Factors associated with parametrial involvement in patients with stage IB1 cervical cancer: Who is suitable for less radical surgery?

OBJECTIVE: To detect the possible clinicopathologic factors associated with parametrial involvement in patients with stage IB1 cervical cancer and to identify a cohort of patients who may benefit from less radical surgery. METHODS: We retrospectively reviewed 120 patients who underwent radical hysterectomy and pelvic lymphadenectomy as treatment for stage IB1 cervical cancer. RESULTS: Overall, 18 (15.0%) patients had parametrial tumor involvement. Tumor size larger than 2 cm, invasion depth greater than 1 cm, presence of lymphovascular space involvement (LVSI), corpus involvement, and positive lymph nodes were statistically associated with parametrial involvement. Multivariate analysis for other factors showed invasion depth >1 cm (P=0.029), and corpus involvement (P=0.022) were significantly associated with parametrial involvement. A subgroup with tumor size smaller than 2 cm showed no parametrial involvement, regardless of invasion depth or presence of LVSI. CONCLUSION: Tumor size smaller than 2 cm showed no parametrial involvement, regardless of invasion depth or presence of LVSI. Invasion depth >1 cm and corpus involvement were significantly associated with parametrial involvement in multivariate analysis. These finding may suggest that tumor size may a strong predictor of parametrial involvement in International Federation of Gynecology and Obstetrics stage IB1 cervical cancer, which can be used to select a subgroup population for less radical surgery.

Suppression of MicroRNA let-7a Expression by Agmatine Regulates Neural Stem Cell Differentiation

PURPOSE: Neural stem cells (NSCs) effectively reverse some severe central nervous system (CNS) disorders, due to their ability to differentiate into neurons. Agmatine, a biogenic amine, has cellular protective effects and contributes to cellular proliferation and differentiation in the CNS. Recent studies have elucidated the function of microRNA let-7a (let-7a) as a regulator of cell differentiation with roles in regulating genes associated with CNS neurogenesis. MATERIALS AND METHODS: This study aimed to investigate whether agmatine modulates the expression of crucial regulators of NSC differentiation including DCX, TLX, c-Myc, and ERK by controlling let-7a expression. RESULTS: Our data suggest that high levels of let-7a promoted the expression of TLX and c-Myc, as well as repressed DCX and ERK expression. In addition, agmatine attenuated expression of TLX and increased expression of ERK by negatively regulating let-7a. CONCLUSION: Our study therefore enhances the present understanding of the therapeutic potential of NSCs in CNS disorders.

Suppression of MicroRNA let-7a Expression by Agmatine Regulates Neural Stem Cell Differentiation

PURPOSE: Neural stem cells (NSCs) effectively reverse some severe central nervous system (CNS) disorders, due to their ability to differentiate into neurons. Agmatine, a biogenic amine, has cellular protective effects and contributes to cellular proliferation and differentiation in the CNS. Recent studies have elucidated the function of microRNA let-7a (let-7a) as a regulator of cell differentiation with roles in regulating genes associated with CNS neurogenesis. MATERIALS AND METHODS: This study aimed to investigate whether agmatine modulates the expression of crucial regulators of NSC differentiation including DCX, TLX, c-Myc, and ERK by controlling let-7a expression. RESULTS: Our data suggest that high levels of let-7a promoted the expression of TLX and c-Myc, as well as repressed DCX and ERK expression. In addition, agmatine attenuated expression of TLX and increased expression of ERK by negatively regulating let-7a. CONCLUSION: Our study therefore enhances the present understanding of the therapeutic potential of NSCs in CNS disorders.

Apoptosis signal-regulating kinase 1 (ASK1) is linked to neural stem cell differentiation after ischemic brain injury

Neural stem cells (NSCs) have been suggested as a groundbreaking solution for stroke patients because they have the potential for self-renewal and differentiation into neurons. The differentiation of NSCs into neurons is integral for increasing the therapeutic efficiency of NSCs during inflammation. Apoptosis signal-regulating kinase 1 (ASK1) is preferentially activated by oxidative stress and inflammation, which is the fundamental pathology of brain damage in stroke. ASK1 may be involved in the early inflammation response after stroke and may be related to the differentiation of NSCs because of the relationship between ASK1 and the p38 mitogen-activated protein kinase pathway. Therefore, we investigated whether ASK1 is linked to the differentiation of NSCs under the context of inflammation. On the basis of the results of a microarray analysis, we performed the following experiments: western blot analysis to confirm ASK1, DCX, MAP2, phospho-p38 expression; fluorescence-activated cell sorting assay to estimate cell death; and immunocytochemistry to visualize and confirm the differentiation of cells in brain tissue. Neurosphere size and cell survival were highly maintained in ASK1-suppressed, lipopolysaccharide (LPS)-treated brains compared with only LPS-treated brains. The number of positive cells for MAP2, a neuronal marker, was lower in the ASK1-suppressed group than in the control group. According to our microarray data, phospho-p38 expression was inversely linked to ASK1 suppression, and our immunohistochemistry data showed that slight upregulation of ASK1 by LPS promoted the differentiation of endogenous, neuronal stem cells into neurons, but highly increased ASK1 levels after cerebral ischemic damage led to high levels of cell death. We conclude that ASK1 is regulated in response to the early inflammation phase and regulates the differentiation of NSCs after inflammatory-inducing events, such as ischemic stroke.

