Cabozantinib in combination with immune checkpoint inhibitors for renal cell carcinoma: a systematic review and meta-analysis.

Context: Cabozantinib combined with immune checkpoint inhibitors (ICIs) has brought a new therapeutic effect for the medical treatment of renal cell carcinoma (RCC). Objectives: We performed a meta-analysis of randomized controlled trials and single-arm trials to evaluate the efficacy and safety of cabozantinib plus ICIs in RCC. Methods: We extracted data from PubMed, Cochrane, Medline and Embase databases, and rated literature quality through Cochrane risk of bias tool and MINORS. RevMan5.3 software was used to analyze the results of randomized controlled trials and single-arm trials. Results: A total of 7 studies were included. Treatment with cabozantinib plus ICIs improved PFS [HR 0.75, (95%CI: 0.52, 1.08), p = 0.12] and the OS [HR 0.80, (95%CI: 0.60, 1.07), p = 0.13] in randomized controlled trials. Meanwhile, the result of the ORR in randomized controlled trials was [risk ratio (RR) 1.37, (95%CI: 1.21, 1.54), p < 0.00001] and in single-arm trials was [risk difference (RD) 0.49, (95%CI: 0.26, 0.71), p < 0.0001]. Conclusion: Cabozantinib plus ICIs prolonged the PFS and OS, and improved ORR in patients with RCC. Our recommendation is to use cabozantinib plus ICIs to treat advanced RCC, and to continuous monitor and manage the drug-related adverse events. Systematic Review Registration: identifier CRD42023455878.

Comparative efficacy and safety of cabozantinib for malignant tumors: a systematic review and meta-analysis.

OBJECTIVES: To provide a more comprehensive understanding of the efficacy and safety profile of cabozantinib versus placebo in malignant tumors, we conducted a systematic review and meta-analysis. This involved analyzing a collection of published randomized controlled trials to assess the outcomes. METHODS: We used RevMan5.3 software to evaluate the outcomes of the collected studies. The primary outcome we focused on was progression-free survival (PFS), and the secondary outcomes included overall survival (OS) and disease control rate (DCR). RESULTS: Our findings revealed that compared to placebo, cabozantinib significantly extended the PFS of patients [hazard ratios (HR) 0.37, 95% confidence intervals (CI): 0.32, 0.43, p < 0.00001]. Additionally, cabozantinib improved the OS of patients [HR 0.78, 95%CI: 0.68, 0.91, p = 0.002]. While it is important to note that cabozantinib was associated with a higher likelihood of causing digestive, cutaneous, and cardiovascular related adverse events [relative risk (RR) 4.40, 95% CI: 3.10, 6.25, p < 0.00001]. CONCLUSION: Based on our analysis, cabozantinib significantly prolonged the PFS and OS of patients with malignant tumors (p < 0.01). We recommend the use of cabozantinib in treating advanced malignant tumors. However, it is important to continuously monitor and manage the drug-related adverse events. REGISTRATION: PROSPERO (No. CRD42023449261).

Leveraging molecular targeted drugs and immune checkpoint inhibitors treat advanced thyroid carcinoma to achieve thyroid carcinoma redifferentiation.

Thyroid cancer can be classified into three different types based on the degree of differentiation: well-differentiated, poorly differentiated, and anaplastic thyroid carcinoma. Well-differentiated thyroid cancer refers to cancer cells that closely resemble normal thyroid cells, while poorly differentiated and anaplastic thyroid carcinoma are characterized by cells that have lost their resemblance to normal thyroid cells. Advanced thyroid carcinoma, regardless of its degree of differentiation, is known to have a higher likelihood of disease progression and is generally associated with a poor prognosis. However, the process through which well-differentiated thyroid carcinoma transforms into anaplastic thyroid carcinoma, also known as "dedifferentiation", has been a subject of intensive research. In recent years, there have been significant breakthroughs in the treatment of refractory advanced thyroid cancer. Clinical studies have been conducted to evaluate the efficacy and safety of molecular targeted drugs and immune checkpoint inhibitors in the treatment of dedifferentiated thyroid cancer. These drugs work by targeting specific molecules or proteins in cancer cells to inhibit their growth or by enhancing the body's immune response against the cancer cells. This article aims to explore some of the possible mechanisms behind the dedifferentiation process in well-differentiated thyroid carcinoma. It also discusses the clinical effects of molecular targeted drugs and immune checkpoint inhibitors in thyroid cancer patients with different degrees of differentiation. Furthermore, it offers insights into the future trends in the treatment of advanced thyroid cancer, highlighting the potential for improved outcomes and better patient care.

