tbuckley/cabot-search huggingface dataset:
Second-Generation Tyrosine Kinase Inhibitors: The Future of Frontline CML Therapy
Authors: Hagop M. Kantarjian, Michele Baccarani, Elias Jabbour, Giuseppe Saglio, Jorge E. Cortes
Journal: Clinical Cancer Research (2011)

All available data from ongoing studies of second-generation tyrosine kinase inhibitors (TKIs) for treatment of patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) were reviewed. In two nilotinib phase 2 trials, the speed and depth of molecular and cytogenetic responses were greater than responses to imatinib. Furthermore, only one patient in each study progressed to accelerated or blastic phase. In the phase 3 ENESTnd study, molecular and cytogenetic responses to nilotinib were superior to imatinib, and more patients achieved undetectable levels of disease with nilotinib. Nilotinib also demonstrated significantly lower progression than did imatinib. In the ongoing phase 2 study of dasatinib, the speed and depth of molecular and cytogenetic responses were higher compared with expected responses to imatinib; no patient to date has progressed. In the phase 3 DASISION study, molecular and cytogenetic responses to dasatinib were superior to those of imatinib and fewer patients progressed. The results suggest that second-generation TKIs have the potential to replace imatinib as the standard of care for patients with early CML-CP. Future CML therapy might include earlier use of these agents to help more patients achieve complete molecular response and may be a path to a CML cure.
Tumor-associated copy number changes in the circulation of patients with prostate cancer identified through whole-genome sequencing
Authors: Ellen Heitzer, Peter Ulz, Jelena Belic, Stefan Gutschi, Franz Quehenberger, Katja Fischereder, Theresa Benezeder, Martina Auer, Carina Pischler, Sebastian Mannweiler, Martin Pichler, Florian Eisner, Martin Haeusler, Sabine Riethdorf, Klaus Pantel, Hellmut Samonigg, Gerald Hoefler, Herbert Augustin, Jochen B Geigl, Michael R Speicher
Journal: Genome Medicine (2013)

Patients with prostate cancer may present with metastatic or recurrent disease despite initial curative treatment. The propensity of metastatic prostate cancer to spread to the bone has limited repeated sampling of tumor deposits. Hence, considerably less is understood about this lethal metastatic disease, as it is not commonly studied. Here we explored whole-genome sequencing of plasma DNA to scan the tumor genomes of these patients non-invasively.We wanted to make whole-genome analysis from plasma DNA amenable to clinical routine applications and developed an approach based on a benchtop high-throughput platform, that is, Illuminas MiSeq instrument. We performed whole-genome sequencing from plasma at a shallow sequencing depth to establish a genome-wide copy number profile of the tumor at low costs within 2 days. In parallel, we sequenced a panel of 55 high-interest genes and 38 introns with frequent fusion breakpoints such as the TMPRSS2-ERG fusion with high coverage. After intensive testing of our approach with samples from 25 individuals without cancer we analyzed 13 plasma samples derived from five patients with castration resistant (CRPC) and four patients with castration sensitive prostate cancer (CSPC).The genome-wide profiling in the plasma of our patients revealed multiple copy number aberrations including those previously reported in prostate tumors, such as losses in 8p and gains in 8q. High-level copy number gains in the AR locus were observed in patients with CRPC but not with CSPC disease. We identified the TMPRSS2-ERG rearrangement associated 3-Mbp deletion on chromosome 21 and found corresponding fusion plasma fragments in these cases. In an index case multiregional sequencing of the primary tumor identified different copy number changes in each sector, suggesting multifocal disease. Our plasma analyses of this index case, performed 13 years after resection of the primary tumor, revealed novel chromosomal rearrangements, which were stable in serial plasma analyses over a 9-month period, which is consistent with the presence of one metastatic clone.The genomic landscape of prostate cancer can be established by non-invasive means from plasma DNA. Our approach provides specific genomic signatures within 2 days which may therefore serve as 'liquid biopsy'.
Predictors of Aromatase Inhibitor Discontinuation as a Result of Treatment-Emergent Symptoms in Early-Stage Breast Cancer
Authors: N. Lynn Henry, Faouzi Azzouz, Zereunesay Desta, Lang Li, Anne T. Nguyen, Suzanne Lemler, Jill Hayden, Karineh Tarpinian, Elizabeth Yakim, David A. Flockhart, Vered Stearns, Daniel F. Hayes, Anna Maria Storniolo
Journal: Journal of Clinical Oncology (2012)

