The Influence of Drug-Eluting Beads Transarterial Chemoembolization on Serum Levels of Soluble Programmed Cell Death Protein-1 in Advanced Hepatocellular Carcinoma Patients.

Aim: This study aims to explore the role of soluble programmed cell death protein 1 (sPD-1) in individuals with hepatocellular carcinoma (HCC) undergoing treatment with drug-eluting beads transarterial chemoembolization (D-TACE). Additionally, we aim to assess the potential utility of sPD-1 for determining the optimal timing for combining D-TACE with immune checkpoint inhibitors (ICIs). Materials and Methods: A total of 44 HCC patients eligible for D-TACE and 55 healthy volunteers were enrolled in this study. Three milliliters of peripheral venous blood from the patients were collected on the day before D-TACE and 3, 7, and 30 days after D-TACE, respectively, for the assay of sPD-1. The relationships between sPD-1 levels, clinical features, outcomes, and the fluctuation of sPD-1 during treatment were analyzed. Results: The initial sPD-1 levels in patients were found to be significantly higher than those in the control group. Although the initial sPD-1 levels displayed a decreasing trend with an increase in BCLC stage, no significant differences were observed among patients at different BCLC stages. The sPD-1 level on day 3 after D-TACE was similar to that on day 7 after D-TACE and significantly lower than the initial level. The sPD-1 level on day 30 after D-TACE was significantly higher than that on day 3 and day 7 after D-TACE and nearly returned to the initial level before D-TACE. Conclusion: The level of sPD-1 was found to be significantly elevated in patients with HCC. However, further research is deemed necessary to fully understand the role of sPD-1 as a potential biomarker in the initiation, progression, and prognosis of HCC. The decrease in sPD-1 following D-TACE suggests that immune effector cells might potentially be reduced, as well as immune function weakened, highlighting the need to avoid the prompt administration of ICIs after D-TACE.

Levomilnacipran ameliorates lipopolysaccharide-induced depression-like behaviors and suppressed the TLR4/Ras signaling pathway.

Levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, has been reported to have anti-depressive effects. However, the detailed mechanisms underlying these effects are still unclear. This study aimed to investigate the antidepressant mechanisms of levomilnacipran to discover new perspectives on the treatment of depression in male rats. Intraperitoneal injection of lipopolysaccharide (LPS) was used to induce depressive behaviors in rats. Activation of microglia and apoptosis of neurons verified by immunofluorescence. Inflammatory related proteins and neurotrophic related proteins were verified by immunoblotting. The mRNA expression of apoptosis markers was verified by real-time quantitative PCR. Finally, electron microscopy analysis was used to observe the ultrastructural pathology of neuron. Here, we found that the anti-depression and anti-anxiety effects of levomilnacipran in the LPS-induced rat model of depression was resulted from the suppression of neuroinflammation and neuronal apoptosis within prefrontal cortex of rats. Furthermore, we found that levomilnacipran could decrease the number of microglia and suppress its activation in prefrontal cortex of rats. This effect may be mediated by suppressing the TLR4/NF-κB and Ras/p38 signaling pathways. In addition, levomilnacipran plays a neuroprotective role by increasing the expression of neurotrophic factors. Taken together, these results suggest that levomilnacipran exerts antidepressant effects by attenuating neuroinflammation to inhibit the damage in central nervous system and plays a neuroprotective role to improve depressive behaviors. These findings suggest that suppression of neuroinflammation in prefrontal cortex could ameliorate depressive behavioral disorder of rats induced by LPS, which provided a new perspective for the treatment of depression.

Pharmacological Inhibition of HDAC6 Attenuates NLRP3 Inflammatory Response and Protects Dopaminergic Neurons in Experimental Models of Parkinson's Disease.

AIM: To investigate the role of histone deacetylase 6 (HDAC6) deacetylation activity in nucleotide-binding oligomerization domain and leucine-rich repeat pyrin 3 domain (NLRP3) inflammatory response and explore the effects of pharmacological inhibition of HDAC6 with tubastatin A (TBA) on dopaminergic injury. METHODS: Using 6-OHDA-induced Parkinson's disease (PD) models, we examined the effects of TBA on NLRP3 activation and cell injury in SH-SY5Y cells. We also investigated the effects of TBA on NLRP3 inflammatory responses and dopaminergic injury in the nigrostriatal system in mice and analyzed the acetylation levels of peroxiredoxin2 (Prx2) and oxidative stress. RESULTS: TBA inhibited 6-OHDA-induced NLRP3 activation, as demonstrated by decreased expressions of NLRP3 and matured caspase-1 and IL-1ß, and also alleviated glial proliferation and dopaminergic neuronal degeneration. Notably, TBA recovered acetylation levels of Prx2 and reduced oxidative stress. CONCLUSION: Our findings indicate that pharmacological inhibition of HDAC6 with TBA attenuates NLRP3 inflammation and protects dopaminergic neurons, probably through Prx2 acetylation. This study suggests that the deacetylase catalytic domain of HDAC6 is a potential target for PD treatment.

