Microscopic Electric Rotary Grinding of Plaques Combined with Graft Repair in the Management of Peyronie's Disease.

Peyronie's Disease (PD) is clinically characterized by the development of localized fibrous plaques, primarily on the tunica albuginea, especially on the dorsal area of the penis. These plaques are the hallmark feature of this condition, resulting in penile curvature, deformity, and painful erections for affected individuals. Although various nonsurgical treatment options exist, their overall effectiveness is limited. As a result, surgical intervention has become the ultimate choice for patients with severe penile curvature deformities and associated erectile dysfunction. Our research team has successfully employed a combined approach involving microscopic electric rotary grinding of the fibrous plaques and the use of tunica vaginalis or bovine pericardium as graft materials for the repairing of the defects of tunica albuginea in the treatment of PD. This approach has consistently yielded highly satisfactory results regarding the restoration of penile shape, with excellent cosmetic results and significantly improved sexual satisfaction. This protocol aims to present a comprehensive surgical management strategy utilizing electric rotary grinding of the plaques and repairing the defects of tunica albuginea by using the tunica vaginalis, which represents an optimal surgical strategy for treating PD.

Antibody responses following the surge of SARS-CoV-2 Omicron infection among patients with systemic autoimmune rheumatic diseases.

Objectives: The surge of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant Omicron infections has affected most Chinese residents at the end of 2022, including a number of patients with systemic autoimmune rheumatic diseases (SARDs). Methods: To investigate the antibody level of the Omicron variant in SARD patients after SARS-CoV-2 Omicron infection, we tested BA.5.2 and BF.7 Omicron variant IgG antibody levels using ELISA on blood samples collected from 102 SARD patients and 19 healthy controls (HCs). The type of SARD, demographics, concurrent treatment, doses of SARS-CoV-2 vaccines and outcomes were also recorded. Results: A total of 102 SARD patients (mean age: 40.3 years; 89.2% female), including 60 SLE, 32 RA and 10 other SARDs, were identified. Of these, 87 (85.3%) were infected with SARS-CoV-2. We found that the BA.5.2 and BF.7 antibody levels of infected SARD patients were lower than those of HCs (P < 0.05). Sixty-five (63.7%) patients had at least one dose of a SARS-CoV-2 vaccine. SARD patients with at least two doses of SARS-CoV-2 vaccine had a higher level of BA.5.2 and BF.7 antibodies than the unvaccinated group (P < 0.05). There was no evidence for a significant inhibitory effect of glucocorticoids (GCs) on the BA.5.2 and BF.7 Omicron variant antibody levels in SARD patients. SLE patients using biologic DMARDs had a lower BA.5.2 Omicron variant antibody level than patients using GCs and/or HCQ. Conclusion: These data suggest that patients with SARDs had a lower antibody response than HCs after Omicron infection.

Postoperative Pneumonia in Geriatric Patients With a Hip Fracture: Incidence, Risk Factors and a Predictive Nomogram.

