphy. It is concluded that tuberculous mediastinal lymphadenopathy should be included in the differential diagnosis of reduced lung perfusion due to proximal pulmonary artery occlusion.
Pathologic Outcomes in Favorable-risk Prostate Cancer: Comparative Analysis of Men Electing Active Surveillance and Immediate Surgery
Authors: Jeffrey J. Tosoian, Debasish Sundi, Bruce J. Trock, Patricia Landis, Jonathan I. Epstein, Edward M. Schaeffer, H. Ballentine Carter, Mufaddal Mamawala
Journal: European Urology (2015)
Water Arsenic Exposure and Intellectual Function in 6-Year-Old Children in Araihazar, Bangladesh
Authors: Gail A. Wasserman, Xinhua Liu, Faruque Parvez, Habibul Ahsan, Pam Factor-Litvak, Jennie Kline, Alexander van Geen, Vesna Slavkovich, Nancy J. LoIacono, Diane Levy, Zhongqi Cheng, Joseph H. Graziano
Journal: Environmental Health Perspectives (2006)

We recently reported results of a cross-sectional investigation of intellectual function in 10-year-olds in Bangladesh, who had been exposed to arsenic from drinking water in their home wells.We present results of a similar investigation of 301 randomly selected 6-year-olds whose parents participated in our ongoing prospective study of the health effects of As exposure in 12,000 residents of Araihazar, Bangladesh.Water As and manganese concentrations of tube wells at each home were obtained by surveying all study region wells. Children and mothers were first visited at home, where the quality of home stimulation was measured, and then seen in our field clinic, where children received a medical examination wherein weight, height, and head circumference were assessed. We assessed children's intellectual function using subtests drawn from the Wechsler Preschool and Primary Scale of Intelligence, version III, by summing weighted items across domains to create Verbal, Performance, Processing Speed, and Full-Scale raw scores. Children provided urine specimens for measuring urinary As and were asked to provide blood samples for blood lead measurements.Exposure to As from drinking water was associated with reduced intellectual function before and after adjusting for water Mn, for blood lead levels, and for sociodemographic features known to contribute to intellectual function. With covariate adjustment, water As remained significantly negatively associated with both Performance and Processing Speed raw scores; associations were less strong than in our previously studied 10-year-olds.This second cross-sectional study of As exposure expands our concerns about As neurotoxicity to a younger age group.
Natural killer cells activated in a human mixed lymphocyte response culture identified by expression of Leu-11 and class II histocompatibility antigens.
Authors: J H Phillips, A M Le, L L Lanier
Journal: The Journal of Experimental Medicine (1984)

Lymphoid cells with natural killer (NK)-like function, morphology, and antigenic phenotype have been identified in a mixed lymphocyte culture generated by co-culture of human peripheral blood mononuclear cells with an allogeneic human B lymphoblastoid cell line CCRF-SB. The majority of these mixed lymphocyte (MLR)-response activated NK cells express the Leu-11 surface antigen, but do not express certain T cell-associated antigens (Leu-1, Leu-3, and Leu-4) or the mature monocyte specific antigen, Leu-M3. Unlike most freshly isolated Leu-11+ human NK cells, the MLR-activated Leu-11+ cells expressed class II major histocompatibility antigens, DR and DC. Concomitant with expression of class II gene products, the Leu-11+,DR+ NK cells demonstrate enhanced cytotoxicity against the NK-sensitive tumor cell line K562. The presence of mitotic cells in the Leu-11+,DR+ population and the acquisition of increased levels of transferrin receptor on the cell surface were further indicators of activation of these cells. The direct precursors of the MLR-activated Leu-11+,DR+ cell were Leu-11+ cells that lacked expression of another NK-associated antigen Leu-7, i.e., Leu-7-,11+. These studies provided a definitive identification of the "NK-like" cell in MLR cultures and thus allow quantitation and isolation of these cells for further study.
Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse
Authors: Nilamadhab Mishra, Christopher M. Reilly, Doris R. Brown, Phil Ruiz, Gary S. Gilkeson
Journal: Journal of Clinical Investigation (2003)

