SEARCH · Search PubMed

Results for “actionable alterations”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 505 records · Page 28Linked to original sources

PubMed1980

Electrophysiological effects of imipramine on bovine ventricular muscle and Purkinje fibres.

1 The effect of imipramine in concentrations between 0.01 microM and 50 microM has been studied on bovine Purkinje fibres and ventricular muscle transmembrane potentials. 2 In electrically stimulated fibres, imipramine had no effect on the resting membrane potential, but decreased the action potential amplitude, overshoot and maximum rate of depolarization (Vmax). 3 In Purkinje fibres, imipramine also decreased the conduction velocity and shifted the membrane responsiveness and recovery time curves downward and to the right. 4 In both Purkinje fibres and ventricular muscle, imipramine decreased the amplitude of phase 2 and prolonged phase 3. In Purkinje fibres, imipramine did not alter the action potential duration (APD) but prolonged the effective refractory period (ERP). In ventricular muscle, at concentrations higher than 1 microM imipramine shortened both the APD and the ERP and made the ERP long as compared to APD. 5 Imipramine decreased the slope of phase 4 diastolic depolarization in spontaneously beating Purkinje fibres. 6 These properties of imipramine are quite similar to those of quinidine or procainamide (class 1 antiarrhythmics). The mechanisms responsible for the cardiac effect of imipramine are discussed.

Action Potentials↗

PubMed1982

Endocrine factors in human carcinogenesis.

Endogenous hormones probably do not initiate cancer directly but may influence carcinogenesis by facilitation or inhibition of endogenous production of carcinogens; effects on the metabolic activation or inactivation of carcinogens; alteration of the susceptibility of tissues to the initiation of cancer; promotion of the development of clinical cancer from initiated cells; and (theoretically) alteration of the body's capacity to eliminate initiated cells. Evidence exists for a role of endogenous hormones in cancers of the salivary gland, colon and rectum, liver, gall-bladder, pancreas, breast, cervix uteri, corpus uteri, ovary, prostate, testis, kidney, thyroid and pituitary glands and malignant melanoma. Oestrogens are the most commonly implicated hormone, and there is sufficient evidence for their causal association with cancers of the breast and endometrium. The most commonly postulated mechanisms of action are alteration of the susceptibility of tissues to initiation, and promotion of the once-initiated cancer. In human beings and, to some extent, in animals it is difficult to distinguish between these two mechanisms, both of which are based on hormone-induced cell proliferation, because the time of initiation cannot be pinpointed. Environmental factors may influence carcinogenesis by effects on the production, transport, peripheral action, inactivation and excretion of endogenous hormones. Examples that illustrate some of these possibilities may be derived from the effects of diet on risk of breast, endometrial and thyroid cancers.

Biotransformation↗

PubMed1990

Prolactin inhibition of pregnant mare's serum stimulated follicle development in the rat ovary.

Prolactin (PRL) effects on the female reproductive system have been presumed to occur primarily at the hypothalamic-pituitary level. The following studies were designed to evaluate whether PRL can directly alter gonadotropin actions at the ovarian level. In the first experiment, 10 groups of 7 cycling adult female rats were given a daily dose of pregnant mare's serum (PMS: 25 IU) and either saline (SAL) or PRL (0.25, 0.8, 2.5, 8, or 25 micrograms) twice daily for 4 days. In the second experiment, PMS (6 doses: 0-75 IU/d; 16 animals/dose) was administered to all animals while half the animals at each PMS dose received PRL (25 micrograms twice daily) and half received an equal volume of diluent. Finally, hypophysectomized (hypox) adult rats (n = 5-6/group) received 25 IU PMS/d and PRL (0-75 micrograms) twice daily. An additional group received 0 PRL and 0 PMS. Ovarian weight and histology were evaluated at the completion of each study. In the first experiment, PRL inhibited PMS-stimulated ovarian weight gain in a dose-dependent manner (p less than 0.01). Numbers of preantral (p less than 0.005) and antral (p less than 0.05) follicles were decreased in animals receiving an inhibitory dose of PRL (25 micrograms BID) compared to controls. In the second experiment PRL (25 micrograms BID) again inhibited PMS-stimulated ovarian weight (p less than 0.01) at all doses of PMS. Finally, in hypox animals, PRL inhibited PMS-stimulated ovarian weight gain (25 and 75 micrograms PRL: p = 0.001), and mean number (p less than 0.001) and diameter (p less than 0.001) of antral ovarian follicles (8-75 micrograms PRL) compared to controls. In summary, administration of PRL inhibited PMS-stimulated ovarian weight gain, and antral follicle diameter (in hypox animals only) and number in adult female rats suggesting that in states of hyperprolactinemia, PRL alters gonadotropin-mediated activities (i.e., folliculogenesis) directly at the ovarian level in addition to its hypothalamic and pituitary actions.

