tbuckley/cabot-search huggingface dataset:
The disparate effects of “MEK-specific” inhibitors PD09059 and U0126 on1,25D3-induced differentiation of HL60 cells
Authors: Jing Zhang, Xuening Wang, George P. Studzinski
Journal: Cancer Research (2005)

5520  Chlorotoxin, also called TM-601, is a 36-amino acid peptide originally derived from the venom of the Giant Israeli scorpion Leiurus quinquestriatus. In previous studies, chlorotoxin appeared to bind specifically to glioblastoma cell lines and glioblastoma sections, but not to normal brain tissue, and tumor-specific binding was later extended to neuroectodermal tissue. In the present study, using colorimetric binding assays, histochemical staining, and FACS analysis, we demonstrate that chlorotoxin binds to multiple human cancer cell lines and tissues, including solid tumors (glioma, lung, breast, prostate, melanoma, colorectal), as well as hematologic tumor cell lines (leukemia, lymphoma, myeloma). Furthermore, we have dissected the amino acid sequence of chlorotoxin and demonstrated that there are two distinct binding domains in this small molecule, designated α and β, each capable of binding tumor cells. The specific target and mechanism of action of chlorotoxin has remained unclear. To address this, multiple human tumor cell lines were used to localize chlorotoxin binding. In all cell lines tested, chlorotoxin binding was predominantly localized to cellular lamellipodia, organelles involved in signal transduction, cell invasion, adhesion, and motility. Because membrane phospholipids are crucial regulatory components of intracellular signaling pathways, the ability of chlorotoxin to bind phosphatidylinositol phosphates was investigated. Using an in vitro binding assay, we illustrate that chlorotoxin binds multiple phosphatidylinositol isoforms and binds with greatest affinity to phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2), a membrane phospholipid vital to the PI3K-Akt pathway that has been implicated in multiple human cancers. This binding could profoundly affect many cellular functions, including subsequent signal transduction events, cell cycle changes, protein and DNA synthesis, and cell movement. In summary, these data provide solid evidence that chlorotoxin binds multiple human cancer types, including solid and hematologic tumors, and that the α and β domains of chlorotoxin facilitate binding of chlorotoxin to cancer cells through a membrane phosphatidylinositol localized to the lamellipodia of cancer cells. 131I-TM-601, a synthetic version of chlorotoxin conjugated to a radioisotope of iodine, is currently in Phase II clinical development for the treatment of malignant brain tumors.
Low-dose versus standard-dose lenograstim prophylaxis after chemotherapy: a randomized, crossover comparison.
Authors: G C Toner, J D Shapiro, C R Laidlaw, D Rischin, M J Millward, M Wolf, H Januszewicz, S V Mitchell, A C Curran, J P Matthews, J F Bishop
Journal: Journal of Clinical Oncology (1998)

PURPOSE Granulocyte colony-stimulating factor (G-CSF) administered prophylactically after chemotherapy reduces the duration and severity of neutropenia. This randomized crossover study was designed to assess whether a lower dose of G-CSF is as effective as a standard dose of 5 microg/kg daily. PATIENTS AND METHODS Patients who received standard-dose chemotherapy regimens expected to cause neutropenia received G-CSF (lenograstim) that started the day after chemotherapy for 14 days or until the absolute neutrophil count (ANC) recovered to greater than 10 x 10(9)/L. The lenograstim dose was randomly allocated to be 2 or 5 microg/kg daily in the first cycle of chemotherapy and crossed over to the alternate dose for the second cycle. The study was designed to accrue 40 assessable patients to provide a power of 80% to detect a difference in duration of neutropenia of 1 day. Fifty-two patients were randomized to treatment and 43 patients completed two cycles of identical chemotherapy. RESULTS There was little neutropenia irrespective of the dose used. Twenty-three patients (53%) had no grade III or IV neutropenia and 30 patients (70%) had no grade IV neutropenia. Crossover trial methodology was used to assess the difference in outcome caused by the lower dose compared with the standard dose (estimated treatment effect). There was no significant difference in the measures of neutropenia, hospitalization, or other clinical outcomes. The 95% confidence interval (one-sided) for the additional duration of neutropenia caused by the lower dose of lenograstim was 0.43 days or less for grade III or IV neutropenia and 0.34 days or less for grade IV neutropenia. CONCLUSION Lenograstim 2 microg/kg provides similar protection to 5 microg/kg against neutropenia that complicates standard-dose chemotherapy. The use of a lower dose has important implications for the cost-effectiveness of prophylactic G-CSF therapy.
A new<i>KCNQ1</i>mutation at the S5 segment that impairs its association with KCNE1 is responsible for short QT syndrome
Authors: Cristina Moreno, Anna Oliveras, Alicia de la Cruz, Chiara Bartolucci, Carmen Muñoz, Eladia Salar, Juan R. Gimeno, Stefano Severi, Nuria Comes, Antonio Felipe, Teresa González, Pier Lambiase, Carmen Valenzuela
Journal: Cardiovascular Research (2015)