Objectives: To evaluate the incidence and risk factors of postoperative pneumonia (POP) in geriatric patients with a hip fracture after surgery, to design a predictive nomogram, and to validate the accuracy of the nomogram. Design: Retrospective study. Setting: A tertiary hospital affiliated to a medical university. Patients/Participants: We retrospectively studied 1285 surgical-treated geriatric patients with a hip fracture from April 2010 to April 2018. Intervention: Surgical treatment was performed on the patients of this study. The procedure methods were classified as: total hip arthroplasty, hemiarthroplasty, percutaneous fixation, intramedullary nail fixation, and plate/screw fixation. Main Outcome Measurement: The primary interest of end point of this study is the development of POP during the postoperative period. The postoperative period in this study was defined as the time from 24 hours after surgery to discharge. The diagnostic criteria for pneumonia were set according to the guidelines built by the Infectious Diseases Society of America and the American Thoracic Society (Guidelines for the Management of Adults with Hospital-Acquired, Ventilator-Associated, and Healthcare-Associated Pneumonia, 2005). Potential variables for developing POP were identified using logistic regression analyses initially and were further selected via the method of LASSO. Then the independent risk factors were identified by multivariable regression analyses. A predictive nomogram was built based on the multiple regression model, and the calibration abilities of the nomogram was measured by Harrel C-index, calibration plot and Hosmer-Lemeshow test, respectively. Decision curve analysis was carried out to assess the net benefit due to threshold probability and an on-line questionnaire survey was conducted among the clinicians to assess the applicability of the nomogram coherently. Results: Of the 1285 patients, 70 (5.4%) developed POP. COPD, number of comorbidities, ASA classification >2, preoperative dependent functional status and cognitive impairment were identified as independent risk factors of POP. The nomogram built based on the results showed good accordance between the predicted probabilities and the observed frequency. The decision curve analysis confirmed the clinical utility of the nomogram when the threshold probabilities were between 5% and 65% due to the net benefit, while the results of on-line questionnaire among 200 clinicians showed that 91.5% of the participants had a mental threshold of intervention between 5-50%. Conclusion: (1). COPD, number of comorbidities, ASA classification >2, preoperative dependent functional status and cognitive impairment are independent risk factors for POP. (2). The nomogram built in this study has a good accordance between the predictive risk and the observational incidence. The results of decision curve and questionnaire among clinicians show well applicability of the nomogram.

[The molecular mechanism of apical hook development in dicot plant].

After the seeds of the dicot model plant Arabidopsis germinate in the soil, the tip of the hypocotyl will form a specialized structure called apical hooks to protect the cotyledons and shoot apical meristems from the mechanical damage during the soil emerging process. The development process of the apical hook is divided into three stages: the apical hook formation, maintenance, and opening. In recent decades, studies have shown that different kinds of plant hormones and environmental signals play a vital role in the development of the apical hook. As the downstream of a variety of signals, the asymmetric distribution of auxin and the signal transduction pathways play a decisive role in the development of the apical hook. However, the detailed mechanism of the asymmetric signal transduction pathway of the cells on both sides of the apical hook is still unclear. In this review, we summarize the molecular mechanisms of the development of apical hook and further refine the role of auxin in the development of apical hook, and prospect for future research directions in this field.

[Evaluation of land ecosystem health in Shaanxi Province, Northwest China based on PSR Model.] / 基于PSR模型的陕西省土地生态系统健康评价.

Based on the pressure-state-response (PSR) model and entropy method, we analyzed the health status of land ecosystem and the temporal and spatial variations from 2009 to 2017 in ten cities and one district in Shaanxi Province. The driving factors affecting the health of the land ecosystem was examined. Results showed that during 2009-2017, the overall health of the land ecosystem in Shaanxi Province was improved, which was lower during 2009-2014 and being obviously improved after 2014. The health level of land ecosystems in Xi'an, Baoji, Weinan and Hanzhong was high and with substantial variation, while that in Yan'an, Yulin, and Ankang was low and stable, decreasing in order of South Shaanxi, Guanzhong region and North Shaanxi. Overall, the pressure, state and response indices of the land ecosystem in Shaanxi Province increased during 2014-2017 with a gentle growth, which were basically flat after 2014. Those results indicated that the land ecosystem in Shaanxi Province was at a stable and healthy state. Population growth, urbanization level, fertilizer load per unit of arable land, forest coverage rate, industrial wastewater discharge compliance rate and comprehensive utilization rate of industrial solid waste were the main driving factors for the health of land ecosystems in Shaanxi. Controlling the use of fertilizers and pesticides, optimizing the structure of land use and improving land use efficiency are necessary strategies to promote the construction of ecological civilization and implement the red line of ecological protection for Shaanxi Province.

Risk factors for and predictive nomogram of postoperative hypoxaemia in elderly patients with femoral neck fractures.

