tbuckley/cabot-search huggingface dataset:
Structure of the gene coding for the alpha polypeptide chain of the human complement component C4b-binding protein.
Authors: S Rodriguez de Cordoba, P Sanchez-Corral, J Rey-Campos
Journal: The Journal of Experimental Medicine (1991)

The human gene coding for the 70-kD polypeptide of the complement regulatory component C4b-binding protein (C4BP alpha) spans over 40 kb of DNA and is composed of twelve exons. Upon transcription in liver, or in Hep-G2 cells, this gene produces a single transcript of 2,262 nucleotides, excepting the poly A tail, that presents an unusually long 5' untranslated region (5' UTR) of 223 nucleotides. The C4BP alpha gene is organized as follows: the first exon codes for the first 198 nucleotides of the 5' UTR. It is separated by a large intron from the second exon including the remaining of the 5' UTR and the coding region for the signal peptide. Each of the eight 60-amino acid repeats (short consensus repeats [SCRs]) that compose the C4BP alpha polypeptide chain is encoded by a single exon, except for the second SCR, which is split in two exons. At the 3' end of the C4BP alpha gene, the twelfth exon codes for the COOH-terminal 57 amino acids of the mature protein, which have no similarities to the SCRs, and the 245 nucleotides of the 3' UTR. Examination of the nucleotide sequence of the first exon revealed an interesting characteristic, strongly suggesting that this exon may specify a functional domain of the C4BP alpha transcript. It includes two in-phase ATG codons, in a different frame respect to that coding the C4BP alpha polypeptide, followed by an in-frame termination codon, also within the first exon. Comparison between mouse and human C4BP alpha transcripts indicates conservation of this structure within the 5' UTR. C4BP is expressed in the liver and is an acute phase protein. A computer search of the genomic sequences upstream the transcription start site demonstrates the presence of potential cis-acting regulatory elements similar to those found in the promoters of other liver-expressed and/or acute phase genes.
Outcomes in low-risk babies treated with half-dose chemotherapy according to the Third National Wilms' Tumor Study.
Authors: B W Corn, J W Goldwein, I Evans, G J D'Angio
Journal: Journal of Clinical Oncology (1992)

