Immunotherapy has revolutionized the landscape of cancer treatment. However, single immunotherapy only works well in a small subset of patients. Combined immunotherapy with antitumor synergism holds considerable potential to boost the therapeutic outcome. Nevertheless, the synergistic, additive or antagonistic antitumor effects of combined immunotherapies have been rarely explored. Herein, we established a novel combined cancer treatment modality by synergizing p21-activated kinase 4 (PAK4) silencing with immunogenic phototherapy in engineered extracellular vesicles (EVs) that were fabricated by coating M1 macrophage-derived EVs on the surface of the nano-complex cores assembled with siRNA against PAK4 and a photoactivatable polyethyleneimine. The engineered EVs induced potent PAK4 silencing and robust immunogenic phototherapy, thus contributing to effective antitumor effects in vitro and in vivo. Moreover, the antitumor synergism of the combined treatment was quantitatively determined by the CompuSyn method. The combination index (CI) and isobologram results confirmed that there was an antitumor synergism for the combined treatment. Furthermore, the dose reduction index (DRI) showed favorable dose reduction, revealing lower toxicity and higher biocompatibility of the engineered EVs. Collectively, the study presents a synergistically potentiated cancer treatment modality by combining PAK4 silencing with immunogenic phototherapy in engineered EVs, which is promising for boosting the therapeutic outcome of cancer immunotherapy.

Objective:To quantitatively evaluate the energy loss (EL) and vortex characteristics in the left ventricle by vector flow mapping (VFM) technique in heart failure patients with mid-range ejection fraction (HFmrEF) and reduced ejection fraction (HFrEF).Methods:One hundred and five patients in Qilu Hospital of Shandong University from October 2016 to November 2017 with heart failure and left ventricular ejection fraction (LVEF)<50% were enrolled and divided into HFmrEF Group (LVEF40%~<50%, 56 cases) and HFrEF group (LVEF<40%, 49 cases). Another 32 healthy people at the same period were matched as control group. The EL, vortex area and circulation of isovolumic relaxation phase (IVR), rapid filling phase (RFP), atrial contraction phase (ACP), isovolumic contraction phase (IVC) and rapid ejection phase (REP) in the left ventricle was measured by VFM technique.Results:The EL in HFmrEF group and HFrEF group was lower than that in the control group. In ACP, the EL was gradually decreased among the control group, HFmrEF group and HFrEF group( P<0.05). In ACP, the vortex area and circulation was larger in heart failure patients than those in the control group, and gradually increased from control group, to HFrEF group( P<0.05). Positive correlation between EL and E/e ′ was evidenced in the RFP ( r=0.524, P< 0.001). While in ACP, there was a positive correlation between EL and A peak ( r=0.492, P<0.001), and a negative correlation between EL and vortex area ( r=-0.235, P=0.040). Conclusions:VFM can be applied to evaluate the EL in left ventricle. The EL in the left ventricle of patients with HFmrEF and HFrEF is significantly lower than that in control group. El is correlated with cardiac systolic and diastolic function and vortex area.

Objective To investigate the value of the reverse shock index multiplied by GlasgowComa scale score (rSIG) and serum translocator protein 18000 in the prognosis of patients with severe traumatic brain injury. Methods One hundred and fifteen patients with severe traumatic brain injury were divided into the survival group and death group. SPSS 20.0 software was used to compare the vital signs, rSIG and TSPO between the two groups, and the relationship between rSIG and TSPO was analyzed. Receiver operating characteristic (ROC) curve was used to predict the value of rSIG and TSPO and their combination in the prognosis of patients with severe traumatic brain injury. According to the best cut-off value of rSIG and TSPO of ROC curve, patients were divided into the rSIG ≤ 14.8 group and rSIG>14.8 group, and the TSPO ≤ 1.84 ng/mL group and TSPO>1.84 ng/mL group, and the mortality between the groups was compared. Results In 115 patients, rSIG of the survival group was significantly higher than that of the death group, and TSPO was significantly lower than that of the death group [(10.5±4.4) vs. (6.4±4.1), 1.0(0.3,1.9) ng/mL vs.3.4 (2.0, 4.6) ng/mL, P<0.01]. The ability of rSIG combined with TSPO to forecast the mortality of patients with severe traumatic brain injury is not superior to the predictive power of these two indicators alone. The serum TSPO value and 28-day mortality in the rSIG > 4.15 group were significantly higher than those in the rSIG ≤ 4.15 group. The rSIG value of the TSPO ≤ 1.84 ng/mL group was significantly higher than that of the TSPO>1.84 ng/mL group; the 28-day mortality was significantly lower than that in the TSPO>1.84 ng/mL group. The rSIG value was negatively correlated with serum TSPO value (r=-0.611, P<0.01). Conclusions rSIG value and serum TSPO value have good predictive value for the prognosis of patients with severe traumatic brain injury, and can provide certain guiding significance in clinical practice.

