Clinical Factors Influencing the Radiation Dose of Circulating Immune Cells during Radiotherapy for Small Cell Lung Cancer.

Small cell lung cancer (SCLC) has garnered significant attention due to its high malignancy, propensity for distant metastasis, and poor prognosis. Radiotherapy remains the cornerstone of treatment for limited-stage small cell lung cancer (LS-SCLC). However, outcomes with radiotherapy alone or in combination with chemotherapy remain suboptimal. Radiotherapy can induce lymphopenia by directly irradiating hematopoietic organs or destroying mature circulating lymphocytes, leading to immunosuppression and consequently diminishing therapeutic efficacy. The estimated dose of radiation to immune cells (EDRIC) model integrates factors such as hemodynamics, lymphocyte radiosensitivity, and proliferation capacity. This study employs the EDRIC model with enhancements to calculate the circulating immune cell radiation dose. By utilizing the EDRIC methodology, the study explores the correlation between EDRIC and tumor target size, average lung dose, average heart dose, clinical features, and peripheral blood lymphocytopenia during radiotherapy for LS-SCLC, aiming to inform personalized patient treatment strategies. This study analyzed data from 64 LS-SCLC patients who met the inclusion criteria at the General Hospital of Ningxia Medical University from January 2023 to January 2024, all of whom received radical thoracic conventional fractionated radiotherapy. Lymphocyte counts were recorded at the following points: before radiotherapy, at the lowest observed value during radiotherapy, at the end of radiotherapy, and one-month post-radiotherapy. Dosimetric data, including average lung, heart, and body doses, were extracted from the treatment planning system, and the circulating EDRIC was calculated using this model. The relationship between EDRIC values and therapeutic outcomes was analyzed. In LS-SCLC, the EDRIC model effectively predicts lymphocyte count reduction, correlating with planning target volume (PTV; cm3), TNM stage, and the percentage of target lesion shrinkage. Post-radiotherapy, there was a significant decrease in peripheral blood lymphocyte counts, with greater EDRIC values indicating more pronounced lymphocyte reduction.

Effect of Comprehensive Nursing Based on Risk Factors in Liver Cancer Patients Accepted Intervention Therapy On Quality of Life and Prognosis.

Objective: To explore the effect of comprehensive nursing measures, based on the risk factors of dementia, in liver cancer patients, who accepted intervention therapy. Methods: 86 patients met the inclusion criteria, and exclusion criteria were divided into an experimental group (EG group) and a control group (CG group). The general baseline data of age, sex, and education level of groups were evaluated before intervention. CG group adopted routine nursing measures, while EG group gave comprehensive nursing measures on the basis of routine nursing measures. Cognitive function, severity, Barthel index (BI), and quality of life were evaluated on admission day, discharge day, and three months after discharge. Results: The scores of cognitive function, mental state, and self-care ability of daily life in the EG group were significantly higher than those in the CG group on the day of discharge and 3 months after discharge. Three months after discharge, the quality of life total score of EG group was significantly higher than that in CG group, and the scores in the family role, language, activity, self-care ability, social role, thinking and social function were also higher than those in CG group (P < .05). Three months after discharge, the readmission rate and retraining rate in the EG group were significantly lower than those in the CG group (P < .05), but there was no significant difference in mortality between the two groups(P > .05). Conclusion: Comprehensive nursing measures based on prognostic factors in patients undergoing interventional therapy for hepatocellular carcinoma can more effectively enhance patient recovery.

Wearing individualized 3D printed oral stent to protect normal tissues in patients with nasopharyngeal carcinoma during radiotherapy.

