Coordinated regulation of GABA_A,fast and GABA_A,slow currents is the key for generating theta-nested gamma oscillations.

<p>(A) Three different response behaviors of the network to a stimulus: (A1) Only gamma rhythm (by blocking INs→EX connection); (A2) only theta rhythm (by blocking INf→EX connections); (A3) theta-nested gamma rhythm (in the presence of both INs→EX and INf→EX connection). The three traces from the upper to the bottom are the time-frequency power spectrum, the firing behaviors of EX cells and the firing behavior of a downstream neuron, respectively. (B-C) Effects of increasing g and on the theta and gamma amplitudes, the coherence of cross-frequency coupling, the tightness of theta phase.</p

Stimulus-enhanced theta wave as well as CFC.

<p>(A) A network of 100 excitatory (EX), 50 fast inhibitory (INf) and 50 slow inhibitory neurons (INs). The outputs of EX neurons are projected to a downstream neuron. (B) The firing behaviors of single INs, INf and EX neurons. The bottom trace is the firing pattern of 50 EX neurons. (C) Input stimulus (Iapp), the LFP which is the average of membrane potentials of all EX neurons, the time-dependent power spectrum of the LFP of mean powers in the theta (red curve) and in the gamma band (blue curve). (D) Coherence of CFC between the theta phase and the gamma amplitude for the pre and during stimulus epochs.</p

Relationship of theta amplitude, shape of nested gamma wave and the phase precision.

<p>(<b>A</b>)<b>.</b> Variation of theta phase vs. theta amplitude. The increased theta amplitude is realized by increasing the conductance . (<b>B</b>) and (<b>C</b>)<b>.</b> From the upper panel to the bottom panel are corresponding to three points chosen for low, intermediate and high theta powers in (A) for . It was shown in that with the increase of theta amplitude, gamma oscillation becomes more and more shallowly nested in the theta rhythm, and meanwhile, the theta-band phases among EX neurons become more and more concentrated.</p

Effect of coordinately regulating synaptic gains of NMDA and GABA_A,slow to simulate learning effects.

<p>(A1–A3) Theta amplitude. (B1–B3) The coherence of CFC. (C1–C3) The temporal dynamics of theta phase. The stimulus is applied during 0–500 ms. To mimic different learning stages, we set NMDA receptor mediated conductances , and the GABA_A,slow mediated conductance as: 0.0001, 0.001, 0.05 (1st), 0.00025, 0.0025,0.06 (2nd), 0.00035 and 0.004, 0.07 (3rd), 0.00045, 0.005, 0.08(4th). The values of and in the three panels in A1–C1 are corresponding to the three marked points (1^st, 2^nd and 3^rd) in A2–C3. The values of other parameters are stated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036472#pone-0036472-t001" target="_blank">Table 1</a>. (A4–C4) Variations of theta and gamma amplitudes, the coherence of cross-frequency coupling and the phase variation with the increase of . (D) The firing rates of a downstream neuron vs.. (E) Comparison of the membrane potentials of single EX neurons before and after learning. In (C) the blue curve where represents before learning, while the red one where represents after learning.</p

Effects of modulating GABA conductances between and within inhibitory cells.

<p>The amplitudes of theta and gamma oscillations, the coherence of CFC, theta phase variation and the firing of excitatory neurons as a function of changes in the strength of (A) <i>g_GAss</i>_’ (B<i>) g_Gff</i> (C) <i>g_GAsf</i> are shown.</p

Relationship of maximal theta amplitude, the number of nested spikes per theta cycle and theta-phase concentration.

<p>(A-B) From the upper trace to the bottom trace:Theta amplitudes vs. the stimulus strength , the corresponding number of nested spikes per theta cycle vs., theta phase variation vs. , and the time-frequency spectra at of one curve. In (A), the three curves correspond to . In (B), , the three curves correspond to . (C) The number of nested spikes per theta cycle calculated at vs. the frequency of the corresponding maximal gamma power. The marked points are obtained from different curves of theta amplitude vs. . One can see that for low gamma power (20–50 Hz), around 5±2 spikes could be nested in each theta cycle, while for high gamma power (>50 Hz), around 7±2 spikes could be nested. (D) Theta phases of the EX cells for different stimulus strength. It was shown that for too weak and too strong stimulus, the theta phases of neurons are less synchronized than that of the intermediate stimulus strength.</p

Effects of modulating NMDA conductances from excitatory to inhibitory neurons.