Treatment with MnTBAP Protects Against Early Nuclear Translocation of Endonuclease G and Reduces Cerebral Infarction after Focal Cerebral Ischemia/Reperfusion in Mice

BACKGROUND: Reactive Oxygen Species (ROS) have been implicated in the pathophysiology of brain injury after ischemia/reperfusion. Recently, it has been reported that endonuclease G (EndoG), a mitochondrial protein, is activated by neuronal excitotoxicity and translocated into nucleus inducing apoptosis. However, it is not elucidated whether ROS are involved in the nuclear translocation of EndoG in focal cerebral ischemia/reperfusion in mice. We investigated whether treatment of manganese tetrakis (4-benzoic acid) porphyrin (MnTBAP) protects against early nuclear translocation of EndoG and reduces cerebral infarction after ischemia/reperfusion in mice METHODS: Adult male mice were subjected to middle cerebral artery occlusion (MCAO) for 60 min, followed by reperfusion. Immunohistochemistry and Western blot analysis for EndoG were performed at various time points after ischemia/reperfusion. Double staining with EndoG and Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end-labeling (TUNEL) was also performed. MnTBAP was used to determine whether the production of ROS could inhibit translocation of EndoG into the nucleus. RESULTS: Western blot analysis and Immunohistochemistry of EndoG showed that nuclear EndoG was detected as early as 4 hrs after reperfusion, and mitochondrial EndoG was significantly reduced at the same time. Double staining with EndoG and TUNEL showed a spatial relationship between EndoG expression and DNA fragmentation. MnTBAP-treated mice showed that the translocation of EndoG was attenuated in comparison with the vehicle- treated mice and decreased infarction volume after ischemia/reperfusion. CONCLUSIONS: MnTBAP reduced the generation of ROS, and inhibited the early translocation of EndoG, which was followed by the reduction of infarction volume in the ischemic brain after ischemia/reperfusion.

Minocycline Inhibits Caspase-Dependent Cell Death Pathway and is Neuroprotective against Hippocampal Damage after Kainic Acid-Induced Seizure in Mice / 대한간질학회지

PURPOSE: Despite current acceptance of its neuroprotective property, whether the minocycline affords neuroprotection or how it protects neurons against seizures in the animal model of epilepsy is not clear. This prompts us to investigate whether minocycline is neuroprotective against kainic acid (KA)-induced seizure in mice through inhibition of caspase-dependent mitochondrial apoptotic pathways. METHODS: Adult male ICR mice were subjected to seizures by intrahippocampal KA injection with treatment of vehicle or minocycline. For cell death analysis, histological analysis using cresyl-violet staining, TdT-mediated dUTP-biotin nick end labeling (TUNEL), and histone-associated DNA fragmentation analysis were performed. Evaluation of cytochrome c, cleaved caspase-3, and caspase-3 activity were also performed. RESULTS: Hippocampal neuronal death was evident by cresyl violet staining, TUNEL, and cell death assay in vehicle-treated mice after KA injection; however, there was significant reduction of cell death in the minocycline-treated group. Significant decrease of both cytosolic translocation of cytochrome c and subsequent activation of caspase-3 after treatment of minocycline were demonstrated by Western blot analysis, immunohistochemical staining, and caspase-3 activity assay. CONCLUSION: This study suggests that minocycline may be neuroprotective against hippocampal damage after KA-induced seizure through inhibition of caspase-dependent cell death pathways.

The Role of MMP-9 on the Hippocampal Neuronal Cell Death and Mossy Fiber Sprouting due to Pilocarpine-Induced Status Epilepticus in Mice / 대한간질학회지

PURPOSE: Matrix metalloproteinases (MMPs) have been known to participate in various pathologic situations by modulating extracellular matrix. Although MMP-9 upregulation has been reported in some experimental seizure models, the exact role of MMP-9 in hippocampal cell death during epileptogenesis and subsequent mossy fiber sprouting (MFS) is not clear. Here, we investigated the role of MMP-9 on hippocampal cell death and MFS after pilocarpine-induced status epilepticus (SE) in mice, using highly specific hydroxamic MMP-9 inhibitor. METHODS: SE was induced by intraperitoneal pilocarpine administration in adult male C57BL/6 mice. MMP-9 specific inhibitor was administered intracerebroventrically 3 h after pilocarpine-induced SE. Expression and activation of MMP-9 were assessed by zymography and Western blot analysis. TdT-mediated UTP-biotin nick end labeling (TUNEL) and caspase-3 activity assay were also performed. MFS was investigated using Timm staining. RESULTS: Increased expression and activation of MMP-9 after pilocarpine-induced SE were observed in zymography and Western blot analysis. MMP-9 specific inhibitor decreased MMP-9 activity in in situ zymography and hippocampal cell death in cresyl violet staining. DNA fragmentation and caspase-3 activity were also attenuated by MMP-9 specific inhibitor. Four months after pilocarpine-induced SE, MFS was evident in vehicle-treated mice; in contrast, MFS was barely observed in MMP-9 specific inhibitor-treated mice. CONCLUSIONS: This study suggests MMP-9 is associated with hippocampal cell death and MFS after pilocarpine-induced SE. Furthermore, the findings that MMP-9 specific inhibitor ameliorates cell death and MFS offers the possibility of MMP-9 specific hydroxamic inhibitor as novel therapeutic strategy to reduce hippocampal damage and epileptogenesis.