PURPOSE: To demonstrate a new individualized 3D printed oral stent in radiotherapy of nasopharyngeal carcinoma (NPC) patients and carry out a comparative analysis combining with clinical case. MATERIAL AND METHODS: Thirty NPC patients treated in our institution from September 2021 to October 2022 were prospectively enrolled. An individualized 3D printed oral stent was designed for each patient, and one set of computed tomography (CT) slices were obtained with /without wearing the oral stent, respectively. After delineation of target volumes and organs at risk (OARs) on the two CT slices, we finished two treatment plans by using the same target objectives, critical constraints and plan setup for each patient. Finally, the dose distribution and other dosimetric parameters of target volumes and OARs between the two plans were compared. RESULTS: Tongue volume and tongue length outside of mouth was 10.4 ± 2.5 cm3 and 2.8 ± 0.6 cm, respectively, distance between dorsal surface of oral tongue and plate increased from 0.3 ± 0.3 cm to 2.2 ± 0.5 cm by wearing the oral stent. For the target volume, there was no significant difference. However, Dmax of tongue, tongue tip and periglottis decreased significantly from 6352.6 ± 259.9 cGy to 5994.9 ± 478.9 cGy, 3499.8 ± 250.6 cGy to 3357.7 ± 158.0 cGy and 6345.5 ± 171.0 cGy to 6133.4 ± 263.3 cGy, respectively (p = 0.000); Dmean of tongue, tongue tip and periglottis decreased significantly from 3714.7 ± 204.2 cGy to 3169.7 ± 200.9 cGy, 3060.8 ± 216.2 cGy to 2509.6 ± 196.7 cGy and 3853.3 ± 224.9 cGy to 3079.3 ± 222.0 cGy, respectively (p = 0.000). CONCLUSION: The individualized 3D printed oral stent can reduce the dose of oral tissues and organs, so as to reduce the oral adverse reactions and improve the compliance of patients and the quality of their life. The technique can be used in radiotherapy of NPC patients.

Circadian rhythm disturbance and delirium in ICU patients: a prospective cohort study.

BACKGROUND: Patients treated in the intensive care unit (ICU) may experience a reversal of day and night. The circadian rhythm in ICU patients can be disturbed. METHODS: To explore the relationship between ICU delirium and the circadian rhythms of melatonin, cortisol and sleep. A prospective cohort study was carried out in a surgical ICU of a tertiary teaching hospital. Patients who were conscious during the ICU stay after surgery and were scheduled to stay in the ICU for more than 24 h were enrolled. Serum melatonin and plasma cortisol levels were measured three times a day by drawing arterial blood on the first three days after ICU admission. Daily sleep quality was assessed by the Richard-Campbell Sleep Questionnaire (RCSQ). The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) was performed twice a day to screen for ICU delirium. RESULTS: A total of 76 patients were included in this study, and 17 patients developed delirium during their ICU stay. Melatonin levels were different at 8:00 (p = 0.048) on day 1, at 3:00 (p = 0.002) and at 8:00 (p = 0.009) on day 2, and at all three time points on day 3 (p = 0.032, 0.014, 0.047) between delirium and non-delirium patients. The plasma cortisol level in the delirium patients was significantly lower than that in the non-delirium patients at 16:00 on day 1 (p = 0.025). The changes in melatonin and cortisol secretion levels exhibited obvious biological rhythmicity in non-delirium patients (p < 0.001 for melatonin, p = 0.026 for cortisol), while no rhythmicity was found in melatonin and cortisol secretion levels in the delirium group (p = 0.064 for melatonin, p = 0.454 for cortisol). There was no significant difference in RCSQ scores in the first three days between the two groups. CONCLUSIONS: The disturbance of the circadian rhythm of melatonin and cortisol secretion was associated with the development of delirium in ICU patients. Clinical staff should pay more attention to the importance of maintaining patients' normal circadian rhythms in the ICU. TRIAL REGISTRATION: The study was registered with the US National Institutes of Health ClinicalTrials.gov(NCT05342987) (25/04/2022).

Two-stage prediction model for postoperative delirium in patients in the intensive care unit after cardiac surgery.

