tbuckley/cabot-search huggingface dataset:
SOCS2 negatively regulates growth hormone action in vitro and in vivo
Authors: Christopher J. Greenhalgh, Elizabeth Rico-Bautista, Mattias Lorentzon, Anne L. Thaus, Phillip O. Morgan, Tracy A. Willson, Panagiota Zervoudakis, Donald Metcalf, Ian Street, Nicos A. Nicola, Andrew D. Nash, Louis J. Fabri, Gunnar Norstedt, Claes Ohlsson, Amilcar Flores-Morales, Warren S. Alexander, Douglas J. Hilton
Journal: Journal of Clinical Investigation (2005)

Mice deficient in SOCS2 display an excessive growth phenotype characterized by a 30-50% increase in mature body size. Here we show that the SOCS2-/- phenotype is dependent upon the presence of endogenous growth hormone (GH) and that treatment with exogenous GH induced excessive growth in mice lacking both endogenous GH and SOCS2. This was reflected in terms of overall body weight, body and bone lengths, and the weight of internal organs and tissues. A heightened response to GH was also measured by examining GH-responsive genes expressed in the liver after exogenous GH administration. To further understand the link between SOCS2 and the GH-signaling cascade, we investigated the nature of these interactions using structure/function and biochemical interaction studies. Analysis of the 3 structural motifs of the SOCS2 molecule revealed that each plays a crucial role in SOCS2 function, with the conserved SOCS-box motif being essential for all inhibitory function. SOCS2 was found to bind 2 phosphorylated tyrosines on the GH receptor, and mutational analysis of these amino acids showed that both were essential for SOCS2 function. Together, the data provide clear evidence that SOCS2 is a negative regulator of GH signaling.
Re-Treatment With I-131 Tositumomab in Patients With Non-Hodgkin's Lymphoma Who Had Previously Responded to I-131 Tositumomab
Authors: Mark S. Kaminski, John A. Radford, Stephanie A. Gregory, John P. Leonard, Susan J. Knox, Stewart Kroll, Richard L. Wahl
Journal: Journal of Clinical Oncology (2005)

To study efficacy and safety of re-treatment with I-131 tositumomab in patients with low-grade, follicular, or transformed low-grade B-cell lymphoma who relapsed following a response to I-131 tositumomab.A prior response > or = 3 months to I-131 tositumomab was required. The single therapeutic dose following a dosimetric dose was adjusted to give the same total body dose (in Gy) as that used for the original dose, or was attenuated if the platelet count was less than 150,000 per mm(3) or if the prior treatment resulted in grade 4 cytopenias lasting longer than 7 days.Of 32 patients enrolled, 28 completed the therapeutic dose. A median of four therapies were given before re-treatment. Eighteen (56%) of 32 patients had a complete or partial response (median duration, 15.2 months); eight (25%) had a complete response (median duration, 35 months). Five continue in response from 1.8 to 5.7 years, with a median follow-up of 35 months. The overall median response duration was not significantly different for the two treatments, with no clinical factors predicting response or its duration. Ten of 18 re-responders had longer responses with re-treatment, with five having responses > or = 1.5 years longer. Grade 3/4 neutropenia and thrombocytopenia occurred in 50% and 43% of patients, respectively, similar to initial treatment. Antimouse antibodies developed in 10% of patients, and 12% developed elevated serum thyroid-stimulating hormone. Six patients were diagnosed with second malignancies, including four patients who developed myelodysplastic syndrome (one who had not received the therapeutic dose) and one with acute myelogenous leukemia.Re-treatment with I-131 tositumomab following a previous response can produce second responses that can be durable.
STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia
Authors: Andres Jerez, Michael J. Clemente, Hideki Makishima, Hanna Koskela, Francis LeBlanc, Kwok Peng Ng, Thomas Olson, Bartlomiej Przychodzen, Manuel Afable, Ines Gomez-Segui, Kathryn Guinta, Lisa Durkin, Eric D. Hsi, Kathy McGraw, Dan Zhang, Marcin W. Wlodarski, Kimmo Porkka, Mikkael A. Sekeres, Alan List, Satu Mustjoki, Thomas P. Loughran, Jaroslaw P. Maciejewski
Journal: Blood (2012)
Nausea, Vomiting, and Retching: Complex Problems in Palliative Care
Authors: V. A. Rhodes, R. W. McDaniel
Journal: CA A Cancer Journal for Clinicians (2001)