Effect of vegetable consumption on risk of gastric cancer: a systematic review and multi-level meta-analysis of prospective studies.

Vegetables are known to be beneficial to human health, but the association between vegetable consumption and gastric cancer remains uncertain. To synthesise knowledge about the relationship between vegetable group consumption and gastric cancer risk, update present meta-analyses and estimate associations between vegetable consumption and gastric cancer risk based solely on prospective studies, we perform a PRISMA-compliant three-level meta-analysis. Systematic search identified thirteen prospective studies with fifty-two effect sizes that met all inclusion criteria and no exclusion criteria for our meta-analysis. Pooled risk ratios (RRs) showed a positive association between high vegetable consumption and low gastric cancer risk (pooled RR 0·93, 95% confidence interval 0·90-0·97, P = 0·06). In moderator analyses for indicators of gender, region and quantity of vegetable intake, there was no significant difference between subgroups. However, the effect became significant in populations with lower than the minimum risk exposure level (TMREL) of vegetable consumption (P < 0·05). Higher vegetable intake is associated with a decreased risk of gastric cancer. This effect may be limited to specific populations, such as ones with lower vegetable consumption. Evidence from our study has important public health implications for dietary recommendations.

Efficacy and safety of dorzagliatin, a novel glucokinase activators, in the treatment of T2DM: A meta-analysis of randomized controlled trials.

OBJECT: To evaluate the efficacy and safety of dorzagliatin for the treatment of type 2 diabetes (T2DM). METHODS: Seven databases were systematically searched, spanning the interval from 2016 to August 2023. Randomized controlled trials (RCTS) comparing dorzagliatin with placebo for the treatment of T2DM were applicable for containing this study. The relevant data were extracted, and a meta-analysis was implemented using RevMan 5.4 software. RESULTS: A total of 3 studies involving 1332 patients were included. We use glycated hemoglobin (HbA1c) levels as the major indicator of efficacy, FBG, 2h postprandial blood glucose, Homa-ß and Homa-IR to be Secondary outcome measures. Compared with placebo group, dorzagliatin significantly reduced blood glucose levels as well as enhanced insulin resistance. In terms of safety, no serious adverse events occurred. However, lipid-related indicators, especially triglycerides levels, and the incidence of hypoglycemia were higher in patients in the dorzagliatin group compared with those in the control group, but the increase from baseline was mild. CONCLUSIONS: Dorzagliatin exerted favorable effects in hypoglycemic control, effectively reduced the HbA1c, FBG, and 2h postprandial blood glucose levels in T2DM patients, stimulated the secretion of insulin during the initial phase, and exerted a consistent hypoglycemic effect. However, the incidence of adverse events such as elevated blood lipids and cardiovascular risk warrants further investigations through long-term clinical trials.

Efficacy and safety of trastuzumab deruxtecan in patients with solid tumors: a systematic review and meta-analysis of 3 randomized controlled trials.

