2013 Vol. 27, No. 4
There is a critical shortage of organs, cells, and corneas from deceased human donors worldwide. There are also shortages of human blood for transfusion. A potential solution to all of these problems is the transplantation of organs, cells, and corneas from a readily available animal species, such as the pig, and the transfusion of red blood cells from pigs into humans. However, to achieve these ends, major immunologic and other barriers have to be overcome. Considerable progress has been made in this respect by the genetic modification of pigs to protect their tissues from the primate immune response and to correct several molecular incompatibilities that exist between pig and primate. These have included knockout of genes responsible for the expression of major antigenic targets for primate natural anti-pig antibodies, insertion of human complement- and coagulation-regulatory transgenes, and knockdown of swine leukocyte antigens that stimulate the primate's adaptive immune response. As a result of these manipulations, the administration of novel immunosuppressive agents, and other innovations, pig hearts have now functioned in baboons for 6-8 months, pig islets have maintained normoglycemia in diabetic monkeys for > 1 year, and pig corneas have maintained transparency for several months. Clinical trials of pig islet trans?plantation are already in progress. Future developments will involve further genetic manipulations of the organ-source pig, with most of the genes that are likely to be beneficial already identified.
The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better un-derstand the pathway and exploit it for anticancer therapy.
Clinical, biochemical and molecular evidence for the sickle cell anemia (SCA) crisis in Nigerian patients arising from parvovirus b19 infection remains inadequate. This study determined the prevalence and correlates of anti-parvovirus b19 antibodies in a population of SCA patients and non-SCA healthy controls in Lagos, Nigeria. In this prospective cross-sectional study, we enrolled 73 confirmed SCA patients from 5 district hospitals in Lagos and 81 sex and age-matched non-SCA healthy controls. Serum sample from each study participant was screened for anti-parvovirus b19 by ELISA and PCR techniques. Standard biomedical assays were also done. Anti-parvovirus b19 IgM and IgG antibodies were detected in 22 (14.3%) and 97 (62.9%) of the 154 sera screened, 13 (17.8%) and 45 (61.6%) in SCA patients; 9 (11.1%) and 52 (64.2%) in non-SCA controls. The overall seronegativity rate was 19.5%. Parvovirus B19 DNA was found in 2 (11.1%) of the 18 IgM seropositive SCA serum samples screened. On the whole, parvovirus b19 infection was more commonly asymptomatic in non-SCA controls but caused significant elevation in liver enzymes in infected SCA patients (P < 0.05). The risk of acute parvovirus b19 infection increased 65 times during unsteady state among the SCA patients. Although no deaths of infected patients were recorded during the study, age below 12 years, hospitalization and overcrowded environment were risk factors for infection. We conclude that parvovirus b19 is common in SCA patients, incurring greater susceptibility to infections.
2013, 27(4): 283-290. doi: 10.7555/JBR.27.20130069
The CXCR4 and Nrf2 signaling pathways are abnormally activated in response to cellular stress in various types of human cancers. In this study, we examined the expression of CXCR4 and Nrf2 in colorectal cancer (CRC) tissue specimens and investigated their correlation with patient clinicopathologic characteristics. We determined CXCR4 and Nrf2 expression in 76 CRC tissue specimens and paired normal tissue specimens by immunohisto-chemistry and real-time PCR. We found that the protein and mRNA transcript levels of CXCR4 were significantly higher in CRC tissue specimens than in paired normal tissues, while the expressions of Nrf2 protein and mRNA were increased in CRC tissues compared to distant non-cancerous tissues. High expression level of CXCR4 was positively correlated with poorly differentiated (P = 0.031), more advanced tumor-node-metastasis (TNM) stage (P = 0.019), lymph node metastasis (P = 0.007) and distant metastasis (P = 0.018). However, the expression of Nrf2 protein was positively correlated with larger tumor size (P = 0.049), more advanced TNM stage (P = 0.013), lymph node metastasis (P = 0.016) and distant metastasis (P = 0.023). Moreover, there was a strong relation-ship between CXCR4 and Nrf2 expression in CRC tissues, indicating that high Nrf2 expression may contribute to CXCR4 overexpression. In addition, combined expression of CXCR4 and Nrf2 strongly correlated with lymph node metastasis and distant metastasis (P = 0.003). Furthermore, we found that combined high expression of CXCR4 and Nrf2 had stronger correlation with lymph node metastasis and distant metastasis than any single molecule did. This study indicated that the abnormal expression of CXCR4 and Nrf2 contributed to the progression of CRC.
