tbuckley/cabot-search huggingface dataset:
K-Ras Mutations and Treatment Outcome in Colorectal Cancer Patients Receiving Exclusive Fluoropyrimidine Therapy
Authors: Marie-Christine Etienne-Grimaldi, Jean-Louis Formento, Mireille Francoual, Eric François, Patricia Formento, Nicole Renée, Pierre Laurent-Puig, Maurice Chazal, Daniel Benchimol, Jean-Robert Delpero, Christian Letoublon, Denis Pezet, Jean-François Seitz, Gérard Milano
Journal: Clinical Cancer Research (2008)

Abstract Purpose: K-Ras mutations predict resistance to anti–epidermal growth factor receptor (EGFR) monoclonal antibodies. Because combinations of anti-EGFR with 5-fluorouracil (5-FU)-based chemotherapy are promising treatments, we analyzed the effect of K-Ras mutations in patients having received exclusive 5-FU therapy. Experimental Design: This study was conducted on 93 stage IV colorectal cancer patients with unresectable measurable liver metastasis receiving 5-FU-leucovorin (56 men and 37 women; 77 cancer deaths). Liver metastases (n = 93) along with primary tumors (n = 48) were analyzed for K-Ras mutations (codons 12 and 13), p53 mutations (exons 4-9), p53 polymorphism (codon 72), thymidylate synthase (TS) polymorphism (28-bp repeats including G&amp;gt;C mutation), methylenetetrahydrofolate reductase polymorphism (677C&amp;gt;T, 1298A&amp;gt;C), thymidylate synthase (TS) activity, dihydropyrimidine dehydrogenase activity, folylpolyglutamate synthase activity, and p53 protein expression. Results: Thirty-six of 93 (38.7%) metastases were K-Ras mutated (30 at codon 12 and 6 at codon 13). Mutated primary tumors (16 of 48) matched perfectly with mutated metastases. The additional analyzed tumor markers were not different between K-Ras mutated and wild-type tumors. The objective response rate was 37%: 44.4% in K-Ras mutated versus 32.1% in wild-type K-Ras metastasis (P = 0.27). Low TS activity in metastasis was the only significant predictor of tumor response (P = 0.047). K-Ras status did not influence specific survival. Conclusions: The present data indicate a perfect concordance of K-Ras mutations between primary and liver metastasis and suggest that any predictive and/or prognostic value of K-Ras mutations in treatments combining anti-EGFR monoclonal antibodies with 5-FU should be exclusively linked to the anti-EGFR agent.
Activation of cytokine genes in T cells during primary and secondary murine influenza pneumonia.
Authors: S R Carding, W Allan, A McMickle, P C Doherty
Journal: The Journal of Experimental Medicine (1993)

The patterns of cytokine mRNA expression in mice with primary or secondary influenza pneumonia have been assessed by in situ hybridization analysis of cells from both the mediastinal lymph node (MLN) and the virus-infected lung. Evidence of substantial transcriptional activity was found in all lymphocyte subsets recovered from both anatomical sites. The kinetics of cytokine mRNA expression after primary infection with an H3N2 virus were in accord with the idea that the initial response occurs in regional lymphoid tissue, with the effector T cells later moving to the lung. This temporal separation was much less apparent for the more rapid secondary response resulting from challenge of H3N2-primed mice with an H1N1 virus. Among the T cell receptor alpha/beta+ subsets, transcripts for interferon (IFN) gamma and tumor necrosis factor beta were most commonly found in the CD8+ population whereas mRNA for interleukin (IL) 4 and IL-10 was much more prevalent in CD4+ T cells. The gamma/delta T cells expressed mRNA for all cytokines tested, with IL-2, IL-4, and IFN-gamma predominating among those recovered from the inflammatory exudate. At particular time points, especially early in the MLN and late in the infected lung, the frequency of mRNA+ lymphocytes was much higher than would be expected from current understanding of the prevalence of virus-specific precursors and effectors. If this response is typical, induction of cytokine gene expression for T cells that are not responding directly to the invading pathogen may be a prominent feature of acute virus infections.
Degenerative disc disease and pre-existing spinal pain
Authors: C J Centeno
Journal: Annals of the Rheumatic Diseases (2003)

A pportioning pain and disability after a car accident or work related injury can be difficult. Many doctors who undertake this task often state that because an x ray examination or magnetic resonance imaging (MRI) scan soon after the injury shows degenerative disc disease (DDD), some or all of the patient’s spinal pain and disability must be pre-existing. This interpretation of imaging is not consistent with the peer reviewed medical published reports.