Trastuzumab deruxtecan (T-DXd, DS-8201) is a targeted antibody-drug conjugate that specifically targets human epidermal growth factor receptor 2 (HER2). In 2019, it was approved by the US Food and Drug Administration for the treatment of HER2-positive breast cancer. However, ongoing research is exploring its potential efficacy in other solid tumors, such as non-small-cell lung cancer and colorectal cancer, as well as in tumors with low HER2 levels. It is important to examine the safety and effectiveness of trastuzumab deruxtecan in these various types of solid tumors, as some studies have raised concerns about potential serious adverse events associated with its use. In this meta-analysis, we conducted a comprehensive search of PubMed, EMBASE, Cochrane Library, and Web of Science to identify randomized controlled trials (RCTs) that evaluated the efficacy and safety of trastuzumab deruxtecan in solid tumors. We used RevMan 5.4 software to perform a meta-analysis, calculating odds ratios (OR), risk ratios (RR), and weighted mean differences (WMD) with 95% confidence intervals (CIs). After an exhaustive search, we identified three articles that met our inclusion criteria, which included a total of 1268 patients. The results of the meta-analysis showed that the treatment group had significantly higher overall survival (WMD=5.12, 95% CI (2.79, 7.44), P<0.0001), progression-free survival (WMD=3.45, 95% CI (0.8, 6.1), P=0.01), overall response rate (OR=6.49, 95% CI (4.90, 8.58), P<0.00001), and disease control rate (OR=4.68, 95% CI (2.78, 7.89), P<0.00001), TRAEs (RR=6.93, 95% CI (2.06, 23.25), P=0.002). However, there was no significant difference in TRAEs≥3 (RR=1.08, 95% CI (0.75, 1.56), P=0.68) between the trials. Based on the available evidence, trastuzumab deruxtecan appears to be an effective and safe treatment option for HER2-positive solid tumors. Although the number of studies included in this analysis is limited, ongoing trials are being conducted, further evaluating its potential in various solid tumors. The results of these trials will enhance our understanding of trastuzumab deruxtecan and potentially expand its applications, bringing hope to more patients with solid tumors.

Efficacy Study of Multidisciplinary Team Participating in the Perioperative Administration for Elderly Patients With Intertrochanteric Fractures: A Prospective Randomized Controlled Trail.

OBJECTIVE: To evaluate the efficacy of the multidisciplinary team (MDT) participating in the perioperative administration and 1-year follow-up for elderly patients with intertrochanteric fractures. METHOD: Elderly patients who underwent surgical treatment of intertrochanteric fractures in our hospital, from January 2018 to December 2020, were taken as the research object. According to the inclusion and exclusion criteria, a total of 76 patients were prospectively included and equally allocated to form a MDT group and a conventional group in this trial by the random number table method. The MDT was composed of doctors from nine disciplines, who would work jointly to evaluate the perioperative risk and formulate the treatment plan and the rehabilitation program. RESULTS: Compared with the conventional group, the time before weight-bearing (59.93 ± 5.93 days vs 67.93 ± 5.87 days), fracture healing time (68.98 ± 7.82 days vs 78.91 ± 7.09 days), and the length of hospital stay (10.43 ± 2.01 days vs 13.87 ± 2.13 days) in the MDT group were all shorter, P < 0.001, and the VAS declined from 3.18 ± 0.81 to 2.28 ± 0.87 at 3 days after the operation and from 0.26 ± 0.04 to 0.23 ± 0.03 at 3 months after the operation in the MDT group, P < 0.001. Compared with the only case in the MDT group which had postoperative complications, postoperative complications were more common in the conventional group, and the difference was statistically significant, P = 0.025. At 1 month and 1 year after the operation, the Harris hip score results of the MDT group were all higher in the seven aspects than those in the conventional group; the difference was statistically significant ( P < 0.001). CONCLUSION: The MDT participated in the perioperative management and the guidance of postoperative rehabilitation of elderly patients with intertrochanteric fractures can markedly improve perioperative symptoms, promote postoperative recovery, and improve long-term hip joint function.

Prevalence of Diabetic Retinopathy and Use of Common Oral Hypoglycemic Agents Increase the Risk of Diabetic Nephropathy-A Cross-Sectional Study in Patients with Type 2 Diabetes.

OBJECTIVE: This study investigated the effect of amino acid metabolism on the risk of diabetic nephropathy under different conditions of the diabetic retinopathy, and the use of different oral hypoglycemic agents. METHODS: This study retrieved 1031 patients with type 2 diabetes from the First Affiliated Hospital of Liaoning Medical University in Jinzhou, which is located in Liaoning Province, China. We conducted a spearman correlation study between diabetic retinopathy and amino acids that have an impact on the prevalence of diabetic nephropathy. Logistic regression was used to analyze the changes of amino acid metabolism in different diabetic retinopathy conditions. Finally, the additive interaction between different drugs and diabetic retinopathy was explored. RESULTS: It is showed that the protective effect of some amino acids on the risk of developing diabetic nephropathy is masked in diabetic retinopathy. Additionally, the additive effect of the combination of different drugs on the risk of diabetic nephropathy was greater than that of any one drug alone. CONCLUSIONS: We found that diabetic retinopathy patients have a higher risk of developing diabetic nephropathy than the general type 2 diabetes population. Additionally, the use of oral hypoglycemic agents can also increase the risk of diabetic nephropathy.

