tbuckley/cabot-search huggingface dataset:
P21Cip1 Is a Critical Mediator of the Cytotoxic Action of Thymidylate Synthase Inhibitors in Colorectal Carcinoma Cells
Authors: James I. Geller, Kinga Szekely-Szucs, Istvan Petak, Belinda Doyle, Janet A. Houghton
Journal: Cancer Research (2004)

Abstract We have demonstrated previously that interferon (IFN)-γ sensitizes human colon carcinoma cell lines to the cytotoxic effects of 5-fluorouracil combined with leucovorin and to the thymidylate synthase inhibitor, ZD9331, dependent on thymineless stress-induced DNA damage, independent of p53. Here we demonstrate that the cyclin-dependent kinase (CDK) inhibitor p21Cip1 regulates thymineless stress-induced cytotoxicity in these cells. HCT116 wild-type (wt) and p53−/− cells underwent apoptosis and loss in clonogenic survival when exposed to ZD9331, whereas p21Cip1−/− cells were resistant. In contrast, IFN-γ induced marked cytotoxicity in p21Cip1−/− cells only. ZD9331 induced p21Cip1 up-regulation in all of the cell lines examined, as did thymidine deprivation in thymidylate synthase-deficient (thymidylate synthase−) cells. Furthermore, selective induction of p21Cip1 in RKO was sufficient to induce apoptosis. P21Cip1, cdk1, cdk2, and cyclin E mRNA expression increased coincident with S-phase accumulation in HT29 cells treated with ZD9331 or 5fluorouracil/leucovorin, as demonstrated by cDNA microarray analyses. Cell cycle analyses revealed that HCT116 wt and p21Cip1 −/− cells accumulated in S phase within 24 h of ZD9331 exposure; however, wt cells exited S-phase more rapidly, where apoptosis occurred before mitosis, either in late S or G2. Finally, the CDK inhibitor roscovitine potentiated the cytotoxic activity of ZD9331 in both wt and p21Cip1−/− cells, strongly suggesting a role for p21Cip1-dependent CDK inhibition in cytotoxicity induced by thymidylate synthase inhibition. In summary, p21Cip1 positively regulates the cytotoxic action of thymidylate synthase inhibitors, negatively regulates the cytotoxic action of IFN-γ, and enhances S-phase exit after thymineless stress, possibly via interaction with CDK-cyclin complexes.
992 AN EARLY DECISION FOR PTFE-TIPS IMPROVES SURVIVAL IN HIGH RISK CIRRHOTIC PATIENTS ADMITTED WITH AN ACUTE VARICEAL BLEEDING. A MULTICENTER RCT
Authors: J.C. Garcia-Pagan, K. Caca, C. Bureau, W. Laleman, T. Sauerbruch, A. Luca, F. Nevens, J.P. Vinel, J. Bosch
Journal: Journal of Hepatology (2008)
A population study of factors associated with general practitioner consultation for non-inflammatory musculoskeletal pain
Authors: K. B Hagen
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVE</h3> To investigate factors associated with visiting a general practitioner (GP) for non-inflammatory musculoskeletal pain, and to examine whether these factors were affected by duration (chronic <i>v</i>non-chronic) or location (widespread <i>v</i>regional) of pain. <h3>METHODS</h3> From a cross sectional postal survey of 20 000 (response rate 59%) randomly selected adults in two counties of Norway, 6408 subjects who had experienced musculoskeletal pain during the past month were included. Patients who reported inflammatory rheumatic diagnoses made by a doctor were excluded. <h3>RESULTS</h3> 2909 (45%) had consulted a GP for their musculoskeletal pain during the past 12 months. The odds of consulting were significantly increased by being a woman, by having a higher age and lower education, and by being a pensioner or on sick leave. Patients with widespread pain were more likely to consult than those with regional pain, as were patients with chronic compared with non-chronic pain. Greater than median pain intensity was the factor most prominently associated with consultation for men (odds ratio (OR)=2.4; 95% confidence interval (95% CI) 2.0 to 2.9) and for women (OR=2.6; 95% CI 2.3 to 2.9). Overall, consultation was significantly associated with mental distress for women but not for men. Subgroup analyses showed that consultation for chronic pain was significantly associated with greater than median mental distress for both women (OR=1.3; 95% CI 1.1 to 1.6) and men (OR=1.2; 95% CI 1.0 to 1.4), whereas consultation for non-chronic pain was not. <h3>CONCLUSION</h3> The results show that about half of the patients with musculoskeletal pain consult a general practitioner (GP) each year, that demographic factors are associated with consulting, and that the role of mental distress for consulting a GP varies with duration of pain.
Genetics of the idotype of BALB/c myeloma S117: multiple chromosomal loci for Vh genes encoding specificity for group A streptococcal carbohydrate.
Authors: C Berek, B A Taylor, K Eichmann
Journal: The Journal of Experimental Medicine (1976)