Analysis of Variance↗

PubMed2004

Interleukin 11 treatment alters the protein content of Galpha(i2) and adipogenic transcription factors in 3T3-L1 adipocytes.

Exposure of fully differentiated 3T3-L1 adipocytes to 5 nM interleukin 11 (IL-11) resulted in an increase (1.9+/-0.5 fold) in the protein content for the heterotrimeric G protein Galpha(i2). This G protein has been suggested to be involved in the control of the insulin responsive glucose transporter (GLUT4) translocation to the plasma membrane. Conversely, IL-11 had no effect on the content of three other G proteins, involved in insulin action. The alteration in Galpha(i2) protein corresponds to and provides a molecular rationale for our previously described IL-11 induced increase in plasma membrane glucose transporter content and increased rate of glucose transport. In addition, treatment with the cytokine altered the protein content of several transcription factors, C/EBPalpha and CHOP-10 decreased while PPARgamma and C/EBPbeta increased. These changes in transcription factor content are consistent with an alteration of phenotype with the cells reverting to an earlier stage of the differentiation process in response to IL-11.

3T3 Cells↗

PubMedDate not supplied

Neuronal dysfunction in Down syndrome: contribution of neuronal models in cell culture.

Down syndrome (DS) in humans, or trisomy of autosome 21, represents the hyperdiploidy that most frequently survives gestation, reaching an incidence of 1 in 700 live births. The condition is associated with multisystemic anomalies, including those affecting the central nervous system (CNS), determining a characteristic mental retardation. At a neuronal level, our group and others have shown that the condition determines marked alterations of action potential and ionic current kinetics, which may underlie abnormal processing of information by the CNS. Since the use of human tissue presents both practical and ethical problems, animal models of the human condition have been sought. Murine trisomy 16 (Ts16) is a model of the human condition, due to the great homology between human autosome 21 and murine 16. Both conditions share the same alterations of electrical membrane properties. However, the murine Ts16 condition is unviable (animals die in utero), thus limiting the quantity of tissue procurable. To overcome this obstacle, we have established immortal cell lines from normal and Ts16 mice with a method developed by our group that allows the stable in vitro immortalization of mammalian tissue, yielding cell lines which retain the characteristics of the originating cells. Cell lines derived from cerebral cortex, hippocampus, spinal cord and dorsal root ganglion of Ts16 animals show alterations of intracellular Ca2+ signals in response to several neurotransmitters (glutamate, acetylcholine, and GABA). Gene overdose most likely underlies these alterations in cell function, and the identification of the relative contribution of DS associated genes on such specific neuronal dysfunction should be investigated. This could enlighten our understanding on the contribution of these genes in DS, and identify new therapeutic targets.

Animals↗

PubMed1986

The role of endogenous peptides in the action of opioid analgesics.

