tbuckley/cabot-search huggingface dataset:
Treatment of Small-Cell Lung Cancer: American Society of Clinical Oncology Endorsement of the American College of Chest Physicians Guideline
Authors: Charles M. Rudin, Nofisat Ismaila, Christine L. Hann, Narinder Malhotra, Benjamin Movsas, Kim Norris, M. Catherine Pietanza, Suresh S. Ramalingam, Andrew T. Turrisi, Giuseppe Giaccone
Journal: Journal of Clinical Oncology (2015)

The American College of Chest Physicians (ACCP) produced an evidence-based guideline on treatment of patients with small-cell lung cancer (SCLC). Because of the relevance of this guideline to American Society of Clinical Oncology (ASCO) membership, ASCO reviewed the guideline, applying a set of procedures and policies used to critically examine guidelines developed by other organizations.The ACCP guideline on the treatment of SCLC was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel updated the literature search, reviewed the content, and considered additional recommendations.The ASCO Endorsement Panel determined that the recommendations from the ACCP guideline, published in 2013, are clear, thorough, and based on current scientific evidence. ASCO endorses the ACCP guideline on the treatment of SCLC, with the addition of qualifying statements.Surgery is indicated for selected stage I SCLC. Limited-stage disease should be treated with concurrent chemoradiotherapy in patients with good performance status. Thoracic radiotherapy should be administered early in the course of treatment, preferably beginning with cycle one or two of chemotherapy. Chemotherapy should consist of four cycles of a platinum agent and etoposide. Extensive-stage disease should be treated primarily with chemotherapy consisting of a platinum agent plus etoposide or irinotecan. Prophylactic cranial irradiation prolongs survival in patients with limited-stage disease who achieve a complete or partial response to initial therapy and may do so in similarly responding patients with extensive-stage disease as well. Additional information is available at http://www.asco.org/endorsements/sclc and http://www.asco.org/guidelineswiki.
Regulation of transforming growth factor-beta 1 expression by the hepatitis B virus (HBV) X transactivator. Role in HBV pathogenesis.
Authors: Y D Yoo, H Ueda, K Park, K C Flanders, Y I Lee, G Jay, S J Kim
Journal: Journal of Clinical Investigation (1996)

TGF-beta 1 has been implicated in the pathogenesis of liver disease. The high frequency of detection of the hepatitis B virus X (HBx) antigen in liver cells from patients with chronic hepatitis, cirrhosis, and liver cancer suggested that expression of HBx and TGF-beta 1 may be associated. To test this possibility, we examined the expression of TGF-beta 1 in the liver of transgenic mice expressing the HBx gene. We show that the patterns of expression of TGF-beta 1 and Hbx protein are similar in these mice and that HBx activates transcription of the TGF-beta 1 gene in transfected hepatoma cells. The cis-acting element within the TGF-beta 1 gene that is responsive to regulation by Hbx is the binding site for the Egr family of transcription factors. We further show that the Egr-1 protein associates with the HBx protein, allowing HBx to participate in the transcriptional regulation of immediate-early genes. Our results suggest that expression of Hbx might induce expression of TGF-beta 1 in the early stages of infection and raise the possibility that TGF-beta 1 may play a role in hepatitis B virus pathogenesis.
Caenorhabditis elegans chromosome arms are anchored to the nuclear membrane via discontinuous association with LEM-2
Authors: Kohta Ikegami, Thea A Egelhofer, Susan Strome, Jason D Lieb
Journal: Genome biology (2010)