Studies in human systemic lupus erythematosus (SLE) suggest a possible role for histone deacetylases (HDACs) in skewed gene expression and disease pathogenesis. We used the MRL-lpr/lpr murine model of lupus to demonstrate that HDACs play a key role in the heightened levels of both Th1 and Th2 cytokine expression that contribute to disease. The availability of specific HDAC inhibitors (HDIs) such as trichostatin A (TSA) and suberonylanilide hydroxamic acid (SAHA) permits the study of the role of HDACs in gene regulation. Our results indicate that HDIs downregulate IL-12, IFN-gamma, IL-6, and IL-10 mRNA and protein levels in MRL-lpr/lpr splenocytes. This effect on gene transcription is associated with an increased accumulation of acetylated histones H3 and H4 in total cellular chromatin. To elucidate the in vivo effects of TSA on lupuslike disease, we treated MRL-lpr/lpr mice with TSA (0.5 mg/kg/d) for 5 weeks. Compared with vehicle-treated control mice, TSA-treated mice exhibited a significant reduction in proteinuria, glomerulonephritis, and spleen weight. Taken together, these findings suggest that increased expression of HDACs leading to an altered state of histone acetylation may be of pathologic significance in MRL-lpr/lpr mice. In addition, TSA or other HDIs may have therapeutic benefit in the treatment of SLE.
Inter- and Intraspecies Phylogenetic Analyses Reveal Extensive X–Y Gene Conversion in the Evolution of Gametologous Sequences of Human Sex Chromosomes
Authors: Beniamino Trombetta, Daniele Sellitto, Rosaria Scozzari, Fulvio Cruciani
Journal: Molecular Biology and Evolution (2014)

It has long been believed that the male-specific region of the human Y chromosome (MSY) is genetically independent from the X chromosome. This idea has been recently dismissed due to the discovery that X–Y gametologous gene conversion may occur. However, the pervasiveness of this molecular process in the evolution of sex chromosomes has yet to be exhaustively analyzed. In this study, we explored how pervasive X–Y gene conversion has been during the evolution of the youngest stratum of the human sex chromosomes. By comparing about 0.5 Mb of human–chimpanzee gametologous sequences, we identified 19 regions in which extensive gene conversion has occurred. From our analysis, two major features of these emerged: 1) Several of them are evolutionarily conserved between the two species and 2) almost all of the 19 hotspots overlap with regions where X–Y crossing-over has been previously reported to be involved in sex reversal. Furthermore, in order to explore the dynamics of X–Y gametologous conversion in recent human evolution, we resequenced these 19 hotspots in 68 widely divergent Y haplogroups and used publicly available single nucleotide polymorphism data for the X chromosome. We found that at least ten hotspots are still active in humans. Hence, the results of the interspecific analysis are consistent with the hypothesis of widespread reticulate evolution within gametologous sequences in the differentiation of hominini sex chromosomes. In turn, intraspecific analysis demonstrates that X–Y gene conversion may modulate human sex-chromosome-sequence evolution to a greater extent than previously thought.
Genomic Predictors for Recurrence Patterns of Hepatocellular Carcinoma: Model Derivation and Validation
Authors: Ji Hoon Kim, Bo Hwa Sohn, Hyun-Sung Lee, Sang-Bae Kim, Jeong Eun Yoo, Yun-Yong Park, Woojin Jeong, Sung Sook Lee, Eun Sung Park, Ahmed Kaseb, Baek Hui Kim, Wan Bae Kim, Jong Eun Yeon, Kwan Soo Byun, In-Sun Chu, Sung Soo Kim, Xin Wei Wang, Snorri S. Thorgeirsson, John M. Luk, Koo Jeong Kang, Jeonghoon Heo, Young Nyun Park, Ju-Seog Lee
Journal: PLoS Medicine (2014)

