Lipoprotein(a) [Lp(a)] is composed of a low density lipoprotein (LDL)-like particle to which apolipoprotein (a) [apo(a)] is linked by a single disulfide bridge. Lp(a) is considered a causal risk factor for ischemic cardiovascular disease (CVD) and calcific aortic valve stenosis (CAVS). The evidence for a causal role of Lp(a) in CVD and CAVS is based on data from large epidemiological databases, mendelian randomization studies, and genome-wide association studies. Despite the well-established role of Lp(a) as a causal risk factor for CVD and CAVS, the underlying mechanisms are not well understood. A key role in the Lp(a) functionality may be played by its oxidized phospholipids (OxPL) content. Importantly, most of circulating OxPL are associated with Lp(a); however, the underlying mechanisms leading to this preferential sequestration of OxPL on Lp(a) over the other lipoproteins, are mostly unknown. Several studies support the hypothesis that the risk of Lp(a) is primarily driven by its OxPL content. An important role in Lp(a) functionality may be played by the lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme that catalyzes the degradation of OxPL and is bound to plasma lipoproteins including Lp(a). The present review article discusses new data on the pathophysiological role of Lp(a) and particularly focuses on the functional role of OxPL and Lp-PLA2 associated with Lp(a).
We sought to investigate safety of axitinib or sorafenib in renal cell carcinoma (RCC) patients and compare toxicity of these two vascular endothelial growth factor receptor inhibitors. Databases of PubMed and Embase were searched. We included phase II and III prospective trials, as well as retrospective studies, in which patients diagnosed with RCC were treated with axitinib or sorafenib monotherapy at a starting dose of 5 mg and 400 mg twice daily, respectively. The overall incidence of high grade hypertension, fatigue, gastrointestinal toxicity and hand-foot syndrome, along with their 95% confidence intervals (CI), were calculated using fixed- or random- effects model according to heterogeneity test results. A total of 26 trials, including 4790 patients, were included in our meta-analysis. Among them, 6 arms were related to axitinib and 22 were associated with sorafenib. The incidences of hypertension (24.9% vs. 7.9%), fatigue (8.2% vs. 6.6%), and gastrointestinal toxicity (17.6% vs. 11.3%) were higher in patients receiving axitinib versus those receiving sorafenib, while the incidence of hand-foot syndrome was lower in patients receiving axitinib versus those receiving sorafenib (9.5% vs. 13.3%). In conclusion, axitinib showed noticeably higher risks of toxicity versus sorafenib. Close monitoring and effective measures for adverse events are recommended during therapy.
Meiosis-arrest female 1 (MARF1) is a recently identified key oogenic regulator essential for the maintenance of female fertility and genome integrity in mice. However, the detailed functions and the underlying mechanisms of MARF1 remain elusive. Here, in an attempt to create a mouse model expressing fluorescent protein-tagged MARF1 to facilitate further exploration of the roles of MARF1 in oocytes, we produced a Marf1-eGFP knockin (KI) mouse line in which the C-terminal structure and function of MARF1 were interfered by its fusing eGFP peptide. Using these Marf1-eGFP-KI mice, we revealed, unexpectedly, the functions of MARF1 in the control of oocyte meiotic division. We found that the Marf1-eGFP-KI females ovulated mature oocytes with severe meiotic and developmental defects, and thus were infertile. Moreover, meiotic reinitiation was delayed while meiotic completion was accelerated in the KI-oocytes, which was coincident with the increased incidence of oocyte aneuploidy. Therefore, MARF1 is indispensable for maintaining the fidelity of homolog segregation during oocyte maturation, and this function relies on its C-terminal domains.
While management of appendicular fractures has been well described in the setting of osteopetrosis, there is limited information on managing fractures of the axial spine. Here we present an osteopetrotic patient with multiple traumatic multiple, comminuted, unstable cervical spinal fractures managed with non-operative stabilization, and provide a review of the pathophysiology, genetic characteristics, and special considerations that must be explored when determining operative versus non-operative management of spinal injury in osteopetrosis. A PubMed query was performed for English articles in the literature published up to June 2016, and used the following search terms alone and in combination: "osteopetrosis", "spine", "fractures", "osteoclasts", and "operative management". Within four months after initial injury, treatment with halo vest allowed for adequate healing. The patient was asymptomatic with cervical spine dynamic radiographs confirming stability at four months. On four-year follow up examination, the patient remained without neck pain, and CT scan demonstrated partially sclerotic fracture lines with appropriate anatomical alignment. In conclusion, external halo stabilization may be an effective option for treatment of multiple unstable acute traumatic cervical spine fractures in patients with osteopetrosis. Given the challenge of surgical stabilization in osteopetrosis, further research is necessary to elucidate the optimal form of treatment in this select patient population.