Effectiveness and the strategy to treat the side effects of sorafenib administration after transarterial chemoembolization in advanced hepatocellular carcinoma patients.

OBJECTIVE: The aim is to study the effectiveness and side effects of sorafenib administration after transarterial chemoembolization (TACE) in advanced hepatocellular carcinoma (HCC) patients. To evaluate the safety of the combination of sorafenib and TACE to treat HCC. MATERIALS AND METHODS: A total of 36 unresectable HCC patients were enrolled. After TACE, administration of sorafenib was carried out. Follow-up was taken for every 4 weeks. Liver and renal function and alpha-fetoprotein were tested. Modified response evaluation criteria in solid tumors (mRECIST) was used to evaluate the clinical effect. The side effects were recorded. RESULTS: The median overall survival (mOS) and the median time to progress were 12.5 and 8 months with the range from 6 to 32 and 4-30 months, respectively. The mOS of patients with single tumor was 18 months while that of multiple tumors in liver was 10 months (χ2 = 4.1639, P = 0.0413). According to mRECIST, there were no complete response patients, 2 partial response patients, 10 stable disease patients, and 24 progressive disease patients. Response rate was 5.5% (2/36). Disease control rate (DCR) was 33% (12/36). The main adverse events were hand-foot skin reaction and diarrhea. The frequency of Grade II, III hand-foot-skin reaction was 39%. After treatment, it decreased to 5.6%. Forty-four percentage patients suffered from diarrhea of Grades I and II. After treatment, it decreased to 28%. The mean interval of TACE was 45 days before combination therapy and 120 days after combination therapy. CONCLUSION: Administration of sorafenib after TACE could prolong overall survival of advanced HCC patients, keep the stable status longer and extend the interval between TACEs. The side effects are usually treatable, which proves the safety of this combination.

Inhibition of HDAC6 increases acetylation of peroxiredoxin1/2 and ameliorates 6-OHDA induced dopaminergic injury.

OBJECTIVE: Histone deacetylase 6 (HDAC6) has been regarded as an unusual HDAC because of its unique properties. It contains two deacetylase catalytic domains and one ubiquitin-binding domain, thus exerting both enzymatic and non-enzymatic actions on cellular function. To date, the ubiquitin-binding activity of HDAC6 has been implicated in several neurodegenerative disorders including Parkinson's disease (PD). However, the deacetylation effect of HDAC6 in PD has not been fully illustrated. Therefore, the aim of the present study was to explore the role of deacetyation activity of HDAC6 in PD. METHODS: We used an in vivo 6-OHDA induced PD model and a specific HDAC6 inhibitor tubastatin A to investigate the acetylation levels of peroxiredoxin1 (Prx1) and peroxiredoxin2 (Prx2) and to explore the effects of tubastain A on nigrostriatal dopaminergic system. RESULTS: Our results showed that expression of HDAC6 significantly increased in dopaminergic neurons after 6-OHDA injury. Acetylation levels of Prx1 and Prx2 decreased. Pharmacological inhibition of HDAC6 with specific inhibitor tubastatin A increased acetylation of Prx1 and Prx2, reduced ROS production and ameliorated dopaminergic neurotoxicity. CONCLUSION: Our results for the first time provide evidence that HDAC6 medicated deacetylation of Prx1 and Prx2 contributes to oxidative injury in PD, suggesting that the development of specific HDAC6 inhibitor is required to develop more effective therapeutic strategies to treat PD.

Combined Endovascular Embolization and Open Surgery for Splenic Artery Aneurysm with Arteriovenous Fistula.

Splenic artery aneurysm with arteriovenous fistula is extremely rare; however, it is clinically important because of the potential of aneurysm rupture and gastroesophageal variceal hemorrhage. Most previous cases were managed by surgery directly. We present a case which was successfully treated with combined endovascular embolization and open surgery. It may be a safe and effective approach to manage this entity.

NOD2 deficiency protects against cardiac remodeling after myocardial infarction in mice.