Typically observed at 2 y after surgical resection, late recurrence is a major challenge in the management of hepatocellular carcinoma (HCC). We aimed to develop a genomic predictor that can identify patients at high risk for late recurrence and assess its clinical implications.Systematic analysis of gene expression data from human liver undergoing hepatic injury and regeneration revealed a 233-gene signature that was significantly associated with late recurrence of HCC. Using this signature, we developed a prognostic predictor that can identify patients at high risk of late recurrence, and tested and validated the robustness of the predictor in patients (n = 396) who underwent surgery between 1990 and 2011 at four centers (210 recurrences during a median of 3.7 y of follow-up). In multivariate analysis, this signature was the strongest risk factor for late recurrence (hazard ratio, 2.2; 95% confidence interval, 1.3-3.7; p = 0.002). In contrast, our previously developed tumor-derived 65-gene risk score was significantly associated with early recurrence (p = 0.005) but not with late recurrence (p = 0.7). In multivariate analysis, the 65-gene risk score was the strongest risk factor for very early recurrence (<1 y after surgical resection) (hazard ratio, 1.7; 95% confidence interval, 1.1-2.6; p = 0.01). The potential significance of STAT3 activation in late recurrence was predicted by gene network analysis and validated later. We also developed and validated 4- and 20-gene predictors from the full 233-gene predictor. The main limitation of the study is that most of the patients in our study were hepatitis B virus-positive. Further investigations are needed to test our prediction models in patients with different etiologies of HCC, such as hepatitis C virus.Two independently developed predictors reflected well the differences between early and late recurrence of HCC at the molecular level and provided new biomarkers for risk stratification. Please see later in the article for the Editors' Summary.
A Feedback Mechanism Responsible for Fixed Coupling in Parasystole
Authors: MATTHEW N. LEVY, MOO H. LEE, HARRISON ZIESKE
Journal: Circulation Research (1972)

The ventricles of open-chest anesthetized dogs were stimulated at a constant frequency to simulate ventricular parasystole. When the stimulation frequency was approximately half the spontaneous discharge frequency of the sinoatrial node, the natural pacemaker became synchronized with the artificial pacemaker. During such entrainment, the parasystolic rhythm resembled bigeminy with fixed coupling. Numerous instances of concealed bigeminy were also observed. Characteristic changes in arterial blood pressure always accompanied the repetitive ectopic beats, and these changes in blood pressure, acting mainly through the baroreceptor reflexes, were principally responsible for the synchronization. When the cardiac autonomic neural pathways were interrupted, synchronization usually could not be achieved. The biological feedback control system producing synchronization may be represented as follows. (1) The difference in timing between the firings of the sinoatrial node and the ectopic focus is the coupling interval. (2) This interval is a determinant of the stroke volumes of the premature and the postextrasystolic beats. (3) The stroke volumes affect the arterial blood pressure. (4) The level of blood pressure influences the neural activity in the baroreceptor reflex arc. (5) This activity in turn alters the frequency of the sinoatrial node. (6) Finally, sinoatrial nodal frequency affects the coupling interval to close the feedback loop.
Transcriptomic and phenotypic analysis of murine embryonic stem cell derived BMP2+ lineage cells: an insight into mesodermal patterning
Authors: Michael Doss, Shuhua Chen, Johannes Winkler, Rita Hippler-Altenburg, Margareta Odenthal, Claudia Wickenhauser, Sridevi Balaraman, Herbert Schulz, Oliver Hummel, Norbert Hübner, Nandini Ghosh-Choudhury, Isaia Sotiriadou, Jürgen Hescheler, Agapios Sachinidis
Journal: Genome biology (2007)

