tbuckley/cabot-search huggingface dataset:
Randomized trial comparing two combination chemotherapy regimens (CHAP-5 v CP) in advanced ovarian carcinoma.
Authors: J P Neijt, W W ten Bokkel Huinink, M E van der Burg, A T van Oosterom, P H Willemse, A P Heintz, M van Lent, J B Trimbos, J Bouma, J B Vermorken
Journal: Journal of Clinical Oncology (1987)

One hundred ninety-one patients with advanced epithelial ovarian carcinoma were treated with either a combination of doxorubicin and a five-day course of cisplatin alternating with cyclophosphamide and hexamethylmelamine orally for 14 days (CHAP-5) or cyclophosphamide and cisplatin both administered intravenously (IV) on a single day at 3-week intervals (CP). At a median follow-up time of 45 months, treatment with each of these combinations resulted in the same remission rates (80% and 74%, respectively) and exactly the same progression-free survival and overall survival (median, 26 months). Despite adequate hydration, more renal toxicity was encountered in the CP-treated patients than in those who received CHAP-5. Disabling neurotoxicity and severe myelosuppression were encountered more frequently in the patients treated with CHAP-5. Because the toxicity was lower and CP treatment required shorter hospitalization, the single-day regimen was considered preferable for future use. The Karnofsky index was the only independent predictor for response, whereas both this index and the size of residual tumor before chemotherapy were predictive of survival. After correcting for other prognostic factors, it was determined that tumor size associated with improved survival was less than 1 cm. The site of metastases in International Federation of Gynecology and Obstetrics (FIGO) stage IV patients did not influence survival within this category. The results of this study confirm our previous findings that patients with microscopic remnants at second-look have a survival similar to that of patients who are histopathologically free of disease. This makes the significance of so-called pathologically confirmed complete remission questionable. The survival benefit of debulking surgery performed during chemotherapy seems only minimal for patients in whom debulking has already been attempted before treatment. Like others, we have found the CP regimen to have a good therapeutic index.
Lack of information on “fit notes” renders them useless, says study:
Authors: Adrian O’Dowd
Journal: BMJ (2015)

General practitioners have not been trained properly in how to use the “fit note” system for managing sick leave and are too vague when it comes to recommending what employers should be doing, a report published on 3 August has found.1

A study by rehabilitation research experts and commissioned by the Institution of Occupational Safety and Health concluded that fit notes were not being used to their full potential by doctors, patients, and employers.

GP fit notes replaced sickness certificates in 2010 and aimed to encourage doctors to help patients stay at work or return to work as soon as they can. The new system allows recommendations to be made on work modifications such as changes to working hours or …
Analysis of postoperative radiation therapy in stage I through III epithelial ovarian carcinoma.
Authors: D B Fuller, W T Sause, H P Plenk, R L Menlove
Journal: Journal of Clinical Oncology (1987)

A retrospective long-term analysis of the results of primary postoperative radiotherapy in 106 women with invasive epithelial ovarian carcinoma is presented. Forty-two women received open-field total abdominopelvic irradiation, and 64 received treatment by various subtotal abdominopelvic techniques. The mean follow-up of living patients in the two groups is 86 and 116 months, respectively. Women who had Federation International Gynecology and Oncology (FIGO) stages I through III-A with no postoperative residual disease, or less than 0.5-cm abdominal and/or less than 2-cm pelvic residual disease formed a favorable group in whom total abdominopelvic irradiation resulted in a 71% 10-year actuarial relapse-free survival rate compared with 40% for those treated by subtotal abdominopelvic techniques (P less than or equal to .0205). The survival improvement due to the total abdominopelvic technique in favorable patients became even more significant (P less than or equal to 0.003) after adjusting for differences in stage, grade, and postoperative residual disease volume (no, or favorable, gross). Increasing grade appeared to be associated with decreasing survival even among favorable patients treated with the optimal technique, although the differences did not approach statistical significance after adjusting for residual disease volume and stage. Surgical bowel complications were equivalent, 7.1% for total abdominopelvic v 8.1% for subtotal abdominopelvic techniques. The addition of intraperitoneal radioactive chromic phosphate increased the surgical bowel complication rate 33% over external pelvic irradiation alone without improving survival. Patients with unfavorable gross residual disease and/or FIGO stages III-B and IV were incurable by any radiation technique. Those with no, or favorable, gross residual tumor constitute a group in whom we believe open-field total abdominopelvic irradiation represents a potentially curative therapy modality.
Peptide Transporters in the Intestine and the Kidney
Authors: Frederick H. Leibach, Vadivel Ganapathy
Journal: Annual Review of Nutrition (1996)