Patients with advanced cancer commonly experience nausea, vomiting, and/or retching (NVR) as a result of the malignant process and its treatment. Recently, increasing attention is being focused on end-of-life care, which includes relief or reduction of symptoms such as NVR. Pre-chemotherapy preparation and patient education in the palliative care setting are essential to preventing acute and delayed distress from NVR, as well as anticipatory symptoms. Careful assessment of chemotherapy-related symptoms should distinguish between the three phenomena rather than taking a global approach. Strategies for preventing anticipatory nausea, for instance, may differ significantly from those designed to reduce frequency of vomiting. Management of anticancer treatment-related NVR should incorporate both pharmacologic and nonpharmacologic approaches, whenever appropriate, with the overall goal of improving and/or maintaining the patient's quality of life.
Intraluminal ATP Concentrations in Rat Renal Tubules
Authors: Renu M. Vekaria, Robert J. Unwin, David G. Shirley
Journal: Journal of the American Society of Nephrology (2006)

It is becoming increasingly recognized that stimulation of apical P2 receptors can influence solute transport in the nephron, but, to date, no information is available on endogenous intraluminal nucleotide concentrations in vivo. This study measured intraluminal ATP concentrations in the renal tubules of anesthetized rats. Proximal tubular concentrations were found to be in the range of 100 to 300 nmol/L, with no significant variation along the S2 segment, whereas concentrations in the early distal tubule were markedly lower. Using collections of varying duration, the half-life of ATP in collected proximal tubular fluid was found to be 3.4 min, indicating significant breakdown by soluble nucleotidases. For assessment of whether proximal tubular ATP was filtered or secreted, experiments were performed in Munich-Wistar rats. The ATP concentration in midproximal tubules (142 +/- 23 nmol/L) was more than four-fold higher than in Bowman's space (32 +/- 7 nmol/L; P < 0.001), whereas fractional water reabsorption between the two sites was modest. In experiments that were designed to determine the effects of (patho)physiologic disturbances on intraluminal ATP, rats were either volume expanded or subjected to hypotensive hemorrhage. Neither maneuver affected proximal tubular luminal ATP concentrations significantly; rapid degradation of secreted ATP by ecto- and soluble nucleotidases is a possible explanation. It is concluded that the proximal tubule secretes ATP into the lumen, where it may have an autocrine/paracrine regulatory role.
Circulating DBP level and prognosis in operated lung cancer: an exploration of pathophysiology
Authors: Alice M. Turner, Laura McGowan, Alan Millen, Pala Rajesh, Craig Webster, Gerald Langman, Gavin Rock, Isao Tachibana, Michael G. Tomlinson, Fedor Berditchevski, Babu Naidu
Journal: European Respiratory Journal (2012)

Vitamin D stimulates transcription of antiangiogenic and apoptotic factors that may suppress tumours, while vitamin D binding protein (DBP) may be a biomarker in murine lung cancer models. We sought to ascertain whether the vitamin D axis is altered in lung cancer or influences prognosis. 148 lung cancer patients, 68 other intrathoracic cancer patients and 33 noncancer controls were studied for up to 5 yrs. Circulating DBP and vitamin D levels were compared between groups and their effect on survival assessed by Cox regression analysis. Expression of DBP and vitamin D receptor (VDR) was examined in lung cancer cell lines and in normal and tumour lung tissue by Western blot and immunohistochemistry. Low serum DBP levels predicted lung cancer-specific death (p=0.04), and DBP was poorly expressed in lung cancer cells on Western blot and immunohistochemistry. Vitamin D did not predict cancer survival and VDR expression was variable in tumours. Preservation of serum DBP is a significant independent factor associated with better cancer outcome in operated lung cancer patients. Given the established role of DBP in macrophage activation and clearance of abnormal cells, further study on its involvement in lung cancer is merited.
Impact of Remote Telemedical Management on Mortality and Hospitalizations in Ambulatory Patients With Chronic Heart Failure
Authors: Friedrich Koehler, Sebastian Winkler, Michael Schieber, Udo Sechtem, Karl Stangl, Michael Böhm, Herbert Boll, Gert Baumann, Marcus Honold, Kerstin Koehler, Goetz Gelbrich, Bridget-Anne Kirwan, Stefan D. Anker
Journal: Circulation (2011)