Since estrogenic pollutants and phytoestrogens can cause the disorder of the reproductive system, the effects of a soybean milk product (Vegemil® containing 162 ppm isoflavones) on the feto-neonatal development, including male reproductive function, were investigated. Pregnant rats were fed the soybean milk (5% or 100% in drinking water) from gestational day (GD) 6 to parturition or to post-natal day (PND) 56. Specifically, the rats were divided into 4 groups: the control group (drinking water), the GD5% group (5% soybean milk during only the GD period), the GD-PND5% group (5% soybean milk during the GD and PND periods), and the GD-PND100% group (100% soybean milk instead of water during the GD and PND periods). During the gestational, lactational, and developmental periods, the reproductive and developmental parameters of dams and offspring were observed. Feeding soybean milk did not affect the birth and physical development of both male and female offspring. At PND57, the weights of the testes and epididymides of F1 males significantly increased by feeding a high concentration of the soybean milk (GD-PND100%). In addition, feeding of the soybean milk during both the GD and PND periods (GD-PND5% and GD-PND100%) enhanced the sperm counts and motility. The results indicate that soybean milk is safe for embryos, fetuses, and offspring, and improves the post-generational development of male reproductive function.
Sample size re-estimation is essential in oncology studies. However, the use of blinded sample size reassessment for survival data has been rarely reported. Based on the density function of the exponential distribution, an expectation-maximization (EM) algorithm of the hazard ratio was derived, and several simulation studies were used to verify its applications. The method had obvious variation in the hazard ratio estimates and overestimation for the relatively small hazard ratios. Our studies showed that the stability of the EM estimation results directly correlated with the sample size, the convergence of the EM algorithm was impacted by the initial values, and a balanced design produced the best estimates. No reliable blinded sample size re-estimation inference can be made in our studies, but the results provide useful information to steer the practitioners in this field from repeating the same endeavor.
Crocus sativus and its bioactive constituent crocin are well known for anti-tumor potential in different models. However, the efficacy of crocin on in-vivo melanoma metastasis is not yet reported. In this study, melanoma metastatic model was developed by tail vein injection of B16F-10 cells in to C57BL/6 mice. Metastatic mice treated with two different doses of crocin (250 and 500 µg/kg of bodyweight) for 10 days and parameters such as lung metastasis inhibition, mean survival time, lung hydroxyproline, uronic acid and hexosamine levels were analyzed after 21 days of treatment. Then blood was collected and serum gamma glutamyl transpeptidase ( g-GGT), sialic acid, tumor necrosis factor alpha (TNF-α), interleukin 10 (IL-10), IL-6, IL-2, and TIMP-1 levels were measured. Further, a lung histological examination was done in crocin treated metastatic mice. Subsequently hallmark metastatic parameters such as matrix metalloproteinases (MMPs), extracellular regulated kinase 2 (ERK2), vascular endothelial growth factor (VEGF), and K-ras gene expression were investigated in the lungs of crocin treated metastatic mice. Further, in-vitro adhesion, invasion and migration of B16F-10 cells were examined after 24 hours of crocin (5 and 10 µg/mL) treatment. Administration of crocin to tumor bearing C57BL/6 mice reduced the lung metastasis by 85%. Elevated levels of hydroxyproline, uronic acid, hexosamine, serum sialic acid and g-GGT in metastatic control were found to be significantly reduced in crocin treated mice. Crocin also inhibited expression of MMP-2, MMP-9, ERK-2, K-ras, and VEGF. Crocin reduced the ability of B16F-10 cells invasion (P<0.05), migration (P<0.05) and adhesion by upregulating E-cadherin expression. In conclusion, crocin elicited marked anti-metastatic potential by regulating the metastasis induced biomarkers.
Systemic sclerosis (SSc) is a complex, multiorgan autoimmune disease of unknown etiology. Manifestation of the disease results from an interaction of three key pathologic features including irregularities of the antigen-specific immune system and the non-specific immune system, resulting in autoantibody production, vascular endothelial activation of small blood vessels, and tissue fibrosis as a result of fibroblast dysfunction. Given the heterogeneity of clinical presentation of the disease, a lack of universal models has impeded adequate testing of potential therapies for SSc. Regardless, recent research has elucidated the roles of various ubiquitous molecular mechanisms that contribute to the clinical manifestation of the disease. Transforming growth factor β (TGF-β) has been identified as a regulator of pathological fibrogenesis in SSc. Various processes, including cell growth, apoptosis, cell differentiation, and extracellular matrix synthesis are regulated by TGF-β, a type of cytokine secreted by macrophages and many other cell types. Understanding the essential role TGF-β pathways play in the pathology of systemic sclerosis could provide a potential outlet for treatment and a better understanding of this severe disease.