tbuckley/cabot-search huggingface dataset:
Progress on new vaccine strategies for the immunotherapy and prevention of cancer
Authors: Jay A. Berzofsky, Masaki Terabe, SangKon Oh, Igor M. Belyakov, Jeffrey D. Ahlers, John E. Janik, John C. Morris
Journal: Journal of Clinical Investigation (2004)

In recent years, great strides in understanding and regulating the immune system have led to new hope for harnessing its exquisite specificity to destroy cancer cells without affecting normal tissues. This review examines the fundamental immunologic advances and the novel vaccine strategies arising from these advances, as well as the early clinical trials studying new approaches to treat or prevent cancer.
Microsatellite instability—a useful diagnostic tool to select patients at high risk for hereditary non-polyposis colorectal cancer: a study in different groups of patients with colorectal cancer
Authors: C Lamberti, R Kruse, C Ruelfs, R Caspari, Y Wang, M Jungck, M Mathiak, H R H Malayeri, W Friedl, T Sauerbruch, P Propping
Journal: Gut (1999)

BACKGROUND Clinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is based on a typical family history. As molecular genetic testing is predominantly restricted to these families, gene carriers not meeting the clinical criteria may be missed. AIMS To examine the value of microsatellite instability (MSI) as a tool to increase the likelihood for uncovering a mismatch repair germline mutation in patients with colorectal cancer and to identify a genotype-phenotype relation in families with verified mutations. METHODS Systematic search for germline mutations (hMSH2 and hMLH1 genes) was performed in 96 patients: 57 fulfilled the Amsterdam criteria (group 1) and 12 the looser HNPCC criteria (group 2). Seventeen patients showed familial clustering of cancers (group 3) and 10 patients under 50 years had sporadic cancer (group 4), the latter of whom all exhibited MSI + tumours. RESULTS A similar proportion of germline mutations was found in patients who fulfilled the clinical criteria of HNPCC and had MSI + tumours (groups 1 and 2; 15/39) compared with patients who did not meet these clinical criteria but who had MSI + tumours (groups 3 and 4; 8/27 patients). Affected relatives of patients with hMLH1 mutations showed a significantly higher frequency of colorectal cancer but a lower frequency of endometrium cancer than those with hMSH2 mutations. CONCLUSIONS MSI in tumour tissue is a useful criterion for selecting patients who should be tested for germline mutations in the mismatch repair genes hMSH2 and hMLH1 irrespective of their family history. Among carriers of hMSH2 mutations the tumour spectrum was broader than among carriers of hMLH1 mutations.
Immunization of Patients with the hTERT:540-548 Peptide Induces Peptide-Reactive T Lymphocytes That Do Not Recognize Tumors Endogenously Expressing Telomerase
Authors: Maria R. Parkhurst, John P. Riley, Takehito Igarashi, Yong Li, Paul F. Robbins, Steven A. Rosenberg
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Telomerase is an attractive target antigen for cancer immunotherapies because it is expressed in &amp;gt;85% of human tumors but is rarely found in normal tissues. A HLA-A*0201-restricted T-cell epitope was previously identified within telomerase reverse transcriptase hTERT:540-548. This peptide was reported to induce CTL that recognized tumor cells and transfectants that endogenously expressed telomerase. Therefore, we initiated a clinical protocol to evaluate the therapeutic and immunological efficacy of this peptide. Experimental Design: Fourteen patients with metastatic cancers were vaccinated with hTERT:540-548 emulsified in incomplete Freund’s adjuvant. Results: In 7 patients, peripheral blood mononuclear cells collected after immunization recognized hTERT:540-548, whereas those collected before vaccination did not. However, none of these CTLs recognized tumors that endogenously expressed telomerase, and none of the patients had an objective clinical response. Several highly avid T-cell clones were generated that recognized T2 cells pulsed with ≤1 nm hTERT:540-548, but none of these recognized HLA-A*0201+ hTERT+ tumors or cells transduced with the human telomerase reverse transcriptase (hTERT) gene. Also, an antibody specific for hTERT:540-548/HLA-A*0201 complexes stained peptide-pulsed cells but not telomerase+ tumors. Conclusions: Our results are discordant with previous studies and those of a clinical trial that claimed peripheral blood mononuclear cells from patients vaccinated with peptide-pulsed dendritic cells lysed hTERT+ tumors. However, our findings are consistent with a previous study that demonstrated that the hTERT:540-548 peptide is cleaved in the proteasome. These results suggest that hTERT:540-548 is not presented on the surfaces of tumor cells in the context of HLA-A*0201 and will not be useful for the immunotherapy of patients with cancer.
A premenopausal woman with abdominal discomfort and iron deficiency anaemia
Authors: Abdulkani Yusuf, Bhamini Vadhwana, core surgical trainee, Ujjwala Mohite, Carole Collins
Journal: BMJ (2015)