Abstract Background Although Caenorhabditis elegans was the first multicellular organism with a completely sequenced genome, how this genome is arranged within the nucleus is not known. Results We determined the genomic regions associated with the nuclear transmembrane protein LEM-2 in mixed-stage C. elegans embryos via chromatin immunoprecipitation. Large regions of several megabases on the arms of each autosome were associated with LEM-2. The center of each autosome was mostly free of such interactions, suggesting that they are largely looped out from the nuclear membrane. Only the left end of the X chromosome was associated with the nuclear membrane. At a finer scale, the large membrane-associated domains consisted of smaller subdomains of LEM-2 associations. These subdomains were characterized by high repeat density, low gene density, high levels of H3K27 trimethylation, and silent genes. The subdomains were punctuated by gaps harboring highly active genes. A chromosome arm translocated to a chromosome center retained its association with LEM-2, although there was a slight decrease in association near the fusion point. Conclusions Local DNA or chromatin properties are the main determinant of interaction with the nuclear membrane, with position along the chromosome making a minor contribution. Genes in small gaps between LEM-2 associated regions tend to be highly expressed, suggesting that these small gaps are especially amenable to highly efficient transcription. Although our data are derived from an amalgamation of cell types in mixed-stage embryos, the results suggest a model for the spatial arrangement of C. elegans chromosomes within the nucleus.
The genomic response to 20-hydroxyecdysone at the onset of Drosophila metamorphosis.
Authors: Robert B Beckstead, Geanette Lam, Carl S Thummel
Journal: Genome biology (2005)

Abstract Background The steroid hormone 20-hydroxyecdysone (20E) triggers the major developmental transitions in Drosophila , including molting and metamorphosis, and provides a model system for defining the developmental and molecular mechanisms of steroid signaling. 20E acts via a heterodimer of two nuclear receptors, the ecdysone receptor (EcR) and Ultraspiracle, to directly regulate target gene transcription. Results Here we identify the genomic transcriptional response to 20E as well as those genes that are dependent on EcR for their proper regulation. We show that genes regulated by 20E, and dependent on EcR , account for many transcripts that are significantly up- or downregulated at puparium formation. We provide evidence that 20E and EcR participate in the regulation of genes involved in metabolism, stress, and immunity at the onset of metamorphosis. We also present an initial characterization of a 20E primary-response regulatory gene identified in this study, brain tumor ( brat ), showing that brat mutations lead to defects during metamorphosis and changes in the expression of key 20E-regulated genes. Conclusion This study provides a genome-wide basis for understanding how 20E and its receptor control metamorphosis, as well as a foundation for functional genomic analysis of key regulatory genes in the 20E signaling pathway during insect development.
Sequential Fluorescent Labeling Observation of Maxillary Sinus Augmentation by a Tissue‐engineered Bone Complex in Canine Model
Authors: Xin‐quan Jiang, Shao‐yi Wang, Jun Zhao, Xiu‐li Zhang, Zhi‐yuan Zhang
Journal: International Journal of Oral Science (2009)