Aromatase inhibitors (AIs) are effective for treatment of hormone receptor-positive breast cancer, but adherence and persistence with therapy are poor. Predictors of treatment discontinuation are not clearly defined. It is unknown whether patients with intolerable toxicity from one AI are able to tolerate another.Women with early-stage breast cancer initiating AI therapy were enrolled onto a multicenter, prospective, open-label randomized trial of exemestane versus letrozole. Patients completed symptom questionnaires at baseline and serially during therapy. Patients who developed AI-associated intolerable symptoms and discontinued treatment were given the option to switch to the other study AI after a 2- to 8-week washout period.Of the 503 enrolled women, 32.4% discontinued initial AI therapy within 2 years because of adverse effects; 24.3% discontinued specifically because of musculoskeletal symptoms. Median time to treatment discontinuation as a result of any symptom was 6.1 months (range, 0.1 to 21.2 months) and was significantly shorter in patients randomly assigned to exemestane (hazard ratio [HR], 1.5; 95% CI, 1.1 to 2.1; P = .02). Younger age and taxane-based chemotherapy were associated with higher likelihood of treatment discontinuation (HR, 1.4; 95% CI, 1.02 to 1.9; P = .04; and HR, 1.9; 95% CI, 1.00 to 3.6; P = .048, respectively). Of the 83 patients who chose to switch to the second AI, 38.6% continued the alternate AI for a median of 13.7 months.Premature discontinuation of initial AI therapy as a result of symptoms is common, although more than one third of patients may be able to tolerate a different AI medication. Additional research is needed to identify predictive tools and interventions for AI-associated treatment-emergent symptoms.
Individual Titration for Maximal Blockade of the Renin-Angiotensin System in Proteinuric Patients
Authors: Liffert Vogt, Gerjan Navis, Dick de Zeeuw
Journal: Journal of the American Society of Nephrology (2005)

Agents that interfere with the renin-angiotensin system (RAS) reduce proteinuria and afford renal protection. The combination of different measures that serve maximization of RAS blockade is thought to improve the antiproteinuric efficacy. The feasibility and the efficacy of such a combination strategy were studied in nondiabetic patients with residual proteinuria during previous RAS blockade by individual antiproteinuric titration. Previous medication was replaced by irbesartan 300 mg combined with a diuretic. Lisinopril was added in increasing doses until a maximal dose of 40 mg/d. Titration stopped when target proteinuria (&lt;1 g/d) was reached or further dose titration was not tolerated because of side effects. Residual proteinuria (median, 3.2 g/d; 95% confidence interval, 1.8 to 5.2 g/d) was significantly reduced with 55.6% (95% confidence interval, 16.0 to 73.2%; <i>P</i> &lt; 0.02) on the maximal additional tolerated dose of lisinopril. The maximal dose of lisinopril was 10 mg in two of eight, 20 mg in two of eight, 30 mg in one of eight, and 40 mg in three of eight patients. At this dose, target proteinuria of &lt;1 g/d was reached in two of eight patients. The number of patients with adverse events during dose titration was five of eight patients: two had cough; two had hyperkalemia (&gt;5.5 mmol/L), one of whom had &gt;50% increase of serum creatinine; and one had dizziness. In conclusion, individual titration for maximal RAS blockade, entailing dose titration of angiotensin-converting enzyme inhibitors on top of high-dose angiotensin II antagonists with diuretic, induces further reduction of residual proteinuria. However, this occurs at the expense of adverse events. To further improve renoprotective treatment strategies, it is important to explore other modes of antiproteinuric intervention in patients with residual proteinuria during RAS blockade.
Increased Risk of Breast Cancer Associated With <i>CHEK2</i>*<i>1100delC</i>
Authors: Maren Weischer, Stig Egil Bojesen, Anne Tybjærg-Hansen, Christen Kirk Axelsson, Børge Grønne Nordestgaard
Journal: Journal of Clinical Oncology (2006)

CHEK2*1100delC heterozygosity has been associated with increased risk of breast, prostate, and colorectal cancer in case-control studies. We tested the hypothesis that CHEK2*1100delC heterozygosity in the general population increases the risk of cancer in general, and breast, prostate, and colorectal cancer in particular.We performed a prospective study of 9,231 individuals from the Danish general population, who were observed for 34 years, and we performed a case-control study including 1,101 cases of breast cancer and 4,665 controls.Of the general population, 0.5% were heterozygotes and 99.5% were noncarriers. In the prospective study, multifactorially adjusted hazard ratios by CHEK2*1100delC heterozygosity versus noncarriers were 1.2 (95% CI, 0.7 to 2.1) for all cancers, 3.2 (95% CI, 1.0 to 9.9) for breast cancer, 2.3 (95% CI, 0.6 to 9.5) for prostate cancer, and 1.6 (95% CI, 0.4 to 6.5) for colorectal cancer. In the case-control study, age-matched odds ratio for breast cancer by CHEK2*1100delC heterozygosity versus noncarriers was 2.6 (95% CI, 1.3 to 5.4). The absolute 10-year risk of breast cancer in CHEK2*1100delC heterozygotes amounted to 24% in women older than 60 years undergoing hormone replacement therapy, with a body mass index of 25 kg/m2 or higher.CHEK2*1100delC heterozygosity is associated with a three-fold risk of breast cancer in women in the general population.
Wnt Signaling Pathway in Non-Small Cell Lung Cancer
Authors: D. J. Stewart
Journal: JNCI Journal of the National Cancer Institute (2013)

