tbuckley/cabot-search huggingface dataset:
A Central Role for HER3 in <i>HER2</i>-Amplified Breast Cancer: Implications for Targeted Therapy
Authors: Si Tuen Lee-Hoeflich, Lisa Crocker, Evelyn Yao, Thinh Pham, Xander Munroe, Klaus P. Hoeflich, Mark X. Sliwkowski, Howard M. Stern
Journal: Cancer Research (2008)

Abstract Epidermal growth factor receptor (EGFR) and HER3 each form heterodimers with HER2 and have independently been implicated as key coreceptors that drive HER2-amplified breast cancer. Some studies suggest a dominant role for EGFR, a notion of renewed interest given the development of dual HER2/EGFR small-molecule inhibitors. Other studies point to HER3 as the primary coreceptor. To clarify the relative contributions of EGFR and HER3 to HER2 signaling, we studied receptor knockdown via small interfering RNA technology across a panel of six HER2-overexpressing cell lines. Interestingly, HER3 was as critical as HER2 for maintaining cell proliferation in most cell lines, whereas EGFR was dispensable. Induction of HER3 knockdown in the HER2-overexpressing BT474M1 cell line was found to inhibit growth in three-dimensional culture and induce rapid tumor regression of in vivo xenografts. Furthermore, preferential phosphorylation of HER3, but not EGFR, was observed in HER2-amplified breast cancer tissues. Given these data suggesting HER3 as an important therapeutic target, we examined the activity of pertuzumab, a HER2 antibody that inhibits HER3 signaling by blocking ligand-induced HER2/HER3 heterodimerization. Pertuzumab inhibited ligand-dependent morphogenesis in three-dimensional culture and induced tumor regression in the heregulin-dependent MDA-MB-175 xenograft model. Importantly, these activities of pertuzumab were distinct from those of trastuzumab, a monoclonal antibody currently used for treatment of HER2-amplified breast cancer patients. Our data suggest that inhibition of HER3 may be more clinically relevant than inhibition of EGFR in HER2-amplified breast cancer and also suggest that adding pertuzumab to trastuzumab may augment therapeutic benefit by blocking HER2/HER3 signaling. [Cancer Res 2008;68(14):5878–87]
Rapid induction of hepatic fibrosis in the gerbil after the parenteral administration of iron-dextran complex
Authors: Philip Carthew, Richard E. Edwards, Andrew G. Smith, Barbara Dorman, Jean E. Francis
Journal: Hepatology (1991)

The parenteral administration of iron-dextran complex to gerbils caused hepatic hemosiderosis and fibrosis after 6 wk. Type I and III collagen synthesis in the liver developed from perisinusoidal stellate cells that are often referred to as myofibroblasts. Immunohistologically these cells were shown to have large intracellular deposits of ferritin. The hepatic fibrosis appeared to be associated with aggregates of these cells rather than the aggregates of Kupffer cells, which also occur in hemosiderosis in the liver. No appreciable necrosis of hepatocytes to trigger the fibrotic response was found, so that the fibrosis appeared to be related to the accumulation of ferritin in the perisinusoidal stellate cells. In contrast, rats and mice did not accumulate ferritin in their perisinusoidal cells or develop hepatic fibrosis in response to parenterally administered iron, although they accumulated similar or greater amounts of total iron in their livers. The rapid induction of hepatic fibrosis in gerbils in response to parenterally administered iron will provide a model to investigate the mechanism of induction of collagen deposition in response to iron overload and a means of quickly evaluating therapeutic treatments for iron overload-induced fibrosis in vivo using iron-chelating drugs.
Release of vasoactive intestinal polypeptide from the cat small intestine exposed to cholera toxin.
Authors: J Cassuto, J Fahrenkrug, M Jodal, R Tuttle, O Lundgren
Journal: Gut (1981)

During a four hour observation period vasoactive intestinal polypeptide (VIP) is released in increasing amounts from the feline small intestine exposed to cholera toxin. As VIP is known to be located almost exclusively in the intestinal nerves, the present findings strongly suggest that cholera toxin activates the enteric nervous system. The findings of this and other studies performed in this laboratory lead to the proposal that the choleraic secretion is, at least in part, secondary to the activation of intramural nervous reflexes in the gut.
NOTIFICATION OF HIV CARRIERS: POSSIBLE EFFECT ON UPTAKE OF AIDS TESTING
Authors: Gen Ohi, Tomonori Hasegawa, Ichiro Kai, Yutaka Inaba, Tomoyo Miyama, Mitsuhiro Kamakura, Hiroaki Terao, Wataru Hirano, Yasuki Kobayashi, Yasuko Muramatsu, Masami Ashizawa, Ichiro Uemura, Takeshi Niimi
Journal: The Lancet (1988)
Variability in vibration perception threshold among sites: a potential source of error in biothesiometry
Authors: G. Williams, J. S Gill, V. Aber, H. M Mather
Journal: BMJ (1988)

