tbuckley/cabot-search huggingface dataset:
Local Biosynthesis of Estrogen in Human Endometrial Carcinoma through Tumor-Stromal Cell Interactions
Authors: Naomi Takahashi-Shiga, Hiroki Utsunomiya, Yasuhiro Miki, Satoru Nagase, Rika Kobayashi, Mitsuyo Matsumoto, Hitoshi Niikura, Kiyoshi Ito, Nobuo Yaegashi
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The metabolism and synthesis of intratumoral estrogens are thought to play a very important role in the etiology and progression of endometrial carcinoma. Aromatase is a key enzyme in the conversion of androgens to estrogens, and aromatase localization studies have reported that aromatase immunoreactivity and mRNA were detected mainly in stromal cells. However, the effect of tumor-stromal interactions on local estrogen biosynthesis in endometrial carcinomas remains largely unknown. Experimental Design: The endometrial carcinoma cell lines (Ishikawa and RL95-2) and breast carcinoma cell line (MCF-7) were cocultured with stromal cells isolated from endometrial carcinomas, and aromatization activity was measured using liquid chromatography-tandem mass spectrometry. We then confirmed the local biosynthesis of estrogens and tumor-stromal interactions on aromatase activity in Ishikawa and RL95-2 cells. In addition, we also examined the effects of aromatase inhibitors on cell proliferation. Results: Aromatase activity was significantly higher in cocultures with Ishikawa or RL95-2 than in each monoculture, respectively. Estrone (E1) concentrations were significantly higher than estradiol (E2) concentrations in Ishikawa and RL95-2 cells, whereas E2 was significantly higher than E1 in MCF-7 cells. Cell proliferation was significantly inhibited in Ishikawa and RL95-2 cell cultures treated with aromatase inhibitors compared with control cultures. Conclusions: These results indicate the contribution of not only E2 but also E1 to cancer cell proliferation in endometrial carcinoma. Our study may provide important information on metabolism and synthesis of intratumoral estrogens with regard to the etiology and progression of endometrial carcinoma, thus helping to achieve improved clinical responses in patients with endometrial carcinoma, who are treated with aromatase inhibitors. (Clin Cancer Res 2009;15(19):6028–34)
Interaction between p53 codon 72 polymorphism and melanocortin 1 receptor variants on suntan response and cutaneous melanoma risk
Authors: H. Nan, A.A. Qureshi, D.J. Hunter, J. Han
Journal: British Journal of Dermatology (2008)

Journal Article Interaction between p53 codon 72 polymorphism and melanocortin 1 receptor variants on suntan response and cutaneous melanoma risk Get access H. Nan, H. Nan Program in Molecular and Genetic EpidemiologyDepartment of Epidemiology, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115, U.S.A.Channing Laboratory, Department of Medicine Correspondence: Hongmei Nan. E‐mail: hnan@hsph.harvard.edu Search for other works by this author on: Oxford Academic Google Scholar A.A. Qureshi, A.A. Qureshi Channing Laboratory, Department of MedicineDepartment of Dermatology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar D.J. Hunter, D.J. Hunter Program in Molecular and Genetic EpidemiologyDepartment of Epidemiology, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115, U.S.A.Channing Laboratory, Department of Medicine Search for other works by this author on: Oxford Academic Google Scholar J. Han J. Han Program in Molecular and Genetic EpidemiologyChanning Laboratory, Department of Medicine Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 159, Issue 2, 1 August 2008, Pages 314–321, https://doi.org/10.1111/j.1365-2133.2008.08624.x Published: 01 August 2008
Transplantation tolerance in adult rats using total lymphoid irradiation: permanent survival of skin, heart, and marrow allografts.
Authors: S Slavin, B Reitz, C P Bieber, H S Kaplan, S Strober
Journal: The Journal of Experimental Medicine (1978)

Lewis rats given total lymphoid irradiation (TLI) accepted bone marrow allografts from AgB-incompatible donors. The chimeras showed no clinical signs of graft-versus-host disease. Skin allografts from the marrow donor strain survived for more than 150 days on the chimeras. However, third-party skin grafts were rejected promptly. Although heart allografts survived more than 300 days in Lewis recipients given TLI and bone marrow allografts, detectable levels of chimerism were not required for permanent survival.
Innovations in Health Care Delivery
Authors: Donald Berwick, Howard Bauchner, Phil B. Fontanarosa
Journal: JAMA (2015)

