Immune checkpoint inhibitors as the second-line treatment for advanced esophageal squamous cell carcinoma: a cost-effectiveness analysis based on network meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated superior clinical efficacy in prolonging overall survival (OS) as the second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC), and were recommended by the guidelines. However, it remains uncertain which ICI is the most cost-effective. This study assessed the cost-effectiveness of ICIs as the second-line treatment for ESCC based on the perspective of the Chinese healthcare system. METHODS: A network meta-analysis (NMA) was performed to obtain the Hazard ratios (HRs) for indirect comparisons. A three-state Markov model with a 10-year time horizon was conducted to assess the cost-effectiveness. The state transition probabilities were calculated with Kaplan-Meier (KM) curves data from clinical trial and HRs from the NMA. Utilities and costs were derived from local charges or previously published studies. Univariate and probabilistic sensitivity analyses (PSA) were performed to examine model robustness. The results were assessed based on the total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: Five clinical trials (ATTRACTION-3, ESCORT, KEYNOTE-181, ORIENT-2, RATIONALE-302) with a total of 1797 patients were included in the NMA. The NMA showed that both camrelizumab and tislelizumab received relatively high rankings for progression-free survival (PFS) and OS. Compared with sintilimab, treatment with tislelizumab and camrelizumab gained 0.018 and 0.034 additional QALYs, resulting in incremental ICERs of $75,472.65/QALY and $175,681.9/QALY, respectively. Nivolumab and pembrolizumab produced lower QALYs and greater costs, suggesting that both were dominated in comparison to sintilimab. HRs and health state utilities were the most influential parameters in most univariate sensitivity analyses of paired comparisons. PSA results suggested that sintilimab had an 84.4% chance of being the most cost-effective treatment regimen at the WTP threshold of $38,223.34/QALY. In the scenario analysis, sintilimab would no longer be cost-effective, if the price of camrelizumab was assumed to decrease by 64.6% or the price of tislelizumab was assumed to decrease by 16.9%. CONCLUSIONS AND RELEVANCE: Among the five potential competing ICIs, sintilimab was likely to be the most cost-effective regimen as the second-line treatment for locally advanced or metastatic ESCC in China.

Development of Megaselia scalaris at constant temperatures and its significance in estimating the time of death.

Megaselia scalaris (Schmitz, 1938) (Diptera: Phoridae) is a common insect in forensic science that is frequently found in indoor cases, particularly on corpses in closed environments. Although this species is useful for estimating the minimum postmortem interval (PMImin) in the absence of Calliphoridae, there is a lack of data on its development in China. Herein, we studied the development of M. scalaris exposed to seven constant temperatures ranging from 16 to 34 °C. The mean (± SD) developmental durations of M. scalaris from egg to adult stage at 16, 19, 22, 25, 28, 31, and 34 °C were 1486.9 ± 75.3, 823.7 ± 42.8, 448.2 ± 59.8, 417.7 ± 19.7, 297.2 ± 27.3, 272.9 ± 10.4, and 253.0 ± 5.0 h, respectively. The mean (± SE) lower developmental threshold temperature (TL) and the thermal summation constant (K) were determined by a linear model as 12.69 ± 0.3 °C and 4965.8 ± 227.9-degree hours, respectively. A nonlinear model estimated the lower developmental threshold temperature, intrinsic optimum temperature, and upper lethal developmental threshold temperature as 14.58, 21.00, and 34.15 °C, respectively. We established three development models to estimate the age of the immature insect, namely the isomegalen diagram, isomorphen diagram, and thermal summation model. In addition, a regression analysis of the relationship between body length and total development time from hatching to pupariation was performed. Our findings provide a basis for applications of M. scalaris in PMImin estimations.

Cost-effectiveness of aumolertinib as first-line treatment for EGFR-mutated advanced nonsmall-cell lung cancer.

Aim: To evaluate the cost-effectiveness of aumolertinib as the epidermal growth factor receptor-mutated advanced nonsmall-cell lung cancer first-line treatment from the Chinese healthcare system perspective.Methods: A Markov model was developed based on the AENEAS trial. Only direct medical costs were considered in the model. Utilities were obtained from published literature. Sensitivity and scenario analyses were performed to explore the robustness of the model.Results: Compared with gefitinib, aumolertinib yielded an additional 0.941 expected life-years and 0.692 quality-adjusted life-years (QALYs), with an incremental cost of $18,855.55 over a 20-year time horizon. The incremental cost-effectiveness ratios were $20,051.67/life-year and $27,272.29/QALY, that below the willing-to-pay threshold of $38,223.34/QALY.Conclusion: Aumolertinib was a cost-effective alternative first-line treatment for patients with epidermal growth factor receptor-positive advanced nonsmall-cell lung cancer in China.

