Predicting Lung Cancer Survival to the Future: Population-Based Cancer Survival Modeling Study.

BACKGROUND: Lung cancer remains the leading cause of cancer-related mortality globally, with late diagnoses often resulting in poor prognosis. In response, the Lung Ambition Alliance aims to double the 5-year survival rate by 2025. OBJECTIVE: Using the Taiwan Cancer Registry, this study uses the survivorship-period-cohort model to assess the feasibility of achieving this goal by predicting future survival rates of patients with lung cancer in Taiwan. METHODS: This retrospective study analyzed data from 205,104 patients with lung cancer registered between 1997 and 2018. Survival rates were calculated using the survivorship-period-cohort model, focusing on 1-year interval survival rates and extrapolating to predict 5-year outcomes for diagnoses up to 2020, as viewed from 2025. Model validation involved comparing predicted rates with actual data using symmetric mean absolute percentage error. RESULTS: The study identified notable improvements in survival rates beginning in 2004, with the predicted 5-year survival rate for 2020 reaching 38.7%, marking a considerable increase from the most recent available data of 23.8% for patients diagnosed in 2013. Subgroup analysis revealed varied survival improvements across different demographics and histological types. Predictions based on current trends indicate that achieving the Lung Ambition Alliance's goal could be within reach. CONCLUSIONS: The analysis demonstrates notable improvements in lung cancer survival rates in Taiwan, driven by the adoption of low-dose computed tomography screening, alongside advances in diagnostic technologies and treatment strategies. While the ambitious target set by the Lung Ambition Alliance appears achievable, ongoing advancements in medical technology and health policies will be crucial. The study underscores the potential impact of continued enhancements in lung cancer management and the importance of strategic health interventions to further improve survival outcomes.

Comparison between drug-coated balloons and drug-eluting stents in very small coronary artery interventions.

The optimal management of very small vessel (reference diameter from 2.0 to 2.25 mm) in percutaneous coronary interventions (PCIs) is controversial. We aimed to compare the efficacy and safety of drug-coated balloons (DCBs) and drug-eluting stents (DESs) for de-novo very small vessel interventions. We conducted a retrospective analysis of consecutive patients who received very small vessel PCI with a DCB or DES between January 2018 and March 2021. The outcome measures were the incidence of ischemia-driven target lesion revascularization (TLR) and major adverse cardiac and cerebrovascular events (MACCEs) within 1 year after PCI. MACCEs were defined as the composite of ischemia-driven TLR, all-cause death, non-fatal acute coronary syndrome, stroke, or heart failure requiring hospitalization. A total of 205 patients undergoing PCI with a DCB or DES were enrolled in this study. The procedural complication rate was 2.5% in the DES group and 1.7% in the DCB group (P = 1.000). After 1-year of follow-up, the cumulative incidence of TLR was 7.2% in the DCB group and 4.9% in the DES group (P = 0.530). The cumulative incidence of MACCEs was 10.6% in the DCB group and 12.7% in the DES group (P = 0.769). Only female gender, acute coronary syndrome on presentation, and dual antiplatelet therapy duration < 3 months were significantly associated with MACCEs at 1 year, but the use of DCB or DES was not. The use of DCBs or DESs in de novo very small vessel intervention was not associated with different outcomes at 1 year.

Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders.

Although the brains of patients with schizophrenia and bipolar disorder exhibit decreased brain pH relative to those of healthy controls upon postmortem examination, it remains controversial whether this finding reflects a primary feature of the diseases or is a result of confounding factors such as medication and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models that can be studied without confounds inherent in human studies. In the present study, we first reevaluated the pH of the postmortem brains of patients with schizophrenia and bipolar disorder by conducting a meta-analysis of existing data sets from 10 studies. We then measured pH, lactate levels, and related metabolite levels in brain homogenates from five neurodevelopmental mouse models of psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder. All mice were drug naive with the same agonal state, postmortem interval, and age within each strain. Our meta-analysis revealed that brain pH was significantly lower in patients with schizophrenia and bipolar disorder than in control participants, even when a few potential confounding factors (postmortem interval, age, and history of antipsychotic use) were considered. In animal experiments, we observed significantly lower pH and higher lactate levels in the brains of model mice relative to controls, as well as a significant negative correlation between pH and lactate levels. Our findings suggest that lower pH associated with increased lactate levels is not a mere artifact, but rather implicated in the underlying pathophysiology of schizophrenia and bipolar disorder.