OBJECTIVES: Postoperative delirium is a common severe complication in patients in the intensive care unit after cardiac surgery. We developed a two-stage prediction model and quantified the risk of developing postoperative delirium to assist in early prevention before and after surgery. METHODS: We conducted a prospective cohort study and consecutively recruited adult patients after cardiac surgery. The Confusion Assessment Method for patients in the intensive care unit was used to diagnose delirium 5 days postoperatively. The stage I model was constructed using patient demographics, health conditions and laboratory results obtained preoperatively, whereas the stage II model was built on both pre- and postoperative predictors. The model was validated internally using the bootstrap method and externally using data from an external cohort. RESULTS: The two-stage model was developed with 654 patients and was externally validated with 214 patients undergoing cardiac surgery. The stage I model contained 6 predictors, whereas the stage II model included 10 predictors. The stage I model had an area under the receiver operating characteristic curve of 0.76 (95% confidence interval: 0.68-0.81), and the stage II model's area under the receiver operating characteristic curve increased to 0.85 [95% confidence interval (CI): 0.81-0.89]. The external validation resulted in an area under the curve of 0.76 (95% CI: 0.67-0.86) for the stage I model and 0.78 (95% CI: 0.69-0.86) for the stage II model. CONCLUSIONS: The two-stage model assisted medical staff in identifying patients at high risk for postoperative delirium before and 24 h after cardiac surgery. This model showed good discriminative power and predictive accuracy and can be easily accessed in clinical settings. TRIAL REGISTRATION: The study was registered with the US National Institutes of Health ClinicalTrials.gov (NCT03704324; registered 11 October 2018).

Prediction models for postoperative delirium after cardiac surgery: Systematic review and critical appraisal.

BACKGROUND: Many studies have developed or validated prediction models to estimate the risk of delirium after cardiac surgery, but the quality of the model development and model applicability remain unknown. OBJECTIVES: To systematically review and critically evaluate currently available prediction models for delirium after cardiac surgery. DATA SOURCES: PubMed, EMBASE, and MEDLINE were systematically searched. This systematic review was registered in PROSPERO (Registration ID: CRD42021251226). STUDY SELECTION: Prospective or retrospective cohort studies were considered eligible if they developed or validated prediction models or scoring systems for delirium in the ICU. We included studies involving adults (age ≥18 years) undergoing cardiac surgery and excluded studies that did not validate a prediction model. DATA EXTRACTION: Data extraction was independently performed by two authors using a standardized data extraction form based on the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies checklist. Quality of the models was assessed with the Prediction Model Risk of Bias Assessment Tool (PROBAST). DATA SYNTHESIS: Of 5469 screened studies, 13 studies described 10 prediction models. The postoperative delirium incidence varied from 11.3 % to 51.6 %. The most frequently used predictors were age and cognitive impairment. The reported areas under the curve or C-statistics were between of 0.74 and 0.91 in the derivation set. The reported AUCs in the external validation set were between 0.54 and 0.90. All the studies had a high risk of bias, mainly owing to poor reporting of the outcome domain and analysis domain; 10 studies were of high concern regarding applicability. CONCLUSIONS: The current models for predicting postoperative delirium in the ICU after cardiac surgery had a high risk of bias according to the PROBAST. Future studies should focus on improving current prediction models or developing new models with rigorous methodology.

Effects of Enteral Nutrition on Patients With Oesophageal Carcinoma Treated With Concurrent Chemoradiotherapy: A Prospective, Multicentre, Randomised, Controlled Study.