A 48 year old premenopausal woman presented to our clinic with a 12 month history of intermittent abdominal discomfort associated with bloating, constipation, and weight loss of 6.3 kg. Her medical history included chronic iron deficiency anaemia, vitamin D deficiency, and episodes of fresh rectal bleeding caused by haemorrhoids, which required sclerotherapy. She had undergone a diagnostic laparoscopy for abdominal pains, which did not detect any abnormalities. There was no family history of colorectal cancer. On examination she looked well, weighed 50 kg, with a body mass index of 20. Her abdomen was soft, non-tender, and without palpable masses. The results of a digital rectal examination were normal. Routine blood tests showed iron deficiency anaemia, with haemoglobin 109 g/L (reference range 117-155), mean corpuscular volume 80.6 fL (80-100), mean corpuscular haemoglobin 27.3 pg/cell (27-33), and ferritin 4 ng/mL (10-232)





### 1. What are the most important common causes of iron deficiency anaemia in Western countries?

#### Short answer

The most important common causes of iron deficiency anaemia in men and postmenopausal women in Western countries are colorectal cancer and malabsorptive disorders. In premenopausal women menstrual blood loss is the primary cause.1 2

#### Discussion

Iron deficiency anaemia is the most common form of anaemia worldwide,3 4 and it occurs in 2-5% of the Western adult population.1 A cause can be identified in most cases. In men and postmenopausal women, occult gastrointestinal blood loss from aspirin or non-steroidal anti-inflammatory drug use, colorectal cancer, benign gastric ulceration, and angiodysplasia are the most common causes. Malabsorptive disorders, such as coeliac disease, are also important causes and can manifest with no overt bleeding or gastrointestinal symptoms. …
The angiogenic switch occurs at the adenoma stage of the adenoma carcinoma sequence in colorectal cancer
Authors: C. A Staton, A. S A Chetwood, I. C Cameron, S. S Cross, N. J Brown, M. W R Reed
Journal: Gut (2007)

The aim of this study was to examine the relationship between tissue factor (TF), vascular endothelial growth factor (VEGF) and the onset of angiogenesis in the adenoma-carcinoma sequence (ACS), the stepwise process encompassing colorectal cancer (CRC) disease progression.210 surgical specimens comprising the ACS were immunohistochemically stained for endothelial cells (CD31), VEGF and TF. Angiogenesis quantified using Chalkley grid analysis (microvascular density; MVD), and VEGF/TF expression were semiquantitatively graded and correlated with standard prognostic indicators including 5 year follow-up. VEGF and TF were measured by ELISA in tumour specimens and normal mucosa from an additional 90 CRC patients.There was a significant increase in MVD across the ACS (p < 0.0005) with significant correlations with Dukes' stage (p = 0.01) and lymph node involvement (p = 0.02). The greatest increase in MVD was related to the onset of dysplasia, with an associated significant increase in VEGF expression (p < 0.0005). There was a significant relationship between VEGF and TF expression in the initial phase of the ACS (k = 0.44, p < 0.005), although no correlation between VEGF or TF, and MVD, tumour size, Dukes' classification, lymph node involvement or survival was found.These findings are the first to suggest that the angiogenic switch occurs at the onset of dysplasia in the ACS, and provide further evidence of the close association between VEGF and TF in the early stages of CRC development.
Selective Killing of Hypoxia-Inducible Factor-1–Active Cells Improves Survival in a Mouse Model of Invasive and Metastatic Pancreatic Cancer
Authors: Shinae Kizaka-Kondoh, Satoshi Itasaka, Lihua Zeng, Shotaro Tanaka, Tao Zhao, Yumi Takahashi, Keiko Shibuya, Kiichi Hirota, Gregg L. Semenza, Masahiro Hiraoka
Journal: Clinical Cancer Research (2009)