Calcium-Sensitive Translocation of Calmodulin and Neurogranin between Soma and Dendrites of Mouse Hippocampal CA1 Neurons.

Calmodulin (CaM) and neurogranin (Ng) are two abundant neuronal proteins whose interactions are implicated in the regulation of synaptic responses and plasticity. We employed the "low-calcium" model of epilepsy in hippocampal slices to investigate the mobilization of these two proteins in CA1 pyramidal neurons. Perfusion of mouse hippocampal slices with Ca(2+)-free artificial CSF (ACSF) caused a suppression of synaptic transmission and generation of epileptic activity; these responses could be reversed by normal Ca(2+)-containing ACSF. Fluorescence immunochemical staining of control hippocampal slices bathed in normal ACSF revealed that CaM and Ng were more concentrated in soma than in dendrites; especially for CaM, it was concentrated in the nucleus. Perfusion of hippocampal slices with Ca(2+)-free ACSF caused translocation of these two proteins from soma to dendrites, and this trafficking was also reversed by Ca(2+)-containing buffer. A reduction of ∼15 and 40 nM intracellular Ca(2+), [Ca(2+)](i), caused half-maximum translocation of Ng and CaM, respectively. Hippocampal CA1 pyramidal neurons were the most responsive to this Ca(2+)-sensitive translocation as compared to those from other areas of the hippocampus. These results illustrated the unique feature of hippocampal CA1 pyramidal neurons in sequestering high concentrations of CaM and Ng in soma and releasing them to distal dendrites at reducing level of [Ca(2+)](i).

Ischemia-elicited oxidative modulation of Ca2+/calmodulin-dependent protein kinase II.

Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) plays a critical role in neuronal signal transduction and synaptic plasticity. Here, we showed that this kinase was very susceptible to oxidative modulation. Treatment of mouse brain synaptosomes with H2O2, diamide, and sodium nitroprusside caused aggregation of CaMKII through formation of disulfide and non-disulfide linkages, and partial inhibition of the kinase activity. These CaMKII aggregates were found to associate with the post synaptic density. However, treatment of purified CaMKII with these oxidants did not replicate those effects observed in the synaptosomes. Using two previously identified potential mediators of oxidants in the brain, glutathione disulfide S-monoxide (GS-DSMO) and glutathione disulfide S-dioxide (GS-DSDO), we showed that they oxidized and inhibited CaMKII in a manner partly related to those of the oxidant-treated synaptosomes as well as the ischemia-elicited oxidative stress in the acutely prepared hippocampal slices. Interestingly, the autophosphorylated and activated CaMKII was relatively refractory to GS-DSMO- and GS-DSDO-mediated aggregation. Short term ischemia (10 min) caused a depression of basal synaptic response of the hippocampal slices, and re-oxygenation (after 10 min) reversed the depression. However, oxidation of CaMKII remained at above the pre-ischemic level throughout the treatment. Oxidation of CaMKII also prevented full recovery of CaMKII autophosphorylation after re-oxygenation. Subsequently, the high frequency stimulation-mediated synaptic potentiation in the hippocampal CA1 region was significantly reduced compared with the control without ischemia. Thus, ischemia-evoked oxidation of CaMKII, probably via the action of glutathione disulfide S-oxides or their analogues, may be involved in the suppression of synaptic plasticity.

Long-term enrichment enhances the cognitive behavior of the aging neurogranin null mice without affecting their hippocampal LTP.