Background: The oesophageal carcinoma patients show high incidence of malnutrition, which negatively affects their therapy outcome. Moreover, benefits of enteral nutrition remain to be studied in details in these patients. Therefore, we set to assess the effects of enteral nutrition on the nutritional status, treatment toxicities and survival in the oesophageal carcinoma patients treated with concurrent chemoradiotherapy (CCRT). Materials and Methods: Eligible patients were randomly assigned to either the experimental or control group. The patients in the experimental group were treated with a whole-course enteral nutrition management, while the control group were provided a unsystematic nutrition without setting intake goals for energy and protein. The primary endpoint was a change in body weight, while the secondary endpoints included nutrition-related haematological indicators, toxicities, completion rate of treatment and survival. Results: A total of 222 patients were randomised to either the experimental (n=148) or control (n=74) group. Patients in the experimental group showed significantly less decrease in body weight, serum albumin and haemoglobin levels, a lower incidence rates of grade ≥3 myelosuppression and infection, and a higher completion rate of CCRT than those in the control group. While analyses of the 2 and 3 year overall survival (OS) and progression-free survival (PFS) did not reveal differences between these groups, we observed a significantly higher OS at 1 year (83.6% vs. 70.0%). In the subgroup analysis, patients with patient-generated subjective global assessment (PG-SGA)=C were likely to have better OS and PFS with enteral nutrition. Conclusions: In EC patients treated with CCRT, enteral nutrition conferred positive effects on the nutritional status, treatment toxicities and prognosis, which mandate its inclusion in clinical practice. Clinical Trial Registration: This prospective trial has been registered with www.clinicaltrials.gov as NCT02399306.

Effect of a nursing intervention strategy oriented by Orem's self-care theory on the recovery of gastrointestinal function in patients after colon cancer surgery.

OBJECTIVE: To investigate the effect of nursing intervention strategies based on the Orem self-care theory on the recovery of gastrointestinal function in patients after colon cancer surgery. METHODS: In this prospective study, a total of 115 patients with colon cancer who had radical resection of the colon cancer tissue were selected as the research subjects and randomized into two groups: an Orem group (59 cases), which was given nursing based on the Orem self-care model and a control group (56 cases), which was given regular nursing. The postoperative recovery of the two groups was compared. RESULTS: After the intervention, the time to first getting out of bed, gastric tube removal, first postoperative flatus, first fluid food intake and general food intake were significantly earlier than those of the control group. Time of intestinal peristalsis and the average length of hospital stay of the Orem group were much shorter than those of the control group (all P<0.001). The cost of nutrient supply of the Orem group was significantly lower than that of the control group (P<0.001), and the postoperative pain and incidence of complications of patients in the Orem group were significantly lower than those in the control group (P<0.05). After 3 months of follow-up, the scores of positive attitude, intimacy and total score of hope in the hope level of the patients in the Orem group were significantly higher than those in the control group (all P<0.01). There was no significant difference in the positive action scores (P>0.05). Besides, the scores of the Orem group in all dimensions of the quality of life were significantly higher than those of the control group (all P<0.01). CONCLUSION: Nursing intervention based on the Orem self-care theory can promote the recovery of patients with colon cancer after surgery, speed up the recovery of their gastrointestinal function, and ultimately improve their level of hope and quality of life. Therefore, it is worthy of promotion in clinical practice.

The predictive prognostic values of serum interleukin-2, interleukin-6, interleukin-8, tumor necrosis factor-α, and procalcitonin in surgical intensive care unit patients.