A small proportion of the antibodies to Group A streptococcal carbohydrate (A-CHO) elicited in BALB/c mice by immunization with Group A streptococci, has idiotypic determinants in common with the BALB/c myeloma protein S117 which has specificity for N-acetyl-glucosamine, the major antigenic determinant of A-CHO. The expression of these idiotypic determinants is under the control of a gene which is linked to the Ig-1a+ allotype locus in strain BALB/c and in other strains carrying the same Ig-1 haplotype. This gene (S117+) segregates in breeding experiments as if it were an allele to the gene A5A+ which controls the expression of the A5A idiotype in association with antibodies to A-CHO in strain A/J and which is linked to the Ig-1e allotype locus. Another possible allele, linked to the Ig-1c allotype locus, controls the expression of both S117 and A5A cross-reactive determinants (S117cr, A5Acr). The distribution of these idiotypic determinants in various lines that carry recombinant Ig-1 haplotypes suggests that the A5A and S117 loci are nonallelic and map at different positions in the Ig-1 region. The data suggest complex pseudollelic relationships between different Ig-1 haplotypes that allow the expression of the same genes in allelic and in nonallelic fashion.
Purified lymphocyte function-associated antigen 3 binds to CD2 and mediates T lymphocyte adhesion.
Authors: M L Dustin, M E Sanders, S Shaw, T A Springer
Journal: The Journal of Experimental Medicine (1987)

CD2 is a T lymphocyte glycoprotein that functions in adhesion of T lymphocytes and also as a putative receptor for activation signals. Functional data suggest that LFA-3, a widely distributed cell surface glycoprotein, may be the biological ligand of CD2. We have purified LFA-3 from human erythrocytes and characterized the purified protein functionally. LFA-3 bound specifically to CD2+ cells, and this binding was inhibited by CD2 mAb. Conversely, purified LFA-3 inhibited binding of CD2 mAb to cells, and the concentration required for this effect suggests that LFA-3 half-saturated CD2 at 1-5 nM LFA-3. Purified LFA-3 inhibited rosetting of human and sheep erythrocytes with CD2+ T lymphoma cells and T lymphocytes, and mediated aggregation of a CD2+ T lymphoma cell line. Purified LFA-3 reconstituted into planar membranes mediated efficient CD2-dependent adhesion of T lymphoblasts. These data demonstrate that LFA-3 is a ligand for CD2 and that LFA-3 can mediate T lymphocyte adhesion.
Hapten-specific T-cell responses to 4-hydroxy-3-nitrophenyl acetyl. I. Genetic control of delayed-type hypersensitivity by VH and I-A-region genes.
Authors: J Z Weinberger, M I Greene, B Benacerraf, M E Dorf
Journal: The Journal of Experimental Medicine (1979)

Hapten-specific delayed-type hypersensitivity (DTH) was induced in several strains of mice. (4-hydroxy-3-nitrophenyl)acetyl-bovine gamma globulin (NP-BGG)-primed mice which did not bear the Ig1b heavy-chain linkage group made a NP-specific DTH response when challenged with NP bovine serum albumin (BSA) and failed to respond to challenge with (4-hydroxy-5-iodo-3-nitrophenyl)acetyl-bovine serum albumin (NIP-BSA). Strains of NP-BGG-primed mice bearing the Ig1b allotype, including SJL, responded to challenges of either NP-BSA or NIP-BSA. F1 hybrids between a cross-reactive strain, C57BL/6, and two other noncross-reactive strains were cross-reactive. Genetic mapping of the NIP-cross-reactive DTH response localized the trait to the VH-region of the Ig1b heavy-chain linkage group. The fine-specificity pattern of the T-cell anti-NP response, and the genetic mapping of this trait, were analogous to the reported fine specificity and mapping data of the humoral heteroclitic anti-NP response. Adoptive transfer studies on the ability to transfer NP-specific DTH between various strain combinations showed that the T-cell donors and the recipient must have homology for at least the I-A subregion. Whenever NP-specific reactivity was transferred from a strain which cross-reactively responded to NIP, the recipient also responded to both NP and NIP. The implications of the control of NP-primed DTH-reactive populations of T cells by two distinct genetic regions, VH and H-2, were discussed.
Comparison of different lipid substrates on intestinal adaptation in the rat.
Authors: M Galluser, B Czernichow, H Dreyfus, F Gosse, B Guerold, J Kachelhoffer, M Doffoel, F Raul
Journal: Gut (1993)

