tbuckley/cabot-search huggingface dataset:
Malignant B Cells at the Helm in Follicular Lymphoma
Authors: Stephen M. Ansell
Journal: Journal of Clinical Oncology (2013)

Lymph nodes in patients with follicular lymphoma contain not just malignant B cells but normal immune cells including T cells, intratumoral macrophages, monocytes, dendritic cells, and natural-killer cells. Recent data have shown that the tumor microenvironment plays an important role in the outcome of patients with non-Hodgkin lymphoma and that the composition of the microenvironment has prognostic significance for patients with follicular lymphoma. It is becoming increasingly clear that, although the tumor microenvironment supports the growth and survival of malignant B cells, the malignant B cells also define the constitution of the tumor microenvironment. Malignant B cells from biopsies of tumors in patients with lymphoma do not play a passive role but instead clearly drive the differentiation and function of intratumoral T cells (Fig 1). Malignant B cells have been found to express multiple ligands responsible for inducing regulatory T cells (Treg cells) and suppressing other intratumoral effector cells. Lymphoma B cells have been found to express CD70, and CD70/CD27 signaling promotes the induction of FoxP3positive Treg cells. 2 Malignant cells also express PD-L1, and interactions with PD1 expressed on intratumoral immune cells results in immune suppression. B cells from lymphoma biopsies have been found to secrete chemokines and cytokines responsible for further immune suppression. CCL22 secreted by lymphoma B cells is involved in chemotaxis and migration of intratumoral Treg cells that express the receptor CCR4, which results in recruitment of Treg cells to the tumor microenvironment. Treg cells recruited to sites of lymphoma have been shown to suppress both effector CD8 T cells and intratumoral CD4 cells. Cytokines and chemokines such as interleukin 12 and CXCL10 produced by the malignant B cells also have a role in regulating effector T-cell function. However, interleukin 12 has been shown to induce T-cell exhaustion, resulting in ineffective T cells that are unable to proliferate or lyse target B cells. Overall, malignant B cells skew the T-cell balance within lymph nodes promoting Treg cells and inhibiting effector T cells or TH17 cells. 9
Genotyping Lung Cancer Is an Investment in the Future
Authors: Christopher G. Azzoli, Jeffrey Engelman, Panos Fidias, Justin F. Gainor, Rebecca S. Heist, Elizabeth B. Lamont, Inga T. Lennes, Rachel P. Rosovsky, Lecia V. Sequist, Alice Tsang Shaw, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2014)

TO THEEDITOR:Intheircost-effectivenessanalysisof ALKtesting and crizotinib treatment, Djalalov et al 1 put a price tag on this emerging standard of care to shed light on its sustainability in a world of rising health care costs and limited resources. 2 Although we favor prudent measures that decrease health care costs, we believe it is important to distinguish money wasted from money invested. We believe that detecting and treating ALK-positive lung cancer is part of a new paradigm that has significantly improved cancer care and, as such, deserves our investment and advocacy. It is especially challenging to assess proximal costs when the future payoff is immeasurable. This is such a fast-moving field that the single, static, Markov model that the authors used is already out of date. The authors observe that the major driver of cost effectiveness is drug price. 1 To foster cost effectiveness, they point out the need for increased drug effectiveness, cheaper molecular testing, and lower drugprices.Weagree.Fortunately,thesethreetrendsaretakingshape. Discoveryhasaccelerated,andtheUSFoodandDrugAdministration hasgrantedbreakthroughtherapydesignationstatustotwonewALK inhibitors, ceritinib (LDK378) and alectinib (RO5424802), with at least seven other ALK inhibitors in early-phase testing. 3,4 The efficacy observed in phase I studies of these new drugs, plus the favorable survival and dramatic quality-of-life improvement demonstrated in a recently published phase III study of crizotinib, 5 indicate that the utilityestimatesusedinthisinitialcostanalysisarealreadyoutofdate. It is our hope that competition in the marketplace and limits on exclusive production based on patent law will ultimately bring down the price of these drugs over time. Regarding molecular testing, we find the representation in the modelofidentifyingpatientswith ALK-positivelungcancerbyDjala
Response to Comment on: Bardenheier et al. Variation in Prevalence of Gestational Diabetes Mellitus Among Hospital Discharges for Obstetric Delivery Across 23 States in the United States. Diabetes Care 2013;36:1209–1214
Authors: Barbara Bardenheier, Adolfo Correa, Henry S. Kahn, Karen Kirtland, Linda Geiss
Journal: Diabetes Care (2013)