BACKGROUND: The pathophysiological roles of serum cytokine levels in critically ill surgical patients has yet to be determined. This study aimed to determine the predictive prognostic values of serum interleukin IL-2, IL-6, IL-8, tumor necrosis factor-α (TNF-α), and procalcitonin (PCT) in surgical intensive care unit (ICU) patients. METHODS: Cytokine concentrations were measured with an IMMULITE 1000 Immunoassay System (Siemens Healthcare Diagnostics GmbH, Berlin, Germany). The study population was divided into quartiles according to the patients' cytokine levels: Q1, Q2, Q3, and Q4. The optimal cutoff values of IL-2, IL-6, IL-8, TNF-α, and PCT level for predicting mortality were established by drawing receiver operating characteristic curves. RESULTS: The levels of IL-2 in Q3 [odds ratio (OR) =4.434, 95% confidence intervals (95% CI): 1.527-12.874] and Q4 (OR =7.715, 95% CI: 2.744-21.693) were significantly higher than those in the Q1. The same results were noted in IL-6 and IL-8, and only Q4 (OR =2.383, 95% CI: 1.419-4.001) showed significance in the level of TNF-α. For IL-2, a cutoff value of 930.5 U/mL yielded a sensitivity of 69.39% and a specificity of 80.16% for the prediction of clinical outcome [area under the curve (AUC): 0.822; 95% CI: 0.789-0.855]. For IL-6, a cutoff value of 50.95 pg/mL showed discrimination ability, yielding a sensitivity of 71.43% and a specificity of 61.75% for (AUC: 0.704; 95% CI: 0.660-0.748). For IL-8, a cutoff value of 44.1 pg/mL yielded a sensitivity of 57.82% and a specificity of 79.58% for predicting clinical outcome (AUC: 0.753; 95% CI: 0.713-0.793). For TNF-α, a cutoff value of 11.95 pg/mL yielded a sensitivity and specificity of 68.66% and 72.90%, respectively, in predicting clinical outcome (AUC: 0.758; 95% CI: 0.717-0.800). The positive likelihood ratios for IL-2, IL-6, IL-8, and TNF-α were 3.50, 1.87, 2.83 and 2.53, and the negative likelihood ratios were 0.38, 0.46, 0.53, and 0.43, respectively. CONCLUSIONS: In critically ill patients, high levels of IL-2, IL-6, IL-8, and TNF-α in the first 24 h postoperatively were associated with clinical outcome. However, the effect of PCT level on prognosis still requires further study.

External use of Mirabilite combined with Lactulose improves postoperative gastrointestinal mobility among older patients undergoing abdominal surgery.

AIMS: To evaluate the feasibility and efficacy of Mirabilite combined with Lactulose in older patients after abdominal surgery. DESIGN: It is a retrospective observational cohort study with a pre and post intervention group. METHODS: Medical records were retrospectively reviewed of postoperative Intensive Care patients with postoperative gastrointestinal tract dysfunction (aged >60 years) in the Surgical Intensive Care Unit from January 2017-December 2018. RESULTS: One hundred and sixty-seven post-surgical Intensive Care patients with postoperative gastrointestinal tract dysfunction were analysed; 74 patients received Mirabilite + Lactulose treatment and 93 patients received Lactulose treatment. The recovery rate of bowel sounds was better in the Mirabilite + Lactulose group (62.16%) compared with the Lactulose group (37.63%) after 3-day treatment (p = 0.002) and the relative risk (RR) was 1.65 (95% CI, 1.20, 2.27). Moreover 70.27% patients in the Mirabilite + Lactulose group finally had flatus or defecation compared with 46.24% patients in Lactulose group (p = 0.003) and the RR was 1.52 (1.17, 1.98). The abdominal girth and Inter Abdominal Pressure in Mirabilite + Lactulose group showed significantly greater decrease over a 3-day period compared with Lactulose group (4.86 vs. 3.46 cm, p = 0.027; 4.80 vs. 3.11 mmHg, p = 0.002 respectively). The pain score had greater decrease from the baseline in Mirabilite + Lactulose group than in Lactulose group (2.40 vs. 1.11; p < 0.01). Patients in the Mirabilite + Lactulose group had shorter hospital stay than the Lactulose group 12.5 (SD 3.51) versus 13.9 (SD 5.14), p = 0.05. CONCLUSIONS: This study demonstrated that external use of Mirabilite combined with Lactulose can be considered as an easy intervention to improve postoperative gastrointestinal mobility in older intensive care patients who suffer from postoperative gastrointestinal tract dysfunction after surgery. IMPACT: Our results provide a great option to alleviate the sufferings of postoperative patients. The externally use Mirabilite is a painless and safe interventions that is easy to implement by ICU nurses.

Preoperative cardiac function parameters as valuable predictors for nurses to recognise delirium after cardiac surgery: A prospective cohort study.