A meta-analysis of the efficacy and toxicity of tyrosine kinase inhibitors in treating patients with different types of thyroid cancer: how to choose drugs appropriately?

PURPOSE OF REVIEW: Because the high risk of death and poor prognosis of patients with refractory thyroid cancer (TC), studies related to tyrosine kinase inhibitors (TKIs) in treating different types of refractory TC have gradually attracted attention. Thus, we conducted a meta-analysis of published randomized controlled trials and single-arm trials to evaluate tyrosine kinase inhibitors' efficacy and safety profile treatment in TC patients. RECENT FINDINGS: The studies of 29 in 287 met the criteria, 9 were randomized controlled trials and 20 were single-arm trials, involving 11 TKIs (Apatinib, Anlotinib, Cabozantinib, Imatinib, Lenvatinib, Motesanib, Pazopanib, Sorafenib, Sunitinib, Vandetanib, Vemurafenib). Treatment with TKIs significantly improved progression-free survival [hazard ratio [HR] 0.34 (95% confidence interval [CI]: 0.24, 0.48), P < 0.00001] and overall survival [OS] [HR 0.76, (95% CI: 0.64, 0.91), P = 0.003] in randomized controlled trials, but adverse events (AEs) were higher than those in the control group (P < 0.00001). The result of the objective response rate (ORR) in single-arm trials was statistically significant [odds ratio [OR] 0.49 (95% CI: 0.32, 0.75), P = 0.001]. SUMMARY: TKIs significantly prolonged progression-free survival and OS or improved ORR in patients with different types of TC (P < 0.01). Our recommendation is to select appropriate TKIs to treat different types of TC patients, and to prevent and manage drug-related AEs after using TKIs.

Efficacy and safety of HER2-targeted therapy in patients with colorectal cancer: What should we expect from a meta-analysis?

BACKGROUND AND OBJECTIVE: Human epidermal growth factor receptor 2 (HER2) is an effective therapeutic target for breast and stomach cancers. However, the application of HER2-targeted therapy in colorectal cancer (CRC) remains controversial. We sought to assess the efficacy and safety of HER2-targeted therapy in CRC by performing a meta-analysis of relevant studies. METHODS: We searched PubMed, Embase, Cochrane Library, Web of Science, and the ClinicalTrials.gov database to retrieve relevant studies. STATA 16 was used for the statistical analysis. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and incidence of treatment­related adverse events (TRAEs) were used as the outcome indicators analyzed by random- or fixed-effects models. RESULTS: A total of 267 patients from nine studies were included in this meta-analysis. The overall ORR and DCR were 27.5% (95% CI 16.8% to 39.6%) and 68.9% (95% CI 55.4% to 81.0%), respectively. No significant heterogeneity was found in PFS among these studies and the overall median PFS was 4.35 months (95% CI 3.70 to 4.99). The overall incidence of all-grade and grade 3 or higher adverse events were 93.5% (95% CI 88.4% to 97.4%) and 16.8% (95% CI 4.8% to 33.3%). CONCLUSIONS: HER2-targeted therapy was confirmed as a promising treatment for colorectal cancer, warranting further high-quality clinical randomized controlled trials to verify.

Analysis of Factors Influencing Postoperative Femoral Head Collapse in Patients With Ficat I, II, and III Stages of Aseptic Necrosis of the Femoral Head.