OBJECTIVE: To investigate the related risk factors and predictive nomogram of postoperative hypoxaemia in elderly patients with femoral neck fractures. METHODS: This study included patients aged ≥65 years who underwent surgical treatment of acute femoral neck fractures. Univariate and multivariate logistic analyses were performed to determine the incidence of and risk factors for postoperative hypoxaemia. A predictive nomogram was constructed based on the multivariable model. Using the bootstrap method, discrimination was determined by the C-index and calibration plot. RESULTS: The logistic regression analysis showed that the anaesthesia type, surgical procedure, American Society of Anesthesiologists (ASA) classification, preoperative hypoxaemia occurrence, and age were independent predictors of development of postoperative hypoxaemia. The predictive formula for hypoxaemia was established as follows: hypoxaemia=-0.8668×spinal anaesthesia (whether)+0.1162×nerve anaesthesia (whether)+1.9555×plate/screw fixation (whether)+1.4950×hip replacement (whether)+0.4883×ASA classification+1.7153×preoperative oxygenation index+0.1608×age. With the bootstrap method, the prediction curve fit well with the ideal curve, suggesting that the prediction curve constructed in this study has good predictive ability. CONCLUSIONS: Anaesthesia type, surgical procedure, ASA classification, preoperative hypoxaemia occurrence, and age were risk factors for postoperative hypoxaemia in elderly patients with femoral neck fractures. The predictive nomogram was designed for preoperative assessment of the risk of postoperative hypoxaemia by calculating the risk score.

Characterization of B cell-mediated PD-1/PD-L1 interaction in pancreatic cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) is a common type of pancreatic cancer with one of the worst survival rate of all malignancies. Recent studies have identified that immunosuppressive B cells could employ the PD-1/PD-L1 pathway to suppress antitumour T cell responses; hence, we examined the expression and function of PD-L1 in B cells. We found that the PD-L1 expression was significantly enriched in tumour-infiltrating (TI) B cells than in peripheral blood (PB) B cells from the same patients. Additionally, the PB B cells from stage III and stage IV PDAC patients presented significantly higher PD-L1 than the PB B cells from healthy controls. High PD-L1 expression in PB B cells could be achieved by stimulation via CpG and less effectively via anti-BCR plus CD40L, but not by coculture with pancreatic cancer cell lines in vitro. Also, STAT1 and STAT3 inhibition significantly suppressed PD-L1 upregulation in stimulated B cells. CpG-stimulated PB B cells could inhibit the IFN-γ expression and proliferation of CD8 T cells in a PD-L1-dependent manner. Also, TI CD8 T cells incubated with whole TI B cells presented significantly lower IFN-γ expression and lower proliferation, than TI CD8 T cells incubated with PD-L1+  cell-depleted TI B cells, suggesting that PD-L1+  B cells could also suppress CD8 T cells in the tumour. Overall, this study identified that B cells could suppress CD8 T cells via PD-L1 expression, indicating a novel pathway of immuno-regulation in pancreatic cancer.

A Near-Infrared Peptide Probe with Tumor-Specific Excretion-Retarded Effect for Image-Guided Surgery of Renal Cell Carcinoma.

Image-guided surgery plays a crucial role in realizing complete tumor removal, reducing postoperative recurrence and increasing patient survival. However, imaging of tumor lesion in the typical metabolic organs, e.g., kidney and liver, still has great challenges due to the intrinsic nonspecific accumulation of imaging probes in those organs. Herein, we report an in situ self-assembled near-infrared (NIR) peptide probe with tumor-specific excretion-retarded (TER) effect in tumor lesions, enabling high-performance imaging of human renal cell carcinoma (RCC) and achieving complete tumor removal, ultimately reducing postoperative recurrence. The NIR peptide probe first specifically recognizes αvß3 integrin overexpressed in renal cancer cells, then is cleaved by MMP-2/9, which is up-regulated in the tumor microenvironment. The probe residue spontaneously self-assembles into nanofibers that exhibit an excretion-retarded effect in the kidney, which contributes to a high signal-to-noise (S/N) ratio in orthotopic RCC mice. Intriguingly, the TER effect also enables precisely identifying eye-invisible tiny lesions (<1 mm), which contributes to complete tumor removal and significantly reduces the postoperative recurrence compared with traditional surgery. Finally, the TER strategy is successfully employed in high-performance identification of human RCC in an ex vivo kidney perfusion model. Taken together, this NIR peptide probe based on the TER strategy is a promising method for detecting tumors in metabolic organs in diverse biomedical applications.

