tbuckley/cabot-search huggingface dataset:
Optimal Length of Continuation Therapy in Depression: A Prospective Assessment During Long-Term Fluoxetine Treatment
Authors: Frederick W. Reimherr, Jay D. Amsterdam, Frederic M. Quitkin, Jerrold F. Rosenbaum, Maurizio Fava, John Zajecka, Charles M. Beasley, Jr., David Michelson, Paul Roback, Karen Sundell
Journal: American Journal of Psychiatry (1998)

Objective: The purpose of this study was to determine prospectively the optimal length of therapy in a long-term, placebo-controlled continuation study of patients who responded to acute fluoxetine treatment for major depression (defined by DSM-III-R). Method: The study was conducted at five outpatient psychiatric clinics in the United States. Patients who met criteria for remission after 12 or 14 weeks of open-label acute fluoxetine therapy, 20 mg/day (N=395 of 839 patients), were randomly assigned to one of four arms of a double-blind treatment study (50 weeks of placebo, 14 weeks of fluoxetine and then 36 weeks of placebo, 38 weeks of fluoxetine and then 12 weeks of placebo, or 50 weeks of fluoxetine). Relapse rate was the primary outcome measure. Both Kaplan-Meier estimates and observed relapse rates were assessed in three fixed 12-week intervals after double-blind transfers from fluoxetine to placebo at the start of the double-blind period and after 14 and 38 weeks of continued fluoxetine treatment.Results: Relapse rates (Kaplan-Meier estimates) were lower among the patients who continued to take fluoxetine compared with those transferred to placebo in both the first interval, after 24 total weeks of treatment (fluoxetine, 26.4%; placebo, 48.6%), and the second interval, after 38 total weeks of treatment (fluoxetine, 9.0%; placebo, 23.2%). In the third interval, after 62 total weeks of treatment, rates were not significantly different between the groups (fluoxetine, 10.7%; placebo, 16.2%). Conclusions: Patients treated with fluoxetine for 12 weeks whose depressive symptoms remit should continue treatment with fluoxetine for at least an additional 26 weeks to minimize the risk of relapse. Am J Psychiatry 1998; 155: 1247-1253
The Technique of Hypothermic Perfusion
Authors: P. J. Molloy, R. I. Lindfield
Journal: Thorax (1961)

Interaction of exposed membrane-lipid regions after mixing of immune peritoneal exudate T lymphocytes (PEL) and target cells (TC) was studied by monitoring the degree of fluorescence polarization (P) of 1,6-diphenyl 1,3,5-hexatriene (DPH), a lipophilic probe, which can be transferred upon contact of lipid phases. Since the P of DPH-labeled PEL and labeled TC differed significantly, detection of DPH translocation between labeled and nonlabeled cells was possible. A decrease in P was observed after interaction of DPH-labeled PEL and nonlabeled TC. Conversely, an increase in P was detected after nonlabeled PEL were allowed to react with DPH-labeled TC. These changes in P were evident when TC were reacted with specific PEL. However, substantial changes were also monitored with PEL immunized against third-party target cells. No significant changes in P were obtained when DPH-labeled TC were reacted with normal or immune lymph node cells or thymocytes, or with anti-TC antibody. These findings suggest that nonspecific collision of exposed membrane lipid regions occurs during immune PEL-TC interaction. We propose that binding of cytotoxic lymphocytes and TC is preceded by an unstable and nonspecific hydrophobic interaction of cells, which facilitates specific and stable binding. In support of this proposal is the finding that changes in the composition of membrane lipid constituents prevent binding of PEL and TC.
Evaluation of the Value of Attribution in the Interpretation of Adverse Event Data: A North Central Cancer Treatment Group and American College of Surgeons Oncology Group Investigation
Authors: Shauna L. Hillman, Sumithra J. Mandrekar, Brian Bot, Ronald P. DeMatteo, Edith A. Perez, Karla V. Ballman, Heidi Nelson, Jan C. Buckner, Daniel J. Sargent
Journal: Journal of Clinical Oncology (2010)