We thank Dr. Grant (1) for his interest in our study (2). Dr. Grant pointed out that our analysis overlooked any discussion of the role of vitamin D in the variability of gestational diabetes mellitus (GDM) prevalence across states. Although we might have speculated about a possible role for vitamin D in the regional variability of GDM prevalence, we chose not to for several reasons. First, state-level data available from the Healthcare Cost and Utilization Project (HCUP) are insufficient to fully assess potential sunlight exposure before or during pregnancy …
Activation-induced cytidine deaminase acts as a mutator in <i>BCR-ABL1</i>–transformed acute lymphoblastic leukemia cells
Authors: Niklas Feldhahn, Nadine Henke, Kai Melchior, Cihangir Duy, Bonaventure Ndikung Soh, Florian Klein, Gregor von Levetzow, Bernd Giebel, Aihong Li, Wolf-Karsten Hofmann, Hassan Jumaa, Markus Müschen
Journal: The Journal of Experimental Medicine (2007)

The Philadelphia chromosome (Ph) encoding the oncogenic BCR-ABL1 kinase defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. ALL cells are derived from B cell precursors in most cases and typically carry rearranged immunoglobulin heavy chain (IGH) variable (V) region genes devoid of somatic mutations. Somatic hypermutation is restricted to mature germinal center B cells and depends on activation-induced cytidine deaminase (AID). Studying AID expression in 108 cases of ALL, we detected AID mRNA in 24 of 28 Ph(+) ALLs as compared with 6 of 80 Ph(-) ALLs. Forced expression of BCR-ABL1 in Ph(-) ALL cells and inhibition of the BCR-ABL1 kinase showed that aberrant expression of AID depends on BCR-ABL1 kinase activity. Consistent with aberrant AID expression in Ph(+) ALL, IGH V region genes and BCL6 were mutated in many Ph(+) but unmutated in most Ph(-) cases. In addition, AID introduced DNA single-strand breaks within the tumor suppressor gene CDKN2B in Ph(+) ALL cells, which was sensitive to BCR-ABL1 kinase inhibition and silencing of AID expression by RNA interference. These findings identify AID as a BCR-ABL1-induced mutator in Ph(+) ALL cells, which may be relevant with respect to the particularly unfavorable prognosis of this leukemia subset.
β4 Integrin Is a Transforming Molecule that Unleashes Met Tyrosine Kinase Tumorigenesis
Authors: Andrea Bertotti, Paolo M. Comoglio, Livio Trusolino
Journal: Cancer Research (2005)

Abstract Cell multiplication in the absence of integrin-derived adhesive signals (anchorage-independent growth) is the phenotypic hallmark of neoplastic transformation. Therefore, the frequently observed up-regulation of some integrins in tumors has been interpreted as an epiphenomenon and not as a causative factor of oncogenic conversion. β4 integrin stimulates proliferation and survival of epithelial cells and is overexpressed in human carcinomas, often in concomitance with up-regulation of the Met tyrosine kinase receptor for hepatocyte growth factor. Met is not endowed with transforming ability but can exploit the β4 cytoplasmic tail as a substrate/adaptor for amplification of mitogenic and antiapoptotic responses, independently of cell adhesion. Here, we show that overexpression of β4 is sufficient to transform rodent fibroblasts, enhances anchorage-independent growth of breast carcinoma cells, and induces tumorigenesis in nude mice; conversely, RNA interference–mediated depletion abrogates the transformed phenotype of neoplastic cells. These autonomous oncogenic properties are dramatically exacerbated upon Met coexpression, suggesting that the integrin can instigate the latent tumorigenic potential of the kinase. A β4 nonadhesive variant still cooperates with Met for cellular transformation, confirming the adhesion-independent function of β4 in magnification of Met biological effects. Conversely, a β4 signaling-incompetent mutant that cannot be efficiently tyrosine phosphorylated by Met and displays reduced ability to activate phosphatidylinositol 3-kinase–dependent and Ras-dependent pathways aborts transformation. Our findings define β4 as a signaling accomplice (a “servo-oncogene”) of tyrosine kinase proto-oncogenes in primary carcinogenesis, evoke an unorthodox function for a prototypic adhesion molecule in the positive regulation of anchorage-independent growth, and suggest the use of β4 as a target for anticancer therapy.
Interleukin 15 Controls both Proliferation and Survival of a Subset of Memory-Phenotype CD8+ T Cells
Authors: Adam D. Judge, Xiaohong Zhang, Hideki Fujii, Charles D. Surh, Jonathan Sprent
Journal: The Journal of Experimental Medicine (2002)