Vibration perception threshold was measured with a biothesiometer by a single observer at both medial malleoli and both big toes in 110 diabetic patients aged 15-65 selected at random and in 64 non-diabetic subjects aged 20-65. The vibration perception threshold showed appreciable individual variation both between contralateral sites and between ipsilateral sites, differing by at least 30% between the big toes in 26 (24%) of the diabetic patients and 16 (25%) of the non-diabetic group. Variability between sites was significantly greater in the diabetics than the normal subjects. The vibration perception threshold exceeded published normal values at one or more sites in 22 of the diabetic patients but at all four sites in only four. The wide variability in vibration perception threshold among sites may be due to the tissue characteristics locally and, in diabetic patients, possibly to asymmetric neuropathy. Biothesiometer readings at single or unilateral sites may be unrepresentative or misleading.
Dose-Adjusted EPOCH-Rituximab Combined With Fludarabine Provides an Effective Bridge to Reduced-Intensity Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Lymphoid Malignancies
Authors: Rachel B. Salit, Daniel H. Fowler, Wyndham H. Wilson, Robert M. Dean, Steven Z. Pavletic, Kieron Dunleavy, Frances Hakim, Terry J. Fry, Seth M. Steinberg, Thomas E. Hughes, Jeanne Odom, Kelly Bryant, Ronald E. Gress, Michael R. Bishop
Journal: Journal of Clinical Oncology (2012)

There is currently no standard chemotherapy regimen for patients with lymphoid malignancies being considered for reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation (RIC-alloHSCT). The ideal regimen would provide disease control and result in lymphocyte depletion to facilitate engraftment. To this end, we developed a novel regimen by adding fludarabine to dose-adjusted continuous-infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus with or without rituximab (DA-EPOCH-F/R).One hundred forty-seven patients with lymphoid malignancy (median age, 50 years) who had heavily pretreated (median prior regimens, three) and chemo-refractory (47%) disease were treated with DA-EPOCH-F/R before RIC-alloHSCT. Patients received one to three consecutive cycles until achieving lymphocyte depletion (CD4(+) count < 200/μL) or progressive disease.Overall response rate was 41%; 39% of patients had stable disease. Toxicity included grade 4 neutropenia in 65% and thrombocytopenia in 25% of patients. DA-EPOCH-F/R resulted in lymphocyte depletion (P < .001), which was inversely associated with serum interleukin (IL) 7 and IL-15 levels. Of 147 patients, 143 patients proceeded to RIC-alloHSCT. Patients with lower CD3(+) (P < .001), CD4(+) (P < .001), and CD8(+) (P < .001) T-cell counts after DA-EPOCH-F/R were more likely to achieve full donor lymphoid chimerism by day +14 after transplant. Relative to nonresponders to DA-EPOCH-F/R, patients with complete and partial response had increased event-free survival (77.4 v 4.8 months; P < .001) and overall survival (98.5 v 16.2 months; P < .001).DA-EPOCH-F/R safely provides tumor cytoreduction and lymphocyte depletion, thereby offering a bridge to RIC-alloHSCT in patients with aggressive lymphoid malignancies.
1992 Homer Smith Award. Fluid secretion, cellular proliferation, and the pathogenesis of renal epithelial cysts.
Authors: J J Grantham
Journal: Journal of the American Society of Nephrology (1993)