In March 1998, Common Toxicity Criteria (CTC) version 2.0 introduced the collection of attribution of adverse events (AEs) to study drug. We investigate whether attribution adds value to the interpretation of AE data.Patients in the placebo arm of two phase III trials-North Central Cancer Treatment Group Trial 97-24-51 (carboxyamino-triazole v placebo in advanced non-small-cell lung cancer) and American College of Surgeons Oncology Group Trial Z9001 (imatinib mesylate v placebo after resection of primary gastrointestinal stromal tumors)-were studied. Attribution was categorized as unrelated (not related or unlikely) and related (possible, probable, or definite).In total, 398 patients (84 from Trial 97-24-51 and 314 from Trial Z9001) and 7,736 AEs were included; 47% and 50% of the placebo-arm AEs, respectively, were reported as related. When the same AE was reported in the same patient on multiple visits, the attribution category changed at least once 36% and 31% of the time. AE type and sex (Trial Z9001) and AE type and performance status (Trial 97-24-51) were associated with a higher likelihood of AEs being deemed related.Nearly 50% of AEs were reported as attributed to study drug on the placebo arm of two randomized clinical trials. These data provide strong evidence that AE attribution is difficult to determine, unreliable, and of questionable value in interpreting AE data in randomized clinical trials.
Interleukin-6 induces proliferation of rat hepatocytes in vivo
Authors: Hiromasa Ohira, Masayuki Miyata, Masahito Kuroda, Tohru Takagi, Jun Tojo, Hironobu Ochiai, Masae Kokubun, Tomoe Nishimaki, Reiji Kasukawa, Katsutoshi Obara
Journal: Journal of Hepatology (1996)
Aplastic anemia associated with bone marrow suppressor T‐Cell hyperactivity: Successful treatment with antithymocyte globulin
Authors: Mammo Amare, Nabih I. Abdou, Maria G. Robinson, Nancy L. Abdou
Journal: American Journal of Hematology (1978)

Abstract In five patients with idiopathic aplastic anemia, the colony‐forming unit (CFU‐c) assay was used to quantitate stem cells and test the possible presence of supressor cells inhibiting bone marrow differentiation. All five marrows failed to form CFU‐c. In one out of the five cases tested, coculture of the patient's marrow with normal marrow suppressed the latter to form CFU‐c. Removal of T‐cells from the patient's bone marrow freed the aplastic marrow to produce more colonies and, in the coculture study, abrogated its inhibitory activity on the normal bone marrow. Treatment of the patient with horse antihuman thymocyte globulin (ATG), improved the peripheral blood count and myelopoiesis. Furthermore, the aplastic marrow increased its colony forming capacity from &lt; 1% pre‐ATG to 46% post‐ATG of the normal control, and its inhibitory activity on the normal marrow was ablated. In selected cases of aplastic anemia, with evidence of T‐suppressor cell hyperactivity, treatment with ATG may offer an alternative approach to bone‐marrow transplantation.
Ischemia Imaging and Plaque Imaging in Diabetes
Authors: Paolo Raggi, Antonio Bellasi, Carlo Ratti
Journal: Diabetes Care (2005)

Cardiovascular disease is the most frequent cause of death and disability in diabetes, and the morbidity and mortality for coronary artery disease (CAD) in this population is two to four times higher than in nondiabetic subjects. Traditional risk factors do not fully explain the level of cardiovascular risk, and coronary disease events are often silent in diabetic patients. Thus, research has recently focused on improving the risk assessment of an individual patient with new tools in an effort to better identify subjects at highest risk and in need of aggressive management. Cardiovascular imaging has proven very helpful in this regard. Traditional methods to assess CAD are based on detection of obstructive luminal disease responsible for myocardial ischemia. However, acute coronary syndromes often occur in the absence of luminal stenoses. Hence, the utilization of imaging methodologies to visualize atherosclerosis in its presymptomatic stages has received mounting attention in recent years. In this article, we review the current literature on the utility of traditional imaging modalities for obstructive CAD (nuclear and echocardiographic stress testing) as well as atherosclerosis plaque imaging with carotid intima-media thickness and coronary artery calcium for risk stratification of diabetic patients.
Complications of an Addisonian crisis
Authors: S Hellmig
Journal: Gut (2004)

Gastric cancer is a major health burden worldwide and prevention is the most promising strategy to control the disease.The available scientific evidence indicates that curing Helicobacter pylori infection results in a modest retardation of the precancerous process but does not prevent all cancers.Individuals at the highest risk should be cured of their infection and monitored endoscopically to detect dysplasia and ''early'' cancer, amenable to successful treatment. . . . . . . . . . . .
Renal handling of calcium and sodium in metastatic and non-metastatic malignancy.
Authors: J A Kanis, R C Percival, G H Urwin, S A Murray, N A Hamdy, A J Yates
Journal: BMJ (1986)

and within the body.Magnesium deficiency will produce kaliuresis.2For this reason profound hypokalaemia or hypokalaemia unresponsive to potassium therapy should also raise the possibility of hypomagnesaemia and the need for magnesium supplements.3
Expression of the small heat shock protein HSP 27 in developing human skin
Authors: None Jantschitsch, None Kindas-MÜgge, None Metze, None Amann, None Micksche, None Trautinger
Journal: British Journal of Dermatology (1998)