KCNQ1 and KCNE1 encode Kv7.1 and KCNE1, respectively, the pore-forming and the accessory subunits of the slow delayed rectifier potassium current, IKs. KCNQ1 mutations are associated with long and short QT syndrome. The aim of this study was to characterize the biophysical and cellular phenotype of a KCNQ1 missense mutation, F279I, found in a 23-year-old man with a corrected QT interval (QTc) of 356 ms and a family history of sudden cardiac death. Experiments were performed using perforated patch-clamp, western blot, co-immunoprecipitation, biotinylation, and immunocytochemistry techniques in HEK293, COS7 cells and in cardiomyocytes transfected with WT Kv7.1/KCNE1 or F279I Kv7.1/KCNE1 channels. In the absence of KCNE1, F279I Kv7.1 current exhibited a lesser degree of inactivation than WT Kv7.1. Also, functional analysis of F279I Kv7.1 in the presence of KCNE1 revealed a negative shift in the activation curve and an acceleration of the activation kinetics leading to a gain of function in IKs. The co-assembly between F279I Kv7.1 channels and KCNE1 was markedly decreased compared with WT Kv7.1 channels, as revealed by co-immunoprecipitation and Föster Resonance Energy Transfer experiments. All these effects contribute to the increase of IKs when channels incorporate F279I Kv7.1 subunits, as shown by a computer model simulation of these data that predicts a shortening of the action potential (AP) consistent with the patient phenotype. The F279I mutation induces a gain of function of IKs due to an impaired gating modulation of Kv7.1 induced by KCNE1, leading to a shortening of the cardiac AP.
Combined treatment with chemotherapy and neutron irradiation for limited non-small-cell lung cancer: a Southwest Oncology Group Study.
Authors: R B Livingston, B R Griffin, C S Higano, G E Laramore, S E Rivkin, R S Goldberg, S F Schulman
Journal: Journal of Clinical Oncology (1987)

Seventy-three patients with regional, inoperable non-small-cell lung cancer received treatment with initial chemotherapy for two cycles (vinblastine-mitomycin followed in 3 weeks by vinblastine-cisplatin), with planned subsequent neutron irradiation to the primary site and concurrent, elective whole-brain irradiation using photons, followed by two more cycles of identical chemotherapy. Histology was reported as adenocarcinoma or large cell in 75%, and 60% had Radiation Therapy Oncology Group (RTOG) stage 3 disease; the remainder had stage 4. The response rate to chemotherapy induction was 51%. There were 58 patients in a second phase of the study who were potentially eligible for treatment with a medically dedicated cyclotron having more favorable characteristics with regard to treatment planning and dose delivery (neutrons "B"). The overall response rate in this group was 79%. Chemotherapy toxicity included four fatalities (5%), with three related to mitomycin C induced bilateral pneumonitis, and an additional five patients (7%) with life-threatening events that required hospitalization. Two fatalities were attributed to combined effects of chemotherapy and radiation, and six more to chest radiation therapy, for an overall treatment-related death incidence of 12 of 73 (16%). Four of the six deaths related to chest irradiation occurred after treatment with a "physics-based" neutron generator (neutrons "A"). Among the 45 who received neutrons in the B group, two (4%) had radiation-related deaths, and another four (10%) had clinically evident radiation pneumonitis. Pretreatment performance status (PS) and response to chemotherapy, but not RTOG stage or weight loss, were significantly associated with survival. Among patients who actually received chest irradiation, only initial response to chemotherapy remained as a significant predictor of survival in univariate analysis, with a median survival of 20 months in responders v 9 months in chemotherapy nonresponders. The patterns of first relapse observed in B group patients revealed that 28% were distant, while 64% were locoregional. This represents a reversal of the usual pattern in studies of chest irradiation alone. It probably reflects elimination of brain relapse by the use of elective whole-brain irradiation, impact of systemic chemotherapy on micrometastases elsewhere, and conservative treatment volumes employed for the chest irradiation in an attempt to minimize its toxicity. Further exploration of combined modality therapy is indicated for regional non-small-cell disease, with a real potential for survival impact if the therapeutic index can be improved.
Dose-response in the treatment of hypercalcemia of malignancy by a single infusion of the bisphosphonate AHPrBP.
Authors: D Thiébaud, P Jaeger, A F Jacquet, P Burckhardt
Journal: Journal of Clinical Oncology (1988)