The pace of innovation has become a gauge for the health of national economies, individual businesses, and educational systems.It is a crucial gauge, too, for the health of the health care industry.Health care innovation has centuries of tradition, as far back as Galen, Vesalius, and the champions of the scientific method.It is now a vast field.In 2015, health care innovation comprises entire subindustries developing new drugs, diagnostic tests, therapeutic devices, prosthetics, information technologies, and more.In 2012, total estimated US medical and health research expenditures were about $130 billion, or just over 4.4% of total US health care expenditures. 1The vast majority of this investment is in biomedical and technological research and underlying basic sciences.From the viewpoint of health care delivery, however, aggravating shortfalls persist in health care innovation.First is the translational shortfall.Biomedical and biotechnical innovations can improve health only if they actually reach patients and communities, only if their value is accurately assessed, and only if choices about which innovations are used for whom and when reflect those assessments.This proper and prudent translation of innovations into practice is famously slow and deficient. 2Recent efforts have been mounted to speed up the process, such as the Bench-to-Bedside initiative of the National Institutes of Health, 3 but how much they are helping, and at what cost, is not yet known.Second is a shortfall in focus.The bulk of innovations in health care have added cost, often with little proven benefit, to an industry reeling from outside and inside cost pressures.Whereas innovations in other industries have often steadily reduced costs to consumers while improving functionality (eg, laptop computers, cellphones, and web-based access to information), health care shifts more and more costs to consumers, 4 takes an ever-increasing share of public and private budgets, and even flirts with rationing as allegedly inevitable.Under these circumstances, it could be expected, and hoped for, that a vast and authentic shift of innovation energies would occur toward changes that reduce costs while improving the outcomes and experiences of patients, families, and communities.No such shift is evident yet at anything near the scale needed.Third is a shortfall in the democratization of capacity.The millennial ethos and new information capabilities have combined through innovations to produce previously undreamed-of capacities for people to meet their own needs, with less intermediation of layers of supply.People use ATMs instead of bank tellers and queues, make travel reservations on-
The relationship between the repetitive extrasystole threshold and the ventricular fibrillation threshold in the dog. Non-parallel changes following pharmacological intervention.
Authors: P Jaillon, I Schnittger, J C Griffin, R A Winkle
Journal: Circulation Research (1980)

We studied the relationship between the repetitive (two or more) extrasystole threshold (RET) and ventricular fibrillation threshold (VFT) in 38 pentobarbital anesthetized dogs.A 100-Hz train of 16 4-msec stimuli was delivered to the right ventricle during the T wave of every 12th paced supraventricular beat.Current was increased in 1-mA steps until ventricular fibrillation occurred.Five measurements were made in each dog at 15-minute intervals.In 10.3% of the VFT determinations, VF was not preceded by a repetitive extrasystolic activity.For the remainder regression analysis of the correlation between RET and VFT revealed an r = 0.37 (P< 0.001).The average RET was 54.6% of the VFT (5.4 ± 1.6 vs. 10.2 ± 2.4 mA); however, it ranged from 5% to 98%.Five animals received a 90minute lidocaine infusion (0.3 mg/kg per min).Although lidocaine significantly increased both RET and VFT as a linear function of log lidocaine plasma concentration (C p ), the mean slope of the VFT vs. log lidocaine C p regression line was significantly different from that of RET vs. log lidocaine C p regression line (P < 0.05).Nine dogs infused with the /S-blocker acebutolol (0.5 mg/kg in five and 2 mg/ kg in four dogs) showed a concentration-dependent increase of VFT without significant increase of RET, and the mean slopes of the response vs. log C p regression lines were significantly different (P <0.01).We conclude that in the control state the RET may be related to the VFT.However, during pharmacological studies, VFT and RET do not necessarily change in parallel.
Contribution of Plantar Fascia to the Increased Forefoot Pressures in Diabetic Patients
Authors: Emanuela D’Ambrogi, Laura Giurato, Maria Antonietta D’Agostino, Claudia Giacomozzi, Velio Macellari, Antonella Caselli, Luigi Uccioli
Journal: Diabetes Care (2003)