BACKGROUND/AIMS: Although the pathogenesis of myocardial infarction (MI) is multifactorial, activation of innate immune system to induce inflammation has emerged as a key pathophysiological process in MI. NOD2, one member of the NOD-like receptor (NLR) family, plays an important role in the innate immune response. This study was to examine the role of NOD2 during MI. METHODS: MI was induced by permanent ligation of the left coronary artery in wild type and NOD2(-/-) mice and cardiac fibroblasts were isolated. RESULTS: NOD2 expression was significantly increased in myocardium in post-MI mice. NOD2 deficiency improved cardiac dysfunction and remodeling after MI as evidenced by echocardiographic analysis, reduced the levels of cytokines, inflammatory cell infiltration and matrix metalloproteinase-9 (MMP-9) activity. In vitro, we further found that NOD2 activation induced the activation of MAPK signaling pathways, production of proinflammatory mediators and MMP-9 activity in cardiac fibroblasts. CONCLUSIONS: Our studies demonstrate that NOD2 is a critical component of a signal transduction pathway that links cardiac injury by exacerbation of inflammation and MMP-9 activity. Pharmacological targeting of NOD2-mediated signaling pathways may provide a novel approach to treatment of cardiovascular diseases.

HDAC4/5-HMGB1 signalling mediated by NADPH oxidase activity contributes to cerebral ischaemia/reperfusion injury.

Histone deacetylases (HDACs)-mediated epigenetic mechanisms play critical roles in the homeostasis of histone acetylation and gene transcription. HDAC inhibitors have displayed neuroprotective properties in animal models for various neurological diseases including Alzheimer's disease and ischaemic stroke. However, some studies have also reported that HDAC enzymes exert protective effects in several pathological conditions including ischaemic stress. The mixed results indicate the specific roles of each HDAC protein in different diseased states. However, the subtypes of HDACs associated with ischaemic stroke keep unclear. Therefore, in this study, we used an in vivo middle cerebral artery occlusion (MCAO) model and in vitro cell cultures by the model of oxygen glucose deprivation to investigate the expression patterns of HDACs and explore the roles of individual HDACs in ischaemic stroke. Our results showed that inhibition of NADPH oxidase activity ameliorated cerebral ischaemia/reperfusion (I/R) injury and among Zn(2+) -dependent HDACs, HDAC4 and HDAC5 were significantly decreased both in vivo and in vitro, which can be reversed by NADPH oxidase inhibitor apocynin. We further found that both HDAC4 and HDAC5 increased cell viability through inhibition of HMGB1, a central mediator of tissue damage following acute injury, expression and release in PC12 cells. Our results for the first time provide evidence that NADPH oxidase-mediated HDAC4 and HDAC5 expression contributes to cerebral ischaemia injury via HMGB1 signalling pathway, suggesting that it is important to elucidate the role of individual HDACs within the brain, and the development of HDAC inhibitors with improved specificity is required to develop effective therapeutic strategies to treat stroke.

Therapeutic management of superior mesenteric artery aneurysms.

OBJECTIVE: Superior mesenteric artery (SMA) aneurysms are rare but life-threatening entities. This study summarizes our experience in providing therapeutic management for true aneurysms of the SMA. METHODS: Between February 1998 and March 2010, 10 patients were diagnosed with true SMA aneurysms in our hospital. Medical data for demographics, clinical presentation, diagnosis, aneurysm characteristics, treatment modalities, outcomes, and follow-up were retrospectively analyzed. RESULTS: Ten patients (six women, four men) were enrolled with a mean age of 56.7 years (range, 42-69 years). One patient (10%) had aneurysm rupture and presented with abdominal pain, and seven (70%) were asymptomatic. The size of nonruptured aneurysms ranged from 1.2 to 8.0 cm (mean, 3.5 cm). Of 10 patients, five received endovascular stent graft repair, two were treated surgically, two were observed, and one with aneurysm rupture died of hemorrhagic shock before surgery. The two surgical patients underwent SMA reconstruction after aneurysmectomy, and segmental bowel resection was performed in one patient after reconstruction. The overall mortality rate was 10%. Postoperative gastroparesis was identified in one patient (14.3%). Mean operation time was 3.6 hours in the surgical group and 1.3 hours in the endovascular group. Mean postoperative hospital stay for the two groups was 20.0 days and 2.2 days, respectively. Mean follow-up was 30.9 months (range, 3-72 months). Endoleak was found in one patient 3 months after endovascular repair. CONCLUSION: True SMA aneurysms are uncommon entities with definite rupture risk and mortality. Compared with surgical intervention, endovascular stent graft placement is associated with less trauma and rapid recovery. It may be a promising alternative to surgical intervention. The most appropriate treatment depends on the characteristics of the lesion and the condition of the patient.