<p>The amplitudes of theta and gamma oscillations, the coherence of CFC, the phase variation vs. and are depicted, respectively. (A) shows the effect of increasing , (B) shows the effect of increasing , (C) shows the effect of increasing .</p

DataSheet1_Combination therapy for high-volume versus low-volume metastatic hormone-sensitive prostate cancer: A systematic review and network meta-analysis.PDF

Purpose: To conduct a systematic review and network meta-analysis (NMA) to compare the efficacy of currently available combination therapies in patients with metastatic hormone-sensitive prostate cancer (mHSPC).Methods: Qualified publications were searched in the PubMed, Embase, and Cochrane CENTRAL databases. Overall survival (OS) and radiographic progression-free survival (rPFS) were indirectly compared and assessed using NMA and the surface under the cumulative ranking curve, respectively. Adverse events (AEs) were also compared.Results: Eighteen publications from 12 trials were analyzed in the NMA. In the overall population, triplet therapy was ranked first for OS (hazard ratio [HR]: 0.57, 95% credible interval [CrI]: 0.48–0.67) and rPFS (HR: 0.33, 95% CrI:0.26–0.41) compared with androgen deprivation therapy (ADT) with or without standard non-steroidal antiandrogen. In high-volume mHSPC, triplet therapy was also ranked first in OS (HR, 0.57; 95% CrI:0.44–0.75) and rPFS(HR, 0.29; 95% CrI: 0.23–0.37). Specifically, abiraterone triplet therapy was ranked first in OS (HR, 0.52; 95% CrI:0.38–0.72) and rPFS (HR, 0.28; 95% CrI:0.21–0.38) among all therapies. ADT plus rezvilutamide was ranked first among doublet therapies (OS: HR, 0.58; 95% CrI:0.44–0.77; rPFS: HR, 0.44; 95% CrI:0.33–0.58). In low-volume mHSPC, doublet and triplet therapies were ranked first in OS (HR:0.68, 95% CrI:0.58–0.80) and rPFS (HR:0.37, 95% CrI:0.25–0.55), respectively. ADT plus apalutamide was ranked first in OS among all therapies (HR:0.53, 95% CrI:0.35–0.79), whereas enzalutamide triplet therapy was ranked first in rPFS (HR:0.27, 95% CrI:0.15–0.51). ADT plus rezvilutamide showed a relatively lower incidence of AE among all therapies (OR:1.00, 95% CrI:0.31–3.15), and a lower risk of specific AEs among doublet therapies, particularly regarding seizure (OR, 0.29; 95% CrI:0.01–8.18) and fatigue (OR, 0.96; 95% CrI:0.63–1.46). Docetaxel-based doublet or triplet therapies significantly increased the risk of any AEs or grade ≥3 AEs.Conclusion: Triplet therapy was the best treatment option for the overall population. In high-volume mHSPC, triplet therapy and ADT plus rezvilutamide had the greatest potential to benefit patients. Patients with low-volume mHSPC were most likely to benefit from ADT plus androgen receptor-targeted agents. Triplet therapy was associated with a higher risk of AEs than the other therapies.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022375347, identifier PROSPERO:CRD42022375347.</p

DataSheet2_Systemic triplet therapy for metastatic hormone-sensitive prostate cancer: A systematic review and network meta-analysis.pdf