To evaluate the effects of maxillary sinus floor elevation by a tissue‐engineered bone complex of β‐tricalcium phosphate (β‐TCP) and autologous osteoblasts in dogs. Autologous osteoblasts from adult Beagle dogs were cultured in vitro. They were further combined with β‐TCP to construct the tissue‐engineered bone complex. 12 cases of maxillary sinus floor elevation surgery were made bilaterally in 6 animals and randomly repaired with the following 3 groups of materials: Group A (osteoblasts/β‐TCP); Group B (β‐TCP); Group C (autogenous bone) (n=4 per group). A polychrome sequential fluorescent labeling was performed post‐operatively and the animals were sacrificed 24 weeks after operation for histological observation. Our results showed that autologous osteoblasts were successfully expanded and the osteoblastic phenol‐types were confirmed by ALP and Alizarin red staining. The cells could attach and proliferate well on the surface of the β‐TCP scaffold. The fluorescent and histological observation showed that the tissue‐engineered bone complex had an earlier mineralization and more bone formation inside the scaffold than β‐TCP along or even autologous bone. It had also maximally maintained the elevated sinus height than both control groups. Porous β‐TCP has served as a good scaffold for autologous osteoblasts seeding. The tissue‐engineered bone complex with β‐TCP and autologous osteoblasts might be a better alternative to autologous bone for the clinical edentulous maxillary sinus augmentation.
Association of Visceral Fat Accumulation and Plasma Adiponectin with Colorectal Adenoma: Evidence for Participation of Insulin Resistance
Authors: Sayaka Otake, Hiroaki Takeda, Yasukuni Suzuki, Tadahisa Fukui, Shinichiro Watanabe, Katsuyoshi Ishihama, Takafumi Saito, Hitoshi Togashi, Tadashi Nakamura, Yuji Matsuzawa, Sumio Kawata
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Colorectal carcinogenesis is thought to be related to abdominal obesity and insulin resistance. To investigate whether visceral fat accumulation contributes to colorectal carcinogenesis, we examined its accumulation and the levels of the adipose tissue–derived hormone adiponectin in Japanese patients with colorectal adenoma. Experimental Design: Fifty-one consecutive Japanese patients ages ≥40 years and with colorectal adenoma were subjected to measurement of visceral fat area by computed tomography scanning and plasma adiponectin concentration. The patients also underwent the 75-g oral glucose tolerance test. Insulin resistance was calculated by the homeostasis metabolic assessment (HOMA-IR) method. The controls were 52 Japanese subjects ages ≥40 years and without colorectal polyp. Cigarette smokers and subjects who consumed alcohol (≥30 g ethanol/d) were excluded. Results: The patients with colorectal adenoma showed significantly more visceral fat area and significantly less plasma adiponectin concentration in comparison with the controls [odds ratio (OR), 2.19; 95% confidence interval (95% CI), 1.47-3.28; P &amp;lt; 0.001 and OR, 0.24; 95% CI, 0.14-0.41; P &amp;lt; 0.001, respectively] by logistic regression analysis. HOMA-IR index was also associated with colorectal adenoma (OR 2.60; 95% CI, 1.20-5.64; P = 0.040). Visceral fat area and adiponectin were associated with adenoma number (1, 2, ≥ 3), the size of the largest adenoma (&amp;lt;10 and ≥10 mm), and adenoma histology (tubular and tubulovillous/villous). Conclusions: These results suggest an association of visceral fat accumulation and decreased plasma adiponectin concentration with colorectal adenoma in Japanese patients. This study may offer a new insight to understanding the relationship of colorectal carcinogenesis with abdominal obesity and insulin resistance.
Randomized Controlled Trial of Motivational Interviewing, Cognitive Behavior Therapy, and Family Intervention for Patients With Comorbid Schizophrenia and Substance Use Disorders
Authors: Christine Barrowclough, Gillian Haddock, Nicholas Tarrier, Shôn W. Lewis, Jan Moring, Rob O’Brien, Nichola Schofield, John McGovern
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: Comorbidity of substance abuse disorders with schizophrenia is associated with a greater risk for serious illness complications and poorer outcome. Methodologically sound studies investigating treatment approaches for patients with these disorders are rare, although recommendations for integrated and comprehensive treatment programs abound. This study investigates the relative benefit of adding an integrated psychological and psychosocial treatment program to routine psychiatric care for patients with schizophrenia and substance use disorders. METHOD: The authors conducted a randomized, single-blind controlled comparison of routine care with a program of routine care integrated with motivational interviewing, cognitive behavior therapy, and family or caregiver intervention. RESULTS: The integrated treatment program resulted in significantly greater improvement in patients’ general functioning than routine care alone at the end of treatment and 12 months after the beginning of the study. Other benefits of the program included a reduction in positive symptoms and in symptom exacerbations and an increase in the percent of days of abstinence from drugs or alcohol over the 12-month period from baseline to follow-up. CONCLUSIONS: These findings demonstrate the effectiveness of a program of routine care integrated with motivational interviewing, cognitive behavior therapy, and family intervention over routine psychiatric care alone for patients with comorbid schizophrenia and alcohol or drug abuse or dependence.
Characterization of a naturally-occurring p27 mutation predisposing to multiple endocrine tumors
Authors: Sara Molatore, Eva Kiermaier, Christian B Jung, Misu Lee, Elke Pulz, Heinz Höfler, Michael J Atkinson, Natalia S Pellegata
Journal: Molecular Cancer (2010)