Renal cysts, caused by hereditary or acquired disorders, develop in tubule segments. The central pathogenetic elements of cyst formation include abnormal cellular proliferation, accumulation of intratubular liquid, and remodeling of the extracellular matrix. This review addresses the pathogenetic basis of liquid collection and cellular proliferation. Cavity liquid. At an early stage of growth, most renal cysts become detached from the tubule segment of origin; thus, transepithelial fluid secretion is the source of the liquid in most macroscopic cysts. Evidence from in situ and in vitro studies of intact cysts and epithelium cultured from cyst walls and normal renal tubules indicates that: (1) solutes (NaCl) are secreted into the cysts and water flows secondarily by osmosis; (2) active Na+ transport has a primary or secondary role in the secretion of Na+ and Cl-; and (3) the rate of liquid secretion can be modulated by hormones (arginine vasopressin), autocoids (prostaglandin E1 and E2), growth factors (epidermal growth factor), and unknown factors in cyst fluids. Cellular proliferation. Epithelial cells of renal cysts appear to proliferate more than normal. Each cyst resembles a tumor, except that the mass is composed primarily of liquid rather than cells. The proliferation of cyst epithelial cells is associated with: (1) abnormal expression of proto-oncogenes; (2) abnormal displays of morphologic and biochemical phenotypic markers; and (3) abnormal responsiveness to growth factors. The maturation arrest hypothesis, introduced as a framework to explore the pathogenetic basis of all renal cysts, supposes that the epithelial cells comprising cysts are "locked" in an immature, dedifferentiated state. Therapeutic strategies to control the growth of renal cysts may reasonably target processes that inhibit fluid secretion, maximize fluid absorption, and redifferentiate the immature and abnormally proliferative epithelial cells within cysts.
Response of C3H-A vy fB Female Mice to a Low Oncogenic, Milk-Borne Mammary Tumor Virus
Authors: George Vlahakis
Journal: JNCI Journal of the National Cancer Institute (1975)

When low oncogenic milk-borne mammary tumor virus (MTV) of strain DD was tested in C3H-AvyfB mice, as compared with the similar strain C3HfB, mammary tumors occurred with a higher incidence and at lower age in C3H-AvyfBfDD (with DD-MTV) than in C3HfBfDD (with DD-MTV), as observed in virgin females. Since the effect of breeding tended to mask any difference between the breeders, mammary tumor incidences were similar with a slightly higher age at tumor occurrence in the C3H-AvyfBfDD females. Thus the C3H-AvyfB virgins (with the Avy gene) were almost as susceptible to mammary tumors with the less potent DD-MTV as were C3HfB virgins with the more virulent C3H-MTV of strain C3H.
Pharmacogenetics and ethnically targeted therapies
Authors: Raj Bhopal, Taslin Rahemtulla
Journal: BMJ (2005)

Health inequalities under New Labour Relative rather than absolute gaps are important over time and placeEditor-We agree with Shaw et al that the method of measuring inequality in health outcomes used in setting the government targets is problematic (A Low, UKPHA (UK Public Health Association), 13th annual public health forum, Gateshead, April 2005). 1 However, the government's targets are based on reducing relative gaps in life expectancy and infant mortality. 2 The slope index of inequality (SII) used by Shaw et al measures absolute gaps.
Ranitidine does not affect psoriasis: A multicenter, double-blind, placebo-controlled study
Authors: I.M. Zonneveld, M.M.H.M. Meinardi, T. Karlsmark, U. Broby Johansen, G.R.R. Kuiters, L. Hamminga, B. Staberg, A.J. van't Veen, P.M.M. Bossuyt, J.C.G. van Niel, J.D. Bos
Journal: Journal of the American Academy of Dermatology (1997)
Protein kinase C mediates platelet secretion and thrombus formation through protein kinase D2
Authors: Olga Konopatskaya, Sharon A. Matthews, Matthew T. Harper, Karen Gilio, Judith M. E. M. Cosemans, Christopher M. Williams, Maria N. Navarro, Deborah A. Carter, Johan W. M. Heemskerk, Michael Leitges, Doreen Cantrell, Alastair W. Poole
Journal: Blood (2011)
Properties of RBL-5 Leukemia Cells Cultivated In Vitro
Authors: Wu-Tse Liu, Michael J. Rogers, Lloyd L. Law, Kenneth S. S. Chang
Journal: JNCI Journal of the National Cancer Institute (1977)