BACKGROUND: Delirium is a common postoperative complication after cardiac surgery. The relationship between delirium and cardiac function has not been fully elucidated. AIMS: The aim of this study was to identify the association between preoperative cardiac function and delirium among patients after cardiac surgery. METHODS: We prospectively recruited 635 cardiac surgery patients with a planned cardiac intensive care unit admission. Postoperative delirium was diagnosed using the confusion assessment method for the intensive care unit. Preoperative cardiac function was assessed using N-terminal prohormone of brain natriuretic peptide (NT-proBNP), New York Heart Association functional classification and left ventricular ejection fraction. RESULTS: Delirium developed in 73 patients (11.5%) during intensive care unit stay. NT-proBNP level (odds ratio (OR) 1.24, 95% confidence interval (CI) 1.01-1.52) and New York Heart Association functional classification (OR 2.34, 95% CI 1.27-4.31) were both independently associated with the occurrence of delirium after adjusting for various confounders. The OR of delirium increased with increasing NT-proBNP levels after the turning point of 7.8 (log-transformed pg/ml). The adjusted regression coefficients were 1.19 (95% CI 0.95-1.49, P=0.134) for NT-proBNP less than 7.8 (log-transformed pg/ml) and 2.78 (95% CI 1.09-7.12, P=0.033) for NT-proBNP greater than 7.8 (log-transformed pg/ml). No association was found between left ventricular ejection fraction and postoperative delirium. CONCLUSION: Preoperative cardiac function parameters including NT-proBNP and New York Heart Association functional classification can predict the incidence of delirium following cardiac surgery. We suggest incorporating an early determination of preoperative cardiac function as a readily available risk assessment for delirium prior to cardiac surgery.

Combing NLR, V20 and mean lung dose to predict radiation induced lung injury in patients with lung cancer treated with intensity modulated radiation therapy and chemotherapy.

The purpose was to evaluate the predictive value of baseline neutrophil to lymphocyte ratio (NLR) level in the incidence of grade 3 or higher radiation induced lung injury (RILI) for lung cancer patients. A retrospectively analysis with 166 lung cancer patients was performed. All of the enrolled patients received chemoradiotherapy at our hospital between April 2014 and May 2016. The Cox proportional hazard model was used to identify the potential risk factors for RILI. In this cohort, the incidence of grade 3 or higher RILI was 23.8%. Univariate analysis showed that radiation dose, volume at least received 20Gy (V20), mean lung dose and NLR were significantly associated with the incidence of grade 3 or higher RILI (P = 0.012, 0.008, 0.012, and 0.039, respectively). Multivariate analysis revealed that total dose ≥ 60 Gy, V20 ≥ 20%, mean lung dose ≥ 12 Gy, and NLR ≥ 2.2 were still independent predictive factors for RILI (P = 0.010, 0.043, 0.028, and 0.015, respectively). A predictive model of RILI based on the identified risk factors was established using receiver operator characteristic curves. The results demonstrated that the combination analysis of V20, mean lung dose and NLR was superior to either of the variables alone. Additionally, we found that the constraint of V20 and mean lung dose were meaningful for patients with higher baseline NLR level. If the value of V20 and mean lung dose lower than the threshold value, the incidence of grade 3 or higher RILI for the high NLR level patients could be decreased from 63.3% to 8.7%. Our study showed that radiation dose, V20, mean lung dose and NLR were independent predictors for RILI. Combination analysis of V20, mean lung dose and NLR may provide a more accurate model for RILI prediction.

Design, synthesis and biological evaluation of quinoline derivatives as HDAC class I inhibitors.

Inhibition of histone deacetylase (HDAC) has been regarded as a potential therapeutic approach for treatment of multiple diseases including cancer. Based on pharmacophore model of HDAC inhibitors, a series of quinoline-based N-hydroxycinnamamides and N-hydroxybenzamides were designed and synthesized as potent HDAC inhibitors. All target compounds were evaluated for their in vitro HDAC inhibitory activities and anti-proliferative activities and the best compound 4a surpass Vorinostat in both enzymatic inhibitory activity and cellular anti-proliferative activity. In terms of HDAC isoforms selectivity, compounds 4a exhibited preferable inhibition for class I HDACs, especially for HDAC8, the IC50 value (442 nM) was much lower than that of Vorinostat (7468 nM). Subsequently, we performed class I & IIa HDACs whole cell enzyme assay to evaluate inhibitory activity in whole cell context. Compounds 4a and 4e displayed much better cellular activity for class I HDACs than that for class IIa HDACs, which indicated that 4a and 4e might be potent class I HDAC inhibitors. Meanwhile, flow cytometry analysis showed that compound 4a and 4e can promote cell apoptosis in vitro.