For this statement to be true, there would need to be a strong connection between MRI or x ray evidence of DDD and pain/disability. If we look at this concept and compare it with the published reports, we see that DDD, …
Journeying down the long and winding road: the whole picture of volume-activated Cl- channel activation in cardiac myocytes
Authors: S. J. Kim, Y. E. Earm
Journal: Cardiovascular Research (2007)

Patch-clamp studies of anion channels show a bewildering variety in their properties and regulation mechanisms.2 Amongst them, the anion channels activated by hypo-osmotic cell swelling ( I Cl,swell) have drawn attention because of their wide expression in virtually every vertebrate cell(s), including cardiac myocytes, and their critical roles in cell volume regulation.2–4 Cells need to regulate their volume in the face of several external and internal challenges. For this purpose, cells are endowed with various ion channels and transporters that become activated upon cell swelling or shrinkage. I Cl,swell are also called by different names like volume-regulated anion channels and volume-stimulated osmolyte and anion channels, implicating their permeability to a wide variety of anionic molecules including organic substances and ATP4−. In spite of their importance and ubiquitous expression, their molecular nature is still the subject of controversy and remains unclear.2,3

One of the key issues in I Cl,swell is the activation mechanism, i.e. how is the hypo-osmotic stress transduced into anion channel activation? A direct mechanical gating is unlikely with regard to the considerable time lag between hypotonic challenge and steady-state activation of I Cl,swell. The list of suggested mechanisms or critical factors supported by experimental evidence include … 

*Corresponding author. Tel: +82 2 740 8224; fax: +82 2 763 9667. E-mail address : earmye{at}snu.ac.kr
The provision of a percutaneously placed enteral tube feeding service
Authors: David Westaby, Alison Young, Paul O'Toole, Geoff Smith, David S Sanders
Journal: Gut (2010)

There is overwhelming evidence that the maintenance of enteral feeding is beneficial in patients in whom oral access has been diminished or lost. Short-term enteral access is usually achieved via naso-enteral tube placement. For longer term tube feeding there are recognised advantages for enteral feeding tubes placed percutaneously. The provision of a percutaneous enteral tube feeding service should be within the remit of the hospital nutrition support team (NST). This designated team should provide a framework for patient selection, pre-assessment and post-procedural care. Close working relations with community-based services should be established. An accredited therapeutic endoscopist should be a member of the NST and direct the technical aspects of the service. Every endoscopy unit in an acute hospital setting should provide a basic percutaneous endoscopic gastrostomy (PEG) service. This should include provision for fitting a PEG jejunal extension (PEGJ) if required. Specialist units should be identified where a more comprehensive service is provided, including direct jejunal placement (DPEJ), as well as radiological and laparoscopically placed tubes. Good understanding of the indications for percutaneous enteral tube feeding will prevent inappropriate procedures and ensure that the correct feeding route is selected at the appropriate time. Each unit should adopt and become familiar with a limited range of PEG tube equipment. Careful adherence to the important technical details of tube insertion will reduce peri-procedural complications. Post-procedural complications remain relatively common, however, and an awareness of the correct approach to managing them is essential for all clinicians involved in providing a percutaneous enteral tube feeding service. Finally, ethical considerations should always be taken into account when considering long-term enteral feeding, especially for patients with a poor quality of life.
Sport and delinquency: an examination of the deterrence hypothesis in a longitudinal study.
Authors: D J Begg, J D Langley, T Moffitt, S W Marshall
Journal: British Journal of Sports Medicine (1996)

To determine whether involvement in sporting activity in mid-adolescence would deter delinquent behaviour in late adolescence.Members of a longitudinal cohort study were interviewed at ages 15 and 18 years and, among other topics, were asked questions relating to involvement in physical activity and delinquent behaviour. Logistic regression models were used to examine the relation between sports involvement and delinquency at age 15 years and delinquency at age 18.After controlling for delinquent behaviour and psychosocial factors at age 15, females with moderate or high levels of sporting activity, and males with high levels of sporting activity, were significantly more likely to be delinquent at age 18 years than those with low levels of sporting activity. No significant association was found between sporting activity and aggressive behaviour, team sport participation and delinquency, and team sport participation and aggressive behaviour.This study did not support the deterrence hypothesis and showed that high involvement in sporting activity, but not team sport, was associated with a subsequent increase in delinquent behaviour.
Hepatic leukostasis and hypoxic stress in adhesion molecule-deficient mice after gut ischemia/reperfusion.
Authors: Y Horie, R Wolf, D C Anderson, D N Granger
Journal: Journal of Clinical Investigation (1997)