Bone morphogenetic protein (BMP)2 is a late mesodermal marker expressed during vertebrate development and plays a crucial role in early embryonic development. The nature of the BMP2-expressing cells during the early stages of embryonic development, their transcriptome and cell phenotypes developed from these cells have not yet been characterized. We generated a transgenic BMP2 embryonic stem (ES) cell lineage expressing both puromycin acetyltransferase and enhanced green fluorescent protein (EGFP) driven by the BMP2 promoter. Puromycin resistant and EGFP positive BMP2+ cells with a purity of over 93% were isolated. Complete transcriptome analysis of BMP2+ cells in comparison to the undifferentiated ES cells and the control population from seven-day-old embryoid bodies (EBs; intersection of genes differentially expressed between undifferentiated ES cells and BMP2+ EBs as well as differentially expressed between seven-day-old control EBs and BMP2+ EBs by t-test, p < 0.01, fold change >2) by microarray analysis led to identification of 479 specifically upregulated and 193 downregulated transcripts. Transcription factors, apoptosis promoting factors and other signaling molecules involved in early embryonic development are mainly upregulated in BMP2+ cells. Long-term differentiation of the BMP2+ cells resulted in neural crest stem cells (NCSCs), smooth muscle cells, epithelial-like cells, neuronal-like cells, osteoblasts and monocytes. Interestingly, development of cardiomyocytes from the BMP2+ cells requires secondary EB formation. This is the first study to identify the complete transcriptome of BMP2+ cells and cell phenotypes from a mesodermal origin, thus offering an insight into the role of BMP2+ cells during embryonic developmental processes in vivo.
Chest computed tomography: is it ready for major studies of chronic obstructive pulmonary disease?
Authors: M.G. Cosio, G.L. Snider
Journal: European Respiratory Journal (2001)

Chronic obstructive pulmonary disease (COPD) requires for diagnosis the presence of chronic airflow limitation and emphysema or chronic bronchitis.In the USA, the disease causes w100,000 deaths annually, it is the fourth most important cause of death and afflicts about 16 million persons.About 1% of COPD in the USA is associated with a 1 -antitrypsin (a 1 -AT) deficiency and is conveniently referred to as a 1 -AT-COPD.This form of the disease occurs in younger persons, progresses more rapidly, is associated with a higher frequency of panlobular emphysema (PLE) than usual COPD, and may be treated by augmentation therapy with concentrated human a 1 -AT.However, there is limited evidence that a 1 -AT replacement modifies the rate of progression of a 1 -AT-COPD.How can the rate of progression be monitored?Using tools derived from usual COPD to monitor a 1 -AT-COPD might not be correct.These diseases share pathophysiological similarities but there are also important differences.a 1 -AT-COPD is mostly due to the rapid development of PLE predominantly in the lower lobes; airflow obstruction and hyperinflation are mainly due to emphysema and losses of elastic recoil.In usual COPD, airflow limitation is largely secondary to airway damage and remodelling and emphysema (mainly centrilobular emphysema (CLE)) predominates in the upper lobes with a heterogeneous distribution in the lung.The extent of CLE is quite variable for a given level of airflow limitation.Moreover, SANDERS et al. [1] and SANTIS et al. [2] found that 68 -80% of smokers showed emphysema by high-resolution computed tomography (HRCT) in the presence of normal lung function tests.These facts highlight the complexity of COPD and the relative independence and at the same time interdependence of airway remodelling and emphysema in their contribution to the development of COPD.Which end-points should then be used to assess available and future new drugs for the treatment of both forms of COPD?The rate of decline of forced expiratory volume in one second (FEV1), the traditional end-point used, requires a large number of subjects studied over a period of years [3], and does
Comfort and Support Improve Painful Diabetic Neuropathy, Whereas Disappointment and Frustration Deteriorate the Metabolic and Neuropathic Status Despite an Intensive Diabetes Care Program
Authors: Gloria Kaye, Alison Okada Wollitzer, Lois Jovanovic
Journal: Diabetes Care (2003)

In this small series, we report a pilot study in which diabetic patients with painful neuropathy were closely monitored weekly by a physician skilled in intensified insulin delivery with and without the addition of alternative therapies for pain. Although the literature documents that a supportive health care team can improve diabetes control over and above the impact of simple medication adjustment, there is a paucity of reports on the impact of programs that fail to meet the expectations of patients and cause disappointment and stress. We therefore want to share our experience with five patients who were recruited as part of a pilot project to study the effect of alternative therapies in the treatment of painful diabetic neuropathy (1–5), specifically sessions with a healer and acupuncture, in which the acupuncture arm inadvertently failed.