Previous work has shown that memory-phenotype CD44hi CD8+ cells are controlled by a cytokine, interleukin (IL)-15. However, the dependency of CD44hi CD8+ cells on IL-15 is partial rather than complete. Here, evidence is presented that CD44hi CD8+ cells comprise a mixed population of IL-15–dependent and IL-15–independent cells. The major subset of CD122hi CD44hi CD8+ cells is heavily dependent on IL-15 by three different parameters, namely (1) “bystander” proliferation induced via IFN-induced stimulation of the innate immune system, (2) normal “background” proliferation, and (3) T cell survival; IL-15 dependency is most extreme for the Ly49+ subset of CD122hi CD44hi CD8+ cells. In contrast to CD122hi cells, the CD122lo subset of CD44hi CD8+ cells is IL-15 independent; likewise, being CD122lo, CD44hi CD4+ cells are IL-15 independent. Thus, subsets of memory-phenotype T cells differ radically in their sensitivity to IL-15.
Different Impact of Excision Repair Cross-Complementation Group 1 on Survival in Male and Female Patients With Inoperable Non–Small-Cell Lung Cancer Treated With Carboplatin and Gemcitabine
Authors: Bente Holm, Anders Mellemgaard, Torsten Skov, Birgit Guldhammer Skov
Journal: Journal of Clinical Oncology (2009)

Purpose The excision repair cross-complementation group 1 (ERCC1) status was assessed in patients receiving carboplatin and gemcitabine for inoperable non–small-cell lung cancer (NSCLC). We analyzed the association between the ERCC1 status and the overall survival after the chemotherapy. Patients and Methods We retrospectively identified 163 patients with inoperable NSCLC and sufficient tumor tissue for ERCC1 analysis, who had received carboplatin and gemcitabine as first-line treatment. Immunohistochemistry was used to assess the expression of ERCC1. Results One hundred sixty-three patients were included. Seventy (42%) were ERCC1 positive. Patients treated with carboplatin and gemcitabine and having ERCC1-negative tumors had a significantly increased survival when compared to patients with ERCC1-positive tumors (median survival, 12.0 months v 8.2 months; P = .02). This difference was mainly seen in men, where those with ERCC1-negative tumors had a significantly increased survival compared to men with ERCC1-positive tumors (median survival, 11.8 months v 7.9 months; P = .005). Conversely, women who were ERCC1 negative did not have a survival advantage over ERCC1-positive women. Conclusion We confirmed previous reports that ERCC1 expression is predictive for outcome in patients treated with carboplatin and gemcitabine. Patients with ERCC1-negative tumors had an increased survival compared to patients with ERCC1-positive tumors and this difference was mainly attributable to a survival difference among men.
Food intolerance and Crohn's disease.
Authors: M Pearson, K Teahon, A J Levi, I Bjarnason
Journal: Gut (1993)

It has been claimed that prolonged remissions of Crohn9s disease can be achieved after enteral or parenteral nutrition, by identifying and excluding foods that exacerbate a patient9s symptoms. The occurrence of food intolerances were assessed after induction of remission with elemental diet in 42 eligible patients to whom single foods were introduced over five days. Suspect foods were reinvestigated with open and if possible, double blind rechallenge. Fourteen patients (33%) dropped out of the study because of relapse of disease unrelated to food (n = 8) or because of difficulties in complying with the regimen (n = 6). Twenty (48%) of the patients identified food sensitivities whereas eight (19%) did not. Seventeen of the patients who identified food sensitivities had an open rechallenge with recurrence of symptoms in 10 (24% of total). Food sensitivity was confirmed in three patients on double blind challenge. There was no significant difference in the duration of remission between patients who did or did not identify food sensitivities. During the study three cases of intolerance to the formula diet, and one of severe salicylate sensitivity were encountered. In conclusion food sensitivities are evident after treatment of Crohn9s disease with elemental diet but are variable, often do not persist, and are of insufficient importance to warrant putting all patients through elimination diets.
Twenty-Year Dynamics of Serum Cholesterol Levels in the Middle-Aged Population of Eastern Finland
Authors: Pekka Jousilahti
Journal: Annals of Internal Medicine (1996)