Background— This study was designed to determine whether physician-led remote telemedical management (RTM) compared with usual care would result in reduced mortality in ambulatory patients with chronic heart failure (HF). Methods and Results— We enrolled 710 stable chronic HF patients in New York Heart Association functional class II or III with a left ventricular ejection fraction ≤35% and a history of HF decompensation within the previous 2 years or with a left ventricular ejection fraction ≤25%. Patients were randomly assigned (1:1) to RTM or usual care. Remote telemedical management used portable devices for ECG, blood pressure, and body weight measurements connected to a personal digital assistant that sent automated encrypted transmission via cell phones to the telemedical centers. The primary end point was death from any cause. The first secondary end point was a composite of cardiovascular death and hospitalization for HF. Baseline characteristics were similar between the RTM (n=354) and control (n=356) groups. Of the patients assigned to RTM, 287 (81%) were at least 70% compliant with daily data transfers and no break for &gt;30 days (except during hospitalizations). The median follow-up was 26 months (minimum 12), and was 99.9% complete. Compared with usual care, RTM had no significant effect on all-cause mortality (hazard ratio, 0.97; 95% confidence interval, 0.67 to 1.41; P =0.87) or on cardiovascular death or HF hospitalization (hazard ratio, 0.89; 95% confidence interval, 0.67 to 1.19; P =0.44). Conclusions— In ambulatory patients with chronic HF, RTM compared with usual care was not associated with a reduction in all-cause mortality. Clinical Trial Registration:— URL: http://www.ClinicalTrials.gov . Unique identifier: NCT00543881.
Measurement of cytosolic free calcium concentration in isolated rat ventricular myocytes with quin 2.
Authors: S S Sheu, V K Sharma, S P Banerjee
Journal: Circulation Research (1984)

Cytosolic free calcium concentration was determined in isolated ventricular myocytes from adult rats with the calcium-sensitive indicator, quin 2. The fluorescence signal from resting cells indicated that cytosolic free calcium concentration was 181 +/- 18 nM (mean +/- SEM, n = 18). Inhibition of the sodium-potassium pump with strophanthidin (0.1 mM) resulted in an increase of cytosolic free calcium concentration from 186 +/- 17 to 736 +/- 129 nM (n = 6). The results indicate that it is possible to measure cytosolic free calcium concentration in cardiac muscle cells that have been isolated enzymatically. Moreover, they confirm the observation that inhibition of the sodium-potassium pump increases cytosolic free calcium concentration, presumably via the sodium-calcium exchange mechanism.
Expression of the Qa-2k phenotype encoded by the Q5k gene on the surface of tumor cells derived from H-2k mice.
Authors: N Seo, T Okazaki, C Nakanishi-Ito, T Tanino, Y Matsudaira, T Takahashi, K Egawa
Journal: The Journal of Experimental Medicine (1992)

Immunological and biochemical characteristics of the Qa-2 murine nonclassical histocompatibility class 1 antigen expressed on tumor cells derived from H-2k (Qa-2-) mice were studied. It was found that the Qa-2 antigen on normal H-2b lymphocytes reacted with Qa-2-specific monoclonal antibodies (mAbs) 34-1.2, 59 (both specific to the alpha 1/alpha 2 region) and 141-15.8 (specific to the alpha 3 domain), and the Qa-2 antigen on H-2k tumor cells (Qa-2k antigen) reacted with mAbs 59 and 141-15.8, but not with 34-1.2. The normal Qa-2 antigen was susceptible to treatment with phosphatidylinositol-specific phospholipase C, but the Qa-2k antigen was insensitive to it. By Northern hybridization, polymerase chain reaction (PCR) studies on cDNA, Southern hybridization, Western blotting, and nucleotide sequence analysis, the Q5k gene was identified as the gene encoding the Qa-2k antigen expressed on BW5147 lymphoma cells derived from a mouse of AKR strain (H-2k, Qa-2-). The nucleotide sequence of PCR-amplified BW5147 Q5k cDNA showed complete agreement with the reported sequence of exons 1-5 of the Q5k gene of C3H/He. It also showed complete deletion of the region corresponding to exons 6 and 7, and a very short coding region in exon 8, resulting in very short cytoplasmic domain of the product compared with regular class 1 antigens. These characteristics were expected from the reported Q5k genomic sequence. These results revealed that the Qa-2k antigen was distinct from the normal Qa-2 antigen expressed on H-2b lymphocytes although it cross-reacted with some Qa-2-specific mAbs.
Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911)
Authors: Michel Bolla, Hein van Poppel, Bertrand Tombal, Kris Vekemans, Luigi Da Pozzo, Theo M de Reijke, Antony Verbaeys, Jean-François Bosset, Roland van Velthoven, Marc Colombel, Cees van de Beek, Paul Verhagen, Alphonsus van den Bergh, Cora Sternberg, Thomas Gasser, Geertjan van Tienhoven, Pierre Scalliet, Karin Haustermans, Laurence Collette
Journal: The Lancet (2012)
BARD1 Expression Predicts Outcome in Colon Cancer
Authors: Judith C. Sporn, Torsten Hothorn, Barbara Jung
Journal: Clinical Cancer Research (2011)