What is this article about? This study assesses the costs and health outcomes associated with aumolertinib therapy for Chinese patients diagnosed with advanced or metastatic nonsmall cell lung cancer (NSCLC). Aumolertinib therapy is a specific type of medication used to treat a certain type of lung cancer called nonsmall cell lung cancer. It is a newer treatment that targets certain genetic changes in the cancer cells.How was this done? The costs and treatment benefits were estimated using data from the AENEAS trial, provincial medical cost lists and previously published studies. A Markov model was developed to simulate disease progression. Provincial Medical Cost Lists are official lists maintained by different provincial governments in China that specify the drugs and their prices that are covered by the public healthcare system. A Markov Model is a mathematical tool used to predict how a disease might progress over time. It is like a simulation where the possible outcomes of the disease are analyzed, helping to understand the likely course of the disease and how different treatments might affect it.What were the results? The cost of treatment with aumolertinib for Chinese patients with advanced or metastatic NSCLC was considered to be acceptable based on the benefits it provides.What do the study results mean? The results suggest that aumolertinib is a cost-effective treatment for patients with advanced or metastatic NSCLC in China.

Advanced LD pumped 3.3 J/1 Hz nanosecond Nd:glass preamplifier for SG-II upgrade laser facility.

We demonstrate a laser-diode-pumped multipass Nd:glass laser amplifier with a range of advanced characteristics. The amplifier exhibits high extraction efficiency, enables arbitrary shaping of spatial beam intensity, and effectively suppresses frequency modulation to amplitude modulation conversion. Our approach achieves excellent beam quality via thermal lensing and thermal depolarization compensation. When a 1.82 mJ/5 ns laser pulse was injected into the amplifier, the output energy reached up to 3.3 J with a repetition rate of 1 Hz at a central wavelength of 1053.3 nm. The near-field modulation of the amplified output beam was below 1.2, and the far-field focusing ability of the beam was 90% at 2.9 times the diffraction limit. This laser amplifier system holds potential for integration as a preamplifier within the SG-II upgrade high power laser facility.

A global perspective of forensic entomology case reports from 1935 to 2022.

Forensic entomology case reports are the product of rapid development in the field, the widespread acceptance of the science and the application of forensic entomological knowledge. In this study, we retrospectively summarized information derived from 307 forensic entomology case reports from 1935 to 2022 from a global perspective. Our checklist of relevant information included insect species, specific indoor or outdoor preferences, preferred temperatures, and stages of body decomposition. Finally, a concept and calculation method for postmortem interval (PMI) estimation accuracy was proposed. There were 232 cases using insect developmental data and 28 cases using succession patterns to estimate PMI. A total of 146 species of insects were involved in the cases, of which 62.3% were Diptera and 37.7% were Coleoptera. Postmortem intervals were estimated from eggs in 4 cases, larvae in 180 cases, pupae in 45 cases, and puparia in 38 cases. The majority of cases were from June to October, and the average number of species mentioned in the cases was more at 15-30 °C. Considering the standardization of application, in the majority of cases, insect evidence was collected by other personnel and sent to forensic entomologists, there was a delay in the sampling, and the scene or meteorological data were directly used without correcting. Our data shows that there are still many shortcomings in the universality and standardization of forensic entomology in its practical application.

Climate factors affect forest biomass allocation by altering soil nutrient availability and leaf traits.

Biomass in forests sequesters substantial amounts of carbon; although the contribution of aboveground biomass has been extensively studied, the contribution of belowground biomass remains understudied. Investigating the forest biomass allocation is crucial for understanding the impacts of global change on carbon allocation and cycling. Moreover, the question of how climate factors affect biomass allocation in natural and planted forests remains unresolved. Here, we addressed this question by collecting data from 384 planted forests and 541 natural forests in China. We evaluated the direct and indirect effects of climate factors on the belowground biomass proportion (BGBP). The average BGBP was 31.09% in natural forests and was significantly higher (38.75%) in planted forests. Furthermore, we observed a significant decrease in BGBP with increasing temperature and precipitation. Climate factors, particularly those affecting soil factors, such as pH, strongly affected the BGBP in natural and planted forests. Based on our results, we propose that future studies should consider the effects of forest type (natural or planted) and soil factors on BGBP.