The observation that the narcotic antagonist naloxone could inhibit analgesia produced by electrical stimulation of the brain indicated the involvement of an endogenous chemical in the relief of pain. Multiple endogenous opioid peptides have been identified that have similar pharmacological properties to known narcotic analgesics. The biosynthesis, release, and degradation of opioid peptides have been studied in order to better understand how the manipulation of endogenous opioid systems can be used to produce or augment analgesia. The results of our studies reveal that various conditions and manipulations, such as electrical brain stimulation, acupuncture, stress, and the administration of opioid analgesics, can cause the release of endogenous opioid peptides and possibly endogenous nonpeptide substances. It has also been discovered that nonopioid peptides, such as cholecystokinin, calcitonin, and angiotensin II, can alter the action of opioid analgesics by antagonizing or potentiating their effects. An understanding of the role of endogenous peptides in endogenous opioid mechanisms is necessary for the development of new ways to treat pain and such other disorders as sleep apnea in children (sudden infant death syndrome), head injury, and opioid addiction that involve the activation or alteration of endogenous opioid systems.

Analgesia↗

PubMed2006

Modulation of action potential duration on myocyte hypertrophic pathways.

Prolongation of the action potential duration (APD) has consistently been observed in experimental models of cardiac hypertrophy and failure as well as in humans and is partially attributed to a reduction of a hyperpolarizing current provided by the calcium-independent transient outward K(+) channel (I(to)). In the present study, we examined the effects of manipulating ion channel currents (I(to) and sodium/calcium exchanger (NCX)) and the associated alterations in action potential duration on cardiomyocyte hypertrophy and signaling induced by angiotensin II (AngII). Our aim was to examined whether distinct patterns of intracellular calcium manipulation could generate distinct patterns of MAPkinase activation and cellular hypertrophy. Cultured neonatal rat ventricular myocytes (NRVMs) were infected with Ad. beta-gal/GFP, Ad.Kv4.3, Ad.Kv4.3 antisense or Ad.NCX adenoviruses and hypertrophy induced by incubation with AngII. Overexpression of Kv4.3 increased I(to) density, shortened APD, decreased Ca(2+) influx and inhibited AngII-induced (3)H-leucine incorporation and ANF and beta-MHC expression. These hypertrophic changes were also paralleled by blockade of ERK MAP kinases activation as well as calcineurin expression. These electrical and hypertrophic changes produced by overexpression of Kv4.3 were completely and significantly reversed by Kv4.3 antisense and NCX gene transfer. Our findings indicate that AngII-mediated hypertrophy response in NRVMs can be abrogated by an enhancement of I(to) function through overexpression of Kv4.3 and that modulation of action potential duration can be important in the development of cardiac hypertrophy.

Action Potentials↗

PubMed1999

Angiotensin II induces insulin resistance independent of changes in interstitial insulin.

We set out to examine whether angiotensin-driven hypertension can alter insulin action and whether these changes are reflected as changes in interstitial insulin (the signal to which insulin-sensitive cells respond to increase glucose uptake). To this end, we measured hemodynamic parameters, glucose turnover, and insulin dynamics in both plasma and interstitial fluid (lymph) during hyperinsulinemic euglycemic clamps in anesthetized dogs, with or without simultaneous infusions of angiotensin II (ANG II). Hyperinsulinemia per se failed to alter mean arterial pressure, heart rate, or femoral blood flow. ANG II infusion resulted in increased mean arterial pressure (68 +/- 16 to 94 +/- 14 mmHg, P < 0. 001) with a compensatory decrease in heart rate (110 +/- 7 vs. 86 +/- 4 mmHg, P < 0.05). Peripheral resistance was significantly increased by ANG II from 0.434 to 0.507 mmHg. ml(-1). min (P < 0.05). ANG II infusion increased femoral artery blood flow (176 +/- 4 to 187 +/- 5 ml/min, P < 0.05) and resulted in additional increases in both plasma and lymph insulin (93 +/- 20 to 122 +/- 13 microU/ml and 30 +/- 4 to 45 +/- 8 microU/ml, P < 0.05). However, glucose uptake was not significantly altered and actually had a tendency to be lower (5.9 +/- 1.2 vs. 5.4 +/- 0.7 mg. kg(-1). min(-1), P > 0.10). Mimicking of the ANG II-induced hyperinsulinemia resulted in an additional increase in glucose uptake. These data imply that ANG II induces insulin resistance by an effect independent of a reduction in interstitial insulin.