BARD1 is a BRCA1-binding partner with tumor suppressive properties. Aberrant splice variants of BARD1 have been detected in various cancers, and it has been postulated that the presence of some splice variants is cancer specific. This is the first study assessing BARD1 expression patterns and correlation with clinical outcome in colon cancer.We analyzed colon cancer samples for the occurrence of BARD1 splice variants, characterized novel BARD1 splice variants, and quantified the mRNA expression levels of these isoforms in primary colon cancers and their corresponding normal tissue. We tested the correlation of full-length BARD1 protein expression and clinical outcome in primary colon cancer samples.In addition to the full-length BARD1 mRNA, we now find 19 distinct BARD1 splice variants in colon cancer. Contrary to previous assumptions, these splice variants also occur in the adjacent normal colon tissue. Although BARD1 splice variants account for a considerable amount of BARD1 mRNA in both cancer and normal colon samples, distinct variants show a cancer-specific regulation pattern. Consistent with its role as tumor suppressor, we further find that the expression of the full-length BARD1 protein predicts outcome in colon cancer and that loss of full-length BARD1 protein is associated with a poor prognosis (P = 0.0002).Taken together, this is the first report to suggest that BARD1 regulation is an important pathway in colon cancer and that the BARD1 full-length protein may be a useful marker to improve risk stratification in colon cancer patients.
Heterotachy, an Important Process of Protein Evolution
Authors: P. Lopez, D. Casane, H. Philippe
Journal: Molecular Biology and Evolution (2002)

Because of functional constraints, substitution rates vary among the positions of a protein but are usually assumed to be constant at a given site during evolution. The distribution of the rates across the sequence positions generally fits a Gamma distribution. Models of sequence evolution were accordingly designed and led to improved phylogenetic reconstruction. However, it has been convincingly demonstrated that the evolutionary rate of a given position is not always constant throughout time. We called such within-site rate variations heterotachy (for "different speed" in Greek). Yet, heterotachy was found among homologous sequences of distantly related organisms, often with different functions. In such cases, the functional constraints are likely different, which would explain the different distribution of variable sites. To evaluate the importance of heterotachy, we focused on amino acid sequences of mitochondrial cytochrome b, for which the function is likely the same in all vertebrates. Using 2,038 sequences, we demonstrate that 95% of the variable positions are heterotachous, i.e., underwent dramatic variations of substitution rate among vertebrate lineages. Heterotachy even occurs at small evolutionary scale, and in these cases it is very unlikely to be related to functional changes. Since a large number of sequences are required to efficiently detect heterotachy, the extent of this phenomenon could not be estimated for all proteins yet. It could be as large as for cytochrome b, since this protein is not a peculiar case. The observations made here open several new avenues of research, such as the understanding of the evolution of functional constraints or the improvement of phylogenetic reconstruction methods.
Targeting Tumor-Associated Endothelial Cells: Anti-VEGFR2 Immunoliposomes Mediate Tumor Vessel Disruption and Inhibit Tumor Growth
Authors: Andreas Wicki, Christoph Rochlitz, Annette Orleth, Reto Ritschard, Imke Albrecht, Richard Herrmann, Gerhard Christofori, Christoph Mamot
Journal: Clinical Cancer Research (2011)

Angiogenesis is a key process in tumor progression. By binding VEGF, VEGF receptor-2 (VEGFR2) is a main signaling transducer in tumor-associated angiogenesis. Accordingly, therapeutic approaches against the VEGF/VEGFR2 signaling axis have been designed. However, an efficient and specific chemotherapeutic targeting of tumor-associated endothelial cells has not yet been achieved.We have employed anti-VEGFR2 antibodies covalently linked to pegylated liposomal doxorubicin (PLD) to specifically ablate tumor-associated endothelial cells in the Rip1Tag2 mouse model of insulinoma, in the MMTV-PyMT mouse model of breast cancer, and in the HT-29 human colon cancer xenograft transplantation model.In each model, anti-VEGFR2-targeted immunoliposomes (ILs) loaded with doxorubicin (anti-VEGFR2-ILs-dox) were superior in therapeutic efficacy to empty liposomes, empty anti-VEGFR2-ILs, antibodies alone, and PLD. Efficacy was similar to that of the oral VEGFR1, -2, and -3 inhibitor PTK787. Detailed histopathologic and molecular analysis revealed a strong antiangiogenic effect of anti-VEGFR2-ILs-dox, and the observed antiangiogenic therapy was significantly more efficient in reducing tumor burden in well-vascularized transgenic mouse models as compared with the less-vascularized xenograft model.Anti-VEGFR2 ILs provide a highly efficient approach to selectively deplete VEGFR2-expressing tumor vasculature. They offer a novel and promising anticancer strategy.
Phase II Study of Erlotinib in Patients With Malignant Pleural Mesothelioma: A Southwest Oncology Group Study
Authors: Linda L. Garland, Cathryn Rankin, David R. Gandara, Saul E. Rivkin, Katherine M. Scott, Raymond B. Nagle, Andres J.P. Klein-Szanto, Joseph R. Testa, Deborah A. Altomare, Ernest C. Borden
Journal: Journal of Clinical Oncology (2007)