Rs6757 in microRNA-3976 binding site of CD147 confers risk of hepatocellular carcinoma in South Chinese population.

BACKGROUND: Cluster of differentiation 147 (CD147) overexpression plays a key role in the proliferation, differentiation, invasion, metastasis, and prognosis of hepatocellular carcinoma (HCC). The aim of this study was to explore the relationship between rs6757 and the HCC risk in the South Chinese population, and the functional significance of rs6757 by affecting the efficacy of microRNA-3976 (miR-3976) binding to the CD147 3'-UTR. METHODS: We performed a retrospective case-control study to analyze the association between rs6757 and the risk of HCC. We chose candidate microRNAs with the potential of interacting with rs6757 through a series of silico analyses. A luciferase reporter gene assay was implemented to detect the binding extent of microRNAs to each polymorphic allele of rs6757. RESULTS: An obvious association between rs6757 and the risk of HCC was detected in C vs. T (OR = 1.826, 95% CI [1.263-2.642]), CC vs. TT (OR = 4.513, 95% CI [1.510-13.489]), dominant genetic model (OR = 1.824, 95% CI [1.120-2.965]), and recessive genetic model (OR = 3.765, 95% CI [1.286-11.020]). Bioinformatics analysis indicated that miR-3976 binding sites containing the rs6757-T allele had lower free energies than those with the C allele, the lower free energies, the higher affinities. Luciferase activity was remarkably decreased by miR-3976 binding to the CD147 3'-UTR bearing rs6757 T allele, which could be reversed by miR-3976 inhibitors. Furthermore, miR-3976 reduced the luciferase expression in a manner of dose-dependent when cotransfected with constructs with the CD147-TT-pSICHECK2. CONCLUSIONS: The research we have done suggests that rs6757 confers the CD147 allele-specific translational suppression by miR-3976, which provides a theoretical basis for antineoplastic therapy targeting CD147.

High-contrast OPCPA front end in high-power petawatt laser facility based on the ps-OPCPA seed system.

A high-energy, high-beam-quality, high-contrast picosecond optical parametric chirped-pulse amplification (ps-OPCPA) laser system was demonstrated. The pulse from a femtosecond oscillator was stretched to 4 ps, after which it was amplified from 140 pJ to 600 µJ by an 8 ps/6 mJ pump laser in two non-collinear OPCPA stages. The total gain was >106, and the root mean square of the energy stability of the laser system was 1.6% in 10 h. The contrasts of the solid and fiber mode-locked femtosecond oscillator-seeded ps-OPCPA systems were compared, and a signal-to-noise ratio of >1011 was achieved. Using this system, the contrast of the front end in high-power picosecond petawatt laser facility was improved by ∼40 dB to >1011, beyond ∼200 ps ahead of the main pulse with an output level of 60 mJ.

High-stability, high-energy Nd:glass rod regenerative amplifier with compensation for cavity misalignment.

We report on an Nd:glass large-mode rod regenerative amplifier with a pulse energy of 125 mJ at 1053 nm. The amplifier contains a linear-type resonator, which is designed in Stability Zone II with a misalignment sensitivity factor of 12.9 m. A method is proposed for analyzing the sensitivity of the mode displacement on the gain media to cavity misalignment, and the optimum solution to compensation for cavity misalignment is obtained and applied to the amplifier. The amplifier exhibits excellent energy stability with a fluctuation of 0.47% (RMS) within 7 h and high spatial beam quality with M2=1.17. The beam pointing stability in the horizontal and vertical axes within 7 h is 2.7 and 3.6 µrad (RMS), respectively.

Identification of Common Sarcosaprophagous Flies in the Yangtze River Delta by COâ Gene. / 利用COâ åŸºå› é‰´åˆ«é•¿ä¸‰è§’åœ°åŒºå¸¸è§å—œå°¸æ€§è‡ç±».