OBJECTIVE: To investigate the factors influencing postoperative femoral head collapse (FHC) in patients with Ficat I, II, and III stages of aseptic necrosis of the femoral head (ANFH). METHODS: Retrospective analysis of 178 patients with ANFH admitted to our hospital from October 2018 to October 2021 was studied, and patients were categorized into the FHC group and no FHC group according to whether FHC occurred after surgery. The influencing factors causing postoperative FHC were analyzed by univariate and multifactor logistic regression. RESULTS: In the collapsed group, there were statistically significant differences in etiology, extent of necrosis, mechanism of injury, preoperative waiting time, Japanese Femoral Necrosis Research Society staging, distance from the tip of the tantalum rod to the center of necrosis, and Harris score after treatment ( P < 0.05). The etiology, extent of necrosis, mechanism of injury, preoperative waiting time, Japanese Femoral Osteonecrosis Research Society classification, distance between the tantalum rod tip and the center of necrosis, and Harris score after treatment were set as independent variables, and postoperative FHC in patients with Ficat I, II, and III stages of ANFH was used as the dependent variable in the univariate logistic regression analysis. DISCUSSION: Hormonal osteonecrosis of the femur, extent of necrosis, type C1 and type C2 in the Japanese Society for the Study of Femoral Osteonecrosis staging, and distance of the tip of the tantalum rod from the center of necrosis are risk factors for postoperative FHC in patients with Ficat I, II, and III stages of ANFH.

Binding characteristics of calpastatin domain L to NaV1.5 sodium channel and its IQ motif mutants.

NaV1.5 channel is an integral membrane protein involved in the initiation and conduction of action potentials. IQ motif is located in the C-terminal domain of NaV1.5 sodium channel, which is highly conserved in human sodium channel subtypes. IQ motif is involved in the Ca2+-dependent regulation through interaction with the regulatory proteins such as calpastatin domain L (CSL). Mutations in SCN5A, the gene encoding NaV1.5 channel, have been linked to many cardiac arrhythmias, such as Long QT syndrome type 3 (LQT3) and Brugada syndrome (BRS). LQT3-associated mutations in NaV1.5 IQ motif, IQQ1909R and IQR1913H, have been reported to affect the late INa. A BRS-associated mutation in NaV1.5 IQ motif, IQA1924T, has been reported to affect the peak INa. But the detailed pathogenic mechanisms of LQT3 and BRS remains unclear. To explore the binding properties of CSL to IQ motif and its muants associated with LQT3/BRS, molecular docking and GST pull down assay were performed in this study. As a result, S58 and E59 in CSL activating channel effect region L54-64 were involved in the conformation of the CSL/IQWT complex by protein-protein docking. IQ motif could bind to CSL in a [CSL]-dependent and [Ca2+]-dependent manner by pull down assay. However, the binding affinities of IQQ1909R and IQR1913H to CSL were decreased and its reaction rates with CSL were slower. The binding characteristics of IQA1924T to CSL was opposite in a [Ca2+]-dependent manner and its binding efficacy became smaller. The changes of the binding characteristics of IQmutants to CSL would affect the regulation of NaV1.5 channel, which may be related to LQT3 and BRS.

Efficacy and safety of multi-kinase inhibitors in patients with radioiodine-refractory differentiated thyroid cancer: a systematic review and meta-analysis of clinical trials.

OBJECTIVES: Radioiodine-refractory differentiated thyroid cancer (RAI-rDTC) has frequently been associated with poor prognosis. We conducted a meta-analysis of published randomized controlled trials to evaluate multi-kinase inhibitors' efficacy and safety profile treatment. METHODS: A comprehensive search was conducted using PubMed, Embase, Cochrane, and Medline databases. The quality of literature and trial risk of bias was assessed using the Cochrane risk of bias tool, while the results of progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated using RevMan5.3 software. RESULTS: Treatment with MKIs significantly improved PFS and OS, but AEs were significantly higher than those in the control group (P < 0.01). The studies demonstrated the median PFS (HR 0.30, 95% CI: 0.18-0.50, P < 0.00001) and OS (HR 0.70, 95% CI: 0.57-0.88, P = 0.002) in RAI-rDTC patients treated with MKIs, and the median PFS of papillary thyroid carcinoma (HR0.28, 95% CI: 0.22-0.37, P < 0.00001) along with follicular thyroid carcinoma (HR0.14, 95%CI 0.09-0.24, P < 0.00001) were extended. CONCLUSION: MKIs significantly prolonged PFS and OS in patients with RAI-rDTC (P < 0.01). Our recommendation is to use MKIs carefully in patients after evaluating their health status to maximize treatment benefits and minimize adverse effects.