Malignant pleural mesothelioma (MPM) expresses high levels of epidermal growth factor receptor (EGFR), and preclinical studies have identified antitumor activity of EGFR tyrosine kinase inhibitors (TKIs) in MPM. We conducted a phase II trial of the EGFR TKI erlotinib in previously untreated patients with MPM.Patients with measurable and nonmeasurable disease were treated with erlotinib 150 mg/d on days 1 through 28 of each 28-day dosing cycle. Archived patient tumors were analyzed for immunohistochemical expression of EGFR, phospho-EGFR, human epidermal growth factor receptor 2 (HER2), phospho-extracellular signal-regulated kinase (ERK), and phosphatase and tensin homolog (PTEN) and phosphorylation of members of the phosphatidylinositol 3-kinase/Akt signaling pathway.Sixty-three patients were treated on the study. EGFR was highly expressed in 75% of patient tumors, as was phospho-ERK (82%), phospho-Akt (84%), phospho-mammalian target of rapamycin (74%), and phospho-forkhead (74%). HER2 was rarely expressed, and loss of PTEN was rare. For 33 patients with measurable disease, there were no objective responses; 14 patients (42%) had stable disease, 15 patients (45%) had disease progression, and four patients had inadequate assessments to determine response. Toxicities were mainly constitutional (51%), dermatologic (82%), and GI (52%); there was one death on trial, which was related to dyspnea. Median overall survival time was 10 months; 1-year survival rate was 43%; and median progression-free survival time was 2 months.Single-agent erlotinib was not effective in MPM, despite high expression of EGFR. Activation of the ERK and phosphatidylinositol 3-kinase/Akt downstream pathways are possible resistance mechanisms to EGFR TKI. The activated phosphatidylinositol 3-kinase/Akt pathway is a potential therapeutic target for MPM.
Molecular Genetics and Medicine
Authors: C. Thomas Caskey
Journal: JAMA (1992)

The year 1993 marks the 40th anniversary of the publication of the two short, seminal papers by Watson and Crick<sup>1,2</sup>on the double helix structure of DNA. During these 40 years a revolution in biology and genetics has occurred as the insights gained from this discovery have moved these fields to a new molecular level of understanding. During the past decade we have also witnessed the beginning of another revolution in medical knowledge and therapeutics as the insights and techniques of molecular biology, molecular genetics, and recombinant DNA technology have begun to effect changes in the practice of medicine. These advances in what is now being called molecular medicine are having an ever-increasing impact in many areas of medicine: (1) Molecular diagnostic techniques are moving diagnosis from the phenotypic to the genotypic level (eg, the sweat chloride test for cystic fibrosis vs the identification of a mutation in the
Immunologic Aspects of Endocrine Diseases
Authors: James R. Baker
Journal: JAMA (1992)

OVER THE past several years, autoimmunity has been identified as the cause of most common endocrine disorders. These disorders are clinically important diseases that affect many individuals. In addition, the pathogenesis of these diseases offers unique opportunities for investigations into immune regulation and autoimmunity. While rapid progress has been made in the identification of the autoantigens, autoantibodies, and cellular immune elements involved in the immune destruction or stimulation of endocrine glands, the specific mechanisms and susceptibility factors leading to the development of these diseases are not clear. Research into these unresolved questions will likely provide many insights into autoimmune disease and lead to prevention of endocrine system dysfunction.  Proposed mechanisms for the development of autoimmune endocrine disease generally involve a multistep process. An initiating event likely entails nonspecific inflammation or trauma that results in a specific secondary immune response in a genetically susceptible individual. This specific immune response progressively destroys
Lifebox replies to Gotzsche
Authors: A. Gawande
Journal: BMJ (2012)

Gotzsche’s argument that pulse oximetry provides no benefit is fundamentally flawed. No anaesthesiology department in the world would forgo pulse oximetry.1 2 It forms an essential part of the measures that have improved the safety of anaesthesia in the past two decades, and every anaesthesiologist has an experience where oximetry …