OBJECTIVES: To identify the common sarcosaprophagous flies in the Yangtze River Delta based on mitochondrial cytochrome c oxidase subunit Ⅰ(COⅠ) gene sequence and verify the reliability of this method. METHODS: Seven common genetically stable sarcosaprophagous flies in three families and six genera were collected from large domestic pig carcasses placed in the field and cultured in the laboratory for many generations. The whole genome DNA was extracted and the COⅠ gene fragment was amplified. The forward and reverse sequencing was followed by splicing. The base composition of the amplified fragment and the rate of interspecific evolutionary divergence were analyzed by software such as Mega 7.0.26. The phylogenetic tree of COⅠ gene sequence of common necrophagous flies in the Yangtze River Delta was established by neighbor joining (NJ) method and unweighted pair-group method with arithmetic means (UPGMA) method. RESULTS: The average base composition of different flies was A(30.14%), T(38.23%), C(15.98%), G(15.65%). The rate of interspecific evolutionary divergence ranged from 2.2% to 15.3%, the lowest rate was between Chrysomya megacephala and Chrysomya pinguis, the highest rate was between Muscina stabulans and Boettcherisca peregrina. CONCLUSIONS: COⅠ gene can be used to identify the common necrophagous flies in the Yangtze River Delta.

Research Progress on Developmental Biology of Sarcosaprophagous Insects. / å—œå°¸æ€§æ˜†è™«å‘è‚²ç”Ÿç‰©å­¦ç ”ç©¶è¿›å±•.

Forensic entomology provides a feasible way to estimate postmortem interval (PMI), of which the growth and development of sarcosaprophagous insects is the most widely used indicator in forensic practice. Over the years, forensic entomologists have carried out a large number of studies on the development biology of sarcosaprophagous insects. This paper illustrates the main factors that affect the development of sarcosaprophagous insects, including temperature, humidity, light, food types and poisons. The development indicators of sarcosaprophagous insects were reviewed from the perspectives of morphology, differential gene expression and biochemical characteristics. It is emphasized that future research of development biology on sarcosaprophagous insects should fully absorb and integrate the methods of artificial intelligence and omics, and the research object also needs further expansion in order to establish a more objective and more accurate PMI estimation method.

High-stability, high-beam-quality, and pulse-width-tunable 1319 nm laser system for VISAR applications in high-power laser facilities.

A high-energy, high-beam-quality, and pulse-width-tunable Nd:YAG laser system, pumped by vertical cavity surface emitting laser arrays and laser diodes, is demonstrated and applied to a velocity interferometry system for any reflector (VISAR) application in a high power laser facility. A multistage multipass amplification structure is used to fully extract the amplifier energy and obtain a high-energy pulse. The temporal waveform is compensated to provide a square waveform, with a flatness less than 8% (peak-to-peak value). The peak power is greater than 100 kW with a frequency-doubling efficiency of 25% for a 50 ns pulse width. The laser operates as a single shot with 1-5 Hz repetition frequency and 0.7% rms energy stability.

Development of Megaselia spiracularis (Diptera: Phoridae) at different constant temperatures.

Megaselia spiracularis Schmitz, 1938 (Diptera: Phoridae) is a pest that often appears in human living areas where it can spread pathogens. Besides, the species is of forensic value. Currently, studies focusing on the development of this species are limited. Understanding the developmental patterns of M. spiracularis, therefore, is important for controlling populations of this pest and for estimating the minimum postmortem interval (PMImin). Here, we studied the development of M. spiracularis exposed to seven constant temperatures ranging from 16 to 34 °C. The developmental durations, accumulated degree hours and larval body length changes were measured. Three kinds of development models that can be used to estimate the PMImin were established, including isomorphen diagram, isomegalen diagram and thermal summation model. The duration of M. spiracularis development at 16, 19, 22, 25, 28, 31 and 34 °C from egg to adult stage were 1131.1 ± 34.5, 807.3 ± 9.3, 529.6 ± 1.8, 367.0 ± 8.8, 302.4 ± 7.0, 250.0 ± 2.1 and 232.6 ± 1.9 h, respectively. The developmental threshold temperature and the thermal summation constant were estimated as 12.0 ± 0.5 °C and 4989.7 ± 308.9° hours, respectively. A general model represented by a logistic equation describing how larval body length will change with the time after hatching was fit to data. The present study provides basic developmental data of M. spiracularis, which can be used for achieving better control of this noxious insect as well as for estimation of its PMImin at different temperatures.

Circ_0005075 promotes hepatocellular carcinoma progression by suppression of microRNA-335.