Background: In cross-sectional analyses, serum cholesterol levels differ among different age groups. However, secular time trends in cholesterol levels can be seen across age groups in a population. A birth cohort analysis provides useful information on the combined effect of age and time on changes in serum cholesterol levels. Objective: To analyze the 20-year dynamics of serum total cholesterol levels in relation to age, sex, birth cohort, time period, mortality rate, and changes in the intake of saturated fats. Design: Cross-sectional measurements of serum total cholesterol levels in five independent population surveys done in 1972, 1977, 1982, 1987, and 1992. Setting: Kuopio and North Karelia provinces in eastern Finland. Patients: Random sample of 16 711 men and 17 542 women 25 to 64 years of age. Persons in the oldest birth cohort were born in 1913; persons in the youngest birth cohort were born in 1967. Measurements: Total serum cholesterol levels and daily intake of dietary fat. Results: Between 1972 and 1992, mean cholesterol levels decreased with time in each age group and for both sexes. According to the cross-sectional data, cholesterol levels increased with age and increased more steeply in women than in men. Contrary to these data, cholesterol levels in birth cohorts did not increase with age. Cholesterol levels did not change at all within birth cohorts of women and started to decrease after 45 years of age in birth cohorts of men. Cholesterol levels in the youngest birth cohorts (persons 25 to 29 years of age) entering the study each study year were markedly lower than levels in the same age group in the previous survey of risk factors. Daily intake of saturated fat decreased markedly between 1972 and 1992. Most of this decrease could be explained by change in intake of liquid dairy products and spreadable fats. In both sexes, changes in saturated fat intake were correlated with the time period, whereas the association with age was weak. Conclusions: In this Finnish population, total serum cholesterol levels are more closely associated with birth cohort than with age. Changes in dietary intake of saturated fat over time may account for changes in cholesterol levels. This finding suggests that community-based strategies for preventing cardiovascular disease can affect most of the population.
Mythbusters in rowing medicine and physiotherapy: nine experts tackle five clinical conundrums
Authors: Fiona Wilson, Alison McGregor
Journal: British Journal of Sports Medicine (2014)

### Cardiac arrhythmias

Dr Chris Milne: Medical Director, Rowing New Zealand

What is your experience as a team physician in dealing with insidious onset of cardiac disorders in rowers? 

Any rower who presents with palpitations should be taken seriously, as these may be an indicator of significant cardiac arrhythmia. The many years of hard endurance training causes adaptive changes that are collectively known as ‘the athlete's heart’. Sometimes these changes progress from normal adaptation to volume overload to unhealthy sequelae.

The most common arrhythmia seen in rowers is atrial fibrillation, and the longer the rower has been in heavy training, typically over 10 years, the more likely it is that they will develop this arrhythmia. The exact mechanism is unclear but it may be due to atrial enlargement with dilation and fibrosis plus a contribution from increased vagal tone and bradycardia.

The condition presented dramatically for Rob Waddell in the trials for the single berth at Beijing Olympics. In New Zealand, several athletes’ rowing careers have been affected by atrial fibrillation or other arrhythmias. Nathan Cohen, gold medallist in the London 2012 Olympics, had to retire following several episodes of arrhythmia.

Can these conditions be detected by routine screening? 

The history and physical examination occasionally provide clues. A resting ECG (recently introduced by Federation Internationale des Societes d'Aviron (FISA) as a requirement at World Championships at Under-23 level (U23)) can provide additional clues to underlying cardiac disorders (eg, hypertrophic cardiomyopathy) and may prompt referral for other more advanced investigations, for example, echocardiography or electrophysiological studies. Liaison with a cardiologist who has an interest in these issues is recommended.