Angiotensin II↗

PubMed1994

Mechanical and electrophysiological effects of protamine on isolated ventricular myocardium: evidence for calcium overload.

OBJECTIVE: The aim was to examine in vitro the cellular cardiac effects of protamine, the cationic polypeptide employed to reverse heparin anticoagulation, and to define its mechanisms of action. METHODS: Isometric contractile force and action potential characteristics after rest and at frequencies up to 3 Hz were recorded in guinea pig ventricular papillary muscle. The actions of protamine (10-300 micrograms.ml-1) were compared to those of heparin (10, 30 units.ml-1), and to heparin (10 units.ml-1) neutralised with equivalent (100 micrograms.ml-1) or excess (200 micrograms.ml-1) protamine. The effects of protamine were also examined using (1) muscle rapid cooling contractures (RCC) to assess intracellular Ca2+ stores and (2) the whole cell voltage clamp method to evaluate K+ and Ca2+ currents of isolated ventricular myocytes. RESULTS: Protamine (100-300 micrograms.ml-1) depressed contractions by 35-65% at 3 Hz, whereas contractions were enhanced by 150-500% at lower rates (resting state, 0.5 Hz), with a concomitant rise in resting force. Protamine caused a resting depolarisation from -90 to -76 mV and depressed action potential amplitude. In contrast, heparin altered contractile or action potential characteristics minimally. In 26 mM K+ solution with 0.1 microM isoprenaline, 30-300 micrograms.ml-1 protamine caused dose dependent depression of late peaking force development and slow action potential prolongation. After 15 min rest, when RCC were not normally elicited, rest RCC became prominent in 100-300 micrograms.ml-1 protamine. Effects of heparin with 100 micrograms.ml-1 excess protamine were similar to those of 100 micrograms.ml-1 protamine alone. Voltage clamp of isolated myocytes revealed that 10 micrograms.ml-1 protamine irreversibly decreased current through inwardly rectifying K+ channels (IK1), increased leakage current, and decreased inward Ca2+ current (ICa). CONCLUSIONS: The loss of the normal force-frequency relation, partial depolarisation, rise in resting tension, and appearance of rested state rapid cooling contractures suggest that unbound protamine can lead to excess intracellular Ca2+, mediated by an alteration in membrane ionic conductances.

Action Potentials↗

PubMed1998

Tamoxifen alters dopamine output through direct actions upon superfused corpus striatal tissue fragments.

Tamoxifen (10 pg/ml) was infused directly into superfused striatal tissue fragments of ovariectomized rats for a 50 min period. Immediately following the termination of tamoxifen there was a significant increase in dopamine output compared with non-infused controls. No such significant increase was observed with use of a 100 pg/ml tamoxifen dose. Although dopamine output was again increased upon termination of a 2 h infusion of tamoxifen, these levels failed to differ significantly from that of non-infused controls. Similarly, a shorter 10 min duration infusion of tamoxifen failed to alter dopamine output. Finally, we examined whether the tamoxifen-induced, post-infusion increase in dopamine output, as observed following a 50 min infusion of 10 pg/ml, involved a calcium dependent process. To achieve this goal, superfusions were performed with Calcium/Tamoxifen, No Calcium/Tamoxifen, No Calcium/No Tamoxifen and Calcium/No Tamoxifen. A significant increase in dopamine output post-tamoxifen infusion was obtained for the Calcium/Tamoxifen condition compared with the remaining three groups which failed to differ from one another. Taken together these results show that tamoxifen can alter dopamine output through direct, non-genomic effects upon striatal neurons. Responses to this anti-estrogen are intriguing since they are apparent following removal, but not during tamoxifen infusion and represent a calcium-dependent process. These data suggest that tamoxifen may represent an important modulator of nigrostriatal dopaminergic function.

Animals↗

PubMedDate not supplied

Role of protein kinase C in mediating alpha-1-adrenoceptor-induced negative inotropic response in rat ventricles.