Even though the existence of a transport process for intact peptides in the brush border membrane of intestinal and renal absorptive epithelial cells has been known for almost three decades, it is only recently that the molecular nature of the proteins responsible for the transport process has been elucidated. Two peptide transporters, PEW 1 and PEPT 2, have been cloned. The cloned transporters catalyze active transport of intact di- and tripeptides and utilize a transmembrane electrochemical H + gradient as the driving force. The characteristic of H + coupling makes PEPT 1 and PEPT 2 unique among the transporters thus far identified in mammalian cells. In addition, the peptide transporters have immediate pharmacologic relevance because a number of peptide-like drugs are recognized as substrates by these transporters. Recently, cultured cell lines of intestinal and renal origin that express PEPT 1 and PEPT 2 have been identified. These cell lines are likely to facilitate studies on the regulatory aspects of the peptide transporters.
Neofunctionalization of Androgen Receptor by Gain-of-Function Mutations in Teleost Fish Lineage
Authors: Yukiko Ogino, Shigehiro Kuraku, Hiroshi Ishibashi, Hitoshi Miyakawa, Eri Sumiya, Shinichi Miyagawa, Hajime Matsubara, Gen Yamada, Michael E. Baker, Taisen Iguchi
Journal: Molecular Biology and Evolution (2015)

Steroid hormone receptor family provides an example of evolution of diverse transcription factors through whole-genome duplication (WGD). However, little is known about how their functions have been evolved after the duplication. Teleosts present a good model to investigate an accurate evolutionary history of protein function after WGD, because a teleost-specific WGD (TSGD) resulted in a variety of duplicated genes in modern fishes. This study focused on the evolution of androgen receptor (AR) gene, as two distinct paralogs, ARα and ARβ, have evolved in teleost lineage after TSGD. ARα showed a unique intracellular localization with a higher transactivation response than that of ARβ. Using site-directed mutagenesis and computational prediction of protein–ligand interactions, we identified two key substitutions generating a new functionality of euteleost ARα. The substitution in the hinge region contributes to the unique intracellular localization of ARα. The substitution on helices 10/11 in the ligand-binding domain possibly modulates hydrogen bonds that stabilize the receptor–ligand complex leading to the higher transactivation response of ARα. These substitutions were conserved in Acanthomorpha (spiny-rayed fish) ARαs, but not in an earlier branching lineage among teleosts, Japanese eel. Insertion of these substitutions into ARs from Japanese eel recapitulates the evolutionary novelty of euteleost ARα. These findings together indicate that the substitutions generating a new functionality of teleost ARα were fixed in teleost genome after the divergence of the Elopomorpha lineage. Our findings provide a molecular explanation for an adaptation process leading to generation of the hyperactive AR subtype after TSGD.
The Non-Hodgkin's Lymphomas: Current Concepts and Management
Authors: C S Portlock, E Glatstein
Journal: Annual Review of Medicine (1978)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Cardiac Myocyte KLF5 Regulates <i>Ppara</i> Expression and Cardiac Function
Authors: Konstantinos Drosatos, Nina M. Pollak, Christine J. Pol, Panagiotis Ntziachristos, Florian Willecke, Mesele-Christina Valenti, Chad M. Trent, Yunying Hu, Shaodong Guo, Iannis Aifantis, Ira J. Goldberg
Journal: Circulation Research (2015)