Accumulating evidence suggests that noncoding RNAs play a vital role in cancer biology. Circular RNAs (circRNAs), a newly defined class of endogenously widespread noncoding RNAs, have been intensively reported to influence cell function and development, and even cancer prognosis by sponging microRNAs in various types of cancer. Nevertheless, the circRNAs research in hepatocellular carcinoma (HCC) still remains far insufficient. Herein, we investigated the role of a newly defined circRNAs, circ_0005075, in HCC development. We found circ_0005075 was upregulated in HCC tissues. HCC progression was suppressed by downregulation of circ_0005075 in vitro and in vivo, and the suppression was partially reversed by inhibition of microRNA-335 (miR-335) expression. Further, we found the expression of mitogen-activated protein kinase 1 (MAPK1) was substantially regulated by circ_0005075 and miR-335. Mechanically, it was demonstrated that circ_0005075 could directly bind to miR-335 and miR-335 could bind to MAPK1. Our data provide evidence that circ_0005705 promotes the HCC progression by sponging miR-335 and further regulating MAPK1 expression.

Suppression of FM-to-AM conversion in a broadband Nd:glass regenerative amplifier with an intracavity birefringent filter.

In order to suppress the frequency modulation to amplitude modulation (FM-to-AM) conversion induced by a Nd:glass regenerative laser amplifier, a birefringent quartz crystal was designed by theoretical simulation and inserted into the regenerative amplifier. A broadband Nd:glass regenerative laser amplifier with a flattop region of ∼3.7 nm in the gain spectrum was developed. An all-fiber front-end system was used to generate a 2 ns shaped pulse with a spectral width of ∼0.5 nm, which was broadened by a two-stage phase modulator. Then, the laser pulse was amplified by a spectral-broadened regenerative amplifier. The amplified output temporal waveform modulation depth was reduced from a maximum of 47.7% to 17.3% at a center wavelength of 1053.328 nm. The experimental results show that the FM-to-AM conversion can be effectively suppressed in the spectral-broadened Nd:glass regenerative laser amplifier, which indicates that it has potential application as a preamplifier of large-scale laser facilities.

Detection and analysis of the signal-to-noise ratio in the injection laser system of the Shenguang-II facility.

The temporal contrast levels of laser pulses in the injection laser system of the Shenguang-II facility are accurately measured and analyzed in detail. These signal-to-noise ratio levels are determined by the extinction ratios of an acousto-optic modulator, an electro-optic intensity modulator, and a combination of a Pockels cell and thin film polarizers. In addition, a drifting direct current bias voltage of an electro-optic intensity modulator and phase modulation are also demonstrated to affect the signal-to-noise ratio of the injection laser system. With a precise control of these factors, the injection laser system can output a nanosecond laser pulse with a signal-to-noise ratio of 47.37 dB. Moreover, a nanosecond laser pulse signal-to-noise ratio measuring device with a dynamic range and accuracy of 50 and 1 dB, respectively, is developed to detect the signal-to-noise ratio of a nanosecond laser pulse, which is 47.06 dB within an accuracy range of 1 dB. The signal-to-noise ratio measuring device can detect the high contrast laser pulse for the seed source unit in the high power laser facility accurately and conveniently.

The role of cancer-associated fibroblasts in esophageal cancer.

Fibroblasts are known as critical stromal cells in wound healing by synthesizing extracellular matrix and collagen. A subpopulation of them is called cancer-associated fibroblasts (CAFs), because their production of proteins participated in various biological activities including tumor cell proliferation, invasion and metastasis. Currently some studies shed light on their role in esophageal cancer which was an aggressive cancer with a dismal survival and high rate of metastasis. Thus, to find cures for it relies on elucidating the epithelial-fibroblasts crosstalk. Herein, we reviewed the present knowledge of the CAFs' role in esophageal premalignant condition, cancer initiation, progression, metastasis and prognosis prediction and further provided some insights into its clinical application.

MiR-613: a novel diagnostic and prognostic biomarker for patients with esophageal squamous cell carcinoma.