Objective: To explore the clinical application value of enhanced recovery after surgery (ERAS) in the laparoscopic surgery for cholecystolithiasis comorbid with choledocholithiasis. Methods: The prospective study was conducted. The clinicopathological data of 52 patients with cholecystolithiasis comorbid with choledocholithiasis who were admitted to the Third Affiliated Hospital of Zunyi Medical University from September 2016 to September 2018 were collected. Patients were divided into 2 groups by random number table: patients in observation group received laparoscopic cholecystectomy + choledocholithotomy + choledochoscopic exploration + T-tube drainage (or primary suture of common bile duct) and perioperative management guided by the concept of enhanced recovery after surgery (ERAS), and patients in control group received traditional perioperative management. Observation indicators: (1) surgical situations; (2) postoperative situations; (3) postoperative complications; (4) postoperative pain scores; (5) changes in hepatic function and blood routine during perioperative period. Follow-up using outpatient examination and telephone interview was performed to detect complications during the postoperative 6 months up to March 2019. Measurement data with normal distribution were represented as Mean±SD, and comparison between groups was analyzed using the paired t test or repeated ANOVA. Count data were described as absolute numbers and percentages, and comparison between groups was analyzed using the chi-square test or Fisher exact probability. Results: Fifty-two patients were screened for eligibility, including 20 males and 32 females, aged 25-68 years, with an average age of 53 years. There were 30 patients in the observation group and 22 in the control group. (1) Surgical situations: the operation time and volume of intraoperative blood loss were (133±19)minutes and (47±21)mL in the observation group, and (136±22)minutes and (49±23)mL in the control group, respectively, showing no significant difference between the two groups (t=-0.386, -0.211, P>0.05). (2) Postoperative situations: time to out-of-bed activity, time to initial food intake, time to first anal flatus, duration of postoperative hospital stay, and hospital expenses were (18±4)hours, (19±5)hours, (28±2)hours, (4.0±1.0)days, and (1.82±0.22)×10⁴ yuan in the observation group, and (29±7)hours, (46±9)hours, (37±4)hours, (6.6±1.6)days, and (2.25±0.29)×10⁴ yuan in the control group, respectively, showing significant differences between the two groups (t=-7.054, -14.169, -9.426, -6.582, -5.809, P<0.05). (3) Postoperative complications: 1 of 30 patients in the observation group had postoperative biliary leakage, with a postoperative complication rate of 3.3%, and was cured after symptomatic support treatment. Six of 22 patients in the control group had postoperative complication, with a postoperative complication rate of 27.3%, including 2 of biliary leakage, 1 of hemorrhage, 1 of abdominal infection, 1 of pulmonary infection, 1 of urinary infection, and they were cured after symptomatic support treatment. There was a significant difference between the two groups (χ²=4.358, P<0.05). (4) Postoperative pain scores: from postoperative 6 hours to 48 hours, the postoperative pain score changed from 2.4±0.7 to 1.9±0.9 in the observation group, and from 4.1±0.7 to 2.9±0.9 in the control group, respectively, showing a significant difference in the changing trend between the two groups (F=78.053, P<0.05). (5) Changes in hepatic function and blood routine during perioperative period: from preoperation to postoperative 3 days, levels of alamine aminotransferase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT), total bilirubin (TBil), and count of white blood cells in the observation group changed from (77±20)U/L to (53±12)U/L, from (85±22)U/L to (61±17)U/L, from (166±39)U/L to (55±24)U/L, from (40±13)μmol/L to (29±12)μmol/L, from (7.0±2.0)×10⁹/L to (6.8±1.9)×10⁹/L, and changed from (79±23)U/L to (62±14)U/L, from (88±24)U/L to (64±17)U/L, from (179±34)U/L to (74±29)U/L, from (45±13)μmol/L to (35±12)μmol/L, from (7.9±2.4)×10⁹/L to (7.5±1.9)×10⁹/L in the control group, respectively. The levels of ALT, AST, GGT, TBiL, and count of WBC showed increasing at postoperative 1 day, and decreasing at postoperative 3 days. There was no significant difference in the changing trend between the two groups (F=0.058, 0.471, 3.021, 1.593, 2.172, P>0.05). Conclusion ERAS is safe and effective in the laparoscopic surgery for choledocholithiasis comorbid with cholecystolithiasis.

