A Ba(2+)-sensitive K(+) current contributes to the resting membrane potential of neurons in rat suprachiasmatic nucleus

A Ba(2+)-sensitive K(+) current was studied in neurons of the suprachiasmatic nucleus (SCN) using the whole cell patch-clamp technique in acutely prepared brain slices. This Ba(2+)-sensitive K(+) current was found in approximately 90% of the SCN neurons and was uniformly distributed across the SCN. Current-clamp studies revealed that Ba(2+) (500 microM) reversibly depolarized the membrane potential by 6.7 +/- 1.3 mV (n = 22) and concomitantly Ba(2+) induced an increase in the spontaneous firing rate of 0.8 +/- 0.2 Hz (n = 12). The Ba(2+)-evoked depolarizations did not depend on firing activity or spike dependent synaptic transmission. No significant day/night difference in the hyperpolarizing contribution to the resting membrane potential of the present Ba(2+)-sensitive current was observed. Voltage-clamp experiments showed that Ba(2+) (500 microM) reduced a fast-activating, voltage-dependent K(+) current. This current was activated at levels below firing threshold and exhibited outward rectification. The Ba(2+)-sensitive K(+) current was strongly reduced by tetraethylammonium (TEA; 20 and 60 mM) but was insensitive to 4-aminopyridine (4-AP; 5 mM) and quinine (100 microM). A component of Ba(2+)-sensitive K(+) current remaining in the presence of TEA exhibited no clear voltage dependence and is less likely to contribute to the resting membrane potential. The voltage dependence, kinetics and pharmacological properties of the Ba(2+)- and TEA-sensitive K(+) current make it unlikely that this current is a delayed rectifier, Ca(2+)-activated K(+) current, ATP-sensitive K(+) current, M-current or K(+) inward rectifier. Our data are consistent with the Ba(2+)- and TEA-sensitive K(+) current in SCN neurons being an outward rectifying K(+) current of a novel identity or belonging to a known family of K(+) channels with related properties. Regardless of its precise molecular identity, the current appears to exert a significant hyperpolarizing effect on the resting potential of SCN neurons.     

Cost-Effectiveness Assessment of Monitoring Abiraterone Levels in Metastatic Castration-Resistant Prostate Cancer Patients

ObjectivesAbiraterone acetate is registered for the treatment of metastatic castration-sensitive and resistant prostate cancer (mCRPC). Treatment outcome is associated with plasma trough concentrations (C_min) of abiraterone. Patients with a plasma C_min below the target of 8.4 ng/mL may benefit from treatment optimization by dose increase or concomitant intake with food. This study aims to investigate the cost-effectiveness of monitoring abiraterone C_min in patients with mCRPC.MethodsA Markov model was built with health states progression-free survival, progressed disease, and death. The benefits of monitoring abiraterone C_min followed by a dose increase or food intervention were modeled via a difference in the percentage of patients achieving adequate C_min taking a healthcare payer perspective. Deterministic and probabilistic sensitivity analyses were performed to assess uncertainties and their impac to the incremental cost-effectiveness ratio (ICER).ResultsMonitoring abiraterone followed by a dose increase resulted in 0.149 incremental quality-adjusted life-years (QALYs) with €22 145 incremental costs and an ICER of €177 821/QALY. The food intervention assumed equal effects and estimated incremental costs of €7599, resulting in an ICER of €61 019/QALY. The likelihoods of therapeutic drug monitoring (TDM) with a dose increase or food intervention being cost-effective were 8.04%and 81.9%, respectively.ConclusionsMonitoring abiraterone followed by a dose increase is not cost-effective in patients with mCRPC from a healthcare payer perspective. Monitoring in combination with a food intervention is likely to be cost-effective. This cost-effectiveness assessment may assist decision making in future integration of abiraterone TDM followed by a food intervention into standard abiraterone acetate treatment practices of mCRPC patients.     

Influence of visually guided tracking arm movements on single cell activity in area MT

The behavioral relevance of neuronal activity in primate area MT for motion perception and control of visually guided eye movements is well documented. The projections of area MT comprise connections to subcortical structures and to the parietal network, both of which play a role in visuospatial transformation for guiding eyes and hands. Here, we have investigated, whether area MT is involved in the network needed to control visually guided arm movements. Our results show that half of the neurons tested significantly modulated their activity during visually guided arm movements. We conclude that the main reason for the neuronal modulation is not the arm movement per se, but the use of information from MT for visual feedback in the tracking movement. Moreover, control experiments show that attentional effects cannot solely cause the neuronal modulation. Thus, our study provides strong evidence that area MT is involved in processing visual information for visually guided manual tracking movements.     