Secondary to peripheral neuropathy, plantar hyperpressure is a proven risk factor for foot ulceration. But limited joint mobility (LJM) and soft tissue abnormalities may also contribute. The aim of this study was to evaluate the relationships among thickness of plantar fascia, mobility of the metatarso-phalangeal joint, and forces expressed under the metatarsal heads.We evaluated 61 diabetic patients: 27 without neuropathy (D group), 19 with neuropathy (DN group), and 15 with previous neuropathic foot ulceration (DNPU group). We also examined 21 control subjects (C). Ultrasound evaluation was performed with a high resolution 8- to 10-MHz linear array (Toshiba Tosbee SSA 240). The foot loading pattern was evaluated with a piezo-dynamometric platform. First metatarso-phalangeal joint mobility was assessed with a mechanic goniometer.Diabetic patients presented increased thickness of plantar fascia (D 2.9 +/- 1.2 mm, DN 3.0 +/- 0.8 mm, DNPU 3.1 +/- 1.0 mm, and C 2.0 +/- 0.5.mm; P < 0.05), and significantly reduced motion range at the metatarso-phalangeal joint (D 54.0 +/- 29.4 degrees, DN 54.9 +/- 17.2 degrees, DNPU 46.8 +/- 20.7 degrees, and C 100.0 +/- 10.0 degrees; P < 0.05). The evaluation of foot-floor interaction under the metatarsal heads showed increased vertical forces in DN and DNPU and increased medio-lateral forces in DNPU. An inverse correlation was found between the thickness of plantar fascia and metatarso-phalangeal joint mobility (r = -0.53). The thickness of plantar fascia was directly correlated with vertical forces under the metatarsal heads (r = 0.52).In diabetic patients, soft tissue involvement may contribute to the increase of vertical forces under the metatarsal heads. Changes in the structure of plantar fascia may also influence the mobility of the first metatarso-phalangeal joint.
B7 Blockade Alters the Balance between Regulatory T Cells and Tumor-reactive T Cells for Immunotherapy of Cancer
Authors: Penghui Zhou, Xincheng Zheng, Huiming Zhang, Yang Liu, Pan Zheng
Journal: Clinical Cancer Research (2009)

Abstract Purpose: In prostate cancer-bearing host, regulatory T (Treg) cells restrain activity of tumor antigen-specific T cells. Because B7:CD28 interactions are needed for both function of CD4+CD25+ Treg cells and CD8+ effective T cells, targeting this pathway may help to overcome the immunotherapy barriers. Experimental Design: The anti-B7-1/B7-2 monoclonal antibodies were administered to a transgenic mouse model of prostate cancer (TRAMP) ectopically expressing SV40 large T antigen in different tumor development stages for prevention and therapy of prostate cancer. The treatment was also tested in treating transplanted MC38 colon adenocarcinoma in mice. Results: Here, we showed that short-term administration of anti-B7-1/B7-2 monoclonal antibodies in TRAMP mice leads to significant inhibited primary tumor growth and the size of metastatic lesions. The treatment is effective to inhibit MC38 colon cancer growth. Correspondingly, this treatment results in a transient reduction of Treg in both thymus and the periphery. In vivo cytotoxicity assay revealed T antigen-specific CTL effectors in anti-B7-treated but not control IgG-treated TRAMP mice. Conclusions: Transient blockade of B7-1/B7-2 alters the balance between Treg and cancer-reactive T cells to enhance cancer immunotherapy.
Outcomes Among Black Patients With Stage II and III Colon Cancer Receiving Chemotherapy: An Analysis of ACCENT Adjuvant Trials
Authors: G. Yothers, D. J. Sargent, N. Wolmark, R. M. Goldberg, M. J. O'Connell, J. K. Benedetti, L. B. Saltz, J. J. Dignam, A. W. Blackstock
Journal: JNCI Journal of the National Cancer Institute (2011)