The article entitled "Differential expression of exosomal miRNAs in osteoblasts in osteoarthritis" published on Journal of Central South University (Medical Science), in Volume 43, Issue 12, 2018 (DOI: 10.11817/j.issn.1672-7347.2018.12.003) may have an unclear risk of bias due to insufficient understanding for some results. Further experimental studies are needed. We all agree to retract this article, and apologize to the Journal and readers for the possible negative impact.

Objective To investigate the value of high resolution CT (HRCT) in displaying the anatomic relationship between labyrinth segment of facial canal and cochlea.Methods Totally 110 patients (220 ears) who underwent HRCT were collected.The original images were transferred to workstation for image processing.MPR images were acquired.The anatomic relationship between labyrinth segment of facial canal and cochlea was observed in oblique coronal MPR images.The bony septum between labyrinth segment of facial canal and cochlea was assessed as definite defect (Type Ⅰ),doubtful defect (Type Ⅱ) or complete (Type Ⅲ),respectively.Results There were 71 ears (71/220,32.27％) of Type Ⅰ,diameters of bone fissure ranged from 0.3-1.3 mm (average diameters [0.64±0.26]mm),86 ears (86/220,39.09％) of Type Ⅱ and 63 ears (63/220,28.64％) of Type Ⅲ,with bony septum thickness ranged from 0.3-1.0 mm (average thickness [0.68±0.15]mm).No statistical difference of rates of the above three types was found between different genders,among age groups and between both side of ears (all P＞0.05).Conclusion HRCT is a reliable method to show the anatomic relationship between labyrinth segment of facial canal and cochlea.

To analyze the differentially expressed exosomal miRNAs in subchondral osteoblasts in patients with osteoarthritis (OA) and to investigate the key miRNAs potentially involved in the occurrence and progression of OA.
 Methods: Subchondral bones were harvested from 6 patients with OA. All subjects were divided into two groups which was based on the severity of joint wear: An OA group, severely worn side of subchondral bone, and a control group, less worn side of subchondral bone. The exosomes were extracted from osteoblast cells and their characteristics were identified. Then exosomal miRNAs were extracted and sequencing analysis was conducted to compare the expression in the two groups. The most differentially expressed ones (log2Ratio≥2) were subject to miRNA target prediction and quantitative reverse transcription PCR (RT-qPCR) to further quantify the difference.
 Results: Osteoblast extractions were confirmed to be exosomes, which were small double-membranous vesicles with 30-200 nm in diameter and 50-150 nm in peak value of particle size under the scanning microscope. High-throughput sequencing revealed 124 miRNAs whose expression significantly increased in the OA group. The most differentially expressed one with maximum fold change was hsa-miR-4717-5p and its target gene was RGS2. RT-qPCR demonstrated hsa-miR-4717-5p expression in the OA group was relatively higher than that in the control group (2.243 vs 0.480, P<0.01).
 Conclusion: There is distinct difference in expression profiles of exosomal miRNAs in subchondral osteoblasts between patients with OA and normal subjects. Up-regulated expression of miRANs might participate in OA occurrance and progression.
Bone and Bones ; Exosomes ; genetics ; pathology ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; MicroRNAs ; genetics ; Osteoarthritis ; physiopathology ; Osteoblasts ; pathology