Neurogranin (Ng), a PKC substrate, is abundantly expressed in brain regions important for cognitive functions. Deletion of Ng caused severe deficits in spatial learning and LTP in the hippocampal CA1 region of mice. These Ng-/- mice also exhibit deficits in the amplification of their hippocampal signaling pathways critical for learning and memory. A short-term exposure to an enriched environment failed to improve their behavioral performances. Here, we showed that a long-term enrichment protocol for the aging mice was beneficial to the Ng-/- as well as Ng+/+ and Ng+/- mice in preventing age-related cognitive decline. Enrichment also caused an increase in the hippocampal CREB level of all three genotypes and Ng level of Ng+/+ and Ng+/- mice, but not that of alphaCaMKII or ERK. Interestingly, hippocampal slices of these enriched aging Ng-/- mice, unlike those of Ng+/+ and Ng+/- mice, did not show enhancement in the high frequency stimulation (HFS)-induced LTP in the CA1 region. It appears that the learning and memory processes in these enriched aging Ng-/- mice do not correlate with the HFS-induced LTP, which is facilitated by Ng. These results demonstrated that long-term enrichment for the aging Ng-/- mice may improve their cognitive function through an Ng-independent plasticity pathway.

Modification of protein by disulfide S-monoxide and disulfide S-dioxide: distinctive effects on PKC.

Disulfide S-monoxide (DSMO) and disulfide S-dioxide (DSDO) have been proposed as proximal mediators for the oxidant-mediated modification of proteins. These disulfide S-oxides (DSOs) derived from glutathione (GSH) and captopril (CPSH) were synthesized by iron- or methyltrioxorhenium (VII)-catalyzed oxidation of the thiols with H2O2. Treatment of mouse hippocampal extracts with [35S]GS-DSOs revealed that a large number of proteins were susceptible to thionylation; however, only a limited number of the them were detectable by the commonly used antibody against GS-associated proteins. Using protein kinase C (PKC) as a model, we found that DSOs derived from different thiols modified this kinase with different efficacy and specificity; for example, the inhibitory potency of the kinase was glutathione disulfide S-dioxide (GS-DSDO) (IC50, approximately 30 microM) > captopril disulfide S-dioxide (CPS-DSDO) (IC50, approximately 450 microM) > glutathione disulfide S-monoxide (GS-DSMO) and captopril disulfide S-monoxide (CPS-DSMO). The stoichiometries of thionylation of PKC beta mediated by [35S]GS-DSMO and [35S]GS-DSDO were approximately 1 and 5 mol/mol, respectively, and at least four glutathionylation sites were identified in the GS-DSDO-treated kinase. Modification of PKC by GS-DSDO and CPS-DSDO rendered the kinase very susceptible to limited proteolysis; the former preferentially caused the degradation of the catalytic and the latter the regulatory domain of the kinase. Furthermore, CPS-DSDO-mediated modification of PKC increased the autonomous kinase activity; this was not the case for GS-DSDO-mediated modification. Since DSOs of different oxidative states as well as those derived from different thiols exert different effects on a target protein, these molecules could cause distinct cellular responses if derived from endogenous cellular reactions or even if they arise from exogenous sources.

Environmental enrichment enhances neurogranin expression and hippocampal learning and memory but fails to rescue the impairments of neurogranin null mutant mice.