RBL-5 leukemia induced by Rauscher murine leukemia virus (R-MuLV) carried in the ascites form in C57BL/6 mice was cultivated in vitro and passaged continuously. Both low- and high-passage cells released the same level of murine leukemia virus, as detected by the XC plaque assay. Membrane antigens of the cultivated cells were also detected by the indirect immunofluorescence assay. Both low- and high-passage cells showed the same activity of antigen detectable by anti-R-MuLV serum, whereas only the high-passage cells reacted strongly against a syngeneic antiserum to RBL-5 crude membrane (CM). The oncogenicity of the low and high passages of the cultivated cells was compared with the ascites cells. The results indicated that the oncogenic potential of the cells gradually decreased during in vitro passage. The accumulation or retention of CM antigen on the membrane of the high-passage cells suggested that their decreased oncogenic potential might be due to increased immunogenicity and/or immunosensitivity. This strengthened the hypothesis that the cellular transplantation antigens are not identical to type C viral antigens, since the R-MuLV antigens were not altered during passage in vitro.
Evidence for the Involvement of VAR2CSA in Pregnancy-associated Malaria
Authors: Ali Salanti, Madeleine Dahlbäck, Louise Turner, Morten A. Nielsen, Lea Barfod, Pamela Magistrado, Anja T.R. Jensen, Thomas Lavstsen, Michael F. Ofori, Kevin Marsh, Lars Hviid, Thor G. Theander
Journal: The Journal of Experimental Medicine (2004)

In Plasmodium falciparum-endemic areas, pregnancy-associated malaria (PAM) is an important health problem. The condition is precipitated by accumulation of parasite-infected erythrocytes (IEs) in the placenta, and this process is mediated by parasite-encoded variant surface antigens (VSA) binding to chondroitin sulfate A (CSA). Parasites causing PAM express unique VSA types, VSAPAM, which can be serologically classified as sex specific and parity dependent. It is sex specific because men from malaria-endemic areas do not develop VSAPAM antibodies; it is parity dependent because women acquire anti-VSAPAM immunoglobulin (Ig) G as a function of parity. Previously, it was shown that transcription of var2csa is up-regulated in placental parasites and parasites selected for CSA binding. Here, we show the following: (a) that VAR2CSA is expressed on the surface of CSA-selected IEs; (b) that VAR2CSA is recognized by endemic plasma in a sex-specific and parity-dependent manner; (c) that high anti-VAR2CSA IgG levels can be found in pregnant women from both West and East Africa; and (d) that women with high plasma levels of anti-VAR2CSA IgG give birth to markedly heavier babies and have a much lower risk of delivering low birth weight children than women with low levels.
Adoptive Transfer of Epstein-Barr Virus (EBV) Nuclear Antigen 1–Specific T Cells As Treatment for EBV Reactivation and Lymphoproliferative Disorders After Allogeneic Stem-Cell Transplantation
Authors: Vanya Icheva, Simone Kayser, Daniel Wolff, Sebastian Tuve, Christina Kyzirakos, Wolfgang Bethge, Johann Greil, Michael H. Albert, Wolfgang Schwinger, Michaela Nathrath, Michael Schumm, Stefan Stevanovic, Rupert Handgretinger, Peter Lang, Tobias Feuchtinger
Journal: Journal of Clinical Oncology (2012)

Reactivation of Epstein-Barr virus (EBV) after allogeneic stem-cell transplantation (SCT) can lead to severe life-threatening infections and trigger post-transplantation lymphoproliferative disease (PTLD). Since EBV-specific T cells could prevent PTLD, cellular immunotherapy has been a promising treatment option. However, generation of antigen-specific T-cell populations has been difficult within a short time frame.To improve availability in urgent clinical conditions, we developed a rapid protocol for isolation of polyclonal EBV nuclear antigen 1 (EBNA-1) -specific T cells by using an interferon gamma (IFN-γ) capture technique.We report on the use of adoptive transfer of EBNA-1-specific T cells in 10 pediatric and adult patients with EBV viremia and/or PTLD after SCT. No acute toxicity or graft-versus-host disease (GVHD) of more than grade 2 occurred as a result of adoptive T-cell transfer. In vivo expansion of transferred EBNA-1-specific T cells was observed in eight of 10 patients after a median of 16 days following adoptive transfer that was associated with clinical and virologic response in seven of them (70%). None of the responders had EBV-associated mortality. Within clinical responders, three patients were disease free by the day of last follow-up (2 to 36 months), three patients died of other infectious complications, and one patient died as a result of relapse of malignancy. EBV-related mortality was observed in two of 10 patients, and another patient had ongoing viremia without clinical symptoms at last follow-up.Adoptive ex vivo transfer of EBNA-1-specific T cells is a feasible and well-tolerated therapeutic option, representing a fast and efficient procedure to achieve reconstitution of antiviral T-cell immunity after SCT.
Topical treatment of life threatening haemoptysis from aspergillomas.
Authors: M Rumbak, G Kohler, C Eastrige, H Winer-Muram, M Gavant
Journal: Thorax (1996)