PURPOSE To determine whether the 50% dose reduction of all chemotherapeutic agents recommended for babies (less than or equal to 12 months of age) by the Third National Wilms' Tumor Study (NWTS-3) produced acceptable toxicity without sacrificing any survival benefit. MATERIALS AND METHODS The 365 babies enrolled in NWTS-3 had tumors of varying histologies and stages. The present analysis was restricted to the 256 infants who had tumors of favorable histology, were free of metastasis at diagnosis, and received treatment according to NWTS-3 guidelines. RESULTS Despite the recommended attenuation of drug doses observed in 75% of the chemotherapy courses received, outcomes for these babies were comparable to those obtained in older children given full doses of chemotherapy. Four-year survival rates for 256 babies with stages I (n = 199), II (n = 38), and III (n = 19) favorable-histology tumors were 96%, 95%, and 90%, respectively. The figures for 498 stage I, 342 stage II, and 373 stage III older children with favorable-histology lesions were 92%, 94%, and 91% in that order. There were no deaths from hematologic toxicity or infection among babies who received half-dose chemotherapy. The death rates for their older NWTS-3 counterparts was 1%. CONCLUSION Less aggressive therapies advocated for babies in NWTS-3 provide acceptable levels of morbidity without compromising the excellent results previously reported for low-risk patients of all ages.
Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return
Authors: Hannah Störch, Birgit Zimmermann, Bastian Resch, Lars-Oliver Tykocinski, Babak Moradi, Patrick Horn, Ziya Kaya, Norbert Blank, Stefan Rehart, Marc Thomsen, Hanns-Martin Lorenz, Elena Neumann, Theresa Tretter
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Cross-talk between synovial fibroblasts (SF) and immune cells is suggested to play a crucial role in inflammation and chronification of rheumatoid arthritis (RA). The contribution of B cells in this process is poorly defined. <h3>Methods</h3> Here, primary B cells from healthy donors were polyclonally activated and cocultured with SF of non-synovitic origin from patients with osteoarthritis. <h3>Results</h3> In B–SF cocultures the concentrations of interleukin 6 (IL-6) and IL-8 increased manifold compared with single cultures even under physical separation and remained stable for several days after B-cell removal. Intracellular staining confirmed SF as key producers of IL-6 and IL-8, and B cells as main producers of tumour necrosis factor alpha (TNFα) and IL-1ß. Blocking experiments with a combination of anti-TNFα-antibodies and rIL-1RA significantly reduced SF cytokine production by up to 90%, suggesting that B-cell-derived TNFα and IL-1ß were crucial mediators of SF activation. Interestingly, B-cell cytokine production, CD25 expression and proliferation decreased in cocultures by at least 50%, demonstrating a negative regulatory loop towards the activated B cells. Inhibition of activin receptor-like kinase 5, a crucial component of the tumour growth factor ß (TGFß) signalling pathway, partly restored B-cell proliferation, suggesting a contribution of SF-derived TGFß in B-cell suppression. Besides cytokines, B-cell-activated SF also upregulated secretion of matrix metalloproteases such as MMP-3, thereby acquiring potential tissue destructive properties. This was confirmed by their invasion into human cartilage in the severe combined immunodeficiency mouse fibroblast invasion model in vivo. <h3>Conclusions</h3> Interaction with activated B cells leads to conversion of non-arthritic SF into SF with a proinflammatory and aggressive RA-like phenotype, thereby suggesting a new, so far unrecognised role for B cells in RA pathogenesis.
Risk of familial classical Hodgkin lymphoma by relationship, histology, age, and sex: a joint study from five Nordic countries
Authors: Elham Kharazmi, Mahdi Fallah, Eero Pukkala, Jörgen H. Olsen, Laufey Tryggvadottir, Kristina Sundquist, Steinar Tretli, Kari Hemminki
Journal: Blood (2015)
Multiplexed diagnostic biomarker detection and analysis platform for Qdots™ in FFPE samples
Authors: Anne Carpenter, Linda K. Samadzadeh, Casey Kernag, Ned Haubein, Hiro Nitta, John Hurley, Julie Chatigny, Scott Lett, Thomas M. Grogan, Phillip Miller, Gary A. Pestano
Journal: Clinical Cancer Research (2006)

A103  Analyses of candidate diagnostic biomarkers in intact tissues represent a critical component in the development of therapeutics. In oncology drug development, entire signaling pathways are profiled with a variety of high-throughput techniques. However, in the field of histology, tissue-based diagnostics (IHC and ISH) are generally dominated by single- or dual-analyte tests. In addition, manual methods for slide processing promote inconsistency, are labor demanding and time-consuming. Ventana Medical Systems has developed automated platforms for conducting IHC and ISH in widely available formalin-fixed paraffin-embedded (FFPE) tissues. These instruments enable rapid evaluation and validation of candidate biomarkers in a high-throughput format. Further, advances in key detection technologies, including Quantum Dots (QDots™) conjugates, hyper-spectral imaging and data analysis platforms, provide a growing set of tools that better complement early biomarker discovery. We have applied these methods to monitor biomarkers used for stratification, and as surrogates of drug response, in growth-factor signaling pathways. We use these examples to demonstrate the utility of coupling high-throughput, automated histochemistry with quantifiable, multiplexed biomarkers. Importantly, these findings are reported for individual cells in their true anatomical context.
Three versus five years of maintenance therapy are equivalent in childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group.
Authors: D R Miller, S L Leikin, V C Albo, H Sather, G D Hammond
Journal: Journal of Clinical Oncology (1989)