Wnt/β-catenin alterations are prominent in human malignancies. In non–small cell lung cancer (NSCLC), β-catenin and APC mutations are uncommon, but Wnt signaling is important in NSCLC cell lines, and Wnt inhibition reduces proliferation. Overexpression of Wnt-1 , -2 , -3 , and -5a and of Wnt-pathway components Frizzled-8 , Dishevelled , Porcupine , and TCF-4 is common in resected NSCLC and is associated with poor prognosis. Conversely, noncanonical Wnt-7a suppresses NSCLC development and is often downregulated. Although β-catenin is often expressed in NSCLCs, it was paradoxically associated with improved prognosis in some series, possibly because of E-cadherin interactions. Downregulation of Wnt inhibitors (eg, by hypermethylation) is common in NSCLC tumor cell lines and resected samples; may be associated with high stage, dedifferentiation, and poor prognosis; and has been reported for AXIN , sFRPs 1–5 , WIF-1 , Dkk-1 , Dkk-3 , HDPR1 , RUNX3 , APC , CDX2 , DACT2 , TMEM88 , Chibby, NKD1 , EMX2 , ING4 , and miR-487b. AXIN is also destabilized by tankyrases, and GSK3β may be inactivated through phosphorylation by EGFR. Preclinically, restoration of Wnt inhibitor function is associated with reduced Wnt signaling, decreased cell proliferation, and increased apoptosis. Wnt signaling may also augment resistance to cisplatin, docetaxel, and radiotherapy, and Wnt inhibitors may restore sensitivity. Overall, available data indicate that Wnt signaling substantially impacts NSCLC tumorigenesis, prognosis, and resistance to therapy, with loss of Wnt signaling inhibitors by promoter hypermethylation or other mechanisms appearing to be particularly important. Wnt pathway antagonists warrant exploration clinically in NSCLC. Agents blocking selected specific β-catenin interactions and approaches to increase expression of downregulated Wnt inhibitors may be of particular interest.
Expression of Serotonin Receptors in Human Hepatocellular Cancer
Authors: Christopher Soll, Marc-Oliver Riener, Christian Eugen Oberkofler, Claus Hellerbrand, Peter J. Wild, Michelle L. DeOliveira, Pierre-Alain Clavien
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Serotonin is a well-known neurotransmitter and vasoactive substance. Recent research indicates that serotonin contributes to liver regeneration and promotes tumor growth of human hepatocellular cancer. The aim of this study is to investigate the expression of serotonin receptors in hepatocellular cancer and analyze their potential as a cytotoxic target. Experimental Design: Using a tissue microarray and immunohistochemistry, we analyzed the expression of serotonin receptors in the liver from 176 patients with hepatocellular carcinoma, of which nontumor tissue was available in 109 patients. Relevant clinicopathologic parameters were compared with serotonin receptor expression. Two human hepatocellular cancer cell lines, Huh7 and HepG2, were used to test serotonin antagonists as a possible cytotoxic drug. Results: The serotonin receptors 1B and 2B were expressed, respectively, in 32% and 35% of the patients with hepatocellular cancer. Both receptors were associated with an increased proliferation index, and receptor 1B correlated with the size of the tumor. Serotonin antagonists of receptors 1B and 2B consistently decreased viability and proliferation in Huh7 and HepG2 cell lines. Conclusion: We identified two serotonin receptors that are often overexpressed in human hepatocellular cancer and may serve as a new cytotoxic target. Clin Cancer Res; 18(21); 5902–10. ©2012 AACR.
Bipolar Mixed States: An International Society for Bipolar Disorders Task Force Report of Symptom Structure, Course of Illness, and Diagnosis
Authors: Alan C. Swann, Beny Lafer, Giulio Perugi, Mark A. Frye, Michael Bauer, Won-Myong Bahk, Jan Scott, Kyooseob Ha, Trisha Suppes
Journal: American Journal of Psychiatry (2012)