Among patients with resected colon cancer, black patients have worse survival than whites. We investigated whether disparities in survival and related endpoints would persist when patients were treated with identical therapies in controlled clinical trials.We assessed 14,611 patients (1218 black and 13,393 white) who received standardized adjuvant treatment in 12 randomized controlled clinical trials conducted in North America for resected stage II and stage III colon cancer between 1977 and 2002. Individual patient data on covariates and outcomes were extracted from the Adjuvant Colon Cancer ENdpoinTs (ACCENT) database. The endpoints examined in this meta-analysis were overall survival (time to death), recurrence-free survival (time to recurrence or death), and recurrence-free interval (time to recurrence). Cox models were stratified by study and controlled for sex, stage, age, and treatment to determine the effect of race. Kaplan-Meier estimates were adjusted for similar covariates to control for confounding. All statistical tests were two-sided.Black patients were younger than whites (median age, 58 vs 61 years, respectively; P < .001) and more likely to be female (55% vs 45%, respectively; P < .001). Overall survival was worse in black patients than whites (hazard ratio [HR] of death = 1.22, 95% confidence interval [CI] = 1.11 to 1.34, P < .001). Five-year overall survival rates for blacks and whites were 68.2% and 72.8%, respectively. When subsets defined by sex, stage, and age were analyzed, overall survival was consistently worse in black patients. Recurrence-free survival was worse in black patients than whites (HR of recurrence or death = 1.14, 95% CI = 1.04 to 1.24, P = .0045). Three-year recurrence-free survival rates in blacks and whites were 68.4% and 72.1%, respectively. In contrast, recurrence-free interval was similar in black and white patients (HR of recurrence = 1.08, 95% CI = 0.97 to 1.19, P = .15). Three-year recurrence-free interval rates in blacks and whites were 71.3% and 74.2%, respectively.Black patients with resected stage II and stage III colon cancer who were treated with the same therapy as white patients experienced worse overall and recurrence-free survival, but similar recurrence-free interval, compared with white patients. The differences in survival may be mostly because of factors unrelated to the patients' adjuvant colon cancer treatment.
Supplementation with Branched-chain Amino Acids Inhibits Azoxymethane-induced Colonic Preneoplastic Lesions in Male C57BL/KsJ-<i>db/db</i> Mice
Authors: Masahito Shimizu, Yohei Shirakami, Junpei Iwasa, Makoto Shiraki, Yoichi Yasuda, Kazuya Hata, Yoshinobu Hirose, Hisashi Tsurumi, Takuji Tanaka, Hisataka Moriwaki
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Obesity and related metabolic abnormalities, including insulin resistance and activation of the insulin-like growth factor (IGF)/IGF-I receptor (IGF-IR) axis, are risk factors for colon cancer. Supplementation with branched-chain amino acids (BCAA) reduces the risk of liver cancer in cirrhotic patients who are obese, and this has been associated with an improvement of insulin resistance. The present study examined the effects of BCAA on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice that were obese and had hyperinsulinemia. Experimental Design: Male db/db mice were given 4 weekly s.c. injections of AOM (15 mg/kg of body weight) and then they were fed a diet containing 3.0% BCAA or casein, a nitrogenc content–matched control diet, for 7 weeks. Results: Feeding with BCAA caused a significant reduction in the number of total aberrant crypt foci and β-catenin accumulated crypts, both of which are premalignant lesions of the colon, compared with the control diet–fed groups. BCAA supplementation caused a marked decrease in the expression of IGF-IR, the phosphorylated form of IGF-IR, phosphorylated glycogen synthase kinase 3β, phosphorylated Akt, and cyclooxygenase-2 proteins on the colonic mucosa of AOM-treated mice. The serum levels of insulin, IGF-I, IGF-II, triglyceride, total cholesterol, and leptin were also decreased by supplementation with BCAA. Conclusion: BCAA supplementation in diet improves insulin resistance and inhibits the activation of the IGF/IGF-IR axis, thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model that was also associated with hyperlipidemia and hyperinsulinemia. BCAA, therefore, may be a useful chemoprevention modality for colon cancer in obese people.
FOLFOX2 regimen in the treatment of advanced colorectal cancer: a comparison between elderly and young patients
Authors: M. Berretta, A. Bearz, S. Frustaci, A. Buonadonna, N. La Mura, M. Malaguarnera, A. Fulvi, I. Shehu, U. Tirelli
Journal: Annals of Oncology (2006)
Differential Metabolism of Gefitinib and Erlotinib by Human Cytochrome P450 Enzymes
Authors: Jing Li, Ming Zhao, Ping He, Manuel Hidalgo, Sharyn D. Baker
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To examine the enzyme kinetics of gefitinib and erlotinib metabolism by individual cytochrome P450 (CYP) enzymes, and to compare their effects on CYP3A activity, with the aim to better understand mechanisms underlying pharmacokinetic variability and clinical effects. Experimental Design: Enzyme kinetics were examined by incubating gefitinib or erlotinib (1.5-50 μmol/L) with recombinant human CYP3A4, CYP3A5, CYP2D6, CYP1A1, CYP1A2, and CYP1B1 (10-160 pmol/mL). Their effects on CYP3A activity were examined by comparing midazolam metabolism in the presence and absence of gefitinib or erlotinib in human liver and intestinal microsomes. Parent compounds and metabolites were monitored by high-performance liquid chromatography with a photodiode detector or tandem mass spectrometer. Results: Both drugs were metabolized primarily by CYP3A4, CYP3A5, and CYP1A1, with respective maximum clearance (Clmax) values for metabolism of 0.41, 0.39, and 0.57 mL/min/nmol for gefitinib and 0.24, 0.21, 0.31 mL/min/nmol for erlotinib. CYP2D6 was involved in gefitinib metabolism (Clmax, 0.63 mL/min/nmol) to a large extent, whereas CYP1A2 was considerably involved in erlotinib metabolism (Clmax, 0.15 mL/min/nmol). Both drugs stimulated CYP3A-mediated midazolam disappearance and 1-hydroxymidazolam formation in liver and intestinal microsomes. Conclusions: Gefitinib is more susceptible to CYP3A-mediated metabolism than erlotinib, which may contribute to the higher apparent oral clearance observed for gefitinib. Metabolism by hepatic and extrahepatic CYP1A may represent a determinant of pharmacokinetic variability and response for both drugs. The differential metabolizing enzyme profiles suggest that there may be differences in drug-drug interaction potential and that stimulation of CYP3A4 may likely play a role in drug interactions for erlotinib and gefitinib.
The EUSTAR model for teaching and implementing the modified Rodnan skin score in systemic sclerosis
Authors: L. Czirjak, Z. Nagy, M. Aringer, G. Riemekasten, M. Matucci-Cerinic, D. E Furst
Journal: Annals of the Rheumatic Diseases (2007)