The relative effects of medium chain (MCT) and long chain triglycerides (LCT) on intestinal morphology and functions were compared. Adult rats received intragastrically for 10 days an isoenergetic mixture containing either 50% MCT/50% LCT or 100% LCT. The other constituents of the diets were identical, and animals fed a standard diet orally were used as a reference group. Animals who were given the MCT/LCT diet showed a higher mucosal mass and protein content and increased villus length and crypt depth in the proximal part of the small intestine compared with the LCT and control diet groups. Administration of [3H] thymidine 12 hours before death resulted in a significant increase in the incorporation of the precursor into cellular DNA in the jejunum of rats given MCT. In rats given LCT as the only fat, the free fatty acid content of the microvillus membrane showed a 20 fold increase and at the same time there was a significant drop in the cholesterol content and in the cholesterol/protein ratio. Differences in the lipid composition of enterol diet or in the microvillus membrane did not effect adversely membrane bound hydrolase activities. These findings suggest that MCT in the diet confers advantages in addition to the provision of rapidly available energy.
Comorbidities of asthma during childhood: possibly important, yet poorly studied
Authors: E.P. de Groot, E.J. Duiverman, P.L.P. Brand
Journal: European Respiratory Journal (2010)

Asthma in adults is associated with comorbidities such as obesity, gastro-oesophageal reflux, dysfunctional breathing and mental disorders. Herein, we provide an overview of the current state of evidence on these comorbidities in childhood asthma. The prevalence, known mechanisms and possible treatment options for each comorbid condition will be discussed. Obesity is an increasing health problem in children, but its relationship with asthma remains unclear. Allergic rhinitis is a very common comorbidity in asthma, both in children and in adults, but its effect on childhood asthma severity has not been studied. The prevalence and treatment options of dysfunctional breathing, a known comorbidity in adult asthma, have not yet been studied in paediatric asthma. Food allergies appear to cause more severe reactions in patients with asthma. Depressive disorders are more prevalent in childhood asthma than in healthy children, but seem to be poorly recognised and treated in children. Although gastro-oesophageal reflux is commonly thought to be a comorbid disease complicating asthma, it remains uncertain whether treatment improves asthma control. In conclusion, knowledge of asthma comorbidities in childhood is sparse. Further studies are urgently needed to identify the prevalence, and, more importantly, the effects of these comorbidities and their treatment on the degree of asthma control in children.
Taxane Doublets for Metastatic Breast Cancer: Do We Need Another Cytotoxic Pair or Another Approach?
Authors: E. Claire Dees
Journal: Journal of Clinical Oncology (2011)

In the 15 years since taxanes were approved for use in metastatic breast cancer, they have played a prominent role in clinical trials evaluating combination therapy for this disease. A number of randomizedtrialshavebeenconductedaddressingthequestionofsingleagentversuscombinationtherapyortherelatedquestionofsequential versuscombinationtherapy.Someofthesehaveshownthecombination arm to be superior in response rate (RR), progression-free survival (PFS), and even overall survival (OS). Notable examples of successful taxane doublets include the combination of gemcitabine and paclitaxel 1 and the combination of docetaxel and capecitabine, 2 both of which showed improved time to progression (TTP), RR, and OS for the doublet compared with single-agent taxane alone in firstline treatment of metastatic breast cancer. However, later analysis of the docetaxel and capecitabine study showed that in patients who received single-agent docetaxel, poststudy treatment with capecitabine improved survival more than other poststudy treatments. This finding raises the possibility that sequential single-agent therapy may confer the same benefit as combined doublet therapy. 3 Other trials have shown that combination cytotoxic therapy is no better than single-agent or single-agent sequential therapy, 4 and most studies have shown higher toxicity in the combination arms. A recent Cochrane report 5 concluded that combination chemotherapy regimens yielded statistically significant improvements in OS, TTP, and RR yet greater toxicity. However, this report included primarily nontaxane combinations and did not evaluate sequential single agents as a comparison. The National Comprehensive Cancer Network guidelines, version2.2011, 6 statethatthereislittleornocompellingevidencethat combination chemotherapy is superior to sequential single agents. Thus a common consensus opinion is that combination cytotoxic therapy should be used in patients with rapidly progressive disease or in patients with visceral disease and symptoms, where more rapid response is needed. All others should be treated with single agents in sequence. Inthiscontext,Nielsenetal 7 presentinJournalofClinicalOncology a randomized phase III trial conducted by the Danish Breast Cancer Cooperative Group to evaluate the combination of gemcitabine and docetaxel compared with docetaxel alone in the treatment of metastatic breast cancer. This study was conducted between 2001 and2005andincluded337patientswithmetastaticbreastcancerwho
Pulmonary function before and after anterior spinal surgery in adult idiopathic scoliosis.
Authors: C. A. Wong, A. A. Cole, L. Watson, J. K. Webb, I. D. Johnston, W. J. Kinnear
Journal: Thorax (1996)