The aim of this study was to determine the effect of protein kinase C (PKC) activation on intracellular Ca(2+) transient and its relation to alpha(1)-adrenoceptor (alpha(1)-AR)-stimulated negative inotropic response in rat ventricles. The electromechanical responses to phenylephrine (PE) in rat ventricular muscles were concomitantly examined using the conventional microelectrode method. The responses of intracellular Ca(2+) transient and cell contractions to PE in the absence of certain pharmacological interventions were ascertained in fura-2-loaded myocytes. The influence of PE on L-type Ca(2+) current (I(Ca,L)) was also examined using a voltage clamp in a whole-cell configuration. PE did not alter the action potential parameters during the negative inotropic phase. The negative inotropic effect (NIE) was inhibited by prazosin, chloroethylclonidine (CEC) and staurosporine, but was insensitive to pertussis toxin. Desensitization of PKC after prolonged pretreatment of rat ventricles with PDBu also abolished the NIE of PE. Caffeine modulated the NIE, but thapsigargin did not. The evoked intracellular Ca(2+) transient and cell contraction were initially decreased by PE, while I(Ca,L) was not altered. Prazosin and staurosporine significantly inhibited the responses. Our data indicated that alpha(1)AR-mediated NIE in rat ventricular muscles was due to the decrease of intracellular Ca(2+) transients by the modulation of PKC on Ca(2+)-releasing channels signaling through a CEC-sensitive alpha(1)AR subtype.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2000

Cardiac electrophysiological effects of citalopram in guinea pig papillary muscle comparison with clomipramine.

The effect of citalopram, a selective serotonin reuptake inhibitor (SSRI) antidepressant, was studied on cardiac action potential configuration and compared with that of the tricyclic antidepressant (TCA) clomipramine. Conventional microelectrode techniques were used in right ventricular papillary muscle preparations of the guinea pig. Citalopram caused a concentration-dependent (10-100 microM) shortening of action potential duration (APD), depression of plateau and overshoot potential, and reduction of maximum velocity of depolarization (V(max)). No significant changes in resting membrane potential were observed. Similar results were obtained with clomipramine; however, reduction of V(max) and overshoot was more pronounced with clomipramine, whereas citalopram caused relatively greater shortening of APD. Effects of both drugs were partly reversible. The results indicate that the SSRI antidepressant citalopram, similarly to TCA compounds, alters cardiac action potential configuration in guinea pig ventricular muscle, probably owing to inhibition of cardiac Na(+) and Ca(2+) channels. Differences in cardiac side effects of the two drugs may be related to their different actions on cardiac action potential configuration.

Action Potentials↗

PubMed1999

Effect of lifibrol on the metabolism of low density lipoproteins and cholesterol.

Lifibrol is a powerful cholesterol-lowering drug of unknown mechanism of action. This investigation was carried out to determine whether the major action of lifibrol is to enhance clearance of low density lipoproteins (LDL) through the LDL-receptor pathway, and if so, whether the drug exerts its action by altering the excretion of bile acids (acidic steroids), the absorption of cholesterol, or the synthesis of cholesterol. In a first study, in two patients with complete absence of LDL receptors, lifibrol therapy had essentially no effect on plasma LDL concentrations; in two others who had a marked reduction in LDL-receptor activity, response to the drug was attenuated. These findings suggest that lifibrol requires an intact LDL-receptor pathway to exert its action. In a second study, in patients with primary moderate hypercholesterolemia, isotope kinetic studies showed that lifibrol enhanced the fractional catabolic rate of LDL-apolipoprotein B (apo B), but had no effect on transport rates of LDL; these observations likewise support the probability that lifibrol acts mainly to increase the activity of the LDL-receptor pathway. However, in a third study in hypercholesterolemic patients, lifibrol therapy failed to increase acidic steroid excretion, inhibit cholesterol absorption, or reduce net cholesterol balance. Furthermore, lifibrol treatment did not significantly reduce urinary excretion of mevalonic acid. In contrast, in a parallel study, simvastatin therapy, which is known to inhibit cholesterol synthesis, gave the expected decrease in net cholesterol balance and reduction in urinary excretion of mevalonic acid. Thus, lifibrol, like statins, appears to increase the activity of LDL receptors; but in contrast to findings with statins, it was not possible to detect a significant decreased synthesis of cholesterol, either from balance studies or from urinary excretion of mevalonic acid. This finding raises the possibility that lifibrol activates the LDL-receptor pathway through a different mechanisms which remains to be determined.

