tbuckley/cabot-search huggingface dataset:
Formation of Renal Cysts and Tumors in <i>Vhl/Trp53</i>-Deficient Mice Requires HIF1α and HIF2α
Authors: Désirée Schönenberger, Sabine Harlander, Michal Rajski, Robert A. Jacobs, Anne-Kristine Lundby, Mojca Adlesic, Tomas Hejhal, Peter J. Wild, Carsten Lundby, Ian J. Frew
Journal: Cancer Research (2016)

Abstract The von Hippel–Lindau (VHL) tumor suppressor gene is inactivated in the majority of clear cell renal cell carcinomas (ccRCC), but genetic ablation of Vhl alone in mouse models is insufficient to recapitulate human tumorigenesis. One function of pVHL is to regulate the stability of the hypoxia-inducible factors (HIF), which become constitutively activated in the absence of pVHL. In established ccRCC, HIF1α has been implicated as a renal tumor suppressor, whereas HIF2α is considered an oncoprotein. In this study, we investigated the contributions of HIF1α and HIF2α to ccRCC initiation in the context of Vhl deficiency. We found that deleting Vhl plus Hif1a or Hif2a specifically in the renal epithelium did not induce tumor formation. However, HIF1α and HIF2α differentially regulated cell proliferation, mitochondrial abundance and oxidative capacity, glycogen accumulation, and acquisition of a clear cell phenotype in Vhl-deficient renal epithelial cells. HIF1α, but not HIF2α, induced Warburg-like metabolism characterized by increased glycolysis, decreased oxygen consumption, and decreased ATP production in mouse embryonic fibroblasts, providing insights into the cellular changes potentially occurring in Vhl mutant renal cells before ccRCC formation. Importantly, deletion of either Hif1a or Hif2a completely prevented the formation of renal cysts and tumors in Vhl/Trp53 mutant mice. These findings argue that both HIF1α and HIF2α exert protumorigenic functions during the earliest stages of cyst and tumor formation in the kidney. Cancer Res; 76(7); 2025–36. ©2016 AACR.
Long-term survival after histologic transformation of low-grade follicular lymphoma.
Authors: A R Yuen, O W Kamel, J Halpern, S J Horning
Journal: Journal of Clinical Oncology (1995)

To describe the course of patients following histologic transformation (HT) from low-grade follicular lymphoma to intermediate- or high-grade non-Hodgkin's lymphoma.Patients were identified from data bases in the Division of Oncology and the Department of Surgical Pathology. HT was defined as the conversion of a follicular small cleaved-cell or follicular mixed small cleaved-cell and large-cell lymphoma to a diffuse large-cell, diffuse mixed small cleaved-cell and large-cell or any high-grade lymphoma.We analyzed the clinical course of 74 low-grade lymphoma patients with histologically proven transformation occurring from 1965 to 1988. The median time from diagnosis to HT was 66 months, and the median age at HT was 58 years. The median duration of survival after transformation was 22 months. Anatomic extent of disease at HT (limited v extensive, P = .01), prior chemotherapy (none v any, P = .01), and response to therapy (complete v partial or none, P = .005) at time of HT were identified as significant predictors of survival after HT in backward-selection Cox regression analysis. Thirty patients attained a complete response to therapy at HT. They had a median survival duration of 81 months after HT.A subset of patients with HT from low-grade follicular lymphoma to intermediate- or high-grade lymphoma enjoys relatively long-term survival. Patients with limited disease and no previous exposure to chemotherapy have the most favorable prognosis.
Abstract 293: Inhibition of Nitric Oxide Synthase Decreases Myocardial Injury Following Hemorrhagic Shock and Resuscitation in Rat Model
Authors: Mona Soliman
Journal: Circulation (2014)