Pancreatic cancer is characterized by intratumoral hypoxia, early and aggressive local invasion, and metastatic potential. Hypoxia-inducible factor-1 (HIF-1) is the major transcriptional activator of hypoxia-responsive genes and intratumoral hypoxia is associated with increased risk of metastasis. However, the behavior of the cells having HIF-1 activity during the malignant progression in pancreatic cancer has not been tested.We orthotopically transplanted pancreatic cancer cells stably transfected with a HIF-1-dependent luciferase reporter gene and monitored HIF-1 activity in vivo in control and POP33-treated mice. POP33 is a novel prodrug, which has potential to increase caspase-3 activity and induce apoptosis in HIF-1-active/hypoxic cells.In vivo optical imaging showed that HIF-1 activity proceeded along with local invasion, the peritoneal dissemination, and the liver metastasis. HIF-1-active hypoxic cells were selectively eradicated by POP33. Moreover, selective killing of HIF-1-active hypoxic cells significantly suppressed malignant progression, resulting in a significant improvement in survival rate.These results show that HIF-1-active cells constitute a large proportion of invading and metastatic cells and suggest that eradication of these cells may improve the outcome in advanced pancreatic cancer, a condition for which no effective therapy currently exists.
Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN
Authors: Adrian Schreiber, Friedrich C. Luft, Ralph Kettritz
Journal: Journal of the American Society of Nephrology (2014)

ANCA-activated phagocytes cause vasculitis and necrotizing crescentic GN (NCGN). ANCA-induced phagocyte NADPH oxidase (Phox) may contribute by generating tissue-damaging reactive oxygen species. We tested an alternative hypothesis, in which Phox restrains inflammation by downregulating caspase-1, thereby reducing IL-1β generation and limiting NCGN. In an antimyeloperoxidase (anti-MPO) antibody-mediated disease model, mice transplanted with either gp91(phox)-deficient or p47(phox)-deficient bone marrow showed accelerated disease with increased crescents, necrosis, glomerular monocytes, and renal IL-1β levels compared with mice transplanted with wild-type bone marrow. IL-1β receptor blockade abrogated aggravated NCGN in gp91(phox)-deficient mice. In vitro, challenge with anti-MPO antibody strongly enhanced caspase-1 activity and IL-1β generation in gp91(phox)-deficient and p47(phox)-deficient monocytes compared with wild-type monocytes. This enhanced IL-1β generation was abrogated when caspase-1 was blocked. ANCA-induced superoxide and IL-1β generation were inversely related in human monocytes. Furthermore, transplantation of gp91(phox)/caspase-1 double-deficient bone marrow rescued the accelerated NCGN phenotype in gp91(phox) bone marrow-deficient mice. These results suggest that Phox-generated reactive oxygen species downregulate caspase-1, thereby keeping the inflammasome in check and limiting ANCA-induced inflammation. IL-1 receptor blockade may provide a promising strategy in NCGN, whereas our data question the benefit of antioxidants.
Human Neoplastic and Normal Cells in Tissue Culture. I. Cell Lines Derived From Malignant Melanomas and Normal Melanocytes2
Authors: B. C. Giovanella, J. S. Stehlin, C. Santamaria, S. O. Yim, A. C. Morgan, L. J. Williams, A. Leibovitz, P. J. Fialkow, D. M. Mumford
Journal: JNCI Journal of the National Cancer Institute (1976)