The critical role of ASD-related gene CNTNAP3 in regulating synaptic development and social behavior in mice.

Accumulated genetic evidences indicate that the contactin associated protein-like (CNTNAP) family is implicated in autism spectrum disorders (ASD). In this study, we identified genetic mutations in the CNTNAP3 gene from Chinese Han ASD cohorts and Simons Simplex Collections. We found that CNTNAP3 interacted with synaptic adhesion proteins Neuroligin1 and Neuroligin2, as well as scaffolding proteins PSD95 and Gephyrin. Significantly, we found that CNTNAP3 played an opposite role in controlling the development of excitatory and inhibitory synapses in vitro and in vivo, in which ASD mutants exhibited loss-of-function effects. In this study, we showed that the male Cntnap3-null mice exhibited deficits in social interaction， spatial learning and prominent repetitive behaviors. These evidences elucidate the pivotal role of CNTNAP3 in synapse development and social behaviors, providing mechanistic insights into ASD.

Predictive nomogram for postoperative delirium in elderly patients with a hip fracture.

To evaluate the risk factors for the development of postoperative delirium and design a predictive nomogram for the prevention of delirium in elderly patients with a hip fracture, we retrospectively studied 825 patients who sustained a femoral neck fracture from January 2005 to December 2015. Independent risk factors for developing delirium within 6 months of surgery were identified using multivariable logistic regression analyses. A predictive nomogram model was built based on the results, and the discrimination and calibration were determined by C-index and calibration plot. Of the 825 patients who met inclusion criteria, 118 (14.3%) developed postoperative delirium. According to the results, preoperative cognitive impairment (OR, 4.132, 95% CI, 1.831 to 9.324, P＜0.001), multiple medical comorbidities (OR, 1.452, 95% CI, 0.958-2.202, P = 0.079), ASA classification (OR, 1.655, 95% CI, 1.073-2.553, P = 0.023), transfusion exceeding 2 units of red blood cell (OR, 1.599, 95% CI, 1.043-2.451, P = 0.035), and intensive care (OR, 1.817, 95% CI, 1.127-2.930, P = 0.014) were identified to be the independent predictors of the development of postoperative delirium. The risk of postoperative delirium increased with the increasing risk score of predictive nomogram, and the C-index was 0.67 (0.62 - 0.72). The calibration showed that the predicted probabilities of delirium in the predictive nomogram were close to the observed frequency of delirium, and the decision curve analysis confirmed the clinical utility of the nomogram when the threshold probabilities were between 8% and 35% due to the net benefit.

A new less invasive surgical technique in the management of acute Achilles tendon rupture through limited-open procedure combined with a single-anchor and "circuit" suture technique.