Environmental enrichment is known to enhance hippocampal neurogenesis and cognitive functions. Neurogranin (Ng), a specific substrate of protein kinase C (PKC), is abundantly expressed in brain regions important for cognitive functions. Deletion of Ng in mice causes severe deficits in spatial learning and long-term potentiation (LTP) in the hippocampal CA1 region. These Ng-/- mice, as compared with Ng+/+, respond poorly after treatment of their hippocampal slices with agents that activate signaling molecules important for learning and memory, including Ca2+/calmodulin-dependent protein kinase II (alphaCaMKII), PKC, protein kinase A (PKA), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB). In the present study, adult mice were housed in either regular home cages (control group) or more spacious cages with an exercise wheel and change of toys twice per week (enriched group) for at least 3 weeks. Enriched Ng+/+ and Ng+/- mice showed enhanced LTP in the hippocampal CA1 after high-frequency stimulation, but Ng-/- mice were affected only minimally. Behaviorally, the enriched Ng+/+ and Ng+/-, but not Ng-/- mice, performed significantly better than their respective control cohorts in Morris water maze and in step-down fear conditioning. Enriched Ng+/- mice also showed improvement in the radial arm maze. Quantitative immunoblot analyses showed that the enriched groups of all three genotypes exhibited elevated hippocampal levels of alphaCaMKII and CREB, but not ERK. Interestingly, enrichment caused a significant increase in hippocampal Ng levels both in Ng+/+ and Ng+/- mice that seemed to contribute to their improved LTP and behavioral performances. These results suggest that Ng gates the neuronal signaling reactions involved in learning and memory. During environmental enrichment, these Ng-regulated reactions are also critical for the enhancement of synaptic plasticity and cognitive functions.

Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling.

In neurons, neurogranin (Ng) binds calmodulin (CaM), and its binding affinity is reduced by increasing Ca2+, phosphorylation by PKC, or oxidation by oxidants. Ng concentration in the hippocampus of adult mice varied broadly (Ng+/+, 160-370 and Ng+/-, approximately 70-230 pmol/mg); the level in Ng+/+ mice is one of the highest among all neuronal CaM-binding proteins. Among Ng+/- mice, but less apparent in Ng+/+, a significant relationship existed between their hippocampal levels of Ng and performances in the Morris water maze. Ng-/- mice performed poorly in this task; they also displayed deficits in high-frequency-induced long-term potentiation (LTP) in area CA1 of hippocampal slices, whereas low-frequency-induced long-term depression was enhanced. Thus, compared with Ng+/+ mice, the frequency-response curve of Ng-/- shifted to the right. Paired-pulse facilitation and synaptic fatigue during prolonged stimulation at 10 Hz (900 pulses) were unchanged in Ng-/- slices, indicating their normal presynaptic function. Measurements of Ca2+ transients in CA1 pyramidal neurons after weak and strong tetanic stimulations (100 Hz, 400 and 1000 msec, respectively) revealed a significantly greater intracellular Ca2+ ([Ca2+]i) response in Ng+/+ compared with Ng-/- mice, but the decay time constants did not differ. The diminished Ca2+ dynamics in Ng-/- mice are a likely cause of their decreased propensity to undergo LTP. Thus, Ng may promote a high [Ca2+]i by a "mass-action" mechanism; namely, the higher the Ng concentration, the more Ng-CaM complexes will be formed, which effectively raises [Ca2+]i at any given Ca2+ influx. This mechanism provides potent signal amplification in enhancing synaptic plasticity as well as learning and memory.

Participation of NMDA-mediated phosphorylation and oxidation of neurogranin in the regulation of Ca2+- and Ca2+/calmodulin-dependent neuronal signaling in the hippocampus.

Neurogranin/RC3 (Ng) is a postsynaptic protein kinase C (PKC) substrate and calmodulin (CaM)-binding protein whose CaM-binding affinity is modulated by Ca2+, phosphorylation and oxidation. Ng has been implicated in the modulation of postsynaptic signal transduction pathways and synaptic plasticity. Previously, we showed a severe deficit of spatial memory in Ng knockout (KO) mice. Activation of the NMDA receptor and its downstream signaling molecules are known to be involved in long-term memory formation. In the present study, using mouse hippocampal slices, we demonstrated that NMDA induced a rapid and transient phosphorylation and oxidation of Ng. NMDA also caused activation of PKC as evidenced by their phosphorylations, whereas, such activations were greatly reduced in the KO mice. A higher degree of phosphorylation of Ca2+/CaM-dependent kinase II and activation of cyclic AMP-dependent protein kinase were also evident in the WT compared to those of the KO mice. Phosphorylation of downstream targets, including mitogen-activated protein kinases and cAMP response element-binding protein, were significantly attenuated in the KO mice. These results suggest that by its Ca2+-sensitive CaM-binding feature, and through its phosphorylation and oxidation, Ng regulates the Ca2+- and Ca2+/CaM-dependent signaling pathways subsequent to the stimulation of NMDA receptor. These findings support the hypothesis that the derangement of hippocampal signal transduction cascades in Ng KO mice causes the deficits in synaptic plasticity, learning and memory that occur in these mice.