Childrens Cancer Study Group protocol 141 (CCG-141), a randomized trial, was designed in part to compare 3 v 5 years of maintenance therapy, to evaluate the role of late reinduction, and to identify factors that predict relapse after 3 years of continuous complete remission (CCR) in acute lymphoblastic leukemia (ALL). Of 880 patients entered on study, 827 (94%) achieved complete remission and 499 (56.7%) were in CCR after 3 years of maintenance therapy. Boys were required to have negative testicular biopsies before randomization. A total of 481 patients were eligible for the duration of therapy phase of the study. Of the 310 (64.4%) randomly assigned patients, 101 were entered on regimen A: discontinue therapy; 105 on regimen B: reinduction for 4 weeks, then discontinue therapy; and 104 on regimen C: continue maintenance therapy for 2 more years, then discontinue. After a median follow-up of over 72 months, no significant differences in disease-free survival (DFS) or survival were noted in the three regimens. At 6 years from randomization, 93.0%, 89.1%, and 89.1% of patients on regimens A, B, and C, respectively, remained in CCR. Isolated CNS or overt testicular relapses were not significantly different in any of the study regimens. Isolated testicular relapse after a negative biopsy occurred in only two of 137 randomized males (1.5%). DFS (P = .10) and survival (P = .83) were not significantly different for all boys and girls randomized to regimens A, B, or C. The relapse rate was higher in boys than in girls randomized to discontinue therapy (11% v 4%), but the difference was not statistically significant (P = .14). Except for the presence of occult testicular leukemia (TL) in males, no other factors were identified that predicted for adverse events after 3 years of CCR. We conclude that prolongation of maintenance therapy beyond 3 years does not improve survival or decrease the risk of relapse.
Scientists Probe Role of Vitamin D
Authors: Catherine Meyer
Journal: JAMA (2004)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Sequential use of biologics in the treatment of moderate-to-severe plaque psoriasis
Authors: J. Leman, A.D. Burden
Journal: British Journal of Dermatology (2012)

A number of biologic agents, including the tumour necrosis factor (TNF) antagonists etanercept, adalimumab and infliximab, and the interleukin (IL)-12/IL-23 antagonist ustekinumab, are available for the treatment of moderate-to-severe plaque psoriasis in the U.K. Currently, the selection of the first biologic, and the choice of sequential biologics in the event of efficacy/tolerability concerns, is made using a limited evidence base. The efficacy of biologics, the potential mechanisms of primary and secondary failure and the evidence for sequencing therapy among TNF antagonists and between TNF antagonists and IL-12/IL-23 blockade are reviewed. As psoriasis biologics registers begin to produce long-term safety and efficacy data, therapy decisions in plaque psoriasis may become more objective, and it may be possible to individualize treatment based on clinical or pharmacogenetic information.
Pertussis in young infants: apnoea and intra-familial infection
Authors: J Raymond, J-B Armengaud, C Cosnes-Lambe, M Chalumeau, E Bosdure, H Reglier-Poupet, M-J El Hajje, J-L Iniguez, F Moulin, C Poyart, D Gendrel
Journal: Clinical Microbiology and Infection (2006)
Abstract 887: Proteome scale identification of autoantibody biomarkers in colorectal cancer
Authors: Gokhan Demirkan, Leah Soderberg, Garrick Wallstrom, Emily Szeto, Kristi Barker, Jie Wang, Joshua LaBaer, Noralane M. Lindor, Ji Qiu
Journal: Cancer Research (2014)

Abstract It is widely appreciated that early detection is the key to making inroads in the fight against cancers. Despite the availability of endoscopic screening, compliance is poor. The diagnosis of CRC is often made in advanced stages, and the consequence is a dismal 50% five year survival across all CRC. There is urgent need for biomarkers with performance that can meet the need of early diagnosis. Like most cancers, colorectal cancers (CRCs) express tumor antigens that can induce humoral immune response. The identification of the autoantibodies against tumor antigens may facilitate early diagnosis of CRC. The goal for this pilot project was to demonstrate the feasibility of discovering autoantibody biomarkers for colorectal cancer using Nucleic Acid Programmable Protein Arrays (NAPPA). Autoantibodies in serum samples collected from 40 patients with DNA mismatch repair proficient colorectal cancer who had died of their cancer within 18 months of their blood draw and from 40 age-gender matched healthy controls were profiled on NAPPA arrays with randomly selected 2000 human protein. The fact that p53, a tumor antigen that has been previously reported to be related to various cancers including CRC, was one of the top candidates based on the statistical analysis demonstrates the validity of our discovery platform. Besides p53, thirty-one candidate antigens were identified to have sensitivity greater than or equal to 25% at 95% specificity and fifty-one candidate antigens had an area under the ROC curve (AUC) equal to or greater than 0.6. Validation of the combined 83 unique genes selected based on these two different data analysis methods in an independent sample set in a blind fashion is on-going. This pilot study using late stage cancer samples demonstrates the feasibility and power of an immunoproteomics study using protein arrays. This approach may rapidly lead to identification of markers that could have relevance in monitoring disease progression as well as in early cancer detection. Citation Format: Gokhan Demirkan, Leah Soderberg, Garrick Wallstrom, Emily Szeto, Kristi Barker, Jie Wang, Joshua LaBaer, Noralane M. Lindor, Ji Qiu. Proteome scale identification of autoantibody biomarkers in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 887. doi:10.1158/1538-7445.AM2014-887
An Experimental Animal Model for the Study of Human Scirrhous Carcinoma 2
Authors: Jose Russo, Charles McGrath, Irma H. A. Russo
Journal: JNCI Journal of the National Cancer Institute (1976)