MicroRNA-613 (miR-613) plays important roles in tumorigenesis and cancer progression. We aimed to evaluate its expression level and potential for diagnosis and prognosis in esophageal squamous cell cancer (ESCC). We examined miR-613 expression in 60 pairs of ESCC cancerous and matched paracancerous tissues, serum samples from 75 ESCC patients and 75 healthy volunteers, and 105 formalin-fixed paraffin-embedded (FFPE) tissue samples using quantitative reverse transcription polymerase chain reaction. Receiver-operating characteristic (ROC) curve analysis, Kaplan-Meier method, and Cox regression were applied to analyze its diagnostic and prognostic value. MiR-613 was significantly decreased in ESCC tissue compared with paracancerous tissue (P < 0.001). Moreover, the expression level of miR-613 was significantly reduced with increased T stage of ESCC. Statistically significant difference between ESCC patients and healthy controls in expression level of miR-613 (0.89 ± 0.73 vs. 1.71 ± 1.03, P < 0.001) was found. The area under the ROC curve (AUC) based on serum miR-613 was 0.767 ± 0.040. We also performed analysis on early-stage patients and revealed that the AUC value was 0.728 ± 0.052 (P < 0.001). The Kaplan-Meier curve revealed that the downregulation of miR-613 was related to worse overall survival (OS) and progression-free survival (PFS) of ESCC patients (P = 0.018 and P = 0.035, respectively). Furthermore, the multivariate analysis identified miR-613 to be an independent prognostic factor for OS and PFS (P = 0.031 and P = 0.006, respectively) In conclusion, miR-613 is significantly reduced in cancerous tissue and serum samples of ESCC patients. It can serve as an ideal indicator for the diagnosis and prognosis of ESCC.

Temperature-dependent development and the significance for estimating postmortem interval of Chrysomya nigripes Aubertin, a new forensically important species in China.

In forensic entomology, the developmental duration and larval body length of sarcosaprophagous flies are presently the two major approaches to estimate minimal postmortem interval (PMImin). A full characterization of the developmental stages of Calliphoridae, a predominating species on corpses, is especially important for PMI estimation. Chrysomya nigripes Aubertin, which appears on the corpse mainly during the decay and the post-decay stages, is of significant value for PMImin estimation. However, there are limited detailed reports on the development of such species. Hence, this study was conducted to address the development pattern of C. nigripes, in order to provide the basic data related to PMI estimation. In this study, the larvae of C. nigripes were collected from pig carcasses that were placed in the field. The colonies were cultured at constant temperatures of 16, 20, 24, 28, and 32 (±1) °C. The biological features of C. nigripes, the developmental pattern, and the body length with time at different temperatures were studied. The results showed that the average developmental duration of the C. nigripes larvae at 20, 24, 28, and 32 (±1) °C were 608.0 ± 68.0 h, 327.0 ± 53.8 h, 254.0 ± 36.5 h, and 217.0 ± 28.0 h, respectively. There were two phases of body length increment with developmental time: growing phase and plateau phase. The maximal body length was 11-12 mm, and the relationship between body length and developmental time can be simulated using the following equation: L = a + bT + cT(2) + dT(3). The data for developmental duration and larval body length at 16 °C were not obtained. In summary, this study comprehensively studied the developmental biology of C. nigripes, which has a significant value for estimating PMI from highly decayed carcasses.

Ginsenoside Rd attenuates mitochondrial permeability transition and cytochrome C release in isolated spinal cord mitochondria: involvement of kinase-mediated pathways.

Ginsenoside Rd (Rd), one of the main active ingredients in Panax ginseng, has multifunctional activity via different mechanisms and neuroprotective effects that are exerted probably via its antioxidant or free radical scavenger action. However, the effects of Rd on spinal cord mitochondrial dysfunction and underlying mechanisms are still obscure. In this study, we sought to investigate the in vitro effects of Rd on mitochondrial integrity and redox balance in isolated spinal cord mitochondria. We verified that Ca2+ dissipated the membrane potential, provoked mitochondrial swelling and decreased NAD(P)H matrix content, which were all attenuated by Rd pretreatment in a dose-dependent manner. In contrast, Rd was not able to inhibit Ca2+ induced mitochondrial hydrogen peroxide generation. The results of Western blot showed that Rd significantly increased the expression of p-Akt and p-ERK, but had no effects on phosphorylation of PKC and p38. In addition, Rd treatment significantly attenuated Ca2+ induced cytochrome c release, which was partly reversed by antagonists of Akt and ERK, but not p-38 inhibitor. The effects of bisindolylmaleimide, a PKC inhibitor, on Rd-induced inhibition of cytochrome c release seem to be at the level of its own detrimental activity on mitochondrial function. Furthermore, we also found that pretreatment with Rd in vivo (10 and 50 mg/kg) protected spinal cord mitochondria against Ca2+ induced mitochondrial membrane potential dissipation and cytochrome c release. It is concluded that Rd regulate mitochondrial permeability transition pore formation and cytochrome c release through protein kinases dependent mechanism involving activation of intramitochondrial Akt and ERK pathways.