The Association of Homocysteine and Diabetic Retinopathy in Homocysteine Cycle in Chinese Patients With Type 2 Diabetes.

Objective: This study aimed to explore the relationship between homocysteine (Hcy) and diabetic retinopathy (DR) and the impacts of the Hcy pathway on this relationship against this background. Methods: This study retrieved 1979 patients with type 2 diabetes (T2D) from the First Affiliated Hospital of Liaoning Medical University in Jinzhou, Liaoning Province, China. Multiple logistic regression was used to analyze the effects of Hcy cycle on the relationship between Hcy and DR. Spearman's rank correlation analysis was used to analyze the correlation between risk factors related to DR progression and Hcy. Finally, the results of logistic regression were supplemented by mediation analysis. Results: We found there was a negative correlation between low concentration of Hcy and DR (OR : 0.83, 95%CI: 0.69-1). After stratifying all patients by cysteine (Cys) or Methionine (Met), this relationship remained significant only in low concentration of Cys (OR: 0.75, 95%CI: 0.61-0.94). Through the RCS curve, we found that the effect of Hcy on DR presents a U-shaped curve relationship. Mediating effect in Met and Hcy cycles was also significant [Total effect c (OR: 0.968, 95%CI: 0.938-0.998), Direct effect path c' (OR: 0.969, 95%CI: 0.940-0.999), Path a (OR: 1.047, 95%CI: 1.004-1.091), Path b (OR: 0.964, 95%CI: 0.932-0.998)]. Conclusions: The relationship between Hcy and DR presents a U-shaped curve and the homocysteine cycle pathway has an impact on it. And too low concentration of Hcy indicates a lack of other substances, such as vitamins. It is suggested that the progression of DR is the result of a combination of many risk factors. Further prospective studies are needed to determine the role of Hcy in the pathogenesis of DR.

Immunogenic Cell Death-Relevant Damage-Associated Molecular Patterns and Sensing Receptors in Triple-Negative Breast Cancer Molecular Subtypes and Implications for Immunotherapy.

Objectives: Triple-negative breast cancer (TNBC) is defined as a highly aggressive type of breast cancer which lacks specific biomarkers and drug targets. Damage-associated molecular pattern (DAMP)-induced immunogenic cell death (ICD) may influence the outcome of immunotherapy for TNBC patients. This study aims to develop a DAMPs gene signature to classify TNBC patients and to further predict their prognosis and immunotherapy outcome. Methods: We identified the DAMPs-associated subtypes of 330 TNBCs using K-means analysis. Differences in immune status, genomic alterations, and predicted immunotherapy outcome were compared among each subtype. Results: A total of 330 TNBCs were divided into three subtypes according to DAMPs gene expression: the nuclear DAMPs subtype, featuring the upregulation of nuclear DAMPs; the inflammatory DAMPs subtype, characterized by the gene set enrichment of the adaptive immune system and cytokine signaling in the immune system; and the DAMPs-suppressed subtype, having the lowest level of ICD-associated DAMPs. Among them, the inflammatory subtype patients had the most favorable survival, while the DAMPs-suppressed subtype was associated with the worst prognosis. The DAMPs subtyping system was successfully validated in the TCGA cohort. Furthermore, we systemically revealed the genomic alterations among the three DAMPs subtypes. The inflammatory DAMPs subtype was predicted to have the highest response rate to immunotherapy, suggesting that the constructed DAMPs clustering had potential for immunotherapy efficacy prediction. Conclusion: We established a novel ICD-associated DAMPs subtyping system in TNBC, and DAMPs expression might be a valuable biomarker for immunotherapy strategies. Our work could be helpful to the development of new immunomodulators and may contribute to the development of precision immunotherapy for TNBC.

Activity of putative orexin neurons during cataplexy.