Objective Episodes of bipolar disorder are defined as depressive or manic, but depressive and manic symptoms can combine in the same episode. Coexistence or rapid alternation of depressive and manic symptoms in the same episode may indicate a more severe form of bipolar disorder and may pose diagnostic and treatment challenges. However, definitions of mixed states, especially those with prominent depression, are not well established. Method The authors performed literature searches for bipolar disorder, multivariate analyses, and the appearance of the terms "mixed" in any field; references selected from the articles found after the search were combined after a series of conferences among the authors. Results The authors reviewed the evolution of the concept of mixed states and examined the symptom structure of mixed states studied as predominantly manic, predominantly depressive, and across both manic and depressive episodes, showing essentially parallel structures of mixed states based on manic or depressive episodes. The authors analyzed the relationships between mixed states and a severely recurrent course of illness in bipolar disorder, with early onset and increased co-occurring anxiety-, stress-, and substance-related disorders, and they used this information to derive proposed diagnostic criteria for research or clinical use. Conclusions The definitions and properties of mixed states have generated controversy, but the stability of their characteristics over a range of clinical definitions and diagnostic methods shows that the concept of mixed states is robust. Distinct characteristics related to the course of illness emerge at relatively modest opposite polarity symptom levels in depressive or manic episodes.
No evidence of a specific adaptation
Authors: Ilkka Pyysiäinen
Journal: Behavioral and Brain Sciences (2006)

Bering's findings about the mental representation of dead agents are important, although his opposition between “endemic” and “cultural” concepts is misleading. Endemic and cultural are overlapping, not exclusive categories. It is also diffcult to see why reasoning about the dead would require a specific cognitive mechanism. Bering presents no clear evidence for the claim that the postulated mechanism is an adaptation.
High-dose radioimmunotherapy versus conventional high-dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular non-Hodgkin lymphoma: a multivariable cohort analysis
Authors: Ajay K. Gopal, Theodore A. Gooley, David G. Maloney, Stephen H. Petersdorf, Janet F. Eary, Joseph G. Rajendran, Sharon A. Bush, Lawrence D. Durack, Jane Golden, Paul J. Martin, Dana C. Matthews, Frederick R. Appelbaum, Irwin D. Bernstein, Oliver W. Press
Journal: Blood (2003)
Expression of Cyclooxygenase-1 and Cyclooxygenase-2 in Human Breast Cancer
Authors: D Hwang, D Scollard, J Byrne, E Levine
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: Numerous studies have demonstrated that the levels of prostaglandins are greater in various cancers, including breast cancer and colon cancer, than in normal tissues. In particular, the inducible form of cyclooxygenase (COX), the rate-limiting enzyme in prostaglandin biosynthesis, is overexpressed in colon tumors. Epidemiologic studies have demonstrated that the use of aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs) can reduce the risk of colon cancer and, to a lesser extent, the risk of breast cancer. NSAIDs are known to inhibit COX, suggesting that the beneficial effect of NSAIDs in colon cancer may be related to COX overexpression in this disease. This possibility led us to ask whether COX is also overexpressed in breast cancers. Methods: Surgical specimens from 44 patients with breast cancer who had undergone lumpectomy or mastectomy were analyzed by immunoblot analysis and immunohistochemical analysis to determine the expression profile of the constitutively expressed form of cyclooxygenase (COX-1) and the inducible form (COX-2); the specimens from 14 patients included normal breast tissue. Results: Expression of COX-1 protein was substantially higher in 30 of 44 tumor samples than in any of the 14 normal tissue specimens. Immunoblot analysis revealed extremely high levels of COX-2 protein in two tumor samples. Immunohistochemical staining of specimens that expressed COX-1 and/or COX-2 revealed that COX-1 was localized in stromal cells adjacent to the tumor but not in tumor cells. In contrast, COX-2 was localized primarily in tumor cells but also appeared in stromal cells. Conclusion: Our results suggest that overexpression of COX may not be unique to colon cancer and may be a feature common to other epithelial tumors.
Endoscopic transmission of hepatitis B virus.
Authors: G G Birnie, E M Quigley, G B Clements, E A Follet, G Watkinson
Journal: Gut (1983)