Fatty acid oxidation is transcriptionally regulated by peroxisome proliferator-activated receptor (PPAR)α and under normal conditions accounts for 70% of cardiac ATP content. Reduced Ppara expression during sepsis and heart failure leads to reduced fatty acid oxidation and myocardial energy deficiency. Many of the transcriptional regulators of Ppara are unknown.To determine the role of Krüppel-like factor 5 (KLF5) in transcriptional regulation of Ppara.We discovered that KLF5 activates Ppara gene expression via direct promoter binding. This is blocked in hearts of septic mice by c-Jun, which binds an overlapping site on the Ppara promoter and reduces transcription. We generated cardiac myocyte-specific Klf5 knockout mice that showed reduced expression of cardiac Ppara and its downstream fatty acid metabolism-related targets. These changes were associated with reduced cardiac fatty acid oxidation, ATP levels, increased triglyceride accumulation, and cardiac dysfunction. Diabetic mice showed parallel changes in cardiac Klf5 and Ppara expression levels.Cardiac myocyte KLF5 is a transcriptional regulator of Ppara and cardiac energetics.
Symptomatic Profiles of Patients With Polycythemia Vera: Implications of Inadequately Controlled Disease
Authors: Holly Geyer, Robyn Scherber, Heidi Kosiorek, Amylou C. Dueck, Jean-Jacques Kiladjian, Zhijian Xiao, Stefanie Slot, Sonja Zweegman, Federico Sackmann, Ana Kerguelen Fuentes, Dolores Hernández-Maraver, Konstanze Döhner, Claire N. Harrison, Deepti Radia, Pablo Muxi, Carlos Besses, Francisco Cervantes, Peter L. Johansson, Bjorn Andreasson, Alessandro Rambaldi, Tiziano Barbui, Karin Bonatz, Andreas Reiter, Francoise Boyer, Gabriel Etienne, Jean-Christophe Ianotto, Dana Ranta, Lydia Roy, Jean-Yves Cahn, Norman Maldonado, Giovanni Barosi, Maria L. Ferrari, Robert Peter Gale, Gunnar Birgegard, Zefeng Xu, Yue Zhang, Xiujuan Sun, Junqing Xu, Peihong Zhang, Peter A.W. te Boekhorst, Suzan Commandeur, Harry Schouten, Heike L. Pahl, Martin Griesshammer, Frank Stegelmann, Thomas Lehmann, Zhenya Senyak, Alessandro M. Vannucchi, Francesco Passamonti, Jan Samuelsson, Ruben A. Mesa
Journal: Journal of Clinical Oncology (2015)

Purpose Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with disabling symptoms and a heightened risk of life-threatening complications. Recent studies have demonstrated the effectiveness of JAK inhibitor therapy in patients with PV patients who have a history of prior hydroxyurea (HU) use (including resistance or intolerance), phlebotomy requirements, and palpable splenomegaly. We aimed to determine how these features contribute alone and in aggregate to the PV symptom burden. Patients and Methods Through prospective evaluation of 1,334 patients with PV who had characterized symptom burden, we assessed patient demographics, laboratory data, and the presence of splenomegaly by disease feature (ie, known HU use, known phlebotomy requirements, splenomegaly). Results The presence of each feature in itself is associated with a moderately high symptom burden (MPN symptom assessment form [SAF] total symptom score [TSS] range, 27.7 to 29.2) that persists independent of PV risk category. In addition, symptoms incrementally increase in severity with the addition of other features. Patients with PV who had all three features (PV-HUPS) faced the highest total score (MPN-SAF TSS, 32.5) but had similar individual symptom scores to patients with known HU use (PV-HU), known phlebotomy (PV-P), and splenomegaly (PV-S). Conclusion The results of this study suggest that patients with PV who have any one of the features in question (known HU use, known phlebotomy, or splenomegaly) have significant PV-associated symptoms. Furthermore, it demonstrates that many PV symptoms remain severe independent of the number of features present.
Feasibility and safety of conservative surgery for the treatment of spermatic cord leiomyosarcoma
Authors: G. Bozzini, M. Albersen, J. Romero Otero, M. Margreiter, E. Garcia Cruz, A. Mueller, C. Gratzke, E.C. Serefoglu, J.I. Martinez Salamanca, P. Verze
Journal: International Journal of Surgery (2015)
Phase II studies of single-agent cimetidine and the combination N-phosphonacetyl-L-aspartate (NSC-224131) plus L-alanosine (NSC-153353) in advanced malignant melanoma.
Authors: R F Morton, E T Creagan, S A Cullinan, J A Mailliard, L Ebbert, M H Veeder, M Chang
Journal: Journal of Clinical Oncology (1987)

We conducted parallel phase II trials of cimetidine as a single agent and the combination N-phosphonacetyl-L-aspartate (PALA) plus L-alanosine among 40 previously untreated patients with biopsy-proven, measurable disseminated malignant melanoma. We did not design the trial to be a comparative assessment of the two regimens. Among 19 patients treated with cimetidine, 300 mg orally four times daily, there was one complete response of extensive pleural and pulmonary metastases for 16+ months and two partial regressions of soft tissue lesions for 7 and 21+ months, respectively. Among 21 patients treated with the combination regimen, there was only one partial response in soft tissue for 1 month. The median times to progression and death were 1.4 and 6 months, respectively, for cimetidine, and 1.3 and 4 months, respectively, from the combination of PALA plus L-alanosine. Among patients who progressed on initial treatment, there were no responses in 12 who received crossover therapy with cimetidine and 11 with the combination regimen. Two patients treated with the combination program had severe stomatitis, two developed renal failure, and one had severe leukopenia and thrombocytopenia. Recognizing the limitations of small sample size, these early observations suggest that cimetidine may have intriguing implications in the management of disseminated malignant melanoma.
Roles of Ubiquitinylation in Proteolysis and Cellular Regulation
Authors: Keith D. Wilkinson
Journal: Annual Review of Nutrition (1995)