Forty-six cell lines derived from 31 human melanomas obtained from 28 patients were cultured. Fourteen of 16 lines have produced malignant tumors when injected into nude (thymus-deficient) mice. Tumors in 5 of the nude mice metastasized to distant lymph nodes and/or to the lungs of the mouse host. Extreme variability from line to line was observed for doubling time (34 to 106 hr), plating efficiency (0–86%), and melanin production. All tested lines had type B glucose-6phosphate dehydrogenase, thereby excluding HeLa cell contamination. HeLa cells have been grown for some time in our laboratory. Our results clearly demonstrated that HeLa cell contamination does not occur invariably in heteroploid lines growing in a laboratory simultaneously with Hela cells, provided that proper care is taken to avoid such occurrence. Multiple cell lines derived from the same tumor had identical phosphor-glucomutase enzyme phenotype, which suggested a lack of significant cross-contamination between the lines. Four long-term cultures of normal human uveal embryo melanocytes have also been established and characterized. Although all produced melanin after reaching saturation density, they differed from the melanoma cells morphologically; they were flat, not refringent, and lacked piling up and plating ability. When melanoma cells were exposed to bromodeoxyuridine (BUDR) for long periods, a phenotypic change toward non-neoplastic characteristics was observed. Cells became flat and not refringent and, when injected into nude mice, tumors appeared after a long latent period. These changes were completely reversible in vitro and in vivo. The BUDR-treated cultures were undistinguishable from the untreated mother cultures after 2 to 3 passages. Lines derived from tumors in nude mice (obtained by injection of BUDR-treated cells) were again indistinguishable from the untreated mother line. Normal melanocytes were mostly euploid; all the melanoma cells were aneuploid. All 29 cell lines derived from 14 patients had an average chromosome number higher than 46. Detailed group-by-group chromosome analysis always showed an excess of C chromosomes, which suggested that hyperreduplication of one or more C chromosomes is a specific characteristic of human melanomas.
Angiogenic T cells are decreased in rheumatoid arthritis patients
Authors: Javier Rodríguez-Carrio, Mercedes Alperi-López, Patricia López, Sara Alonso-Castro, Francisco J Ballina-García, Ana Suárez
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objective</h3> The mechanisms underlying the increased cardiovascular risk (CVR) of rheumatoid arthritis (RA) patients remain unclear. Since the recently discovered angiogenic T cells (Tang) could have a role in endothelial repair through cooperating with endothelial progenitor cells (EPC), the main aim of this study was to analyse the Tang and EPC populations in relation to disease-specific features and traditional CVR factors. <h3>Methods</h3> Tang (CD3<sup>+</sup>CD31<sup>+</sup>CXCR4<sup>+</sup>) and EPC (CD34<sup>+</sup>VEGFR2<sup>+</sup>CD133<sup>+</sup>) populations were quantified by flow cytometry in peripheral blood samples from 103 RA patients and 18 matched healthy controls (HC). Clinical features and traditional CVR factors were obtained from clinical records, and 28-joint Disease Activity Score was used for measuring disease activity. Interferon (IFN) α serum levels were measured by immunoassays. <h3>Results</h3> Tang and EPC were strongly decreased in RA patients. In HC, but not in patients, both populations were positively correlated and inversely related to low density lipoprotein- and total-cholesterol levels. Sex, diabetes, dyslipidaemia, hypertension or obesity did not significantly influence Tang in patients, although detected in smokers. However, Tang were closely related to disease activity, autoantibody positivity and IFNα levels. Multiple regression analysis adjusted for traditional CVR factors confirmed that only disease activity, age at diagnosis, antinuclear antibody positivity and smoking habit could predict Tang frequency. Finally, patients who had suffered a CV event since their RA diagnosis presented higher Tang decrease and IFNα levels than those who were CV event-free. <h3>Conclusions</h3> Disease-specific parameters, including disease activity, autoantibody profiles and IFNα levels, are associated with Tang decrease in RA, thus probably accounting for CVR.
Transgenic Mice With Increased Copper/Zinc–Superoxide Dismutase Activity Are Resistant to Hepatic Leukostasis and Capillary No-Reflow After Gut Ischemia/Reperfusion
Authors: Yoshinori Horie, Robert Wolf, Sonia C. Flores, Joe M. McCord, Charles J. Epstein, D. Neil Granger
Journal: Circulation Research (1998)