Patients with long-standing diabetes may suffer complications, including neuropathy or nerve damage. To date, there is no specific treatment for this condition, except analgesic medications (6–10). Although, the mainstay of therapy is to stabilize the glucose levels as …
Digital Transcript Profile Analysis with aRNA-LongSAGE Validates FERMT1 As a Potential Novel Prognostic Marker for Colon Cancer
Authors: Junwei Fan, Dongwang Yan, Mujian Teng, Huamei Tang, Chongzhi Zhou, Xiaoliang Wang, Dawei Li, Guoqiang Qiu, Zhihai Peng
Journal: Clinical Cancer Research (2011)

To use gene transcript profiling to identify cancer-associated gene expression.Methods included (i) marker discovery using laser capture microdissection (LCM)-assisted specimen preparation and antisense RNA-long serial analysis of gene expression (aRNA-LongSAGE) on matched colon cancer and uninvolved colon tissue specimens (n = 5). Candidate tumor-associated genes were selected by combining the LongSAGE libraries reported herein with our previous colon cancer LCM-microarray transcript profiling data; (ii) marker selection and validation by quantitative real-time PCR (n = 15) and immunohistochemistry (n = 31); and (iii) independent validation on multiple tissue microarray (n = 203).Among 30 upregulated and 73 downregulated genes, upregulation of fermitin family member 1 (FERMT1), adenosylhomocysteinase (AHCY), secernin 1 (SCRN1), and SAC3 domain-containing protein 1 (SAC3D1) expression and downregulation of IgJ and MALL expression in colon cancer were confirmed by quantitative PCR. FERMT1 and AHCY protein expression was also upregulated in colon cancer compared with uninvolved colon mucosa, and FERMT1 expression showed upregulation in colon adenoma. Patients with moderate/strong tumor FERMT1 protein expression (n = 122) showed significantly poorer overall survival (OS; P = 0.011) and disease-free survival (DFS; P = 0.005) than patients with negative/weak tumor FERMT1 protein expression (n = 81). Multivariate Cox regression analysis showed that FERMT1 protein expression was also an independent prognostic factor for OS (P = 0.018) and DFS (P = 0.009). In addition, upregulated FERMT1 protein expression appeared to have some specificity among alimentary tract tumors.FERMT1 is a novel prognostic factor for colon carcinoma.
A Novel Cancer Testis Antigen That Is Frequently Expressed in Pancreatic, Lung, and Endometrial Cancers
Authors: Takaho Okada, Masanori Akada, Tomonobu Fujita, Takashi Iwata, Yasufumi Goto, Kenji Kido, Tsutomu Okada, Yuriko Matsuzaki, Kouichi Kobayashi, Seiki Matsuno, Makoto Sunamura, Yutaka Kawakami
Journal: Clinical Cancer Research (2006)

To isolate cancer testis antigens that are expressed in pancreatic cancers and may be useful in clinical applications.To efficiently isolate cancer testis antigens, a testis cDNA library was immunoscreened (SEREX) with serum from a patient with pancreatic ductal adenocarcinoma. The expression of isolated antigens in various cancer cell lines and tissues was evaluated by reverse transcription-PCR and Northern blot analyses. The immunogenicity of the antigen in cancer patients was evaluated by detection of the IgG antibody in sera from patients with various cancers.Of the three clones isolated through screening of a total of 2 x 10(6) cDNA library clones, one clone (KU-CT-1) was found to be expressed in various cancers but only in testis among normal tissues, indicating that it was a novel cancer testis antigen. The KU-CT-1 gene is located on chromosome 10p12 and produces two splice variants, which encode proteins of 397 and 872 amino acids, respectively. KU-CT-1 was expressed in pancreatic cancer tissues (3 of 9, 33%), lung cancer tissues (9 of 24, 38%), and endometrial cancer tissues (7 of 11, 64%). Specific serum IgG antibodies were detected in 3 of 20 pancreatic cancer patients, 2 of 12 endometrial cancer patients, 1 of 18 colon cancer patients, and 1 of 10 prostate cancer patients but not detected in 30 healthy individuals.KU-CT-1 is a new cancer testis antigen that is expressed in pancreatic, lung, and endometrial cancers and may be useful for diagnosis and immunotherapy for patients with various cancers.