Most eukaryotic organisms respond to starvation, nutrient deprivation, and/or stress by increasing the rates of intracellular proteolysis. The amino acids released may be reutilized for synthesis of important proteins, or directly for the production of energy. This enhanced proteolysis is also required for repair of cellular damage due to environmental insults such as heat shock, free radicals, viral infection, or mutation. Finally, intracellular proteolysis is important in determining the steady-state levels of a wide variety of regulatory proteins, particularly those regulating the cell cycle. The ubiquitin-dependent proteolytic system participates in all of these functions. In spite of its cytoplasmic localization, this system is selective and acts only on a limited set of substrates. This review discusses the mechanisms of this selectivity and the potential roles of ubiquitin-dependent proteolysis.
Lung cancer metastatic cells detected in blood by reverse transcriptase-polymerase chain reaction and dot-blot analysis.
Authors: G Castaldo, R Tomaiuolo, A Sanduzzi, M L Bocchino, A Ponticiello, E Barra, D Vitale, F Bariffi, L Sacchetti, F Salvatore
Journal: Journal of Clinical Oncology (1997)

PURPOSE We analyzed the blood of patients with lung cancer at different stages of presentation for the presence of carcinoembryonic antigen (CEA) mRNA detected by reverse transcriptase-polymerase chain reaction (RT-PCR) combined with the dot-blot procedure as an indicator of micrometastatic malignant cells. PATIENTS AND METHODS We studied 24 lung cancer patients (10 with distant metastases and 14 with no evidence of distant metastases), eight age- and sex-matched patients affected by nonneoplastic respiratory diseases (four smokers), and eight healthy subjects. We used immunohistochemistry and RT-PCR dot-blot analysis to evaluate CEA expression in the neoplastic tissue, and the RT-PCR dot-blot procedure to analyze CEA mRNA in circulating cells. RESULTS The RT-PCR dot-blot procedure was highly sensitive aspecific: it detected CEA mRNA in samples of RNA from lung cancer diluted 10(6)-fold with RNA extracted from normal blood cells, and sequence analysis confirmed that the amplified product was CEA. CEA mRNA was found in circulating cells from eight of 10 lung cancer patients with distant metastases (diagnostic sensitivity, 80%) and in four of 14 patients with no evidence of distant metastases. Two of the latter had distant metastases within 6 months of analysis. Thus, the diagnostic specificity of the analysis toward lung cancer without distant metastases was 86%. The analysis was negative in the eight nonneoplastic patients and in the eight healthy controls. CONCLUSION The RT-PCR dot-blot analysis of CEA mRNA in blood cells seems to be a promising tool for the early detection of micrometastatic circulating cells in patients with lung cancer.
Endothelial Gα<sub>q/11</sub>is required for VEGF-induced vascular permeability and angiogenesis
Authors: Kishor K. Sivaraj, Rui Li, Julian Albarran-Juarez, Shengpeng Wang, Denise Tischner, Myriam Grimm, Jakub M. Swiercz, Stefan Offermanns, Nina Wettschureck
Journal: Cardiovascular Research (2015)

VEGF A (VEGF-A) is a central regulator of pre- and postnatal vascular development. In vitro studies suggested that heterotrimeric G-proteins of the Gq/11 family contribute to VEGF receptor 2 (VEGFR2) signalling, but the mechanism and physiological relevance of this finding is unknown. The aim of this study is to understand the role of endothelial Gαq/11 in VEGF-dependent regulation of vascular permeability and angiogenesis. We show here that VEGF-A-induced signalling events, such as VEGFR2 autophosphorylation, calcium mobilization, or phosphorylation of Src and Cdh5, were reduced in Gαq/11-deficient endothelial cells (ECs), resulting in impaired VEGF-dependent barrier opening, tube formation, and proliferation. Agonists at Gq/11-coupled receptors facilitated VEGF-A-induced VEGFR2 autophosphorylation in a Gαq/11-dependent manner, thereby enhancing downstream VEGFR2 signalling. In vivo, EC-specific Gαq/11- and Gαq-deficient mice showed reduced VEGF-induced fluid extravasation, and retinal angiogenesis was significantly impaired. Gαq-deficient ECs showed reduced proliferation, Cdh5 phosphorylation, and fluid extravasation, whereas apoptosis was increased. Gαq/11 critically contributes to VEGF-A-dependent permeability control and angiogenic behaviour in vitro and in vivo.
ICRF-187 permits longer treatment with doxorubicin in women with breast cancer.
Authors: J L Speyer, M D Green, A Zeleniuch-Jacquotte, J C Wernz, M Rey, J Sanger, E Kramer, V Ferrans, H Hochster, M Meyers
Journal: Journal of Clinical Oncology (1992)