Fifty-two patients with malignant hypercalcemia were treated with a single dose of 3-amino-1-hydroxypropylidene-1,1- bisphosphonate (AHPrBP, previously APD), a potent inhibitor of osteoclast-mediated bone resorption. In order to establish a dose-response in humans, patients were divided into four groups receiving 30 mg, 45 mg, 60 mg, or 90 mg, respectively, as a 24-hour infusion. Initial plasma calcium was similar in all groups, except in the group receiving 90 mg, of which some patients had higher initial values. All patients responded to AHPrBP with a rapid decrease of plasma calcium concentration from 3.47 +/- 0.10 mmol/L at day 0 to 2.43 +/- 0.06 at day 6 (P less than .001). Plasma calcium became normal within four to six days in 43 patients. Eight of the nine patients whose calcium did not become normal were in the low-dose (30 and 45 mg of AHPrBP) groups. Slight and asymptomatic hypocalcemia occurred in only tow of the 26 patients in the low-dose groups, but in six of the 26 patients in the high-dose groups. A follow-up study in 40 patients showed that hypercalcemia recurred within 1 month in five of ten patients in the group receiving 30 mg, in three of ten patients in the group receiving 45 mg, and in one of 20 patients in the groups receiving 60 and 90 mg, whereas mortality was almost identical in all four groups. In all groups, plasma phosphate, plasma creatinine, urinary calcium, and hydroxyproline excretion decreased significantly. In conclusion, when administered as a single-day infusion in the treatment of tumor hypercalcemia, AHPrBP leads to a dose-dependent decrease in plasma calcium. To prevent transient hypocalcemia and early relapse, the optimal dose should be adapted to the degree of severity of hypercalcemia.
Correlates of Treatment-Emergent Mania Associated With Antidepressant Treatment in Bipolar Depression
Authors: Mark A Frye, Gerhard Helleman, Susan L McElroy, Lori L Altshuler, David O Black, Paul E Keck, Willem A Nolen, Ralph Kupka, Gabriele S Leverich, Heinz Grunze, Jim Mintz, Robert M Post, Trisha Suppes
Journal: American Journal of Psychiatry (2008)

Treatment-emergent mania can have substantial negative impact on overall mood and psychosocial stability in patients receiving treatment for bipolar depression. This study examined the correlates associated with treatment-emergent mania in patients receiving adjunctive antidepressant treatment for bipolar depression.A total of 176 adult outpatients with bipolar disorder in a 10-week trial of adjunctive antidepressant treatment for depression were categorized into three groups based on the Clinical Global Impression Scale for Bipolar Disorder: those who responded to antidepressant treatment (N=85), those who did not respond to antidepressant treatment (N=45), and those who had treatment-emergent mania or hypomania (N=46). Symptom severity was measured with the Inventory of Depressive Symptomatology and the Young Mania Rating Scale (YMRS) at baseline and bimonthly intervals. Factor analysis was used to examine correlates of treatment-emergent mania.Baseline YMRS scores were significantly different between groups. Otherwise, there were no significant between-group differences in demographic or clinical characteristics. Factor analysis showed that a subset of the YMRS items predicted treatment-emergent mania in this sample: increased motor activity, speech, and language-thought disorder.These data suggest that minimal manic symptoms at baseline coexisting with otherwise full syndromal bipolar depression are associated with antidepressant treatment-emergent mania or hypomania. A careful examination of motor activation, pressured speech, and racing thoughts is warranted before starting antidepressant treatment in bipolar depression.
Lifetime Exposure to Ambient Pollution and Lung Function in Children
Authors: Mary B. Rice, Sheryl L. Rifas-Shiman, Augusto A. Litonjua, Emily Oken, Matthew W. Gillman, Itai Kloog, Heike Luttmann-Gibson, Antonella Zanobetti, Brent A. Coull, Joel Schwartz, Petros Koutrakis, Murray A. Mittleman, Diane R. Gold
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Few studies have examined associations between exposure to air pollution and childhood lung function after implementation of strict air quality regulations in the 1990s.
Factors in the Pathomechanism of Chronic Lymphocytic Leukemia
Authors: H Theml, R Love, H Begemann
Journal: Annual Review of Medicine (1977)