Little is known about the long term effects of anterior spinal surgery on pulmonary function in adult patients with idiopathic scoliosis. A study was therefore undertaken of pulmonary function before and after anterior spinal surgery in this group of patients.Fourteen patients (12 women) of mean age 26.5 years (range 17-50, 10 > or = 20 years) were studied. All 14 patients underwent thoracotomy and anterior arthrodesis, and five also underwent posterior arthrodesis. Scoliosis curves and lung volumes were measured preoperatively and at a mean follow up of 32 months (range 14-49) after surgery.At long term follow up after surgery the mean (SD) Cobb angle of the thoracic curve improved from 59 degrees (25 degrees) to 39 degrees (18 degrees), a correction of 31%. Despite this there was a fall in mean forced vital capacity (FVC) of 0.21 litres (95% confidence interval 0.04 to 0.38). In the patients who underwent anterior surgery without posterior surgery (n = 9) there was a fall in mean FVC of 0.31 litres (95% confidence interval 0.12 to 0.50); mean forced expiratory volume in one second and total lung capacity were also reduced and there was an increase in mean residual volume.Forced vital capacity is reduced at long term follow up in adult patients with idiopathic scoliosis who undergo anterior spinal surgery. The fall in FVC is small and is unlikely to be of clinical significance in patients with reasonable lung function in whom surgery is planned for prevention of curve progression or improvement of cosmetic appearance and pain. However, surgical intervention should not be undertaken in an attempt to improve pulmonary function.
Surgical Management of Advanced Gastrointestinal Stromal Tumors After Treatment With Targeted Systemic Therapy Using Kinase Inhibitors
Authors: Chandrajit P. Raut, Matthew Posner, Jayesh Desai, Jeffrey A. Morgan, Suzanne George, David Zahrieh, Christopher D.M. Fletcher, George D. Demetri, Monica M. Bertagnolli
Journal: Journal of Clinical Oncology (2006)

Purpose While targeted inhibitors of tyrosine kinase activity demonstrate dramatic efficacy in the majority of patients with advanced gastrointestinal stromal tumors (GISTs), cure remains elusive and resistance to systemic therapy is a challenge. To assess the role of surgery in multimodality management of GISTs, we studied postoperative outcomes in patients treated with targeted kinase inhibitors for advanced GIST. Methods We evaluated outcomes in a single institution series of 69 consecutive patients who underwent surgery for advanced GISTs while receiving kinase inhibitors. Patients were categorized based on extent of disease before surgery (stable disease, limited disease progression, generalized disease progression) and surgical result (no evidence of disease, minimal residual disease, bulky residual disease). Results Disease status before surgery was associated with surgical result (P &lt; .0001; median follow-up, 14.6 months). After surgery, there was no evidence of disease in 78%, 25%, and 7% of patients with stable disease, limited progression, and generalized progression, respectively. Bulky residual disease remained after surgery in 4%, 16%, and 43% of the patients with stable disease, limited progression, and generalized progression. Twelve-month progression-free survival was 80%, 33%, and 0% for patients with stable disease, limited progression, and generalized progression (P &lt; .0001). Twelve-month overall survival was 95%, 86%, and 0% for patients with stable disease, limited progression, and generalized progression (P &lt; .0001). Conclusion Patients with advanced GISTs exhibiting stable disease or limited progression on kinase inhibitor therapy have prolonged overall survival after debulking procedures. Surgery has little to offer in the setting of generalized progression.
Coronary Artery Disease in the Transplanted Heart
Authors: M. Weis, W. von Scheidt
Journal: Annual Review of Medicine (2000)