Abstract —The objectives of this study were to (1) determine whether transgenic (Tg) mice overexpressing copper/zinc–superoxide dismutase (CuZn-SOD) are protected from the deleterious effects of gut ischemia/reperfusion (I/R) and (2) compare the effectiveness of Tg SOD overexpression in attenuating I/R injury to intravascularly administered CuZn-SOD or manganese (Mn)-SOD. The accumulation of fluorescently labeled leukocytes and number of nonperfused sinusoids were monitored by intravital microscopy in livers of wild-type mice (C57BL/6), CuZn-SOD Tg mice, and wild-type mice receiving either CuZn-SOD or Mn-SOD. All parameters were measured for 1 hour after release of the occluded (for 15 minutes) superior mesenteric artery. Gut I/R in wild-type mice led to an increased number of stationary leukocytes, while reducing the number of perfused sinusoids (capillary no-reflow). All of these responses were significantly blunted in CuZn-SOD Tg mice, with a corresponding attenuation of liver enzyme release into plasma. Exogenously administered SOD had little or no effect on gut I/R-induced leukostasis or capillary no-reflow in the liver. These observations suggest a role for superoxide in gut I/R-induced leukostasis and hypoxic stress in the liver. Furthermore, the findings suggest that cellular localization of SOD activity is an important determinant of the protective actions of this enzyme in experimental models of I/R injury.
Expression patterns of atopic eczema and respiratory illnesses in a high-risk birth cohort
Authors: Anne Marie Singh, Michael D. Evans, Ronald Gangnon, Kathy A. Roberg, Christopher Tisler, Douglas DaSilva, Tressa Pappas, Lisa Salazar, Elizabeth L. Anderson, James E. Gern, Robert F. Lemanske, Christine M. Seroogy
Journal: Journal of Allergy and Clinical Immunology (2010)
Effect of bottles, cups, and dummies on breast feeding in preterm infants: a randomised controlled trial
Authors: Carmel T Collins, Philip Ryan, Caroline A Crowther, Andrew J McPhee, Susan Paterson, Janet E Hiller
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To determine the effect of artificial teats (bottle and dummy) and cups on breast feeding in preterm infants. <b>Design</b> Randomised controlled trial. <b>Setting</b> Two large tertiary hospitals, 54 peripheral hospitals. <b>Participants</b> 319 preterm infants (born at 23-33 weeks9 gestation) randomly assigned to one of four groups: cup/no dummy (n = 89), cup/dummy (n = 72), bottle/no dummy (n = 73), bottle/dummy (n = 85). Women with singleton or twin infants &lt; 34 weeks9 gestation who wanted to breastfeed were eligible to participate. <b>Interventions</b> Cup or bottle feeding occurred when the mother was unable to be present to breast feed. Infants randomised to the dummy groups received a dummy on entry into the trial. <b>Main outcome measures</b> Full breast feeding (compared with partial and none) and any breast feeding (compared with none) on discharge home. Secondary outcomes: prevalence of breast feeding at three and six months after discharge and length of hospital stay. <b>Results</b> 303 infants (and 278 mothers) were included in the intention to treat analysis. There were no significant differences for any of the study outcomes according to use of a dummy. Infants randomised to cup feeds were more likely to be fully breast fed on discharge home (odds ratio 1.73, 95% confidence interval 1.04 to 2.88, P = 0.03), but had a longer length of stay (hazard ratio 0.71, 0.55 to 0.92, P = 0.01). <b>Conclusions</b> Dummies do not affect breast feeding in preterm infants. Cup feeding significantly increases the likelihood that the baby will be fully breast fed at discharge home, but has no effect on any breast feeding and increases the length of hospital stay.
Menopause, postmenopausal hormone use and risk of incident gout
Authors: A. E. Hak, G. C. Curhan, F. Grodstein, H. K. Choi
Journal: Annals of the Rheumatic Diseases (2009)

To prospectively study the relation between menopause, postmenopausal hormone use and risk of gout, since female sex hormones have been postulated to decrease gout risk among women.In the Nurses' Health Study, the association between menopause, age at menopause, postmenopausal hormone use and risk of self-reported physician-diagnosed incident gout among 92 535 women without gout at baseline was examined. Multivariate proportional hazards regression analysis was used to adjust for other risk factors for gout such as age, body mass index, diuretic use, hypertension, alcohol intake and dietary factors.During 16 years of follow-up (1 240 231 person-years), 1703 incident gout cases were recorded. The incidence rate of gout increased from 0.6 per 1000 person-years in women <45 years of age to 2.5 in women > or =75 years of age (p for trend <0.001). Compared with premenopausal women, postmenopausal women had a higher risk of incident gout (multivariate-adjusted relative risk (RR)=1.26; 95% confidence interval (CI) 1.03 to 1.55). Among women with a natural menopause, women with age at menopause <45 years had a RR of 1.62 (95% CI 1.12 to 2.33) of gout compared with women with age at menopause 50-54 years. Postmenopausal hormone users had a reduced risk of gout (RR=0.82; 95% CI 0.70 to 0.96).These prospective findings indicate that menopause increases the risk of gout, whereas postmenopausal hormone therapy modestly reduces gout risk.
Rapid TNFR1-dependent lymphocyte depletion in vivo with a selective chemical inhibitor of IKKβ
Authors: Kumiko Nagashima, Vito G. Sasseville, Danyi Wen, Andrew Bielecki, Hua Yang, Chris Simpson, Ethan Grant, Michael Hepperle, Gerry Harriman, Bruce Jaffee, Tim Ocain, Yajun Xu, Christopher C. Fraser
Journal: Blood (2006)