Resuscitation following hemorrhagic shock result in myocardial contractile dysfunction and injury. We examined the protective effects of non-selective inhibitor of nitric oxide synthase N(G)-nitro-L-arginine methylester (L-NAME) on myocardial contractile function in the isolated perfused hearts, after ex vivo as well as in vivo treatment with L-NAME and resuscitation following one hour of hemorrhagic shock.Male Sprague Dawley rats (300-350 gm) were assigned to 2 sets of experimental protocols: ex vivo and in vivo treatment and resuscitation. Each set has 3 experimental groups (n= 6 per group): normotensive (N), hemorrhagic shock and resuscitation (HS-R) and hemorrhagic shock rats treated with L-NAME and resuscitated (HS- L-NAME-R). Rats were hemorrhaged over 60 min to reach a mean arterial blood pressure of 40 mmHg. In the ex vivo group, hearts were harvested and ex vivo treated and resuscitated by perfused in the Langendorff System. In the L-NAME treated group, L-NAME was added for the first 5 min . Cardiac function was measured Left ventricular generated pressure and +dP/dt were calculated. In the in vivo group, rats were treated with L-NAME intra-arterially after 60 min hemorrhagic shock. Resuscitation was performed in vivo by the reinfusion of the shed blood for 30 min to restore normo-tension. Inhibition of nitric oxide synthase using L-NAME before resuscitation in ex vivo treated and resuscitated isolated hearts and in in vivo treated and resuscitated rats following hemorrhagic shock improved myocardial contractile function. Left ventricular generated pressure and + dP/dt max was significantly higher in L-NAME treated rats compared to the untreated group.Treatment with L-NAME improved left ventricular generated pressure following hemorrhagic shock in the ex vivo as well as the in vivo treated and resuscitated rats. The results indicate that L-NAME protects the myocardium against dysfunction by inhibiting NOS.
Is There a “Best” Choice of Second-Line Agent in the Treatment of Recurrent, Potentially Platinum-Sensitive Ovarian Cancer?
Authors: Stephen A. Cannistra
Journal: Journal of Clinical Oncology (2002)

Article Tools EDITORIALS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.5.1158 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11870154 Is There a "Best" Choice of Second-Line Agent in the Treatment of Recurrent, Potentially Platinum-Sensitive Ovarian Cancer? Stephen A. CannistraxStephen A. CannistraSearch for articles by this author Show More Beth Israel Deaconess Medical Center, Boston, MA https://doi.org/10.1200/JCO.2002.20.5.1158 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical Oncology
Gemcitabine in Patients With Relapsed or Cisplatin-Refractory Testicular Cancer
Authors: C. Bokemeyer, A. Gerl, P. Schöffski, A. Harstrick, N. Niederle, J. Beyer, J. Casper, H.J. Schmoll, L. Kanz
Journal: Journal of Clinical Oncology (1999)

PURPOSE: Despite generally high cure rates in patients with metastatic testicular germ cell tumors, patients with incomplete response to cisplatin-based first-line therapy or with relapsed disease after high-dose salvage chemotherapy have a very poor prognosis. This phase II study evaluates the use of gemcitabine in patients with intensively pretreated or cisplatin-refractory testicular germ cell cancers. PATIENTS AND METHODS: Thirty-five patients (median age, 33 years) were enrolled; 31 patients were fully assessable. All patients had metastatic nonseminomatous germ cell tumors; eight patients had extragonadal primary tumors. Twenty patients (63%) had lung metastases, and 12 patients (39%) had liver metastases. The median number of prior cisplatin-based chemotherapy cycles was seven; 22 patients (71%) had received high-dose chemotherapy with autologous stem-cell transplantation, and 19 patients (61%) had received treatment with paclitaxel. Seventeen patients (54%) were considered refractory or absolutely refractory to chemotherapy. RESULTS: Six of 31 assessable patients (19%) responded favorably to gemcitabine, 11 patients (35%) displayed no change, and 14 patients (45%) had disease progression. The median time to treatment failure was 4 months (range, 2 to 9+ months), and the median survival was 6 months (range, 2 to 23 months). Patients received a median of six gemcitabine applications. Ten patients (32%) required dose reductions, mainly owing to hematologic toxicity. Grade 3/4 granulocytopenia occurred in four patients (13%) and grade 3/4 thrombocytopenia in seven patients (22%). One case of severe sepsis was observed. CONCLUSION: Gemcitabine displays antitumor activity in intensively pretreated and refractory germ cell tumors. Responses were observed in approximately 20% of patients, including three of 22 patients after previous high-dose chemotherapy and one of four patients with mediastinal tumors. Gemcitabine may be a reasonable palliative option for intensively pretreated patients and should be further investigated to define its role in the risk-adapted treatment strategies for germ cell tumors.
Indian health ministry refutes UK journal editor’s criticism of health sector
Authors: Cheryl Travasso
Journal: BMJ (2015)

A spat has broken out between India’s health ministry and the editor in chief of the Lancet after he lambasted the Indian government for sidelining the health of its people and putting national security at risk.

In an interview with the Times of India Richard Horton criticised Narendra Modi’s government for ignoring the health sector and failing to generate any new ideas or policies and to commit more money to health.1

The Lancet is due to publish a paper in December that will criticise Modi for sidelining his promise to roll out universal healthcare coverage and for neglecting public health.