BACKGROUND: Traditional incision repair and minimally invasive repair for acute Achilles tendon repair have limitations. This study aimed to present our series of 23 patients with acute Achilles tendon rupture that was repaired using two small incisions to assist the anchor repair of the tear and a new "circuit" suture technique. METHODS: This was a retrospective study of 23 patients with acute Achilles tendon rupture treated with the new technique at Changhai Hospital between January 2015 and December 2016 and followed up for 14-33 months. Clinical outcome was assessed using the AOFAS, Leppilahti, and Arner-Lindholm scores. Complications, range of motion (ROM), and time to return to work and light sport activity were assessed. RESULTS: The AOFAS score was 85-96 at 3 months and 92-100 at 12 months. The 3-month ROM was 27°-37°, and the 12-month ROM was 36°-48°. The Leppilahti score was 85-95 at 3 months and 90-100 at 12 months. The recovery time of the patients was 10-18 weeks. The postoperative recovery time to exercise was 16-24 weeks. There was only one case of deep venous thrombosis. According to the Arner-Lindholm assessment criteria, patient outcomes were rated as excellent in 20 (87.0%) cases, good in three (13.0%) cases, and poor in 0 cases. The excellent-to-good rate was 100%. CONCLUSION: The limited-open procedure combined with a single-anchor and "circuit" suture technique could be used to repair torn Achilles sites, with a low occurrence of complications. This new and minimally invasive technique could be an alternative in the management of acute Achilles tendon rupture.

[Manipulative reduction and plaster external fixation for the treatment of the scaphoid fracture and perilunate dislocation].

OBJECTIVE: To investigate the efficacy and complications of manual reduction and external fixation for the treatment of scaphoid fractures and perilunate dislocations. METHODS: From January 2009 to January 2013, 43 patients suffered from scaphoid fractures and perilunate dislocations were retrospective analyzed. Among them, 17 cases were treated with manipulative reduction and plaster external fixation as conservation group including 10 males and 7 females, the other 26 cases were treated with application of surgical as operation group including 15 males and 11 females. The clinical effects were assessed by Cooney function score, radiological analysis and observation of complications. RESULTS: All patients were followed up for(45.00±8.72) months ranging from 36 to 60 months. At the final follow-up, the Cooney score of wrist function was 88.53±4.24 in conservation group and 89.58±4.59in operation group(t=0.455, P>0.05). During the follow-up, 4 patients were found scaphoid avascular necrosis in the imaging performance in the conservation group(χ²=4.32, P<0.05). The difference of other complications between two groups was not statistically significant(P>0.05). CONCLUSIONS: For patients suffered from the scaphoid fractures and perilunate dislocation, the early manipulative reduction and plaster external fixation after injury as soon as possible is necessary. Maintaining a satisfactory reduction and reliable fixation at the same time can lead to good treatment effect and there's no weakness compared to surgical treatment. But there was an increase in danger of complications. The key of conservative treatment lies in early diagnosis and maintenance of reduction, reliable fixation, and timely and appropriate functional exercise.

Performance evaluation of detecting circulating tumor cells and tumor cells in bronchoalveolar lavage fluid in diagnosis of peripheral lung cancer.

BACKGROUND: To evaluate the diagnostic performances of detecting circulating tumor cells (CTCs) and tumor cells in bronchoalveolar lavage fluid (BALF) for peripheral lung cancer. METHODS: A total of 247 patients with lung cancer and 70 cases with benign lung disease were recruited in this study. Peripheral blood and BALF samples were collected, in which the tumor cells were enriched by negative immunomagnetic selection and detected by fluorescence in situ hybridization (FISH) of chromosome enumeration probe 8 (CEP8). The levels of tumor-associated markers (e.g., CEA, CA125, and NSE) in peripheral blood plasma were measured by using electrochemiluminescence. RESULTS: The numbers of CTCs detected in peripheral blood were significantly higher in patients with lung cancer than those with benign lung disease (5.78±0.57 vs. 1.13±0.39, Z=-8.64, P<0.01). Similarly, tumor cells count in BALF of malignancy were higher than that of benign lesions (6.76±0.89 vs. 0.89±0.23, Z=-6.254, P<0.01). However, as for patients with lung cancer and benign lung disease, the numbers of tumor cells in peripheral blood were comparable with those in BALF (both P>0.05). Detecting CTCs and tumor cells in BALF had similar areas under curves (AUC =0.871 and 0.963, respectively; P>0.05) in discriminating benign lesions from lung cancer (sensitivity 83.8% and 92.6%, specificity 86.5% and 99.9%, respectively), both of which were larger than those of NSE, CEA, and CA125 (AUC =0.564, 0.512 and 0.554, respectively; all P<0.05). The diagnostic performances of discriminating benign lesions and lung cancer in BALF and peripheral blood were both in concordance with that of histopathology (kappa values 0.662 and 0.569, respectively; both P<0.001). CONCLUSIONS: Detecting tumor cells in peripheral blood and BALF may sensitive to identify benign and malignant peripheral lung lesions and be of value for early diagnosis of lung cancer.