Parkinson's disease (PD) is a common progressive neurological disorder and is composed of motor and non-motor symptoms. Sleep disturbances are frequent problems for patients with PD. The relationship between sleep disturbances with Hoehn and Yahr (H&Y) staging have been demonstrated. However, the relationship between sleep disorders and H&Y is still unclear in patients with PD without dementia in Chinese PD patients. In this study, we interviewed 487 non-demented PD patients of Chinese Han descents by H&Y classification. We found that night sleep quality was significantly associated with the severity of PD (P = 0.008). Panic disorder severity scale (PDSS) total scores were correlated with PD non-motor symptoms scale (PDNMS) scores (r = -0.528, P < 0.001), the Hamilton depression scale (HAMD) scores (r = -0.545, P < 0.001) and the Hamilton anxiety scale (HAMA) scores (r = -0.498, P < 0.001). Our results indicated that sleep quality deteriorated with the advancing of PD in Chinese non-demented patients with PD. Depression and anxiety may partly explain sleep disturbances in non-demented patients with PD.
Neuroinflammation has been recognized to play a critical role in the pathogenesis of Alzheimer's disease (AD), which is pathologically characterized by the accumulation of senile plaques containing activated microglia and amyloid β-peptides (Aβ). In the present study, we examined the neuroprotective effects of hydrogen sulfide (H2S) on neuroinflammation in rats with Aβ1-40 hippocampal injection. We found that Aβ-induced rats exhibited a disorder of pyramidal cell layer arrangement, and a decrease of mean pyramidal cell number in the CA1 hippoc?ampal region compared with those in sham operated rats. NaHS (a donor of H2S, 5.6 mg/kg/d, i.p.) treatment for 3 weeks rescued neuronal cell death significantly. Moreover, we found that H2S dramatically suppressed the release of TNF-α, IL-1β and IL-6 in the hippocampus. Consistently, both immunohistochemistry and Western blotting assays showed that H2S inhibited the upregulation of COX-2 and the activation of NF-κB in the hippocampus. In conclusion, our data indicate that H2S suppresses neuroinflammation via inhibition of the NF-κB activation path?way in the Aβ-induced rat model and has potential value for AD therapy.
We sought to evaluate the efficacy and effects of low-dose tacrolimus (FK506) to recipients with living donor liver transplantation (LDLT). A total of 66 patients who underwent LDLT between 2001 and 2007 were enrolled in this study. According to different doses of tacrolimus, the recipients were randomly divided into two groups: the low-dose tacrolimus group (group A) and the normal-dose tacrolimus group (group B). The blood concentra-tion of tacrolimus and its side effects including infection, hyperglycemia, hypertension, high blood creatinine and jaundice were monitored once a week at the perioperative period, and once a month thereafter. Besides, the sur-vival rates of the recipients were analyzed at the 1- and 3-year time point after operation. Among these patients, no significant acute rejection was detected after LDLT. The incidences of infection, hyperglycemia, liver dys-function and renal impairment in group A were markedly lower than those in group B. However, no significant differences were detected in the incidence of hypertension between the two groups. Moreover, the recipients in each group had a similar survival rate according to the results of 1- and 3-year follow-up. The incidence of side effects that associated with tacrolimus positively correlated with tacrolimus blood concentration. In conclusion, long-term and low-dose administration of tacrolimus is a safe and effective treatment for LDLT recipients.