Horton told the Times of …
Continuous low-dose infusion of fluorouracil: is the benefit worth the cost?
Authors: J S Macdonald
Journal: Journal of Clinical Oncology (1989)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1989.7.4.412 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 2494306 Continuous low-dose infusion of fluorouracil: is the benefit worth the cost? J S MacdonaldxJ S MacdonaldSearch for articles by this author https://doi.org/10.1200/JCO.1989.7.4.412 First Page PDF © 1989 by American Society of Clinical Oncology
Time-dose factors in chemotherapy: expanding the concept of dose-intensity.
Authors: A J Dembo
Journal: Journal of Clinical Oncology (1987)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1987.5.5.694 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 3572462 Time-dose factors in chemotherapy: expanding the concept of dose-intensity. A J DemboxA J DemboSearch for articles by this author https://doi.org/10.1200/JCO.1987.5.5.694 First Page PDF © 1987 by American Society of Clinical Oncology
Prognostic significance of erythrocyte sedimentation rate in clinical stages I-II of Hodgkin's disease.
Authors: M Tubiana, M Henry-Amar, M V Burgers, B van der Werf-Messing, M Hayat
Journal: Journal of Clinical Oncology (1984)

A prospective study was undertaken in 1963 on the respective prognostic significances of erythrocyte sedimentation rate (ESR) and presence or absence of systemic symptoms in Hodgkin's disease. Six hundred seventy-six patients with clinical stages I or II were included in this study; 376 from 1963 to 1971 who were included in the H1 trial of the European Organization for Research and Treatment of Cancer (EORTC) and 300 who had been enrolled in the EORTC H2 trial from 1972 to 1976. All relevant data and long-term follow-up are available from 649 patients who were analyzed in this study. Multivariate analysis (Cox model) was carried out to assess the prognostic value of ESR independently of the other prognostic parameters and of the treatment. The results showed that of all the prognostic indicators studied, ESR is the one which has the highest correlation with relapse-free survival; however, initial ESR is not correlated with the probability of death after relapse. The presence or absence of systemic symptoms has less prognostic impact. Despite a close correlation between systemic symptoms and ESR, the two are not redundant and it is useful to combine both.
Active-specific immunotherapy for melanoma.
Authors: M S Mitchell, W Harel, R A Kempf, E Hu, J Kan-Mitchell, W D Boswell, G Dean, L Stevenson
Journal: Journal of Clinical Oncology (1990)

Twenty-five patients with metastatic melanoma were treated with a therapeutic vaccine ("theraccine") consisting of allogeneic melanoma lysates and a novel adjuvant, DETOX (Ribi ImmunoChem Research, Inc, Hamilton, MT). Each patient received 200 antigenic units (20 x 10(6) tumor cell equivalents) subcutaneously on weeks 1, 2, 3, 4, and 6. Clinical responses included one complete remission, three partial remissions, and a long-term (17-month) stability. Two other patients had mixed responses, with partial remissions of numerous subcutaneous nodules. Sites of responsive disease included primarily the skin, but ileal, breast, and a liver metastasis also responded. Removal of residual lesions in patients with partial remissions, whose other lesions had disappeared during treatment, led to long disease-free survivals. The median duration of remission was 17 months, with four of the five responders alive for at least 24 months after treatment. An increase in precursors of cytolytic T cells (CTLs) correlated with clinical outcome, when complete, partial, and mixed responses and long-term stability were considered. The CTLs recognized melanoma-associated antigens on many cell lines, but not other types of tumor or normal lymphocytes. Skin-test reactivity to melanoma antigens and serum antibodies against the melanoma cells was unrelated to clinical response. Toxicity was minimal, restricted largely to minor soreness at the site of injection. Only five patients, four of whom were treated with repeated courses, developed severe granulomas. These results confirm that active-specific immunization with allogeneic lysates of melanoma administered with the adjuvant DETOX can induce immunity to melanoma, and can induce regressions of disease in a proportion of patients with metastatic disease with little toxicity.
Erlotinib inhibits signaling mediated by the ligand-independent EGFR variant III mutant
Authors: Sharon Barr, Suzanne Russo, Elizabeth Buck, Stuart Thomson, John Haley, Mark Miglarese, Kenneth Iwata
Journal: Cancer Research (2008)