The concept that leukocyte-endothelial cell adhesion (LECA) is a major determinant of the tissue injury elicited by ischemia/reperfusion (I/R) is largely based on studies employing adhesion molecule-specific monoclonal antibodies. The objective of this study was to assess the contribution of LECA to I/R injury using mutant mice (all on a C57B1 background) that are deficient in either intracellular adhesion molecule-1, P-selectin, or CD11/CD18. The accumulation of fluorescently labeled leukocytes and the number of nonperfused sinusoids in livers of control and adhesion molecule-deficient mice were monitored by intravital microscopy for 1 h after release of the occluded (for 15 min) superior mesenteric artery. Autofluorescence of pyridine nucleotide (NADH) was measured as an indicator of mitochondrial O2 consumption and redox status. The number of stationary leukocytes in the liver after gut I/R was significantly elevated compared with baseline values in C57B1 (control) mice. Autofluorescence of NADH was also significantly increased (indicating hypoxia) after I/R in these mice, especially in the pericentral region. Intercellular adhesion molecule-1-, CD11/CD18-, and P-selectin-deficient mice all exhibited a blunted leukosequestration response to I/R and smaller increments in nonperfused sinusoids, relative to C57B1 mice. All adhesion molecule-deficient mice also exhibited an attenuated increment in NADH autofluorescence in the pericentral region, relative to control mice. These results from adhesion molecule-deficient mice provide additional support for the view that LECA is an important determinant of the liver dysfunction induced by gut I/R.
The Neurotrophins Nerve Growth Factor, Brain-derived Neurotrophic Factor, Neurotrophin-3, and Neurotrophin-4 Are Survival and Activation Factors for Eosinophils in Patients with Allergic Bronchial Asthma
Authors: Christina Nassenstein, Armin Braun, Veit Johannes Erpenbeck, Marek Lommatzsch, Stephanie Schmidt, Norbert Krug, Werner Luttmann, Harald Renz, Johann Christian Virchow
Journal: The Journal of Experimental Medicine (2003)

Neurotrophins (nerve growth factor [NGF], brain-derived neurotrophic factor [BDNF], neurotrophin [NT]-3, and NT-4) have been observed in elevated concentrations in allergic diseases. Neurotrophin levels are up-regulated endobronchially after allergen challenge. This coincides with an influx of activated eosinophils into the bronchial lumen. These eosinophils have an increased viability and CD69 expression 18 h after segmental allergen provocation (SAP) which is not present in peripheral blood. To investigate whether these observations are related we studied the influence of neurotrophins on eosinophil function in allergic asthma. Incubation with NGF, BDNF, NT-3, or NT-4 caused a significant increase in the viability and CD69 expression of isolated eosinophils from bronchoalveolar lavage fluid (BALF) but not from peripheral blood, suggesting a unique sensitivity of endobronchial eosinophils to neurotrophins. To elucidate the underlying mechanisms expression of the neurotrophin receptors p75NTR, trkA, trkB, and trkC on eosinophils was analyzed by RT-PCR and immunocytology. After SAP expression of all neurotrophin receptors was markedly elevated on eosinophils from BALF. Our findings suggest that neurotrophin-mediated activation of bronchial eosinophils might play a role in the regulation of eosinophilic inflammation in allergic asthma.
A proinflammatory activity of interleukin 8 in human skin: expression of the inducible nitric oxide synthase in psoriatic lesions and cultured keratinocytes.
Authors: D Bruch-Gerharz, K Fehsel, C Suschek, G Michel, T Ruzicka, V Kolb-Bachofen
Journal: The Journal of Experimental Medicine (1996)