miR-422a inhibits osteosarcoma proliferation by targeting BCL2L2 and KRAS.

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. However, the underlying mechanism of osteosarcoma carcinogenesis and progression remains unknown. In the present study, we evaluated the expression profile of miRNAs in osteosarcoma tissues and the adjacent normal tissues. We found that the expression of miR-422a was down-regulated in osteosarcoma tissues and cell lines. In addition, we observed significantly elevated levels of repressive H3K9me3 and H3K27me3 and decreased active H3K4me3 on the promote region of miR-422a in osteosarcoma cells and clinical samples. Furthermore, up-regulation of miR-422a exhibited both in vitro and in vivo anti-tumor effects by inhibiting osteosarcoma cell growth and inducing apoptosis and cell cycle arrest. We also found that miR-422a targeted BCL2L2 and KRAS and negatively regulated their protein expression. Furthermore, restoration of miR-422a and knockdown of BCL2L2 and KRAS promoted apoptosis and induce cell cycle arrest in osteosarcoma cells. Taken together, the present study demonstrates that miR-422a may serve as a tumor suppressor in osteosarcoma via inhibiting BCL2L2 and KRAS translation both in vitro and in vivo Therefore, miR-422a could be developed as a novel therapeutic target in osteosarcoma.

In Vivo Biocompatibility and Improved Compression Strength of Reinforced Keratin/Hydroxyapatite Scaffold.

A rapid freezing/lyophilizing/reinforcing process is suggested to fabricate reinforced keratin/hydroxyapatite (HA) scaffold with improved mechanical property and biocompatibility for tissue engineering. The keratin, extracted from human hair, and HA mixture were rapidly frozen with liquid nitrogen and then lyophilized to prepare keratin/HA laminar scaffold. The scaffold was then immersed in PBS for reinforcement treatment, and followed by a second lyophilization to prepare the reinforced keratin/HA scaffold. The morphology, mechanical, chemical, crystal and thermal property of the keratin/HA scaffold were investigated by SEM, FTIR, XRD, DSC, respectively. The results showed that the keratin/HA scaffold had a high porosity of 76.17 ± 3%. The maximum compressive strength and compressive modulus of the reinforced scaffold is 0.778 and 3.3 MPa respectively. Subcutaneous implantation studies in mice showed that in vivo the scaffold was biocompatible since the foreign body reaction seen around the implanted scaffold samples was moderate and became minimal upon increasing implantation time. These results demonstrate that the keratin/HA reinforced scaffold prepared here is promising for biomedical utilization.

The enhanced inhibition of water extract of black tea under baking treatment on α-amylase and α-glucosidase.

This paper studied the inhibition of water extract of natural or baked black tea on the activity of α-amylase and α- glucosidase. Baking treatment was found to be one effective way to enhance the inhibition of black tea on both α-amylase and α- glucosidase, and IC50 of water extract of baked black tea (BBTWE) were 1.213mg/mL and 4.190mg/mL, respectively, while IC50 of water extract of black tea (BTWE) were 1.723mg/mL and 6.056mg/mL, respectively. This study further studied the mechanism of the effect of water extract on α-amylase and α- glucosidase using HPLC, circular dichroism, and synchronous fluorescence. HPLC analysis of tea polyphenols showed that the content of tea polyphenols with low polarity increased after baking. In addition, BBTWE had higer abilty on decreasing the hydrophobicity of tryptophan residues than BTWE for both α-amylase and α- glucosidase.The increase of α-helix proportion of α-amylase when treated with BBTWE was more obvious than that when treated with BTWE. In a word, thermal process of baked foods may be beneficial for tea polyphenols to reduce the rate of starch digestion.