Coronary artery disease in the transplanted heart limits the long-term success of cardiac transplantation. Intravascular ultrasound studies reveal a dual morphology with donor-transmitted and de novo plaques. Coronary vasomotor dysfunction may occur independently of morphological alterations. The disease is characterized by the interaction of activated T lymphocytes with cytokines and donor epicardial and microvascular endothelium. Various noxious stimuli contribute to the continuing inflammatory response. Consequently, adhesion molecule expression is upregulated, leukocytes migrate into the allograft, thrombocytes accumulate, and growth factors are expressed, finally resulting in functional and morphological chronic allograft lesions. Blocking the activation of T cells, CD4+ cytokines, and adhesion molecules may prevent endothelial injury and subsequent intimal thickening. Strategies to decrease the formation of antiendothelial and anti-HLA-DR antibodies may also be protective, as may antiproliferative drugs, augmentation of endogenous nitric oxide bioactivity, and new immunosuppressive regimens. Revascularization procedures have a limited role in treating significant focal lesions. Retransplantation, the only definitive treatment, remains ethically controversial.
Bacterial translocation up-regulates GTP-cyclohydrolase I in mesenteric vasculature of cirrhotic rats
Authors: Reiner Wiest, Gregory Cadelina, Sheldon Milstien, Robert S. McCuskey, Guadalupe Garcia-Tsao, Roberto J. Groszmann
Journal: Hepatology (2003)

In cirrhosis, arterial vasodilation and the associated hemodynamic disturbances are most prominent in the mesenteric circulation, and its severity has been linked to bacterial translocation (BT) and endotoxemia. Synthesis of nitric oxide (NO), the main vasodilator implicated, is dependent on the essential cofactor tetrahydrobiopterin (BH(4)). The key enzyme involved in BH(4) synthesis is GTP-cyclohydrolase I (GTPCH-I), which is stimulated by endotoxin. Therefore, we investigated GTPCH-I activity and BH(4) biosynthesis in the mesenteric vasculature of cirrhotic rats with ascites, as well as their relationship with BT and endotoxemia, serum NO, and mean arterial pressure (MAP). GTPCH-I activity and BH(4) content in mesenteric vasculature was determined by high-performance liquid chromatography. BT was assessed by standard bacteriologic culture of mesenteric lymph nodes (MLNs). Serum endotoxin was measured by a kinetic turbidimetric limulus amebocyte lysate assay, and serum NO metabolite (NOx) concentrations were assessed by chemiluminescence. BT was associated with local lymphatic and systemic appearance of endotoxin and was accompanied by increases in serum NOx levels. GTPCH-I activity and BH(4) content in mesenteric vasculature were both increased in animals with BT and correlated significantly (r = 0.69, P <.01). Both GTPCH-I activity and BH(4) levels significantly correlated with serum endotoxin and NOx levels (r = 0.69 and 0.54, 0.81 and 0.53, P <.05). MAP (a marker of systemic vasodilatation) correlated with endotoxemia (r = 0.58, P <.03) and with GTPCH-I activity (r = 0.69, P <.01). In conclusion, in cirrhotic animals BT appears to lead to endotoxemia, stimulation of GTPCH-I, increased BH(4) synthesis, and further enhancement of vascular NO production that leads to aggravation of vasodilatation.
Use of HIV viral-load suppression to estimate the effect of community-wide home-based HIV counselling and testing and linkage to antiretroviral therapy on HIV incidence in South Africa: a mathematical modelling analysis
Authors: Ruanne Barnabas, Roger Ying, Heidi van Rooyen, Pam Murnane, James Hughes, Jared Baeten, Connie Celum
Journal: The Lancet (2013)
14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial
Authors: Andreas H Diacon, Rodney Dawson, Florian von Groote-Bidlingmaier, Gregory Symons, Amour Venter, Peter R Donald, Christo van Niekerk, Daniel Everitt, Helen Winter, Piet Becker, Carl M Mendel, Melvin K Spigelman
Journal: The Lancet (2012)