PURPOSE To test potential protection by ICRF-187 against cumulative doxorubicin-dose-related cardiac toxicity, we conducted a randomized clinical trial in 150 women with advanced breast cancer. PATIENTS AND METHODS Patients received fluorouracil (5FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days intravenously (IV) (control regimen, 74 patients), or the same regimen preceded by ICRF-187 1,000 mg/m2 IV (experimental regimen, 76 patients). RESULTS We previously reported that ICRF-187 in this dose and schedule provides cardiac protection and does not substantially alter the noncardiac toxicity or antitumor efficacy of the control regimen. In this updated analysis of the entire patient cohort, we provide additional support for these findings and demonstrate that patients in the ICRF-187 group received more cycles (median, 11) and higher cumulative doses (median, 500 mg/m2) of doxorubicin than patients in the control group (median, nine cycles, P less than .01; and 441 mg/m2, P less than .05). Twenty-six patients in the ICRF-187 group received doxorubicin doses of at least 700 mg/m2, and among them, 11 patients received 1,000 mg/m2 or more. Only three patients in the control group received doxorubicin doses of 700 mg/m2; the maximum dose administered to one patient in this group was 950 mg/m2. ICRF-187 cardiac protection was demonstrated by difference in incidence of clinical congestive heart failure (CHF; two patients in the ICRF-187 group v 20 in the control group; P less than .0001) and by differences in resting left ventricular ejection fraction (LVEF) determined by multigated radionuclide (MUGA) scan from baselines and that required patient removal from study (five patients in the ICRF-187 group had a decrease in LVEF to less than 0.45 or a decrease from the baseline LVEF of 0.20 or more v 32 in the control group; P less than .000001). Among the 30 patients who had an assessable endomyocardial biopsy at cumulative doxorubicin 450 mg/m2, none of 16 in the ICRF-187 group and six of 14 in the control group had a score of 2 (P less than .05). ICRF-187 cardiac protection was observed in patients with and without prior chest-wall radiation or other risk factors for developing doxorubicin cardiac toxicity. CONCLUSION By protecting against cumulative doxorubicin-induced cardiac toxicity, ICRF-187 permits significantly greater doses of doxorubicin to be administered to patients with greater safety.
First-Trimester Maternal Abdominal Adiposity Predicts Dysglycemia and Gestational Diabetes Mellitus in Midpregnancy
Authors: Leanne R. De Souza, Howard Berger, Ravi Retnakaran, Jonathon L. Maguire, Avery B. Nathens, Philip W. Connelly, Joel G. Ray
Journal: Diabetes Care (2015)

OBJECTIVE This study assessed the association between first-trimester abdominal adiposity and dysglycemia and gestational diabetes mellitus (GDM) in midpregnancy. RESEARCH DESIGN AND METHODS In a prospective cohort of 485 women, we measured subcutaneous (SAT), visceral (VAT), and total (TAT) adipose tissue depth, using ultrasound at 11–14 weeks’ gestation. Logistic regression analysis assessed the relation between quartiles of SAT, VAT, or TAT depth and the composite outcome of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or GDM, based on a 75-g oral glucose tolerance test at 24–28 weeks. RESULTS Adjusting for maternal age, ethnicity, family history of diabetes, and BMI, quartile 4 versus quartile 1 VAT (adjusted odds ratio [aOR] 3.1, 95% CI 1.1–9.5) and TAT (aOR 2.7, 95% CI 1.1–7.8) were significantly associated with the composite outcome, but SAT was not (aOR 1.8, 95% CI 0.70–4.8). The same was seen for GDM alone. CONCLUSIONS Elevated first-trimester VAT and TAT depth independently predicted the risk of dysglycemia later in pregnancy.
Classroom Fungal Spore Exposure and Asthma Morbidity in Inner-City School Children
Authors: Sachin N. Baxi, Carter R. Petty, Chunxia Fu, William J. Sheehan, Perdita Permaul, Lianne Kopel, Watcharoot Kanchongkittiphon, Jonathan M. Gaffin, Christine A. Rogers, Michael L. Muilenberg, Diane R. Gold, Wanda Phipatanakul
Journal: Journal of Allergy and Clinical Immunology (2013)