Scirrhous-like carcinomas were induced by the inoculation of cloned mouse mammary carcinoma cells into the cleared fat pads of BALB/c mice. The inoculated cells induced palpable tumors in 100% of the animals within 60 days. The epithelial cells in vivo grew in rows and clusters and were attached by short developing desmosomes. Microvilli and organelles were scarce; intracisternal type A particles were observed in all the epithelial cells. Carcinoma cells invaded the dermis and muscle. The stroma was formed by morphologically normal fibroblasts and large masses of collagen. No virus particles were observed budding from the epithelial cell surface or in the stromal fibroblasts. The similarities between the scirrhous-like carcinoma in BALB/c mice and the human scirrhous carcinoma suggest this animal system as a model for the study of the human disease.
Clinical Significance of Apoptosis-Related Factors <i>p53</i>, <i>Mdm2</i>, and <i>Bcl-2</i> in Advanced Ovarian Cancer
Authors: M. Baekelandt, G. B. Kristensen, J. M. Nesland, C. G. Tropé, R. Holm
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To investigate the prognostic and predictive relevance of p53, Mdm2, and Bcl-2 protein expression in advanced ovarian cancer. PATIENTS AND METHODS: Tumor biopsy specimens from 185 consecutive and homogeneously treated patients with stage III ovarian cancer were examined immunohistochemically for expression of p53, Mdm2, and Bcl-2 proteins. Both uni- and multivariate analyses of prognostic factors were performed, and correlations with classical clinicopathologic parameters and response to chemotherapy were examined. RESULTS: Forty-nine percent and 39% of cases were considered positive for expression of p53 and Bcl-2, respectively. p53 expression was correlated with loss of histologic differentiation and Bcl-2 expression with smaller residual disease after primary surgery. The absence of p53 expression and the presence of Bcl-2 expression were associated with improved survival but not with overall response to chemotherapy, although a positive correlation was found between Bcl-2 expression and the possibility of obtaining a completely negative second-look laparotomy. Expression of Mdm2 was found in 17% of cases. Although correlations were found with known favorable clinicopathologic factors, no prognostic significance was demonstrated for Mdm2 in this patient group. In multivariate analyses, histologic type, degree of differentiation, residual disease, and p53 alone or combined with Bcl-2 expression were found to be independently associated with overall survival. CONCLUSION: p53, and especially the combination of p53 and Bcl-2 expression data, represents an independent prognostic predictor in stage III ovarian cancer. Despite their role in the apoptotic process, p53 and Bcl-2 do not seem to be clinically useful predictors of response to combination chemotherapy in these patients.
Stratifin accelerates progression of lung adenocarcinoma at an early stage
Authors: Aya Shiba-Ishii, Yunjung Kim, Toshihiro Shiozawa, Shinji Iyama, Kaishi Satomi, Junko Kano, Shingo Sakashita, Yukio Morishita, Masayuki Noguchi
Journal: Molecular Cancer (2015)