Glutathionylation of proteins by glutathione disulfide S-oxide.

Aqueous solution of S-nitrosoglutathione (GSNO) underwent spontaneous chemical transformation that generated several glutathione derivatives including glutathione sulfonic acid (GSO3H), glutathione disulfide S-oxide (GS(O)SG), glutathione disulfide S-dioxide, and glutathione disulfide. Surprisingly, GS(O)SG (also called glutathione thiosulfinate), which was not identified as a metabolite of GSNO previously, was one of the major products derived from GSNO. This compound was very reactive toward any thiol and the reaction product was a mixed disulfide. The rate of reaction of GS(O)SG with 5-mercapto-2-nitro-benzoate was nearly 20-fold faster than that of GSNO. The mechanism for the formation of GS(O)SG was believed to involve the sulfenic acid (GSOH) and thiosulfinamide (GS(O)NH2) intermediates; the former underwent self-condensation and the latter reacted with GSH to form GS(O)SG. Many reactive oxygen and nitrogen species were also capable of oxidizing GSH or GSSG to form GS(O)SG, which likely played a central role in integrating both the oxidative and nitrosative cellular responses through thionylation of thiols. Treatments of rat brain tissue slices with oxidants resulted in an enhanced thionylation of proteins with a concomitant increase in cellular level of GS(O)SG, suggesting that this compound might play a second messenger role for stimuli that produced a variety of oxidative species.

Attenuation of protein kinase C and cAMP-dependent protein kinase signal transduction in the neurogranin knockout mouse.

Neurogranin (Ng) is a brain-specific, postsynaptically located protein kinase C (PKC) substrate, highly expressed in the cortex, hippocampus, striatum, and amygdala. This protein is a Ca(2+)-sensitive calmodulin (CaM)-binding protein whose CaM-binding affinity is modulated by phosphorylation and oxidation. To investigate the role of Ng in neural function, a strain of Ng knockout mouse (KO) was generated. Previously we reported (Pak, J. H., Huang, F. L., Li, J., Balschun, D., Reymann, K. G., Chiang, C., Westphal, H., and Huang, K.-P. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 11232-11237) that these KO mice displayed no obvious neuroanatomical abnormality, but exhibited deficits in learning and memory and activation of Ca(2+)/CaM-dependent protein kinase II. In this report, we analyzed several downstream phosphorylation targets in phorbol 12-myristate 13-acetate- and forskolin-treated hippocampal slices from wild type (WT) and KO mice. Phorbol 12-myristate 13-acetate caused phosphorylation of Ng in WT mice and promoted the translocation of PKC from the cytosolic to the particulate fractions of both the WT and KO mice, albeit to a lesser extent in the latter. Phosphorylation of downstream targets, including mitogen-activated protein kinases, 90-kDa ribosomal S6 kinase, and the cAMP response element binding protein (CREB) was significantly attenuated in KO mice. Stimulation of hippocampal slices with forskolin also caused greater stimulation of protein kinase A (PKA) in the WT as compared with those of the KO mice. Again, phosphorylation of the downstream targets of PKA was attenuated in the KO mice. These results suggest that Ng plays a pivotal role in regulating both PKC- and PKA-mediated signaling pathways, and that the deficits in learning and memory of spatial tasks detected in the KO mice may be the result of defects in the signaling pathways leading to the phosphorylation of CREB.