Objective To assess the relationship between plaque burden (PB) and area strain (AS) by intravascular ultrasonic elastography (IVUSE).Methods Forty purebred New Zealand rabbits were fed with a high-cholesterol diet.And the abdominal aorta endothelium was balloon-injured after 2 weeks.At the end of the 12th week,2 plaques with moderate echo from each rabbit were chosen for in situ imaging,and 2 consecutive frames near the end-diastole images in situ were used to construct an IVUS elastogram.Cross-sectional external elastic membrane area (EEMare),lumen area (Lumenarea),plaque area (PA),PB,external elastic membrane volume (EEMvolume),lumen volume (Lumenvolume),plaque volume (PV),plaque volume burden (PVB),maximal plaque thickness (Tmax) and minimal plaque thickness (Tmin),eccentric index (EI),remodeling index (RI) and AS were measured and calculated,respectively.According to the PB,the plaques were divided into low PB group (PB≤40 ％) and high PB group (PB＞ 40 ％).The differences of all above parameters between the two groups were compared,and the relationship between the plaque morphological and mechanical parameters were analyzed.Results PA,PV,PB,PVB,Tmin,Tmax,Lumenarea,Lumenvolume and EI were different between the 2 groups (all P＜0.01).On stepwise multiple regression analysis,the regression equation were built,(Y)=-6.921+10.430X1 +12.207X2((Y):AS,X1:EI,X2:PB,R2 =0.272,P＜0.001).After eliminating the effect of EI on the AS,the lower PB group had obviously smaller AS than higher PB group (P =0.010).Conclusion The PB has effect on plaque mechanical stability.The plaques with higher burden are more vulnerable than those with lower burden.

Objective To assess the relationships between area strain (AS) and eccentric index (EI) of atherosclerotic plaques as seen by intravascular ultrasonic elastography (IVUSE),and to reveal the effect of EI on the plaques stability.Methods Forty purebred New Zealand rabbits were fed with a high-cholesterol diet;the abdominal aorta endothelium was balloon-injured after 2 weeks;at the end of week 12,2 plaques with moderate echo from each rabbit were chosen for in situ imaging,and 2 consecutive frames near the end-diastole images in situ were used to construct an IVUS elastogram.Results The eccentric plaques showed significantly greater area stain (AS) than the centripetal plaques [4.77(2.92,8.01)% vs 3.27(2.15,4.82)%,P=0.029] with smaller plaque area and plaque burden (P<0.05).The plaque AS was positively correlated with EI (r=0.392,P=0.003).The eccentric plaques showed significantly greater AS in the shoulder than in body [4.98(3.17,8.48)% vs 4.64(2.51,5.92)%,P=0.008].Conclusions The EI is one of influential factors on plaque AS.Eccentric plaques may be more vulnerable than centripetal plaques,especially in the shoulder of eccentric plaques which have greater AS than their body.

Objective    To explore the factors of postoperative cough in lung cancer patients. Methods    Totally 130 lung cancer patients of single medical team (average age of 58.75±9.34 years, 65 males and 65 females), from February 2016 to February 2017 in the Department of Thoracic Surgery of West China Hospital of Sichuan University, were investigated by Mandarin Chinese version of the Leicester Cough Questionnaire (LCQ-MC). We analyzed and calculated the preoperative and postoperative scores of LCQ-MC, Cronbach α and the influencing factor. Results    The preoperative score of LCQ-MC's physiological dimension was significantly lower in the postoperative cough group (6.30±0.76) than that of the postoperative non-cough group (6.56±0.60, P=0.044), while the preoperative total score of LCQ-MC (19.53±1.78, 20.03±1.45) was not statistically different (P=0.080). The postoperative score of LCQ-MC was significantly lower in the postoperative cough group (17.32±2.79) than that of the postoperative non-cough group (19.70±1.39, P<0.001). And the scores of physiological, psychological and social dimension were significantly lower in the postoperative cough group (5.32 ±1.14, 5.73±1.14, 6.23±0.89) than those of the postoperative non-cough group (6.25±0.63, 6.67±0.54, 6.78±0.49) (P values were all less than 0.001). The result of multi-factor logistic regression analysis showed the condition of preoperative cough symptom (OR=0.354, 95%CI=0.126–0.994, P=0.049) and anesthesia time (OR=1.021, 95%CI=1.003–1.040, P=0.021) were the risk factors. Conclusion    The risk factors of postoperative cough symptoms in lung cancer patients are the condition of preoperative cough symptoms and anesthesia time.