Psoriasis is a common chronic skin disease mediated by cellular immune mechanisms and characterized by an intense neutrophil cell infiltrate and proliferative activation of epidermal keratinocytes. We have previously described the expression of the inducible nitric oxide synthase (iNOS) in epidermal keratinocytes of psoriatic skin lesions. In this study, the role of iNOS in psoriatic inflammation was explored ex vivo in psoriatic skin biopsies and in vitro in primary cultures of human keratinocytes. Messenger RNA for the iNOS enzyme (iNOS mRNA) was detected by reverse transcriptase polymerase chain reaction in skin biopsies from patients with psoriasis, but not in skin specimens from patients with atopic eczema or from healthy volunteers. As demonstrated by in situ hybridization and immunohistochemistry, expression of iNOS mRNA and its gene product was localized to the epidermal keratinocytes of psoriatic skin lesions. In situ hybridization further revealed a complete colocalization of mRNA expression for iNOS with interleukin (IL) 8 receptor-specific mRNA either in the basal germinative cell layer or at focal sites of ongoing neutrophil inflammation in suprabasal cell layers. Because psoriatic keratinocytes have previously been shown to express mRNA transcripts for IL-8, it seemed reasonable to hypothesize that iNOS expression could be induced in an autocrine loop by IL-8. This hypothesis was substantiated by our in vitro experiments showing that a combination of IL-8 and interferon gamma induces the expression of iNOS-specific mRNA and of the functional enzyme in cultured human keratinocytes. These results suggest an important role for iNOS in concert with IL-8 and its receptor early during the formation of psoriatic lesions.
Unexpected effects of the severe combined immunodeficiency mutation on murine lymphomagenesis.
Authors: M Lieberman, G A Hansteen, E K Waller, I L Weissman, A Sen-Majumdar
Journal: The Journal of Experimental Medicine (1992)

Strain C.B17 scid/scid (SCID) mice, which lack functional T and B lymphocytes, show heightened susceptibility to the induction of thymic lymphomas by x-irradiation. Susceptibility is highest in thymus-chimeric SCID-BL mice (thymectomized SCID mice bearing a C57BL thymus graft). All SCID-BL lymphomas originate in the cells of the thymic graft (C57BL type) and lack murine leukemia virus expression. Both SCID and SCID-BL lymphomas are phenotypically CD4-8+ and/or CD4+8+, but only the SCID-BL tumors express CD3. Injection of C57BL or BALB/c bone marrow into irradiated SCID-BL mice prevents lymphoma development, but SCID marrow is completely ineffective. The results suggest that the scid condition enhances the activity of a putative lymphomagenic agent induced in the bone marrow by x-irradiation and that C57BL thymic cells are highly sensitive targets. Moreover, the failure of SCID bone marrow to protect against lymphomagenesis vs. the efficacy of marrow from immunocompetent donors points to involvement of T or B lineage cells in this process.
Doctors are warned against sex with former patients
Authors: Lynn Eaton
Journal: BMJ (2006)

Doctors should think carefully before becoming sexually involved with a former patient, the General Medical Council warns in its updated guidance on acceptable professional practice.

Until now relationships with former patients have not been explicitly proscribed. But supplementary guidance on maintaining boundaries—published alongside the latest guidance on appropriate professional behaviour—says that pursuing a sexual relationship with any former patient will “usually be inappropriate, regardless of the length of time since the therapeutic relationship ended.”

The warning comes because “good medical practice” encourages doctors to work in partnership with patients, fostering relationships that are based on openness, trust, and good communications.

The GMC's president, Graeme Catto, acknowledged that this …
Modulation of Kv Channel Expression and Function by TCR and Costimulatory Signals during Peripheral CD4+ Lymphocyte Differentiation
Authors: Qing-Hua Liu, Bernd K. Fleischmann, Brian Hondowicz, Curtis C. Maier, Laurence A. Turka, Katsuyuki Yui, Michael I. Kotlikoff, Andrew D. Wells, Bruce D. Freedman
Journal: The Journal of Experimental Medicine (2002)

Ionic signaling pathways, including voltage-dependent potassium (Kv) channels, are instrumental in antigen-mediated responses of peripheral T cells. However, how Kv channels cooperate with other signaling pathways involved in T cell activation and differentiation is unknown. We report that multiple Kv channels are expressed by naive CD4+ lymphocytes, and that the current amplitude and kinetics are modulated by antigen receptor–mediated stimulation and costimulatory signals. Currents expressed in naive CD4+ lymphocytes are consistent with Kv1.1, Kv1.2, Kv1.3, and Kv1.6. Effector CD4+ cells generated by optimal TCR and costimulation exhibit only Kv1.3 current, but at approximately sixfold higher levels than naive cells. CD4+ lymphocytes anergized through partial stimulation exhibit similar Kv1.1, Kv1.2, and/or Kv1.6 currents, but approximately threefold more Kv1.3 current than naive cells. To determine if Kv channels contribute to the distinct functions of naive, effector, and anergized T cells, we tested their role in immunoregulatory cytokine production. Each Kv channel is required for maximal IL-2 production by naive CD4+ lymphocytes, whereas none appears to play a role in IL-2, IL-4, or IFN-γ production by effector cells. Interestingly, Kv channels in anergized lymphocytes actively suppress IL-4 production, and these functions are consistent with a role in regulating the membrane potential and calcium signaling.
Importance of gender in diffuse malignant peritoneal mesothelioma
Authors: C. Cao, T.D. Yan, M. Deraco, D. Elias, O. Glehen, E.A. Levine, B.J. Moran, D.L. Morris, T.C. Chua, P. Piso, P.H. Sugarbaker
Journal: Annals of Oncology (2011)
Cardiac screening: time to move forward!
Authors: Mats Borjesson, Jonathan Drezner
Journal: British Journal of Sports Medicine (2012)