Postpartum depression (PPD) is common, disabling, and treatable. The strongest risk factor is a history of mood or anxiety disorder, especially having active symptoms during pregnancy. As PPD is one of the most common complications of childbirth, it is ...Read More
Comment on Boyko and Jensen. Do We Know What Homeostatis Model Assessment Measures? If Not, Does It Matter? Diabetes Care 2007;30:2725–2728
Authors: M. Francisco Rivas-Crespo
Journal: Diabetes Care (2015)

When Boyko and Jensen (1) published their thoughts on the characteristics of HOMA of insulin resistance (HOMA-IR) (2), they resorted to comparing it with QUICKI (3). They searched for a mathematical relationship between these surrogate indices of insulin resistance, which are the most widely used as both have the same biological basis: fasting serum levels of insulin and glucose. For this purpose, the authors estimated the logarithm of HOMA-IR and the inverse …
What we know about primary dysmenorrhea today: a critical review
Authors: Stella Iacovides, Ingrid Avidon, Fiona C. Baker
Journal: Human Reproduction Update (2015)

Primary dysmenorrhea, or painful menstruation in the absence of pelvic pathology, is a common, and often debilitating, gynecological condition that affects between 45 and 95% of menstruating women. Despite the high prevalence, dysmenorrhea is often poorly treated, and even disregarded, by health professionals, pain researchers, and the women themselves, who may accept it as a normal part of the menstrual cycle. This review reports on current knowledge, particularly with regards to the impact and consequences of recurrent menstrual pain on pain sensitivity, mood, quality of life and sleep in women with primary dysmenorrhea. Comprehensive literature searches on primary dysmenorrhea were performed using the electronic databases PubMed, Google Scholar and the Cochrane Library. Full-text manuscripts published between the years 1944 and 2015 were reviewed for relevancy and reference lists were cross-checked for additional relevant studies. In combination with the word 'dysmenorrhea' one or more of the following search terms were used to obtain articles published in peer-reviewed journals only: pain, risk factors, etiology, experimental pain, clinical pain, adenomyosis, chronic pain, women, menstrual cycle, hyperalgesia, pain threshold, pain tolerance, pain sensitivity, pain reactivity, pain perception, central sensitization, quality of life, sleep, treatment, non-steroidal anti-inflammatory drugs. Women with dysmenorrhea, compared with women without dysmenorrhea, have greater sensitivity to experimental pain both within and outside areas of referred menstrual pain. Importantly, the enhanced pain sensitivity is evident even in phases of the menstrual cycle when women are not experiencing menstrual pain, illustrating that long-term differences in pain perception extend outside of the painful menstruation phase. This enhanced pain sensitivity may increase susceptibility to other chronic pain conditions in later life; dysmenorrhea is a risk factor for fibromyalgia. Further, dysmenorrheic pain has an immediate negative impact on quality of life, for up to a few days every month. Women with primary dysmenorrhea have a significantly reduced quality of life, poorer mood and poorer sleep quality during menstruation compared with their pain-free follicular phase, and compared with the menstruation phase of pain-free control women. The prescribed first-line therapy for menstrual pain remains non-steroidal anti-inflammatory drugs, which are effective in relieving daytime and night-time pain. Further study is needed to determine whether effectively blocking dysmenorrheic pain ameliorates risk for the development of chronic pain disorders and to explore whether it is possible to prevent the development—and not just treat—severe dysmenorrheic pain in adolescent girls. In conclusion, we demonstrate the extensive multi-factorial impact of dysmenorrhea and we encourage and direct researchers to necessary future studies.
Arterial Smooth Muscle Mitochondria Amplify Hydrogen Peroxide Microdomains Functionally Coupled to L-Type Calcium Channels
Authors: Nathan L. Chaplin, Madeline Nieves-Cintrón, Adriana M. Fresquez, Manuel F. Navedo, Gregory C. Amberg
Journal: Circulation Research (2015)