Rob Waddell: Athlete, Olympic Champion, single scull (Sydney 2000), 2× world champion.

What was your experience as an athlete with a cardiac abnormality and what challenges did you face in obtaining a diagnosis? 

I was only …
Organ-dependent in vivo priming of naive CD4+,but not CD8+,T cells by plasmacytoid dendritic cells
Authors: Anita Sapoznikov, Jens A.A. Fischer, Tami Zaft, Rita Krauthgamer, Andrzej Dzionek, Steffen Jung
Journal: The Journal of Experimental Medicine (2007)

Plasmacytoid dendritic cells (PDCs) play a pivotal role as cytokine-secreting accessory cells in the antimicrobial immune defense. In contrast, the capacity of PDCs to act as antigen-presenting cells in naive T cell priming remains unclear. By studying T cell responses in mice that lack conventional DCs (cDCs), and by the use of a PDC-specific antigen-targeting strategy, we show that PDCs can initiate productive naive CD4+ T cell responses in lymph nodes, but not in the spleen. PDC-triggered CD4+ T cell responses differed from cDC-driven responses in that they were not associated with concomitant CD8+ T cell priming. Our results establish PDCs as a bona fide DC subset that initiates unique CD4+ Th cell–dominated primary immune responses.
The value of cell line validation
Authors: W. K. A. Yung
Journal: Neuro-Oncology (2012)

Cell line contamination and misidentification was first reported in HeLa cells in 1974 (1). However, the problem is still widespread: at least 15% of reported cell lines may be cross-contaminated or misidentified (2). As a result, numerous research findings have been invalidated, careers have been damaged, and millions of dollars have been wasted. Fortunately, the scientific community has been stepping up its efforts to address the problem. A statement about cell line validation is now a prerequisite for acceptance at all American Association for Cancer Research journals. Testing will also be considered in the review process for all National Institutes of Health grant proposals. Failure to address the issue is likely to lead to a rejection. In addition, many academic institutions require that their researchers validate their cell lines.

Some researchers are reluctant to validate their cell lines because testing costs time and money. However, access to more efficient technologies has made validation easier: short tandem repeat (STR) testing, the most commonly recommended method for cell line validation, can be outsourced; this makes it a viable option for small laboratories.

STR testing commonly involves 9 markers and a cut-off score of 0.8 (this score is a numerical code that can be compared with others in a database). In this issue of Neuro-Oncology, Bady et al (3) provide guidance for researchers who are validating their own cell lines. The authors performed a cell validation study of 39 commonly used glioma cell lines and found that a score of 0.8 was insufficient for reliably distinguishing cell line origins when using 9-marker profiles. The cell line scores were compared with those in the DSMZ database; 3 lines were found to be misidentified. However, a comparison of paired, randomly arranged profiles revealed a score of more than 0.8 for 1 pair and more than 0.7 for 8 pairs. When all markers were used, no pairs scored higher than 0.7. The authors concluded that a reference database with a limited number of duplicates and simulation procedures is useful for more accurately evaluating similarity values.

Hopefully, more precise testing standards, such as those suggested by Bady et al (3), will further minimize the effects of contaminated and misidentified cell lines on the body of scientific knowledge. In furtherance of this goal, Neuro-Oncology may soon require a statement about cell line validation for all submitted papers: where and when the cells were obtained, whether they were authenticated, the testing procedures used, and when they were last authenticated. We understand that requiring this information may be a burden for our authors, but we believe that it is crucial to ensuring the scientific integrity of our journal and the field at large.
Chlamydophila pneumoniae in asthma
Authors: D. L. Hahn
Journal: European Respiratory Journal (2005)

To the Editors: 

Biscione et al . 1 reported a significant association of upper airway Chlamydophila pneumoniae RT-PCR positivity in atopic asthmatics (cumulative rate 22%) compared with nonatopic nonasthmatic spouses (9%). In the discussion, Biscione et al . 1 argued in favour of acute, rather than chronic, infection as the explanation for their observation that detection was mostly intermittent rather than persistent. I would like to address three issues raised by this interesting study.

First, in the introduction, Biscione et al . 1 stated that C. pneumoniae serology could not differentiate acute from other infections. It is correct to state that serology cannot diagnose …