Adolescent↗

PubMed1990

Effects of flecainide and quinidine on human atrial action potentials. Role of rate-dependence and comparison with guinea pig, rabbit, and dog tissues.

Flecainide and other class IC antiarrhythmic drugs are effective in the prevention and termination of atrial fibrillation, but the mechanism of this action is unknown. To gain insights into potential cellular mechanisms, we evaluated the response of human atrial action potentials to equimolar therapeutic concentrations of flecainide and quinidine and compared this response to that of guinea pig, rabbit, and dog atria. Both compounds reduced Vmax more as activation rate increased, but flecainide was more potent than quinidine and had slower kinetics. The rate-dependence of Vmax reduction was similar for all species, but human tissue was more sensitive to the drugs tested. In contrast to changes in Vmax, drug-induced alterations in action potential duration showed opposite rate-dependence for the two drugs. Quinidine increased action potential duration to 95% repolarization (APD95) in human atria by 33 +/- 7% (mean +/- SD) at a cycle length of 1,000 msec, but this effect was reduced as cycle length decreased, to 12 +/- 4% (p less than 0.001) at a cycle length of 300 msec. Flecainide increased APD95 (by 6 +/- 3%) much less than quinidine at a cycle length of 1,000 msec, but its effect was increased by faster pacing, to 27 +/- 12% at a cycle length of 300 msec and 35 +/- 8% (p less than 0.001) at the shortest 1:1 cycle length. The rate-dependent response of APD to drugs was qualitatively similar but quantitatively different among species. Human tissue showed the greatest frequency-dependent drug effects on repolarization, followed by tissue from dogs and rabbits. Guinea pig atria showed the least (and statistically nonsignificant) rate-dependence of drug effect on APD. Drug-induced changes in refractoriness paralleled those in APD. We conclude that: 1) flecainide and quinidine both increase APD in human atrial tissue but with opposite rate-dependence, 2) the effects of flecainide to increase atrial APD and refractoriness are enhanced by the rapid rates typical of atrial fibrillation, and 3) animal tissues may differ importantly from human in both their sensitivity and rate-dependent response to antiarrhythmic drugs. The salutary response of atrial fibrillation to flecainide may be due to enhancement of drug action by the rapid atrial activation rates characteristic of this arrhythmia.

Action Potentials↗

PubMedDate not supplied

Altered timing of hamstring muscle action in anterior cruciate ligament deficient patients.

Recent studies indicate that the hamstrings are essential antagonists in ACL deficient patients. In order to evaluate muscle coordination under physiologic conditions, nine patients with arthroscopically verified total ACL ruptures were compared with nine control volunteers. This comparison was made from electromyograms of the thigh muscles and heel contact recordings made while walking on a treadmill. While walking on a horizontal level, the patient's muscle activity did not differ from controls, but when the knee load was increased by walking uphill, the hamstring muscles in patients were activated significantly earlier than among controls. It is proposed that an altered muscle coordination is probably essential in ACL deficient patients to secure knee stability. This study suggests a new approach to investigate the coordination of muscles under physiologic conditions in ACL deficient patients, and may guide rehabilitation programs in the future.

Adult↗

PubMed1990

A model for body-image care.

It is by no means clear that the diagnosis 'altered body image' is sufficiently clear to enable the nurse to plan and deliver a package of body-image care. This paper proposes a model of body-image care based upon five central concepts, and the accepted metaparadigms of nursing. It is suggested that the nurse is uniquely positioned to deliver the best body-image care, and that this model will assist her to assess body-image needs and to then action the altered body-image diagnosis more effectively.