It is unclear why orexin-deficient animals, but not wild-type mice, show cataplexy. The current hypothesis predicts simultaneous excitation of cataplexy-inhibiting orexin neurons and cataplexy-inducing amygdala neurons. To test this hypothesis, we measured the activity of putative orexin neurons in orexin-knockout mice during cataplexy episodes using fiber photometry. We created two animal models of orexin-knockout mice with a GCaMP6 fluorescent indicator expressed in putative orexin neurons. We first prepared orexin-knockout mice crossed with transgenic mice carrying a tetracycline-controlled transactivator transgene under the control of the orexin promoter. TetO-GCaMP6 was then introduced into mice via an adeno-associated virus injection or natural crossing. The resulting two models showed restricted expression of GCaMP6 in the hypothalamus, where orexin neurons should be located, and showed excitation to an intruder stress that was similar to that observed in orexin-intact mice in our previous study. The activity of these putative orexin neurons increased immediately before the onset of cataplexy-like behavior but decreased (approximately - 20% of the baseline) during the cataplexy-like episode. We propose that the activity of orexin neurons during cataplexy is moderately inhibited by an unknown mechanism. The absence of cataplexy in wild-type mice may be explained by basal or residual activity-induced orexin release, and emotional stimulus-induced counter activation of orexin neurons may not be necessary. This study will serve as a basis for better treatment of cataplexy in narcolepsy patients.

PPM1A as a key target of the application of Jiawei­Maxing­Shigan decoction for the attenuation of radiation­induced epithelial­mesenchymal transition in type II alveolar epithelial cells.

Radiation­induced lung tissue injury is an important reason for the limited application of radiotherapy on thoracic malignancies. Previously, we reported that administration of Jiawei­Maxing­Shigan decoction (JMSD) attenuated the radiation­induced epithelial­mesenchymal transition (EMT) in alveolar epithelial cells (AECs) via TGF­ß/Smad signaling. The present study aimed to examine the role of protein phosphatase Mg2+/Mn2+­dependent 1A (PPM1A) in the anti­EMT activity of JMSD on AECs. The components in the aqueous extract of JMSD were identified by high­performance liquid chromatography coupled with electrospray mass spectrometry. Primary rat type II AECs were treated with radiation (60Co γ­ray at 8 Gy) and JMSD­medicated serum. PPM1A was overexpressed and knocked down in the AECs via lentivirus transduction and the effects of JMSD administration on the key proteins related to TGF­ß1/Smad signaling were measured by western blotting. It was found that radiation decreased the PPM1A expression in the AECs and JMSD­medicated serum upregulated the PPM1A expressions in the radiation­induced AECs. PPM1A overexpression increased the E­cadherin level but decreased the phosphorylated (p­)Smad2/3, vimentin and α­smooth muscle actin (α­SMA) levels in the AECs. By contrast, the PPM1A knockdown decreased the E­cadherin level and increased the p­Smad2/3, vimentin and α­SMA levels in the AECs and these effects could be blocked by SB431542 (TGF­ß1/Smad signaling inhibitor). JMSD administration increased the E­cadherin level and decreased the p­Smad2/3, vimentin and α­SMA levels in the AECs; however, these effects could be blocked by siPPM1A­2. In conclusion, PPM1A is a key target of JMSD administration for the attenuation of the radiation­induced EMT in primary type II AECs via the TGF­ß1/Smad pathway.

Calmodulin mutant in central linker reduces the binding affinity with PreIQ and IQ while interacting with CaV1.2 channels.

Calmodulin (CaM) was reported to interact with PreIQ and IQ of CaV1.2 channels, but to date, no explicit binding sites of CaM were illustrated. Therefore, in the present study, we firstly used MOE (Molecular Operating Environment) for protein-protein docking and we found that the most likely residues of CaM that play an important role in the interface are concentrated in central linker region. Next we examined the binding properties of CaM and its mutants to PreIQ and IQ by GST pull-down assays. Here we confirmed that CaM binds to PreIQ and IQ in a concentration-dependent and [Ca2+]-dependent manner. However, silencing the effect of N-lobe and C-lobe by mutating two Ca2+ binding sites of each lobe abolished [Ca2+]-dependence of CaM binding, but could not influence the combination. And the mutant in central linker reduced the binding of CaM/PreIQ and CaM/IQ especially at low [Ca2+]. We confirmed that N-lobe and C-lobe play vital role in sensing the change of Ca2+, and found that the central linker of CaM is involved in the binding of CaM to CaV1.2 channels in particular at low [Ca2+], not only participates in the combination with PreIQ, but also with IQ.