Circulating follicular helper T cells presented distinctively different responses toward bacterial antigens in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease with unknown causes. The initiation of PBC is associated with bacterial infections and abnormal immune correlates, such as the presence of self-reactive anti-mitochondrial antibodies and shifted balance of T cell subsets. In particular, the CD4+CXCR5+ follicular helper T (Tfh) cells are highly activated in PBC patients and are significantly associated with PBC severity, but the underlying reasons are unknown. In this study, we found that the circulating CD4+CXCR5+ T cells were enriched with the interferon (IFN)-γ-secreting Th1-subtype and the interleukin (IL)-17-secreting Th17-subtype, but not the IL-4-secreting Th2 subtype. We further demonstrated that a host of microbial motifs, including Pam3CSK4, poly(I:C), LPS, imiquimod, and CpG, could significantly stimulate IFN-γ, IL-17, and/or IL-21 from circulating CD4+CXCR5+ T cells in PBC patients, especially in the presence of monocytes and B cells. Whole bacterial cells of Escherichia coli, Novosphingobium aromaticivorans, and Mycobacterium gordonae, could also potently stimulate IFN-γ, IL-17, and/or IL-21 production from circulating CD4+CXCR5+ T cells. But interestingly, while the whole cell could potently stimulate circulating CD4+CXCR5+ T cells from both healthy controls and PBC patients, the cell protein lysate could only potently stimulate circulating CD4+CXCR5+ T cells from PBC patients, but not those from healthy controls, suggesting that circulating CD4+CXCR5+ T cells in PBC patients had distinctive antigen-specificity from those in healthy individuals. Together, these data demonstrated that bacterial antigen stimulation is a potential source of aberrant Tfh cell activation in PBC patients.

Folate-conjugated and pH-responsive polymeric micelles for target-cell-specific anticancer drug delivery.

In this study, we developed a folate (FA)-conjugated and pH-responsive active targeting micellar system for anti-cancer drug delivery. In this system, FA was attached to the terminal of the hydrophilic segment of poly(lactic acid)-poly(L-lysine) (PLA-PLL), and PLL was modified by a citric acid group. The FA receptor-mediated active targeting and electrostatic interaction between micelles and cell membrane due to a negative-to-positive charge reversal was combined in one micellar anti-cancer drug delivery system to enhance the tumour targeting and cellular internalisation of micelles. In vitro and in vivo anti-cancer studies demonstrated that the doxorubicin-loaded, FA-conjugated and pH-responsive polymeric micelles possess an enhanced and effective cancer efficiency. STATEMENT OF SIGNIFICANCE: Negatively charged nano-carriers prolonged anti-cancer drugs' blood circulation. However it is difficult to be internalised. Therefore, a negative-to-positive charged micelle surface could improve selectivity for tumour cells and increase uptake chance. In this study, we developed a folate (FA)-conjugated and pH-responsive active targeting micellar system for anti-cancer drug delivery. The FA receptor-mediated active targeting and electrostatic interaction between micelles and cell membrane due to a negative-to-positive charge reversal was combined in one micellar anti-cancer drug delivery system to enhance the tumour targeting and cellular internalisation of micelles. In vitro and in vivo anti-cancer studies demonstrated that the doxorubicin-loaded, FA-conjugated and pH-responsive polymeric micelles possess an enhanced and effective cancer efficiency.

MicroRNA-191 acts as a tumor promoter by modulating the TET1-p53 pathway in intrahepatic cholangiocarcinoma.