Rationale: Mitochondria are key integrators of convergent intracellular signaling pathways. Two important second messengers modulated by mitochondria are calcium and reactive oxygen species. To date, coherent mechanisms describing mitochondrial integration of calcium and oxidative signaling in arterial smooth muscle are incomplete. Objective: To address and add clarity to this issue, we tested the hypothesis that mitochondria regulate subplasmalemmal calcium and hydrogen peroxide microdomain signaling in cerebral arterial smooth muscle. Methods and Results: Using an image-based approach, we investigated the impact of mitochondrial regulation of L-type calcium channels on subcellular calcium and reactive oxygen species signaling microdomains in isolated arterial smooth muscle cells. Our single-cell observations were then related experimentally to intact arterial segments and to living animals. We found that subplasmalemmal mitochondrial amplification of hydrogen peroxide microdomain signaling stimulates L-type calcium channels, and that this mechanism strongly impacts the functional capacity of the vasoconstrictor angiotensin II. Importantly, we also found that disrupting this mitochondrial amplification mechanism in vivo normalized arterial function and attenuated the hypertensive response to systemic endothelial dysfunction. Conclusions: From these observations, we conclude that mitochondrial amplification of subplasmalemmal calcium and hydrogen peroxide microdomain signaling is a fundamental mechanism regulating arterial smooth muscle function. As the principle components involved are fairly ubiquitous and positioning of mitochondria near the plasma membrane is not restricted to arterial smooth muscle, this mechanism could occur in many cell types and contribute to pathological elevations of intracellular calcium and increased oxidative stress associated with many diseases.
Colophony as a marker for fragrance allergy in the general European population
Authors: T.L. Diepgen, R. Ofenloch, M. Bruze, S. Cazzaniga, P.-J. Coenraads, P. Elsner, M. Goncalo, Å. Svensson, L. Naldi
Journal: British Journal of Dermatology (2015)

Colophony is not used as a fragrance ingredient. However, colophony is a well-established marker of fragrance contact allergy(2-4) . Colophony was therefore included as a fragrance allergy marker in our recent paper in BJD on contact allergy in the general population (prevalence 1.0%; 95%-CI 0.6%-1.3%)(5) . When including colophony as a fragrance marker in the article on fragrance contact allergy(1) together with fragrance mix I (FM I) in the True test containing an evernia prunastri (oak moss) with a high content of atranol and chloratranol or fragrance mix II (FM II) or any of the individual materials in either FM I or FM II or Myroxylon pereirae (MP) or sesquiterpene lactones, some information in table 5 of this article(1) change slightly according to the numbers given here: This article is protected by copyright. All rights reserved. (Less)
Inferring Speciation and Extinction Rates under Different Sampling Schemes
Authors: S. Hohna, T. Stadler, F. Ronquist, T. Britton
Journal: Molecular Biology and Evolution (2011)

The birth–death process is widely used in phylogenetics to model speciation and extinction. Recent studies have shown that the inferred rates are sensitive to assumptions about the sampling probability of lineages. Here, we examine the effect of the method used to sample lineages. Whereas previous studies have assumed random sampling (RS), we consider two extreme cases of biased sampling: "diversified sampling" (DS), where tips are selected to maximize diversity and "cluster sampling (CS)," where sample diversity is minimized. DS appears to be standard practice, for example, in analyses of higher taxa, whereas CS may occur under special circumstances, for example, in studies of geographically defined floras or faunas. Using both simulations and analyses of empirical data, we show that inferred rates may be heavily biased if the sampling strategy is not modeled correctly. In particular, when a diversified sample is treated as if it were a random or complete sample, the extinction rate is severely underestimated, often close to 0. Such dramatic errors may lead to serious consequences, for example, if estimated rates are used in assessing the vulnerability of threatened species to extinction. Using Bayesian model testing across 18 empirical data sets, we show that DS is commonly a better fit to the data than complete, random, or cluster sampling (CS). Inappropriate modeling of the sampling method may at least partly explain anomalous results that have previously been attributed to variation over time in birth and death rates.