2560   The epidermal growth factor receptor (EGFR) has been implicated in the growth and survival of various human tumors of epithelial origin. EGFR variant III (vIII), a truncated form of EGFR that exhibits ligand-independent constitutive activation has been reported to be co-expressed with wild-type EGFR in multiple human tumors, including glioma, lung, head and neck, breast, ovarian and prostate. Expression of EGFR vIII has been shown to confer a proliferative advantage in culture, tumorigencity in nude mice and resistance to cytotoxic therapies. Both monoclonal antibodies and low molecular weight inhibitors of EGFR are clinically approved, however their unique mechanisms of action confer differential effects on EGFR-mediated signal transduction. We investigated the ability of erlotinib, a small molecule inhibitor of EGFR, and Ab225 a neutralizing mouse monoclonal antibody directed against the extracellular domain of EGFR, to inhibit signaling mediated by EGFR vIII. Cetuximab (C225), a human-mouse chimeric antibody approved for the treatment of colorectal and head and neck cancers, was derived from Ab225 and the mechanism of action is identical. Because tumor cells that express endogenous EGFR vIII tend to lose expression of that variant when cultured in  vitro, we used isogenic NIH3T3 cells stably transfected to express human wild-type EGFR(CO12 cells) or EGFR vIII (HC2 cells). Although a previously published report indicated that Ab225 can bind vIII, the mechanistic effects of this interaction have not been reported. Here we show that erlotinib and Ab225 differentially inhibited pathways downstream of EGFR and EGFR vIII. In CO12 cells which stably overexpress wt EGFR, both erlotinib and Ab225 can inhibit EGFR phosphorylation, however we observed differential effects on inhibition of downstream effectors. Both erlotinib and, to a lesser degree, Ab225 inhibited signaling in the MAPK cascade as measured by inhibition of Erk phosphorylation, however only erlotinib was able to inhibit the PI3K pathway, as assessed by inhibition of phospho-Akt. In HC2 cells, which stably overexpress EGFR vIII, erlotinib but not Ab225 abrogated phosphorylation of the mutant EGFR. Erlotinib, but not Ab225, was able to inhibit both MAPK and PI3K signaling, consistent with ligand-independent activation of vIII. Furthermore, erlotinib but not Ab225 was able to inhibit proliferation of wt EGFR and vIII-expressing cells in vitro. Taken together, these data provide a rationale for targeting tumors expressing EGFR vIII with a small molecule inhibitor of the EGFR kinase. Because human tumors can co-express wtEGFR and vIII, a low molecular weight EGFR kinase inhibitor combined with a monoclonal antibody to the EGFR extracellular domain may more effectively target tumors in which both wild-type and EGFRvIII are expressed.
Dennis Mackay Jones
Authors: Nigel Stanbridge, Ray Borrow, Alan Curry
Journal: BMJ (2015)

After house jobs, Dennis Mackay Jones embarked on a career in pathology, specialising in medical microbiology. He joined the Public Health Laboratory Service (PHLS) and trained in the Manchester laboratory at Withington Hospital, south Manchester. He was a founder member of the Royal College of Pathologists in 1965 and proceeded to a fellowship in 1977. In 1964 he was appointed consultant microbiologist to Withington and Christie hospitals and honorary consultant microbiologist in the PHLS.

Dennis succeeded John Tobin as director of the regional public health laboratory in Manchester in 1975; a post he held until his retirement in 1995. He was an honorary lecturer in bacteriology and medical microbiology at the University of Manchester for more than 27 years, where he had a crucial influence in the training of overseas students on the diploma in bacteriology course.

Dennis wore several hats: he was a respected clinical microbiologist, whose opinion was frequently sought after by consultant colleagues; as an epidemiologist, he led outbreak investigations both in hospitals and in the …
Abstract 17763: Inhibition of Bone Morphogenetic Protein Signaling Reduces Endothelial-Mesenchymal Transition and Vascular Smooth Muscle Cell Calcification Associated with Matrix Gla Protein Deficiency
Authors: Megan F Burke, Caitlin O’Rourke, Trejeeve Martyn, Hannah R Shakartzi, Timothy E Thayer, Pingcheng Li, Matthias Derwall, Ester Spagnolli, Starsha A Kolodziej, Claire Mayeur, Pawina Jiramongkolchai, Donald B Bloch, Emmanuel S Buys, Paul B Yu, Kenneth D Bloch, Rajeev Malhotra
Journal: Circulation (2014)