Aneuploidy correlated 100% with chemical transformation of Chinese hamster cells

Aneuploidy or chromosome imbalance is the most massive genetic abnormality of cancer cells. It used to be considered the cause of cancer when it was discovered more than 100 years ago. Since the discovery of the gene, the aneuploidy hypothesis has lost ground to the hypothesis that mutation of cellular genes causes cancer. According to this hypothesis, cancers are diploid and aneuploidy is secondary or nonessential. Here we reexamine the aneuploidy hypothesis in view of the fact that nearly all solid cancers are aneuploid, that many carcinogens are nongenotoxic, and that mutated genes from cancer cells do not transform diploid human or animal cells. By regrouping the gene pool—as in speciation—aneuploidy inevitably will alter many genetic programs. This genetic revolution can explain the numerous unique properties of cancer cells, such as invasiveness, dedifferentiation, distinct morphology, and specific surface antigens, much better than gene mutation, which is limited by the conservation of the existing chromosome structure. To determine whether aneuploidy is a cause or a consequence of transformation, we have analyzed the chromosomes of Chinese hamster embryo (CHE) cells transformed in vitro. This system allows (i) detection of transformation within 2 months and thus about 5 months sooner than carcinogenesis and (ii) the generation of many more transformants per cost than carcinogenesis. To minimize mutation of cellular genes, we have used nongenotoxic carcinogens. It was found that 44 out of 44 colonies of CHE cells transformed by benz[a]pyrene, methylcholanthrene, dimethylbenzanthracene, and colcemid, or spontaneously were between 50 and 100% aneuploid. Thus, aneuploidy originated with transformation. Two of two chemically transformed colonies tested were tumorigenic 2 months after inoculation into hamsters. The cells of transformed colonies were heterogeneous in chromosome number, consistent with the hypothesis that aneuploidy can perpetually destabilize the chromosome number because it unbalances the elements of the mitotic apparatus. Considering that all 44 transformed colonies analyzed were aneuploid, and the early association between aneuploidy, transformation, and tumorigenicity, we conclude that aneuploidy is the cause rather than a consequence of transformation.     

Efficacy of i-Port Advance system on patients satisfaction and glycemic control among patients with type 1 diabetes in Saudi Arabia

Background and aimsTo determine the efficacy of i-Port Advance system on patients satisfaction and glycemic control among patients with type 1 diabetes (T1D).MethodsThis prospective study was performed among 73 patients with T1D (13–29 years) at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. Demographic data were collected at baseline and clinical characteristics were collected at baseline and 12 weeks. Patients’ responses to Morisky Medication Adherence Scale (MMAS-8) and Insulin Delivery Satisfaction Survey (IDSS) were recorded at baseline and 12 weeks after initiating the i-Port Advance system.ResultsAt 12 weeks, significant improvement was evident in the IDSS subscales, which comprises the IDSS effective (p = 0.048), burdensome (p = 0.032), and IDSS inconvenient (p = 0.001), with the total baseline IDSS score being 2.6 ± 0.42, and at 12 weeks being 3.7 ± 0.72 (p = 0.037). The MMAS total score at baseline was 4.6 ± 1.2, and at 12 weeks, it increased to 6.4 (p = 0.028). HbA1c level was 8.4% at baseline and decreased to 7.9% (p = 0.001) at 12 weeks. The total daily dose of insulin at baseline registered 0.9 ± 0.13, which declined to 0.8 ± 0.12 (p = 0.048) at 12 weeks. Fasting blood sugar value was 197 ± 23.4 at baseline, which dropped to 182 ± 24.5 at 12 weeks (p = 0.01); and the postprandial glucose at baseline was 195 ± 21.4 and declined to 177 ± 19.2 at 12 weeks (p = 0.01). The hypoglycemic episodes revealed a noteworthy reduction after the i-Port Advance system usage.ConclusionUse of i-Port Advance system was found to raise the patients’ satisfaction levels and lower both the hypoglycemic episodes as well as the HbA1c levels.     

Reductive Modification of Carbon Nitride Structure by Metals—The Influence on Structure and Photocatalytic Hydrogen Evolution

Pt, Ru, and Ir were introduced onto the surface of graphitic carbon nitride (g-C₃N₄) using the wet impregnation method. A reduction of these photocatalysts with hydrogen causes several changes, such as a significant increase in the specific surface area, a C/N atomic ratio, a number of defects in the crystalline structure of g-C₃N₄, and the contribution of nitrogen bound to the amino and imino groups. According to the X-ray photoelectron spectroscopy results, a transition layer is formed at the g-C₃N₄/metal nanoparticle interphase, which contains metal at a positive degree of oxidation bonded to nitrogen. These structural changes significantly enhanced the photocatalytic activity in the production of hydrogen through the water-splitting reaction. The activity of the platinum photocatalyst was 24 times greater than that of pristine g-C₃N₄. Moreover, the enhanced activity was attributed to significantly better separation of photogenerated electron–hole pairs on metal nanoparticles and structural distortions of g-C₃N₄.     

Phase I study of lapatinib plus trametinib in patients with KRAS -mutant colorectal,non-small cell lung,and pancreatic cancer

KRAS oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in KRAS-mutant (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm and PIK3CA wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R). Patients received escalating doses of continuous or intermittent once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg continuously, respectively. Thirty-four patients (16 CRC, 15 NSCLC, three pancreatic cancers) were enrolled across six dose levels and eight patients experienced dose-limiting toxicities, including grade 3 diarrhea (n = 2), rash (n = 2), nausea (n = 1), multiple grade 2 toxicities (n = 1), and aspartate aminotransferase elevation (n = 1), resulting in the inability to receive 75% of planned doses (n = 2) or treatment delay (n = 2). The RP2R with continuous dosing was 750 mg lapatinib QD plus 1 mg trametinib QD and with intermittent dosing 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Regression of target lesions was seen in 6 of the 24 patients evaluable for response, with one confirmed partial response in NSCLC. Pharmacokinetic results were as expected. Lapatinib and trametinib could be combined in an intermittent dosing schedule in patients with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed and pharmacodynamic target engagement was demonstrated.