The efficacy of topical treatment of 12 episodes of severe life threatening haemoptysis from a pulmonary aspergilloma in 11 patients is reviewed.A retrospective review was performed on five white and six African-American patients of mean age 49 years. The underlying diseases were bronchiectasis, sarcoidosis, tuberculosis, or histoplasmosis. The patients were prospectively considered poor surgical risks because they had a forced expiratory volume in one second (FEV1) of < 50% predicted and an arterial oxygen tension (PaO2) of < 7.95 kPa breathing room air. As surgical intervention was not possible, local intracavitary instillation of sodium or potassium iodide was performed. Two patients were previously treated with amphotericin B. In one patient sodium iodide alone was used and in the remaining eight potassium iodide alone was instilled. The transcricothyroid approach was used in six patients and the percutaneous approach in five.Haemoptysis ceased within 72 hours in all patients after the instillation of sodium or potassium iodide. There was no morbidity or mortality, and side effects included slight irritation on instillation of the iodide solution and occasional cough which was easily controlled. All patients were alive at least one year later.Intracavitary treatment is a viable option in the poor risk patient with life threatening haemoptysis from an aspergilloma.
ChREBP, a Transcriptional Regulator of Glucose and Lipid Metabolism
Authors: Catherine Postic, Renaud Dentin, Pierre-Damien Denechaud, Jean Girard
Journal: Annual Review of Nutrition (2007)

Dysregulations in hepatic lipid synthesis are often associated with obesity and type 2 diabetes, and therefore a perfect understanding of the regulation of this metabolic pathway appears essential to identify potential therapeutic targets. Recently, the transcription factor ChREBP (carbohydrate-responsive element-binding protein) has emerged as a major mediator of glucose action on lipogenic gene expression and as a key determinant of lipid synthesis in vivo. Indeed, liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in obese ob/ob mice. Since ChREBP cellular localization is a determinant of its functional activity, a better knowledge of the mechanisms involved in regulating its nucleo-cytoplasmic shuttling and/or its post-translational activation is crucial in both physiology and physiopathology. Here, we review some of the studies that have begun to elucidate the regulation and function of this key transcription factor in liver.
Molecular Mechanisms of Patupilone Resistance
Authors: Simona Mozzetti, Raffaella Iantomasi, Ilaria De Maria, Silvia Prislei, Marisa Mariani, Alessia Camperchioli, Silvia Bartollino, Daniela Gallo, Giovanni Scambia, Cristiano Ferlini
Journal: Cancer Research (2008)

Abstract Patupilone is an epothilone in advanced clinical development that has shown promising efficacy in heavily pretreated patients. This study aimed at characterizing the mechanisms of patupilone activity in resistant patients. To this end, we generated patupilone-resistant cells using two cellular models, the first characterized by high chemosensitivity and low class III β-tubulin (TUBB3) expression (A2780), and the second by low chemosensitivity and high TUBB3 expression (OVCAR-3). The obtained cell lines were named EPO3 and OVCAR-EPO, respectively. The same selection procedure was done in A2780 cells to generate a paclitaxel-resistant cell line (TAX50). Factors of resistance are expected to increase in the drug-resistant cell lines, whereas factors of drug sensitivity will be down-regulated. Using this approach, we found up-regulation of TUBB3 in TAX50, but not EPO3, cells, showing that TUBB3 mediates the resistance to paclitaxel but not to patupilone. Moreover, TUBB3 was a factor of patupilone sensitivity because OVCAR-EPO cells exhibited a dramatic reduction of TUBB3 and a concomitant sensitization to hypoxia and cisplatin-based chemotherapy. To identify the mechanisms underlying patupilone resistance, tubulin genes were sequenced, thereby revealing that a prominent mechanism of drug resistance is represented by point mutations in class I β-tubulin. Overall, these results suggest that paclitaxel and patupilone have nonoverlapping mechanisms of resistance, thus allowing the use of patupilone for those patients relapsing after paclitaxel-based chemotherapy. Furthermore, patupilone represents a promising first-line option for the treatment of high-risk ovarian cancer patients, who exhibit high TUBB3 levels and poor response to standard paclitaxel-platin chemotherapy. [Cancer Res 2008;68(24):10197–204]