Adenocarcinoma in situ (AIS) of the lung has an extremely favorable prognosis. However, early but invasive adenocarcinoma (eIA) sometimes has a fatal outcome. We had previously compared the expression profiles of AIS with those of eIA showing lymph node metastasis or a fatal outcome, and found that stratifin (SFN, 14-3-3 sigma) was a differentially expressed gene related to cell proliferation. Here, we performed an in vivo study to clarify the role of SFN in initiation and progression of lung adenocarcinoma. Suppression of SFN expression in A549 (a human lung adenocarcinoma cell line) by siSFN significantly reduced cell proliferation activity and the S-phase subpopulation. In vivo, tumor development or metastasis to the lung was reduced in shSFN-transfected A549 cells. Moreover, we generated SFN-transgenic mice (Tg-SPC-SFN+/−) showing lung-specific expression of human SFN under the control of a tissue-specific enhancer, the SPC promoter. We found that Tg-SPC-SFN+/− mice developed lung tumors at a significantly higher rate than control mice after administration of chemical carcinogen, NNK. Interestingly, several Tg-SPC-SFN+/− mice developed tumors without NNK. These tumor cells showed high hSFN expression. These results suggest that SFN facilitates lung tumor development and progression. SFN appears to be a novel oncogene with potential as a therapeutic target.
Long-term exposure to TNF-α and IL-1β reduces vitamin D-mediated expression of the antimicrobial peptide hCAP18/LL-37 in primary bronchial epithelial cells (PBEC)
Authors: Jasmijn Schrumpf, Renate Verhoosel, Pieter Hiemstra
Journal: European Respiratory Journal (2013)

Vitamin D is a regulator of immunity and inflammation, and vitamin D deficiency is associated with chronic obstructive pulmonary disease (COPD). Its circulating metabolite 25D3 increases epithelial expression of hCAP18/LL-37 via local conversion by CYP27B1 into the active 1,25D3. Concurrently, 25D3 induces negative feedback by increasing CYP24A1, which degrades 1,25D3. We hypothesized that long-term exposure of PBEC to inflammatory stimuli such as TNF-α and IL-1β may alter 25D3-metabolism and expression of hCAP18/LL-37.  PBEC were cultured at the air-liquid interface in presence or absence of TNF-α/IL-1β for 14 days and subsequently exposed to 25D3 for 24-48 hrs. Expression of hCAP18/LL-37, CYP27B1, CYP24A1 and vitamin D receptor (VDR) was quantified by qPCR, whereas hCAP18/LL-37 and CYP24A1 protein were also assessed by Western blot.  TNF-α/IL-1β reduced 25D3-mediated hCAP18/LL-37 expression compared to control by 3.4 fold (p = 0.014), which was confirmed by Western blot analysis. Expression of VDR and CYP27B1 was not affected, whereas CYP24A1 was 9.9 fold increased by TNF-α/IL-1β compared to unstimulated PBEC (p = 0.007). After 25D3-stimulation to increase CYP24A1, CYP24A1 mRNA and protein were still elevated in TNF-α/IL-1β exposed cells, although this difference did not reach statistical significance.  TNF-α/IL-1β alters 25D3-metabolism resulting in decreased expression of hCAP18/LL-37. This may indicate that supplementation with vitamin D is not always effective in COPD patients, where it might be degraded by CYP24A1. The mechanism underlying the induction of CYP24A1 by TNF-α/IL-1β needs to be further elucidated.
A dose of humility
Authors: Fiona Godlee
Journal: BMJ (2015)

Cells can communicate with each other by emitting diffusible signaling molecules into the surrounding environment. However, simple diffusion is slow. Even small molecules take hours to diffuse millimeters away from their source, making it difficult for thousands of cells to coordinate their activity over millimeters, as happens routinely during development and immune response. Moreover, simple diffusion creates shallow, Gaussian-tailed concentration profiles. Attempting to move up or down such shallow gradients – to chemotax – is a difficult task for cells, as they see only small spatial and temporal concentration changes. Here, we demonstrate that cells utilizing diffusive relays, in which the presence of one type of diffusible signaling molecule triggers participation in the emission of the same type of molecule, can propagate fast-traveling diffusive waves that give rise to steep chemical gradients. Our methods are general and capture the effects of dimensionality, cell density, signaling molecule degradation, pulsed emission, and cellular chemotaxis on the diffusive wave dynamics. We show that system dimensionality – the size and shape of the extracellular medium and the distribution of the cells within it – can have a particularly dramatic effect on wave initiation and asymptotic propagation, and that these dynamics are insensitive to the details of cellular activation. As an example, we show that neutrophil swarming experiments exhibit dynamical signatures consistent with the proposed signaling motif. Interpreted in the context of these experiments, our results provide insight into the utility of signaling relays in immune response.