Lobectomy with partial removal of the pulmonary artery in video-assisted thoracic surgery (VATS) currently remains a challenge for thoracic surgeons. We were interested in introducing pulmonary vessel blocking tech-niques in open thoracic surgery into video-assisted thoracic surgery (VATS) procedures. In this study, we reported a surgical technique simultaneously blocking the pulmonary artery and the pulmonary vein for partial removal of the pulmonary artery under VATS. Seven patients with non-small-cell lung cancer (NSCLC) received lobec-tomy with partial removal of the pulmonary artery using the technique between December 2007 and March 2012. Briefly, rather than using a small clamp on the distal pulmonary artery to the area of invading cancer, we replaced a vascular clamp with a ribbon and Hem-o-lock clip to block the preserved pulmonary veins so as to prevent back bleeding and yield a better view for surgeons. The mean occlusion time of the pulmonary artery and pulmonary veins were 44.0±10.0 and 41.3±9.7 minutes, respectively. The mean repair time of the pulmonary artery was 25.3±13.7 minutes. No complications occurred. No patients showed abnormal blood flow through the recon-structed vessel. There were no local recurrences on the pulmonary artery. In conclusion, the technique for blocking the pulmonary artery and veins is feasible and safe in VATS and reduces the risk of abrupt intraoperative bleeding and the chance of converting to open thoracotomy, and extends the indications of VATS lobectomy.
Tissue engineering scaffolds require a controlled pore size and interconnected pore structures to support the host tissue growth. In the present study, three dimensional (3D) hybrid scaffolds of poly lactic acid (PLA) and poly glycolic acid (PGA) were fabricated using solvent casting/particulate leaching. In this case, partially fused NaCl particles were used as porogen (200-300μ) to improve the overall porosity ( ≥ 90%) and internal texture of scaffolds. Differential scanning calorimeter (DSC) analysis of these porous scaffolds revealed a gradual reduc-tion in glass transition temperature (Tg) (from 48°C to 42.5°C) with increase in hydrophilic PGA content. The potential applications of these scaffolds as implants were further tested for their biocompatibility and biodegrad-ability in four simulated body fluid (SBF) types in vitro. Whereas, simulated body fluid (SBF) Type1 with the op-timal amount of HCO3- ions was found to be more appropriate and sensible for testing the bioactivity of scaffolds. Among three combinations of polymer scaffolds, sample B with a ratio of 75:25 of PLA: PGA showed greater stability in body fluids (pH 7.2) with an optimum degradation rate (9% to 12% approx). X-ray diffractogram also confirmed a thin layer of hydroxyapatite deposition over sample B with all SBF types in vitro.
Cone beam computed tomography is a 3-dimensional high resolution imaging method. The purpose of this study was to compare the effects of 3 different NiTi rotary instruments used to prepare curved root canals on the final shape of the curved canals and total amount of root canal transportation by using cone-beam computed to?mography. A total of 81 mesial root canals from 42 extracted human mandibular molars, with a curvature ranging from 15 to 45 degrees, were selected. Canals were randomly divided into 3 groups of 27 each. After preparation with Protaper, Revo-S and Hero Shaper, the amount of transportation and centering ability that occurred were as?sessed by using cone beam computed tomography. Utilizing pre- and post-instrumentation radiographs, straight?ening of the canal curvatures was determined with a computer image analysis program. Canals were metrically assessed for changes (surface area, changes in curvature and transportation) during canal preparation by using software SimPlant; instrument failures were also recorded. Mean total widths and outer and inner width measure?ments were determined on each central canal path and differences were statistically analyzed. The results showed that all instruments maintained the original canal curvature well with no significant differences between the dif?ferent files (P = 0.226). During preparation there was failure of only one file (the protaper group). In conclusion, under the conditions of this study, all instruments maintained the original canal curvature well and were safe to use. Areas of uninstrumented root canal wall were left in all regions using the various systems.
Human hepatobiliary cystadenoma is a rare benign cystic tumor of the liver, and is extremely rare in the caudate lobe. We herein present a case of a 70-year-old male with a hepatobiliary cystadenoma originating from the cau-date lobe.