The 27 kDa heat shock protein (HSP 27) is expressed in keratinocytes of the upper epidermal layers, and recent evidence suggests that this protein is involved in the regulation of epidermal differentiation. The expression of HSP 27 was investigated in developing human skin by immunohistochemistry utilizing a specific monoclonal antibody. We used formalin‐fixed, paraffin‐embedded tissue of abdominal skin obtained from 34 human fetuses ranging between 13 and 30 weeks estimated gestational age (EGA). We found that HSP 27 is not expressed in keratinocytes until week 14 EGA. At this stage staining is observed in the periderm and the upper intermediate cells but not in hair germs. During further development, HSP 27 expression correlates with increasing epidermal differentiation, i.e. shedding of the periderm and beginning of keratinization. HSP 27 expression is confined to the upper cell layers and sparse basal cells. In hair follicles, HSP 27 can be detected in the innermost cell layer of the outer root sheath and in keratinocytes of the bulge identical to what is observed in adult skin. The hair papilla, matrix cells and sebaceous glands are negative for HSP 27 and remain so during further development. In eccrine sweat glands of the 24th week EGA, HSP 27 is confined to the superficial cell layer of the sweat ducts. In the present report we demonstrate differentiation‐related expression of HSP 27 in developing human skin. Further in vitro studies will address the molecular function of HSP 27 in epidermal differentiation and development.
Association between the nuclear to cytoplasmic ratio of p27 and the efficacy of adjuvant polychemotherapy in early breast cancer
Authors: F. Andre, R. Conforti, C.B. Moeder, A. Mauguen, M. Arnedos, N. Berrada, S. Delaloge, G. Tomasic, M. Spielmann, F.J. Esteva, D.L. Rimm, S. Michiels
Journal: Annals of Oncology (2012)
Cloning and Characterization of a Specific Receptor for the Novel CC Chemokine MIP-3α from Lung Dendritic Cells
Authors: Christine A. Power, Dennis J. Church, Alexandra Meyer, Sami Alouani, Amanda E.I. Proudfoot, Ian Clark-Lewis, Silvano Sozzani, Alberto Mantovani, Timothy N.C. Wells
Journal: The Journal of Experimental Medicine (1997)

Dendritic cells are potent antigen-presenting cells involved in the initiation of immune responses. The trafficking of these cells to tissues and lymph nodes is mediated by members of the chemokine family. Recently, a novel CC chemokine known as MIP-3α or liver and activation-regulated chemokine has been identified from the EMBL/GenBank/DDBJ expressed sequence tag database. In the present study, we have shown that the messenger RNA for MIP-3α is expressed predominantly in inflamed and mucosal tissues. MIP-3α produced either synthetically or by human embryonic kidney 293 cells is chemotactic for CD34+-derived dendritic cells and T cells, but is inactive on monocytes and neutrophils. MIP-3α was unable to displace the binding of specific CC or CXC chemokines to stable cell lines expressing their respective high affinity receptors, namely CCR1–5 and CXCR1 and CXCR2, suggesting that MIP-3α acts through a novel CC chemokine receptor. Therefore, we used degenerate oligonucleotide-based reverse transcriptase PCR to identify candidate MIP-3α receptors in lung dendritic cells. Our results show that the orphan receptor known as GCY-4, CKRL-3, or STRL-22 is a specific receptor for MIP-3α, and that its activation leads to pertussis toxin–sensitive and phospholipase C–dependent intracellular Ca2+ mobilization when it is expressed in HEK 293 cells.
Impact of Clinical and Pathologic Features on Tumor-Infiltrating Lymphocyte Expansion from Surgically Excised Melanoma Metastases for Adoptive T-cell Therapy
Authors: Richard W. Joseph, Vijay R. Peddareddigari, Ping Liu, Priscilla W. Miller, Willem W. Overwijk, Nebiyou B. Bekele, Merrick I. Ross, Jeffrey E. Lee, Jeffrey E. Gershenwald, Anthony Lucci, Victor G. Prieto, John D. McMannis, Nicholas Papadopoulos, Kevin Kim, Jade Homsi, Agop Bedikian, Wen-Jen Hwu, Patrick Hwu, Laszlo G. Radvanyi
Journal: Clinical Cancer Research (2011)