Cardiac screening of athletes has been passionately discussed for over two decades. Increased attention and controversy emerged after the publication of the 2005 European Society of Cardiology (ESC) guidelines endorsing a screening protocol inclusive of a resting 12-lead ECG.1 The American Heart Association (AHA) also strongly advocates for cardiovascular screening in athletes, but recommends a programme based only on a personal and family history and physical examination.2 After years of fervent debate, it is time to put passion aside and instead focus on the expanding body of knowledge which now exists. With careful analysis and thoughtful perspective, the discussion on cardiac screening can move forward—beyond the usual rhetoric—to benefit athletes and prevent sudden death.

In this issue professors Levine and Thompson (USA) and professors Whyte and Wilson (Great Britain) debate ‘Challenges in Sports Cardiology: US versus European Approaches’ ( see page i9 ). The paper addresses several difficult questions on cardiac screening of athletes which are posed to both ‘sides’. While the expertise of the professionals involved in this debate is unquestionable, we add these comments for readers to consider regarding our current challenges to cardiac screening.

If we could remove ‘mandatory’ from the discussion both sides might be a lot closer to agreeing on a screening protocol. We should consider that the focus on ‘mandatory’ or ‘national’ screening programmes has distracted this discussion from addressing key issues that affect the sports physician when faced with conducting a preparticipation evaluation. The merits of ECG screening are often examined and debated regarding the initiation of a nationalised, mandatory screening programme as existing in Italy.3 However, the questions that a sports physician (or consultant cardiologist) considers when seeing an athlete for a preparticipation evaluation may be very different. Sports physicians may ask: How should I be screening this athlete? What is …
The Role of HuR in Gemcitabine Efficacy in Pancreatic Cancer: HuR Up-regulates the Expression of the Gemcitabine Metabolizing Enzyme Deoxycytidine Kinase
Authors: Christina L. Costantino, Agnieszka K. Witkiewicz, Yuki Kuwano, Joseph A. Cozzitorto, Eugene P. Kennedy, Abhijit Dasgupta, Judith C. Keen, Charles J. Yeo, Myriam Gorospe, Jonathan R. Brody
Journal: Cancer Research (2009)

Abstract RNA-binding protein HuR binds U- or AU-rich sequences in the 3′-untranslated regions of target mRNAs, stabilizing them and/or modulating their translation. Given the links of HuR with cancer, we studied the consequences of modulating HuR levels in pancreatic cancer cells. HuR-overexpressing cancer cells, in some instances, are roughly up to 30-fold more sensitive to treatment with gemcitabine, the main chemotherapeutic component of treatment regimens for pancreatic ductal adenocarcinoma (PDA), compared with control cells. In pancreatic cancer cells, HuR associates with deoxycytidine kinase (dCK) mRNA, which encodes the enzyme that metabolizes and thereby activates gemcitabine. Gemcitabine exposure to pancreatic cancer cells enriches the association between HuR and dCK mRNA and increases cytoplasmic HuR levels. Accordingly, HuR overexpression elevates, whereas HuR silencing reduces, dCK protein expression in pancreatic cancer cells. In a clinical correlate study of gemcitabine treatment, we found a 7-fold increase in risk of mortality in PDA patients with low cytoplasmic HuR levels compared with patients with high HuR levels, after adjusting for other treatments and demographic variables. These data support the notion that HuR is a key mediator of gemcitabine efficacy in cancer cells, at least in part through its ability to regulate dCK levels posttranscriptionally. We propose that HuR levels in PDA modulate the therapeutic efficacy of gemcitabine, thus serving as a marker of the clinical utility of this common chemotherapeutic agent and a potential target for intervention in pancreatic cancer. [Cancer Res 2009;69(11):4567–72]