MicroRNA-346 functions as an oncogene in cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is an epidermal keratinocyte-derived skin tumor, which is the second most common skin cancer in the general population. Recently, studies showed that microRNAs (miRNAs) played an important role in the development of cancer. In our study, we showed that the expression of SRCIN1 was lower in cSCC tissues than in the matched normal tissues. Moreover, there was significant inversed correlation between miR-346 and SRCIN1 in cSCC tissues. The luciferase reporter assay data showed that miR-346 can target the SRCIN1 message via the 3'-untranslated region (UTR) of SRCIN1. Overexpression of miR-346 inhibited the messenger RNA (mRNA) and protein expression of SRCIN1 in the A431 cells. In addition, ectopic expression of miR-346 promoted the A431 cell proliferation and migration. Meanwhile, SRCIN1 overexpression inhibited the A431 cell proliferation and migration. Rescue experiment has showed that SRCIN1 overexpression reduced the miR-346-induced A431 cell proliferation and migration. Herein, this study may provide miR-346 as a new therapeutic target for cSCC.

Use of lipolanthionine peptide, a toll-like receptor 2 inhibitor, enhances transdermal delivery efficiency.

The transdermal delivery system (TDS) is able to obtain a systemic therapeutic effect by administration through the skin, which has low side effects and is able to maintain a sustained blood concentration. However, due to the barrier presented by the stratum corneum, numerous drugs have poor percutaneous permeability. Therefore, the improvement of skin permeability is key to TDS. The main method of promoting transdermal absorption is through the usage of penetration enhancers. Dimethyl sulfoxide (DMSO) is a commonly used penetration enhancer, which has anti­inflammatory analgesic effects and is able to penetrate the skin. Retinoic acid (RA) and lipolanthionine peptide (LP) may also benefit the permeation efficiency of TDS. Therefore, the present study examined the function of DMSO, RA and LP as penetration enhancers in TDS. Firstly, the optimum concentration of DMSO was confirmed by detecting the expression of the LacZ gene in vitro. Secondly, different combinations of LP, RA and DMSO were applied to mouse skin to analyze the penetration enhancer combination with the greatest efficacy. All the animals were divided into five groups: The RA + LP + DMSO + pORF­LacZ group, the RA + DMSO + pORF­LacZ group, the LP + DMSO + pORF­LacZ group, the DMSO + pORF-LacZ group and the control group. Skin was soaked in combinations of LP, RA and DMSO for seven days and then the pORF­LacZ plasmids were daubed onto the skin once daily three days. On the 11th day, all the animals were sacrificed by cervical dislocation and the skin and blood samples were collected. The blood samples were used to detect the expression of the LacZ gene by quantitative polymerase chain reaction and the skin samples were used to detect the expression of claudin­4 and zonula occluden­1 (ZO­1) proteins by immunohistochemistry and western blot analysis. The results demonstrated that the combination of LP, RA and DMSO exhibited the greatest transdermal delivery efficiency, which verified that RA and LP were able to increase the penetration effects. Following treatment with LP, the symptoms of dermal edema were relieved and the capillaries contracted, which suggested that LP was a safe and effective penetration enhancer able to reduce the side­effects caused by DMSO. The present study provides a guideline for the synthesis of novel penetration enhancers.

Interleukin-22 protects rat PC12 pheochromocytoma cells from serum deprivation-induced cell death.