<b>Objective:</b> To evaluate the ability to teach scleroderma experts and young rheumatologists to perform the modified Rodnan skin score test. <b>Methods:</b> Three international "teaching courses for teachers" were conducted with 6–9 experts who performed 3–9 skin score tests each. In addition, an international course for 90 young rheumatologists, in which 18 patients with systemic sclerosis (SSc) participated, was also organised. Finally, a local repeated training course for 5–9 rheumatologists was performed, in which 6–7 patients with SSc participated. <b>Results:</b> When 6–9 scleroderma specialists investigated the patients, the intraclass correlation coefficient (ICC) showed "good" to "excellent" values (0.865 and 0.710, respectively). When 90 young rheumatologists were involved in one teaching course, the coefficient of variation (CV) was relatively satisfactory (35%) owing to the high number of investigators, and with a considerable within-patient SD value of 5.4. Repeated teaching of 5–9 young rheumatologists in local courses clearly improved the consistency. The ICC increased from 0.496 to a "good" level of 0.722. The within-patient SD values for intraobserver variability ranged between 2.5 and 2.9. The intraobserver CV was about 20%. <b>Conclusions:</b> This study strongly supports the need for standardisation among different centres when using skin scoring for clinical trials. The intraobserver variability and within-patient SD values can be significantly reduced by repeated teaching. For inexperienced rheumatologists, at least one repeated teaching course is needed.
The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps
Authors: Sébastien Jaillon, Giuseppe Peri, Yves Delneste, Isabelle Frémaux, Andrea Doni, Federica Moalli, Cecilia Garlanda, Luigina Romani, Hugues Gascan, Silvia Bellocchio, Silvia Bozza, Marco A. Cassatella, Pascale Jeannin, Alberto Mantovani
Journal: The Journal of Experimental Medicine (2007)

The long pentraxin (PTX) 3 is produced by macrophages and myeloid dendritic cells in response to Toll-like receptor agonists and represents a nonredundant component of humoral innate immunity against selected pathogens. We report that, unexpectedly, PTX3 is stored in specific granules and undergoes release in response to microbial recognition and inflammatory signals. Released PTX3 can partially localize in neutrophil extracellular traps formed by extruded DNA. Eosinophils and basophils do not contain preformed PTX3. PTX3-deficient neutrophils have defective microbial recognition and phagocytosis, and PTX3 is nonredundant for neutrophil-mediated resistance against Aspergillus fumigatus. Thus, neutrophils serve as a reservoir, ready for rapid release, of the long PTX3, a key component of humoral innate immunity with opsonic activity.