Clinical trials on adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) have shown response rates of over 50% in refractory melanoma. However, little is known how clinical and pathologic features impact TIL outgrowth isolated from metastatic melanoma tumors.We analyzed the impact of clinical and pathologic features on initial TIL outgrowth in 226 consecutive patients undergoing tumor resection. Successful initial TIL outgrowth was defined as ≥40 million viable lymphocytes harvested from all tumor fragments in a 5-week culture. To normalize for the different size of resected tumors and thus available tumor fragments, we divided the number of expanded TIL by the starting number of tumor fragments (TIL/fragment).Overall, initial TIL outgrowth was successful in 62% of patients, with patients ≤30 years of age (94%; P = 0.01) and female patients (71% vs. 57% for males; P = 0.04) having the highest rate of success. Systemic therapy 30 days before tumor harvest negatively impacted initial TIL outgrowth compared to patients who never received systemic therapy (47% vs. 71%, P = 0.02). Biochemotherapy within 0 to 60 days of tumor harvest negatively impacted the initial TIL outgrowth with a success rate of only 16% (P < 0.0001).Parameters such as age, sex, and the type and timing of prior systemic therapy significantly affect the success rate of the initial TIL outgrowth from tumor fragments for ACT; these parameters may be helpful in selecting patients for melanoma ACT.
Amiodarone: biochemical evidence for binding to a receptor for class I drugs associated with the rat cardiac sodium channel.
Authors: R S Sheldon, R J Hill, N J Cannon, H J Duff
Journal: Circulation Research (1989)

Amiodarone has multiple pharmacological effects in heart. Electrophysiological data suggest that among its other effects, amiodarone is a sodium channel blocker. Using a radioligand assay, we determined whether amiodarone interacted with a previously described receptor for type I agents associated with the cardiac sodium channel. The radioligand was [3H]batrachotoxinin A 20 alpha-benzoate ([ 3H]BTXB), a toxin that binds to the activated state of the sodium channel. We have previously shown that class I antiarrhythmic drugs inhibit [3H]BTXB binding. The purpose of this study was to assess whether amiodarone and other class III agents interact with this receptor. Amiodarone inhibited [3H]BTXB binding in a dose-dependent fashion, with an estimated IC50 value of 3.6 microM. This IC50 value is similar to reported clinically effective serum concentrations of amiodarone. In contrast to amiodarone, the IC50 values for other class III drugs (bretylium, sotalol, bethanidine, N-acetylprocainamide) were much higher than their therapeutic concentrations and bore no relation to them. Scatchard analysis of [3H]BTXB binding showed that amiodarone reduced the maximal binding for [3H]BTXB; this finding indicates irreversible inhibition or (more likely) allosteric inhibition by amiodarone. The latter agrees with electrophysiological data suggesting that amiodarone binds to inactivated sodium channels. Sodium channel blockade by amiodarone may contribute to its overall electrophysiological effect.
The Diabetes Risk Score
Authors: Jaana Lindström, Jaakko Tuomilehto
Journal: Diabetes Care (2003)

OBJECTIVE—Interventions to prevent type 2 diabetes should be directed toward individuals at increased risk for the disease. To identify such individuals without laboratory tests, we developed the Diabetes Risk Score. RESEARCH DESIGN AND METHODS—A random population sample of 35- to 64-year-old men and women with no antidiabetic drug treatment at baseline were followed for 10 years. New cases of drug-treated type 2 diabetes were ascertained from the National Drug Registry. Multivariate logistic regression model coefficients were used to assign each variable category a score. The Diabetes Risk Score was composed as the sum of these individual scores. The validity of the score was tested in an independent population survey performed in 1992 with prospective follow-up for 5 years. RESULTS—Age, BMI, waist circumference, history of antihypertensive drug treatment and high blood glucose, physical activity, and daily consumption of fruits, berries, or vegetables were selected as categorical variables. Complete baseline risk data were found in 4,435 subjects with 182 incident cases of diabetes. The Diabetes Risk Score value varied from 0 to 20. To predict drug-treated diabetes, the score value ≥9 had sensitivity of 0.78 and 0.81, specificity of 0.77 and 0.76, and positive predictive value of 0.13 and 0.05 in the 1987 and 1992 cohorts, respectively. CONCLUSIONS—The Diabetes Risk Score is a simple, fast, inexpensive, noninvasive, and reliable tool to identify individuals at high risk for type 2 diabetes.
MAP Kinase Pathway Alterations in <i>BRAF</i>-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition
Authors: Nikhil Wagle, Eliezer M. Van Allen, Daniel J. Treacy, Dennie T. Frederick, Zachary A. Cooper, Amaro Taylor-Weiner, Mara Rosenberg, Eva M. Goetz, Ryan J. Sullivan, Deborah N. Farlow, Dennis C. Friedrich, Kristin Anderka, Danielle Perrin, Cory M. Johannessen, Aaron McKenna, Kristian Cibulskis, Gregory Kryukov, Eran Hodis, Donald P. Lawrence, Sheila Fisher, Gad Getz, Stacey B. Gabriel, Scott L. Carter, Keith T. Flaherty, Jennifer A. Wargo, Levi A. Garraway
Journal: Cancer Discovery (2013)

Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP-ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (MEK2(Q60P)). MEK2(Q60P) conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal-regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.
Adrenergic Mechanisms for the Effects of Epinephrine on Glucose Production and Clearance in Man
Authors: R. A. Rizza, P. E. Cryer, M. W. Haymond, J. E. Gerich
Journal: Journal of Clinical Investigation (1980)

The present studies were undertaken to assess the adrenergic mechanisms by which epinephrine stimulates glucose production and suppresses glucose clearance in man: epinephrine (50 ng/kg per min) was infused for 180 min alone and during either alpha (phentolamine) or beta (propranolol)-adrenergic blockade in normal subjects under conditions in which plasma insulin, glucagon, and glucose were maintained at comparable levels by infusion of somatostatin (100 μg/h), insulin (0.2 mU/kg per min), and variable amounts of glucose. In additional experiments, to control for the effects of the hyperglycemia caused by epinephrine, variable amounts of glucose without epinephrine were infused along with somatostatin and insulin to produce hyperglycemia comparable with that observed during infusion of epinephrine. This glucose infusion suppressed glucose production from basal rates of 1.8±0.1 to 0.0±0.1 mg/kg per min (P < 0.01), but did not alter glucose clearance. During infusion of epinephrine, glucose production increased transiently from a basal rate of 1.8±0.1 to a maximum of 3.0±0.2 mg/kg per min (P < 0.01) at min 30, and returned to near basal rates at min 180 (1.9±0.1 mg/kg per min). Glucose clearance decreased from a basal rate of 2.0±0.1 to 1.5±0.2 ml/kg per min at the end of the epinephrine infusion (P < 0.01). Infusion of phentolamine did not alter these effects of epinephrine on glucose production and clearance. In contrast, infusion of propranolol completely prevented the suppression of glucose clearance by epinephrine, and inhibited the stimulation of glucose production by epinephrine by 80±6% (P < 0.001). These results indicate that, under conditions in which plasma glucose, insulin, and glucagon are maintained constant, epinephrine stimulates glucose production and inhibits glucose clearance in man predominantly by beta adrenergic mechanisms.
Albumin Is Recycled from the Primary Urine by Tubular Transcytosis
Authors: Verena Tenten, Sylvia Menzel, Uta Kunter, Eva-Maria Sicking, Claudia R. C. van Roeyen, Silja K. Sanden, Michaela Kaldenbach, Peter Boor, Astrid Fuss, Sandra Uhlig, Regina Lanzmich, Brigith Willemsen, Henry Dijkman, Martin Grepl, Klemens Wild, Wilhelm Kriz, Bart Smeets, Jürgen Floege, Marcus J. Moeller
Journal: Journal of the American Society of Nephrology (2013)

Under physiologic conditions, significant amounts of plasma protein pass the renal filter and are reabsorbed by proximal tubular cells, but it is not clear whether the endocytosed protein, particularly albumin, is degraded in lysosomes or returned to the circulatory system intact. To resolve this question, a transgenic mouse with podocyte-specific expression of doxycycline-inducible tagged murine albumin was developed. To assess potential glomerular backfiltration, two types of albumin with different charges were expressed. On administration of doxycycline, podocytes expressed either of the two types of transgenic albumin, which were secreted into the primary filtrate and reabsorbed by proximal tubular cells, resulting in serum accumulation. Renal transplantation experiments confirmed that extrarenal transcription of transgenic albumin was unlikely to account for these results. Genetic deletion of the neonatal Fc receptor (FcRn), which rescues albumin and IgG from lysosomal degradation, abolished transcytosis of both types of transgenic albumin and IgG in proximal tubular cells. In summary, we provide evidence of a transcytosis within the kidney tubular system that protects albumin and IgG from lysosomal degradation, allowing these proteins to be recycled intact.