Therapeutic management of hemorrhage from visceral artery pseudoaneurysms after pancreatic surgery.

INTRODUCTION: Hemorrhage from pseudoaneurysms after pancreatic surgery is a rare but life-threatening and complicated complication. The study presents our experience to provide therapeutic management for this rare condition. METHODS: Between February 1994 and January 2011, 35 patients experienced hemorrhage from pseudoaneurysms in our hospital. Medical data of this rare complication were analyzed retrospectively. RESULTS: The prevalence of hemorrhage from pseudoaneurysms was 3.2% (35/1,102). Sixteen patients (45.7%) experienced sentinel bleeding. Pancreatic fistula (74.3%) and intra-abdominal abscess (57.1%) were two common complications prior to hemorrhage. Of 35 patients, 20 underwent endovascular intervention, 14 received surgical re-laparotomy, and bleeding stopped spontaneously in one. The overall mortality rate was 22.9%. Technical success rate of endovascular treatment was 87%. There were significant differences in the mortality rate (10.0% vs 42.9%), operation time (72.8 vs 123.9 min), estimated blood loss (1,835 vs 3,000 ml), and intensive care unit stay (3.6 vs 8.6 days) between endovascular and surgical treatment. Mean follow-up was 19.2 ± 17.0 (range, 5-63 months). CONCLUSION: Endovascular intervention represents the first-line treatment for hemorrhage from pseudoaneurysms after pancreatic surgery. Endovascular embolization or stent-graft placement should be selected individually depending on the involved artery and its vascular anatomy.

[Application of portal vein chemoembolization in major hepatectomy for initially unresectable primary and secondary hepatic tumors].

OBJECTIVE: To investigate the surgical treatment of initially unresectable primary and secondary hepatic tumors. METHODS: For the patients with multiple and bilobar colonic hepatic metastases, a first-stage hepatectomy consisted in a radical resection of sigmoid colonic carcinoma and left lateral hepatic segment. Subsequently, under the guidance of ultrasonography and radiography, a right portal vein chemoembolization (PVCE) was performed via a percutaneous approach through left portal branch to induce the atrophy of right hemiliver and hypertrophy of left hemiliver. At Week 5 post-PVCE, a second-stage hepatectomy was planned to resect the right hemiliver. For patients with huge hepatocellular carcinoma (HCC), transcatheter arterial chemoembolization (TACE) were performed and it was followed by PVCE 1 week later. At Week 4 post-PVCE, a right trisegmentectomy was attempted to resect the right liver tumor. The volume of liver was evaluated with three-dimensional CT scan at Weeks 2 and 4 weeks post-PVCE. RESULTS: At Week 4 post-PVCE, the atrophy of right lobe was induced and the left lobe underwent compensatory hypertrophy. The remnant volumes of right lobe and right trisegmentectomy for HCC decreased from 1380.0 cm(3), 1685.4 cm(3) at pre-PVCE to 740.2 cm(3), 1228.1 cm(3) at post-PVCE. The values increased from pre-PVCE 435.1 cm(3), 151.5 cm(3) to post-PVCE 624.4 cm(3), 560.2 cm(3) for left hepatic lobe remnant of colonic liver metastases and left lateral segment for HCC. The ratios of liver remnant to estimated total liver volume increased from 25.6%, 13.6% at pre-PVCE to 50.0%, 43.1% post-PVCE respectively. The postoperative course was uneventful. The liver function, serum CEA and AFP decreased to the normal levels. Two patients were followed up for 18 and 8 months respectively. There was no tumor recurrence. CONCLUSION: PVCE prevents the hepatic function failure after a major hepatectomy. And it may benefit more patients with previously unresectable liver tumors.

Screening of deoxyribozyme with high reversal efficiency against multidrug resistance in breast carcinoma cells.