Background: Matrix Gla protein (MGP) is an extracellular matrix protein that inhibits bone morphogenetic protein (BMP) signaling in vitro. MGP deficiency induces vascular calcification associated with osteogenic transdifferentiation of endothelial cells (via endothelial-mesenchymal transition, EndMT) and vascular smooth muscle cells (VSMCs). We previously reported that treatment with two pharmacologic inhibitors of BMP signaling reduced aortic calcification in MGP-/- mice. We hypothesized that BMP signaling is essential for EndMT and VSMC osteogenic transdifferentiation induced by MGP deficiency. Methods and Results: Aortic levels of mRNAs encoding markers of osteogenesis (Runx2 and osteopontin) and EndMT (nanog, Sox2, and Oct3/4) were greater in MGP-/- than in wild-type mice (P&lt;0.01 for all). Aortic expression of markers of VSMC differentiation (α-smooth muscle actin, transgelin, and calponin) was less in MGP-/- than in wild-type mice (P&lt;0.001 for all). Treatment of MGP-/- mice with the BMP signaling inhibitor, LDN-193189, reduced expression of both osteogenic and EndMT markers (P&lt;0.05 for all) but did not prevent VSMC de-differentiation. Depletion of MGP in cultured wild-type VSMCs with siRNA specific for MGP (siMGP) was associated with a 30-40% reduction in levels of mRNAs encoding markers of VSMC differentiation (P&lt;0.05 for all), an effect that was not prevented by LDN-193189. Incubation in phosphate-containing media induced greater calcification in siMGP-treated VSMCs than in cells treated with control siRNA (P&lt;0.0001). Treatment with LDN-193189 reduced calcification in siMGP-treated VSMCs (50%, P=0.0003). Conversely, infection of MGP-/- VSMCs with adenovirus specifying MGP increased expression of markers of VSMC differentiation by 60-80% (P&lt;0.01 for all) and decreased calcification by 74% (P=0.03). Conclusions: Inhibition of BMP signaling suppresses osteogenic and EndMT gene programs in MGP-/- mice and reduces calcification of siMGP-treated VSMCs. However, MGP deficiency induces VSMC de-differentiation via a BMP-independent mechanism. These findings suggest that the processes underlying vascular calcification in MGP deficiency are mediated by both BMP signaling-dependent and -independent mechanisms.
Abstract 16531: Hybrid Coronary Revascularization is Associated with Improved Hospital Outcomes and Low Incidence of Death and Repeat Revascularization at Long-Term Follow-Up
Authors: Vankeepuram S Srinivas, Mark A Greenberg, Ernest S Monrad, Mark A Menegus, Sulejman Celaj, Seth Sokol, Ricardo A Bello, Joseph J DeRose
Journal: Circulation (2012)

Background: Hybrid coronary revascularization (HCR) is the planned use of minimally invasive LITA-LAD grafting with percutaneous coronary intervention (PCI) in the treatment of multivessel coronary...
Gene expression profiling of circulating tumor cells from breast cancer patients
Authors: M. M. Magbanua, J. E. Lang, J. Scott, J. R. Crothers, S. Federman, C. Haqq, J. Park
Journal: Journal of Clinical Oncology (2006)

10769 Background: Levels of circulating tumor cells (CTC) have prognostic and predictive significance in metastatic breast cancer. However, since CTCs are extremely rare, little is known about the actual phenotype of these cells. In order to characterize these cells, we performed cDNA microarray analyses of CTC isolated from peripheral blood (PB) of breast cancer patients. Methods: CTCs were directly isolated via immunomagnetic enrichment (IE) followed by fluorescence activated cell sorting (FACS). Total RNA was then subjected to two rounds of linear amplification and hybridized to cDNA microarrays (∼40,000 cDNAs). Validation studies used spiked BT474 cells. Clinical studies used PB (10–20 ml) from patients with metastatic breast cancer. Results: Rare spiked tumor cells (e.g., 320 cells in 10 mL PB) were efficiently recovered by IE/FACS (50% yield). Expression profiles of recovered cells, both by TaqMan of a 37 gene panel as well as by global gene expression analysis, matched that of BT474 cells in culture. In contrast, these profiles were clearly distinct from that of normal PB, ruling out significant contamination from blood elements. In clinical studies, IE/FACS isolated small numbers of CTCs (10–1000 cells). Expression profiles of CTCs were compared to that of normal blood, primary breast tumors, and normal epithelial samples. Unsupervised hierarchical clustering revealed that CTC profiles were readily distinguished from that of normal blood and normal epithelium; and further analysis revealed that CTC cluster with a subset of primary breast tumors, particularly the basal-like phenotype. Candidate genes associated with the CTC phenotype were also identified. Conclusions: We have developed and validated a method to isolate rare CTCs and profile them via cDNA microarray analysis. In addition, our gene expression analyses of CTC further provide evidence to the malignant nature of these cells. Further expression profiling of CTC may yield insights into their phenotype, pathophysiology and potential as biomarkers. [Table: see text]