Current treatment of intrahepatic cholangiocarcinoma (ICC) remains ineffective because knowledge of ICC carcinogenesis is unclear. Increasing evidence suggests that microRNAs (miRNAs), including miR-191, play an important role in tumorigenesis; but expression and biological functions of miR-191 in ICC remain to be established. This study investigated the functions and underlying mechanisms of miR-191 in ICC. ICC miRNA profiles were generated in five pairs of ICC and matched to normal bile duct tissues by next-generation sequencing technology; ICC miRNA profiles were verified in 18 pairs of ICC tissues and normal bile duct tissues by quantitative RT-PCR. The miR-191-associated mechanisms in ICC were investigated in vitro and in vivo, and clinical outcomes associated with miR-191 were correlated in 84 patients. Our results showed that miR-191 expression was significantly increased in ICC compared with the adjacent normal bile duct tissues (P < 0.001). Overexpression of miR-191 promoted proliferation, invasion, and migration of cholangiocarcinoma cells in vitro and in vivo. The elevated miR-191 expression reduced the expression level of ten-eleven translocation 1 (TET1)-a direct target gene of miR-191 in ICC, which catalyzes demethylation. The reduced TET1 expression level allowed the methylated CpG-rich regions at the p53 gene transcription start site stay methylated, leading to reduced p53 expression level, which compromises p53's anticancer vigor. Finally, miR-191 was found to be an independent risk factor for poor prognosis in patients with ICC (overall survival, hazard ratio = 3.742, 95% confidence interval 2.080-6.733, P < 0.001; disease-free survival, hazard ratio = 2.331, 95% confidence interval 1.346-4.037, P = 0.003). CONCLUSION: Our results suggest that overexpressed miR-191 is associated with ICC progression through the miR-191/TET1/p53 pathway. (Hepatology 2017;66:136-151).

Antioxidative effect of luteolin pretreatment on simulated ischemia/reperfusion injury in cardiomyocyte and perfused rat heart.

OBJECTIVE: To investigate the antioxidative effect and mechanism of luteolin on rat cardiomyocytes and isolated hearts followed by simulated ischemia/reperfusion (SI/R) injury. METHODS: The left ventricular cardiomyocytes and the isolated hearts from adult rats were subjected to SI/R injury. The experiment groups included control, SI/R, luteolin + SI/R (Lut + SI/R), vitamin E (Vit E) + SI/R, and LY294002 + luteolin + SI/R (LY + Lut + SI/R) groups. Cell viability, shortening amplitude, lactate dehydrogenase (LDH) release, superoxide dismutase (SOD) activity, the production of reactive oxygen species (ROS) and malondialdehyde (MDA), expression levels of Akt, phosphorylated Akt, NOX2 (gp91phox), NOX2 mRNA, mitogen-activated protein kinase (p38 MAPK) and phosphorylated p38MAPK were all measured after 3-h simulated ischemia and 2-h simulated reperfusion procedure in cardiomyocytes. Vit E was used as a standard control. The contractile function of isolated hearts was further observed after they were subjected to 30-min global ischemia and 120-min reperfusion. RESULTS: Pretreatment with 8-µmol/L luteolin substantially increased cell viability and shortening amplitude, while reducing evidence of oxidative stress-induced damage in the cells. In addition, the expression of NOX2, NOX2 mRNA and phosphorylation of p38MAPK were all downregulated. Furthermore, pretreatment with 40-µmol/L luteolin improved the recovery of myocardial contractile function following SI/R-induced injury, and luteolin markedly increased phosphorylation of Akt. However, all of the above effects were partially inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002. CONCLUSIONS: Luteolin prevents SI/R-induced myocardial damage by reducing oxidative stress-induced injury in isolated rat hearts and cardiomyocytes, and the cardioprotection induced by luteolin was partially mediated by the PI3K/Akt pathway.