Specific inhibition of P-glycoprotein (Pgp) expression, which is encoded by multidrug resistance gene-1 (MDR1), is considered a well-respected strategy to overcome multidrug resistance (MDR). Deoxyribozymes (DRz) are catalytic nucleic acids that could cleave a target RNA in sequence-specific manner. However, it is difficult to select an effective target site for DRz in living cells. In this study, target sites of DRz were screened according to MDR1 mRNA secondary structure by RNA structure analysis software. Twelve target sites on the surface of MDR1 mRNA were selected. Accordingly, 12 DRzs were synthesized and their suppression effect on the MDR phenotype in breast cancer cells was confirmed. The results showed that 4 (DRz 2, 3, 4, 9) of the 12 DRzs could, in a dose-dependent response, significantly suppress MDR1 mRNA expression and restore chemosensitivity in breast cancer cells with MDR phenotype. This was especially true of DRz 3, which targets the 141 site purine-pyrimidine dinucleotide. Compared with antisense oligonucleotide or anti-miR-27a inhibitor, DRz 3 was more efficient in suppressing MDR1 mRNA and Pgp protein expression or inhibiting Pgp function. The chemosensitivity assay also proved DRz 3 to be the best one to reverse the MDR phenotype. The present study suggests that screening targets of DRzs according to MDR1 mRNA secondary structure could be a useful method to obtain workable ones. We provide evidence that DRzs (DRz 2, 3, 4, 9) are highly efficient at reversing the MDR phenotype in breast carcinoma cells and restoring chemosensitivity.

Alteration of cyclin D1 in Chinese patients with breast carcinoma and its correlation with Ki-67, pRb, and p53.

BACKGROUND: For the female population in Asia, systematic investigation on alterations of cyclin D1 in breast carcinoma is rare, and correlation between cyclin D1 expression with clinicopathological parameters, survival rate, and other prognostic marker associated with cell cycle is unclear. METHODS: Expression of cyclin D1 protein, Ki-67, pRb, and p53 was determined by immunohistochemistry in 18 cases of early breast carcinomas and 80 cases of invasive ductal carcinomas. Genetic alteration of cyclin D1 gene and overexpression of cyclin D1 mRNA were detected by Southern blot and RT-PCR, respectively. RESULTS: Expression of cyclin D1 is negative in usual ductal hyperplasia (UDH) and atypical ductal hyperplasia (ADH). However, in 52.0% (51/98) of all breast carcinomas, positive expression of cyclin D1 was observed. Five-year survival rate of the patients with positive expression of cyclin D1 (52.7%) is significantly lower than the cases with negative expression of cyclin D1 (72.1%). Positive rate of cyclin D1 protein in invasive ductal carcinoma (52.5%) is slightly higher than overexpression rate (40.8%) of cyclin D1 mRNA but significantly higher than amplification rate of cyclin D1 gene (18.4%). Expression of cyclin D1 is correlated with Ki-67 expression, but not correlated with pRb and p53 expression. CONCLUSIONS: Positive expression of cyclin D1 could serve as a poor prognostic marker for Chinese patients with breast carcinoma independent of nodal metastasis and clinical stage. Expression of cyclin D1 protein is affected more directly by overexpression of cyclin D1 mRNA rather than cyclin D1 gene amplification. The cooperation between pRb and p53 with cyclin D1 protein in the carcinogenesis of breast carcinoma is not supported by the results.

[Multiple meningiomas: report of 32 cases].

OBJECTIVE: To explore the genesis and classification and diagnosis as well as the treatment of multiple meningiomas. METHODS: Retrospective study of the materials of 32 cases of multiple meningiomas, simultaneously review of the related articles. RESULTS: All patients were divided into 5 groups, primary 18 cases, postoperative 7 cases, accompanied by neurofibromatosis (NF) 4 cases, meningiomatosis 1 case, accompanied with other intracranial tumor 2 cases, one with pituitary adenoma and the other with glioma. All the patients accepted operation, cured 25 cases, improved 7 cases. CONCLUSIONS: The cytogenesis of different type of multiple meningiomas probably varied. Estrogen may play an important role in the genesis of multiple meningiomas. One stage resection of all the tumors was feasible to most cases and advocated. Most cases had strong tolerance to several times of operation, staging operation was permitted. The prognosis and principle of treatment of different group varied.

[Diagnosis and treatment of cystic acoustic neuroma].

OBJECTIVE: To study the clinical features and treatment of cystic acoustic neuroma. METHODS: Twenty-two patients with cystic acoustic neuromas were diagnosed by CT and MRI preoperatively, and the tumors were resected by retrosigmoid approach, and verified by pathological studies. RESULTS: Of the 22 patients, 18 had tumors totally resected (postoperative house Brackman facial nerve grading: grade II in 4 patients, III in 7, IV in 3, V in 2, VI in 2) and 4 had tumors subtotally resected. CONCLUSION: Because of its specific clinical features and poor operative results, cystic acoustic neuroma should be regarded as a specific subtype.