Although transmission of hepatitis B virus (HBV) infection has long been recognised as a potential hazard of gastrointestinal endoscopy, there has been little evidence of direct patient-to-patient cross-infection after such procedures. We wish to report a case of type B viral hepatitis almost certainly acquired at endoscopy from an instrument sterilised in the conventional manner, but which had been used on the previous day on a patient with bleeding oesophageal varices who was incubating type B viral hepatitis.
La sclerodermie (Scleroderma)
Authors: A. St. J. Dixon
Journal: Annals of the Rheumatic Diseases (1973)

complement and lysosomes, Selye's Adaptation Syn- drome is described, details of the mechansim by which probenecid produces its uricosuric effect are given, an honourable mention is made of intravenous nitrogen mustard in the treatment of rheumatoid disease, and chondrocalcinosis receives its acknowledgement.It is probably true that American patients are more medically sophisticated than English medical students.But one winces to read that 'fibrositis is an inflammation in the
Homozygosity for DNASE2 single nucleotide polymorphisms in the 5′-regulatory region is associated with rheumatoid arthritis
Authors: M Rossol, M Pierer, S Arnold, G Keyßer, H Burkhardt, C Baerwald, U Wagner
Journal: Annals of the Rheumatic Diseases (2008)

Objectives: To analyse the distribution of single nucleotide polymorphisms (SNPs) in the 5′-regulatory region of the DNASE2 gene, in patients with rheumatoid arthritis (RA) and healthy controls. Methods: A total of 906 patients with RA and 878 healthy controls were genotyped. All subjects were of German Caucasian origin. Genotyping was performed by real-time polymerase chain reaction technology, using a TaqMan 5′-allele discrimination assay. Results: In the initial analysis of unrelated case–control samples, three DNASE2 SNP alleles in the 5′-regulatory region were significantly more frequent in patients with RA than in healthy controls. The strongest association was found for the −1066G allele (33.5% vs 27.2%, p = 0.007, odds ratio (OR) = 1.34). Homozygosity for this allele (genotype GG) resulted in an additional increase in disease susceptibility (12.5% vs 6.2%, OR = 2.17). The association was replicated in a second case–control series of 483 patients with RA from two German multicentre studies and 474 controls. The association of DNASE2 −1066 GG homozygosity with RA was limited to rheumatoid factor-positive disease, but was not influenced by the presence of anti-cyclic citrullinated peptide or antinuclear antibodies. Similarly, the presence or absence of the HLA-DRB1 shared epitope or the RA-associated PTPN22 allele had no influence on this association. Conclusions: The association of SNPs in the 5′-regulatory region of the DNA degrading enzyme DNASE2 with RA implies a role for this enzyme in the pathogenesis of this autoimmune disease.
Altered Metastatic Behavior of Human Breast Cancer Cells after Experimental Manipulation of Matrix Metalloproteinase 8 Gene Expression
Authors: Valerie Montel, Jeanine Kleeman, Dianne Agarwal, Dominic Spinella, Kanji Kawai, David Tarin
Journal: Cancer Research (2004)

Previous work in our laboratory led to the cloning, from the same parent tumor cell line (MDA-MB-435), of two human breast cancer cell lines (M-4A4 and NM-2C5) with opposite metastatic phenotypes. Additional investigations revealed that the nonmetastatic cell line NM-2C5 overexpressed the neutrophil collagenase, matrix metalloproteinase (MMP)-8, relative to its partner. Because other studies have implicated the MMP family in promoting tumor metastasis, we investigated the apparently paradoxical expression of MMP-8 in these cell lines. By genetic engineering, we inverted its relative levels of expression in the two partners and studied the effects on the behavior of the tumors that they generated in athymic mice. Knock-down of expression in NM-2C5 cells by transduction with a sequence encoding a specific ribozyme and overexpression of MMP-8 in M-4A4 cells by retroviral transduction both strikingly changed metastatic performance in opposite directions, indicating that this gene plays a role in the regulation of tumor metastasis.
Prevention of Laceration of the Perinaeum in Primiparae
Authors: J. A. Temple
Journal: BMJ (1886)

lfl rf and she most peremptorily dsired that t4e subject shouldc not be metioned again.The tempertur that night rose to 100-lahr., and the pulse to 98, which I attributed to excitement, for both subsided to their fonner rtes before the next momrig.From this moment the injections, which hd done nothing but wash the rectum, were discontinued, and the patient ver grdually and almost imperceptibly nk, until her death, which took place on Sunday, October 11th, 1885, at 11 o'clock Pm., nineteen ant a half
Random and block copolymers of bioreducible poly(amido amine)s with high- and low-basicity amino groups: Study of DNA condensation and buffer capacity on gene transfection
Authors: Chao Lin, Zhiyuan Zhong, Martin C. Lok, Xulin Jiang, Wim E. Hennink, Jan Feijen, Johan F.J. Engbersen
Journal: Journal of Controlled Release (2007)