Adaptation, Psychological↗

PubMed2026

A phase II study to evaluate the efficacy of commercially available molecularly matched targeted therapies in the second-line setting.

BACKGROUND: Initial studies have shown improved outcomes in patients receiving cancer therapies matched to their molecular alterations. To improve the chances of finding a therapeutic match for patients, this study evaluated the preliminary antitumor activity of 3 commercially available multitargeted agents in the United States, regorafenib, afatinib, and cabozantinib. METHODS: In this phase II trial, patients who did not benefit from first-line treatment for non-small cell lung cancer (NSCLC), upper aerodigestive tract cancers, non-colon gastrointestinal cancers, and urothelial carcinoma underwent next-generation sequencing to identify actionable genomic alterations. Eligible patients, based on identified mutations deemed treatable by regorafenib, cabozantinib, or afatinib, were enrolled to receive matched targeted therapies. Outcomes were monitored via Response Evaluation Criteria in Solid Tumors criteria, with dose modifications per National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03 guidelines for adverse events (AEs). RESULTS: One hundred patients with metastatic cancers were enrolled across tumor types. Median treatment durations were 12 weeks (regorafenib), 10.7 weeks (afatinib), and 24.1 weeks (cabozantinib). The overall objective response rate was 7.0%, with 1 complete response and 8 partial responses. The clinical benefit rate, including responses and stable disease >6 months, was 16.0%. Median progression-free survival ranged from 1.9 months for urothelial carcinoma to 3.2 months for NSCLC. Toxicities were common for all medications; for regorafenib, 90.7% of patients had AEs (50% Grade 3/4); for afatinib, 86% of patients had AEs (54% Grade 3/4); for cabozantinib, 100% of patients had AEs (36% Grade 3/4). The most common AEs were diarrhea, fatigue, nausea, decreased appetite, and stomatitis. CONCLUSIONS: Regorafenib, afatinib, and cabozantinib had modest effects when used as molecularly matched targeted therapies in patients with NSCLC, upper aerodigestive tract cancers, non-colon gastrointestinal cancers, and urothelial carcinoma in the second-line setting. Future research could examine more precise matching of therapies to genomic alterations and evaluate combination therapies.

Humans↗

PubMed1982

Effects of reduced PO2 on rapid-drive-induced hyperpolarization of diastolic transmembrane potential in feline cardiac Purkinje strands.

Using standard microelectrode techniques, we evaluated effects of diminished oxygen tension on the magnitude and time course of frequency dependent changes in maximum diastolic transmembrane potential (MDP) and on alteration of action potential duration (APD) in feline Purkinje fibers. MDP was recorded continuously during a control period (cycle length (CL) = 1000 ms), during a 5-min period of rapid drive (CL = 400 ms) and following return to pacing CL = 1000 ms. Rapid drive resulted in hyperpolarization of MDP from control value; and after return to pacing CL = 1000 ms. MDP gradually depolarized, eventually attaining a steady state value within +/- 0.5 mV of the control value. The difference between hyperpolarized MDP value and final steady-state value was designated VH, and the decline of MDP towards steady-state value approximated an exponential function (time constant = tau VH). Exposure to reduced PO2 (75 +/- 2.1 mmHg vs. control 473 +/- 39.1 mmHg) (1 mmHg = 133.322 Pa) resulted in reduction in the magnitude of VH (6.2 +/- 3.43 mV vs. 7.8 +/- 2.73 mV, mean +/- SD, p less than 0.005) and shortening of APD within 0-24 min, while measurable prolongation of tau VH (75 +/- 18.5 vs. 54 +/- 9.0 s, p less than 0.005) began at 25-49 min following onset of reduced PO2. These observations suggest that rate-related changes of MDP in cardiac tissues are oxygen dependent, and they support previously reported analagous observations in nerve which suggested that frequency dependent potential changes may in part reflect alterations of electrogenic Na-K pump activity.

Action Potentials↗