Abstract Background p27Kip1 (p27) is an important negative regulator of the cell cycle and a putative tumor suppressor. The finding that a spontaneous germline frameshift mutation in Cdkn1b (encoding p27) causes the MENX multiple endocrine neoplasia syndrome in the rat provided the first evidence that Cdkn1b is a tumor susceptibility gene for endocrine tumors. Noteworthy, germline p27 mutations were also identified in human patients presenting with endocrine tumors. At present, it is not clear which features of p27 are crucial for this tissue-specific tumor predisposition in both rats and humans. It was shown that the MENX-associated Cdkn1b mutation causes reduced expression of the encoded protein, but the molecular mechanisms are unknown. To better understand the role of p27 in tumor predisposition and to characterize the MENX animal model at the molecular level, a prerequisite for future preclinical studies, we set out to assess the functional properties of the MENX-associated p27 mutant protein (named p27fs177) in vitro and in vivo . Results In vitro , p27fs177 retains some properties of the wild-type p27 (p27wt) protein: it localizes to the nucleus; it interacts with cyclin-dependent kinases and, to lower extent, with cyclins. In contrast to p27wt, p27fs177 is highly unstable and rapidly degraded in every phase of the cell-cycle, including quiescence. It is in part degraded by Skp2-dependent proteasomal proteolysis, similarly to p27wt. Photobleaching studies showed reduced motility of p27fs177 in the nucleus compared to p27wt, suggesting that in this compartment p27fs177 is part of a multi-protein complex, likely together with the degradation machinery. Studies of primary rat newborn fibroblasts (RNF) established from normal and MENX-affected littermates confirmed the rapid degradation of p27fs177 in vivo which can be rescued by Bortezomib (proteasome inhibitor drug). Overexpression of the negative regulators microRNA-221/222 plays no role in regulating the amount of p27fs177 in RNFs and rat tissues. Conclusion Our findings show that reduced p27 levels, not newly acquired properties, trigger tumor formation in rats, similarly to what has been observed in mice. The molecular characteristics of p27fs177 establish MENX as a useful preclinical model to evaluate compounds that inhibit p27 degradation for their efficacy against endocrine tumors.
Intracoronary Stenting and Angiographic Results
Authors: Adnan Kastrati, Julinda Mehilli, Josef Dirschinger, Franz Dotzer, Helmut Schühlen, Franz-Josef Neumann, Martin Fleckenstein, Conrad Pfafferott, Melchior Seyfarth, Albert Schömig
Journal: Circulation (2001)

Increased thrombogenicity and smooth muscle cell proliferative response induced by the metal struts compromise the advantages of coronary stenting. The objective of this randomized, multicenter study was to assess whether a reduced strut thickness of coronary stents is associated with improved follow-up angiographic and clinical results.A total of 651 patients with coronary lesions situated in native vessels >2.8 mm in diameter were randomly assigned to receive 1 of 2 commercially available stents of comparable design but different thickness: 326 patients to the thin-strut stent (strut thickness of 50 microm) and 325 patients to the thick-strut stent (strut thickness of 140 microm). The primary end point was the angiographic restenosis (>/=50% diameter stenosis at follow-up angiography). Secondary end points were the incidence of reinterventions due to restenosis-induced ischemia and the combined rate of death and myocardial infarctions at 1 year. The incidence of angiographic restenosis was 15.0% in the thin-strut group and 25.8% in the thick-strut group (relative risk, 0.58; 95% CI, 0.39 to 0.87; P=0.003). Clinical restenosis was also significantly reduced, with a reintervention rate of 8.6% among thin-strut patients and 13.8% among thick-strut patients (relative risk, 0.62; 95% CI, 0.39 to 0.99; P=0.03). No difference was observed in the combined 1-year rate of death and myocardial infarction.The use of a thinner-strut device is associated with a significant reduction of angiographic and clinical restenosis after coronary artery stenting. These findings may have relevant implications for the currently most widely used percutaneous coronary intervention.
Prognostic Associations of Activated Mitogen-Activated Protein Kinase and Akt Pathways in Glioblastoma
Authors: Christopher E. Pelloski, E Lin, Li Zhang, W.K. Alfred Yung, Howard Colman, Juinn-Lin Liu, Shaio Y. Woo, Amy B. Heimberger, Dima Suki, Michael Prados, Susan Chang, Fredrick G. Barker, Gregory N. Fuller, Kenneth D. Aldape
Journal: Clinical Cancer Research (2006)