Purpose: To perform a systematic review and network meta-analysis to compare the efficacy and safety of currently available docetaxel-based systemic triplet therapies for metastatic hormone-sensitive prostate cancer (mHSPC).Methods: We searched for eligible publications in PubMed, Embase, and Cochrane CENTRAL. Improvements in overall survival (OS) and radiographic progression-free time (rPFS) were compared indirectly using network meta-analysis and evaluated using the surface under the cumulative ranking curve (SUCRA). Other secondary endpoints, such as time to castration-resistant prostate cancer and/or adverse events (AEs), were also compared and evaluated.Results: Five trials were selected and analyzed using a network meta-analysis. Compared to androgen deprivation therapy (ADT) plus docetaxel, darolutamide (hazard ratio [HR]: 0.68, 95% credible interval [CrI]: 0.57–0.80) and abiraterone (HR: 0.75, 95% CrI: 0.59–0.95) triplet therapy had significantly longer OS, and darolutamide triplet therapy was the first treatment ranked. Abiraterone (HR: 0.49, 95% CrI: 0.39–0.61) and enzalutamide (HR: 0.52, 95% CrI: 0.30–0.89) had significantly better rPFS than ADT plus docetaxel; however, all three therapies, including abiraterone, apalutamide, and enzalutamide, were the best options with a similar SUCRA. At most secondary endpoints, systemic triplet therapy was superior to ADT plus docetaxel. The risk of any AEs in darolutamide or abiraterone triplet therapy was comparable with ADT plus docetaxel (odds ratio [OR]: 2.53, 95% credible interval [CrI]: 0.68–12.63; OR: 1.07, 95% CrI: 0.03–36.25). Abiraterone triplet therapy had an increased risk of grade≥3 AEs (OR: 1.56, 95% CrI: 1.15–2.11).Conclusion: Systemic triplet therapy was more effective than ADT plus docetaxel for mHSPC. Of the triplet therapy regimens, darolutamide ranked first in terms of improved OS. Abiraterone and enzalutamide triplet ranked first in terms of rFPS, however, it did not confer a statistically difference among all triplet regimens. The overall risk of AEs was comparable. More studies are required for current and potential combinations of systemic triplet therapy.</p

DataSheet1_Systemic triplet therapy for metastatic hormone-sensitive prostate cancer: A systematic review and network meta-analysis.PDF

Purpose: To perform a systematic review and network meta-analysis to compare the efficacy and safety of currently available docetaxel-based systemic triplet therapies for metastatic hormone-sensitive prostate cancer (mHSPC).Methods: We searched for eligible publications in PubMed, Embase, and Cochrane CENTRAL. Improvements in overall survival (OS) and radiographic progression-free time (rPFS) were compared indirectly using network meta-analysis and evaluated using the surface under the cumulative ranking curve (SUCRA). Other secondary endpoints, such as time to castration-resistant prostate cancer and/or adverse events (AEs), were also compared and evaluated.Results: Five trials were selected and analyzed using a network meta-analysis. Compared to androgen deprivation therapy (ADT) plus docetaxel, darolutamide (hazard ratio [HR]: 0.68, 95% credible interval [CrI]: 0.57–0.80) and abiraterone (HR: 0.75, 95% CrI: 0.59–0.95) triplet therapy had significantly longer OS, and darolutamide triplet therapy was the first treatment ranked. Abiraterone (HR: 0.49, 95% CrI: 0.39–0.61) and enzalutamide (HR: 0.52, 95% CrI: 0.30–0.89) had significantly better rPFS than ADT plus docetaxel; however, all three therapies, including abiraterone, apalutamide, and enzalutamide, were the best options with a similar SUCRA. At most secondary endpoints, systemic triplet therapy was superior to ADT plus docetaxel. The risk of any AEs in darolutamide or abiraterone triplet therapy was comparable with ADT plus docetaxel (odds ratio [OR]: 2.53, 95% credible interval [CrI]: 0.68–12.63; OR: 1.07, 95% CrI: 0.03–36.25). Abiraterone triplet therapy had an increased risk of grade≥3 AEs (OR: 1.56, 95% CrI: 1.15–2.11).Conclusion: Systemic triplet therapy was more effective than ADT plus docetaxel for mHSPC. Of the triplet therapy regimens, darolutamide ranked first in terms of improved OS. Abiraterone and enzalutamide triplet ranked first in terms of rFPS, however, it did not confer a statistically difference among all triplet regimens. The overall risk of AEs was comparable. More studies are required for current and potential combinations of systemic triplet therapy.</p