Interleukin-22 (IL-22), an IL-10 family cytokine, mediates the crosstalk between leukocytes and epithelial cells. Previous studies reported that IL-22 expresses in mouse brain, and the rat PC12 cells are responsive to IL-22 stimulation. However, the biological roles of IL-22 in neuronal cells remain largely unknown. We show here that IL-22 activates Stat3, p38 mitogen-activated protein kinases (MAPK), and Akt pathways and inhibits Erk/MAPK pathway in naïve PC12 cells. We further demonstrate that IL-22 protects naïve PC12 cells from serum starvation-induced cell death via the Jak1/Stat3 and Akt pathways. We also show that IL-22 has no effects on naïve PC12 cell proliferation and cannot protect naïve PC12 cells from 1-methyl-4-phenylpyridinium (MPP(+))-induced cytotoxicity. However, IL-22 exerts a dose-dependent protective effect on MPP(+)-induced neurodegeneration in nerve growth factor-differentiated PC12 cells. Overall, our data suggest that IL-22 might play a role in neurological processes. To our knowledge, this is the first report showing that IL-22 confers a neuroprotective function, which may provide a new therapeutic option for treatment of neurodegenerative diseases.

Participation of Gab1 and Gab2 in IL-22-mediated keratinocyte proliferation, migration, and differentiation.

Interleukin-22 (IL-22) is one of the key mediators of keratinocyte alterations in psoriasis. IL-22 inhibits keratinocyte differentiation and induces the migration of human keratinocytes. Grb2-associated binder 1 (Gab1) has been shown to mediate epidermal growth factor-induced epidermal growth and differentiation via interaction with the Src homology-2-containing protein-tyrosine phosphatase (Shp2). In this investigation, we explore the role of Gab1 and Gab2 in IL-22-mediated keratinocyte activities. We show that both Gab1 and Gab2 were tyrosine phosphorylated in IL-22-stimulated HaCaT cells and human primary epidermal keratinocytes and contributed to the activation of Extracellular signal regulated kinase 1/2 (Erk1/2) through interaction with Shp2. We further demonstrate that HaCaT cells infected with adenoviruses expressing Shp2-binding-defective Gab1/2 mutants exhibited decreased cell proliferation and migration, as well as increased differentiation. Moreover, similar results were observed in HaCaT cells infected with adenovirus-based small interfering RNAs targeting Gab1 and/or Gab2. Altogether, these data underscore the critical roles of Gab1 and Gab2 in IL-22-mediated HaCaT cell proliferation, migration, and differentiation.

Tyrosines 303/343/353 within the Sprouty-related domain of Spred2 are essential for its interaction with p85 and inhibitory effect on Ras/ERK activation.

Sprouty-related EVH1 domain (Spred) proteins modulate growth factor receptor signaling by inhibiting the Ras/ERK pathway. In particular, the Sprouty-related domain (SPR) of Spred2 is essential for the Spred2-mediated inhibitory effect, but the molecular mechanism is largely unknown. We show here that the p85 subunit of phosphatidylinositol 3-kinase (PI3K) is a new binding partner of Spred2 via interaction with the SPR domain. Mutation of three tyrosines 303/343/353 within the SPR domain not only abolish EGF-induced p85 binding to Spred2 but also attenuate the inhibitory effect on Ras/ERK activation by Spred2. This results in increased Hela cell proliferation and neurite outgrowth in PC12 cells. We further demonstrate that p85 binding to Spred2 enhances the Spred2-mediated inhibitory effect via increased Ras binding to Spred2 and decreased Spred2 ubiquitination. We also show that Spred2 constitutively associates with epidermal growth factor receptor (EGFR) via its SPR domain and dissociates from EGFR upon EGF stimulation. Moreover, mutation of tyrosines 303/343/353 together enhances Spred2 binding to EGFR. Taken together, these results suggest critical roles of the three tyrosines 303/343/353 within the SPR domain in regulating Spred2 signaling and provide a mechanism for the SPR domain of Spred2 to mediate the inhibitory effect on the Ras/ERK pathway.