Activation of mitogen-activated protein kinase (MAPK) and members of the Akt pathway have been shown to promote cell proliferation, survival, and resistance to radiation. This study was conducted to determine whether any of these markers are associated with survival time and response to radiation in glioblastoma.The expression of phosphorylated (p-)Akt, mammalian target of rapamycin (p-mTOR), p-p70S6K, and p-MAPK were assessed by immunohistochemical staining in 268 cases of newly diagnosed glioblastoma. YKL-40, a prognostic marker previously examined in these tumors, was also included in the analysis. Expression data were tested for correlations with response to radiation therapy in 131 subtotally resected cases and overall survival (in all cases). Results were validated in an analysis of 60 patients enrolled in clinical trials at a second institution.Elevated p-MAPK expression was most strongly associated with poor response to radiotherapy, a finding corroborated in the validation cohort. For survival, higher expressions of p-mTOR, p-p70S6K, and p-MAPK were associated with worse outcome (all P < 0.03). YKL-40 expression was associated with the expressions of p-MAPK, p-mTOR, and p-p70S6K (all P < 0.02), with a trend toward association with p-Akt expression (P = 0.095). When known clinical variables were added to a multivariate analysis, only age, Karnofsky performance score, and p-MAPK expression emerged as independent prognostic factors.p-MAPK and activated members of the Akt pathway are markers of outcome in glioblastoma. Elevated expression of p-MAPK is associated with increased radiation resistance and represents an independent prognostic factor in these tumors.
Altered Runx1 Subnuclear Targeting Enhances Myeloid Cell Proliferation and Blocks Differentiation by Activating a miR-24/MKP-7/MAPK Network
Authors: Sayyed K. Zaidi, Christopher R. Dowdy, Andre J. van Wijnen, Jane B. Lian, Azra Raza, Janet L. Stein, Carlo M. Croce, Gary S. Stein
Journal: Cancer Research (2009)

Disruption of Runx1/AML1 subnuclear localization, either by a single amino acid substitution or by a chromosomal translocation [e.g., t(8;21)], is linked to the etiology of acute myeloid leukemia (AML). Here, we show that this defect induces a select set of micro-RNAs (miR) in myeloid progenitor cells and AML patients with t(8;21). Both Runx1 and the t(8;21)-encoded AML1-ETO occupy the miR-24-23-27 locus and reciprocally control miR-24 transcription. miR-24 directly downregulates mitogen-activated protein kinase (MAPK) phosphatase-7 and enhances phosphorylation of both c-jun-NH(2)-kinase and p38 kinases. Expression of miR-24 stimulates myeloid cell growth, renders proliferation independent of interleukin-3, and blocks granulocytic differentiation. Thus, compromised Runx1 function induces a miR-dependent mechanism that, through MAPK signaling, enhances myeloid proliferation but blocks differentiation--key steps that contribute to leukemia.
Pilot Anopheles gambiae full-length cDNA study: sequencing and initial characterization of 35,575 clones.
Authors: Shawn M Gomez, Karin Eiglmeier, Beatrice Segurens, Pierre Dehoux, Arnaud Couloux, Claude Scarpelli, Patrick Wincker, Jean Weissenbach, Paul T Brey, Charles W Roth
Journal: Genome biology (2005)

Abstract We describe the preliminary analysis of over 35,000 clones from a full-length enriched cDNA library from the malaria mosquito vector Anopheles gambiae . The clones define nearly 3,700 genes, of which around 2,600 significantly improve current gene definitions. An additional 17% of the genes were not previously annotated, suggesting that an equal percentage may be missing from the current Anopheles genome annotation.
AID Mediates Hypermutation by Deaminating Single Stranded DNA
Authors: Sarah K. Dickerson, Eleonora Market, Eva Besmer, F. Nina Papavasiliou
Journal: The Journal of Experimental Medicine (2003)

Activation-induced deaminase (AID) is a protein indispensable for the diversification of immunoglobulin (Ig) genes by somatic hypermutation (SHM), class switch recombination (CSR), and gene conversion. To date, the precise role of AID in these processes has not been determined. Here we demonstrate that purified, tetrameric AID can deaminate cytidine residues in DNA, but not in RNA. Furthermore, we show that AID will bind and deaminate only single-stranded DNA, which implies a direct, functional link between hypermutation and transcription. Finally, AID does not target mutational hotspots, thus mutational targeting to specific residues must be attributed to different factors.