Ethnic Differences in Survival after Breast Cancer in South East Asia

Background: The burden of breast cancer in Asia is escalating. We evaluated the impact of ethnicity on survival after breast cancer in the multi-ethnic region of South East Asia. Methodology/Principal Findings Using the Singapore-Malaysia hospital-based breast cancer registry, we analyzed the association between ethnicity and mortality following breast cancer in 5,264 patients diagnosed between 1990 and 2007 (Chinese: 71.6%, Malay: 18.4%, Indian: 10.0%). We compared survival rates between ethnic groups and calculated adjusted hazard ratios (HR) to estimate the independent effect of ethnicity on survival. Malays (n = 968) presented at a significantly younger age, with larger tumors, and at later stages than the Chinese and Indians. Malays were also more likely to have axillary lymph node metastasis at similar tumor sizes and to have hormone receptor negative and poorly differentiated tumors. Five year overall survival was highest in the Chinese women (75.8%; 95%CI: 74.4%–77.3%) followed by Indians (68.0%; 95%CI: 63.8%–72.2%), and Malays (58.5%; 95%CI: 55.2%–61.7%). Compared to the Chinese, Malay ethnicity was associated with significantly higher risk of all-cause mortality (HR: 1.34; 95%CI: 1.19–1.51), independent of age, stage, tumor characteristics and treatment. Indian ethnicity was not significantly associated with risk of mortality after breast cancer compared to the Chinese (HR: 1.14; 95%CI: 0.98–1.34). Conclusion: In South East Asia, Malay ethnicity is independently associated with poorer survival after breast cancer. Research into underlying reasons, potentially including variations in tumor biology, psychosocial factors, treatment responsiveness and lifestyle after diagnosis, is warranted

NMR Analysis of the Dynamic Exchange of the NS2B Cofactor between Open and Closed Conformations of the West Nile Virus NS2B-NS3 Protease

Dengue and West Nile virus infections put an estimated 2.5 billion people at risk. Neither drugs nor vaccines are currently available against these diseases. The non-structural protein NS3 is a protease that, together with the cofactor NS2B, is essential for viral maturation. The NS2B-NS3 proteases of dengue and West Nile viruses are highly homologous and present promising drug targets. Crystal structures of the West Nile virus protease with and without bound inhibitor revealed large structural differences in NS2B, while no crystal structure of the dengue virus protease could be determined with a bound inhibitor. We investigated the structural change in solution and found that the C-terminal segment (CTS) of the NS2B cofactor is prone to dissociation from NS3. In the case of the West Nile virus protease, the CTS of NS2B is mostly associated with NS3, especially in the presence of inhibitors. In the case of the dengue virus protease and in the absence of inhibitors, the CTS of NS2B is mostly dissociated from NS3. Finding drug candidates to inhibit the association of the NS2B cofactor may thus be easier for the dengue virus protease

Development of novel therapeutic strategies in spinal cord injury using rodent models of spinal cord compression injury

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

COX5B-Mediated Bioenergetic Alterations Modulate Cell Growth and Anticancer Drug Susceptibility by Orchestrating Claudin-2 Expression in Colorectal Cancers

Oxidative phosphorylation (OXPHOS) consists of four enzyme complexes and ATP synthase, and is crucial for maintaining physiological tissue and cell growth by supporting the main bioenergy pool. Cytochrome c oxidase (COX) has been implicated as a primary regulatory site of OXPHOS. Recently, COX subunit 5B (COX5B) emerged as a potential biomarker associated with unfavorable prognosis by modulating cell behaviors in specific cancer types. However, its molecular mechanism remains unclear, particularly in colorectal cancers (CRCs). To understand the role of COX5B in CRCs, the expression and postoperative outcome associations using independent in-house patient cohorts were evaluated. A higher COX5B tumor/nontumor expression ratio was associated with unfavorable clinical outcomes (p = 0.001 and 0.011 for overall and disease-free survival, respectively. In cell-based experiments, the silencing of COX5B repressed cell growth and enhanced the susceptibility of CRCs cells to anticancer drugs. Finally, downstream effectors identified by RNA sequencing followed by RT-qPCR and functional compensation experiments revealed that the tight junction protein Claudin-2 (CLDN2) acts downstream of COX5B-mediated bioenergetic alterations in controlling cell growth and the sensitivity to anticancer drugs in CRCs cells. In conclusion, it was found that COX5B promoted cell growth and attenuated anticancer drugs susceptibility in CRCs cells by orchestrating CLDN2 expression, which may contribute to unfavorable postoperative outcomes of patients with CRCs

The Influence of Bone Marrow-Secreted IL-10 in a Mouse Model of Cerulein-Induced Pancreatic Fibrosis

This study aimed to understand the role of IL-10 secreted from bone marrow (BM) in a mouse model of pancreatic fibrosis. The severity of cerulein-induced inflammation, fibrosis, and the frequency of BM-derived myofibroblasts were evaluated in the pancreas of mice receiving either a wild-type (WT) BM or an IL-10 knockout (KO) BM transplantation. The area of collagen deposition increased significantly in the 3 weeks after cerulein cessation in mice with an IL-10 KO BM transplant (13.7 ± 0.6% and 18.4 ± 1.1%, p < 0.05), but no further increase was seen in WT BM recipients over this time. The percentage of BM-derived myofibroblasts also increased in the pancreas of the IL-10 KO BM recipients after cessation of cerulein (6.7 ± 1.1% and 11.9 ± 1.3%, p < 0.05), while this figure fell in WT BM recipients after cerulein withdrawal. Furthermore, macrophages were more numerous in the IL-10 KO BM recipients than the WT BM recipients after cerulein cessation (23.2 ± 2.3 versus 15.3 ± 1.7 per HPF, p < 0.05). In conclusion, the degree of fibrosis, inflammatory cell infiltration, and the number of BM-derived myofibroblasts were significantly different between IL-10 KO BM and WT BM transplanted mice, highlighting a likely role of IL-10 in pancreatitis

Evaluation of cerebral blood flow in acute ischemic stroke patients with atrial fibrillation: A sonographic study

Although cerebral emboli are a frequent cause of cardiogenic stroke, the possibility of a reduction in cerebral perfusion consequent to arrhythmia or impaired cardiac function should be considered in patients with atrial fibrillation (AF). Methods: We reviewed sonographic studies and clinical features of patients with acute ischemic stroke. A total of 144 patients with AF and 144 age- and sex-matched patients with small vessel occlusion but without AF were included. Results: Patients with AF had significantly lower peak systolic velocity (PSV), mean velocity, flow volume (p < 0.001), and end-diastolic velocity (p = 0.035) of the internal carotid artery (ICA); significantly lower cerebral blood flow (p < 0.001); and lower flow velocities of the middle cerebral artery (p < 0.01) than patients with small vessel occlusion but without AF. In patients with AF, there was an inverse linear correlation between ICA end-diastolic velocity, mean velocity (p < 0.001), flow volume (p = 0.025), middle cerebral artery flow velocities (p < 0.05), and age. Cardiac ejection fraction had a positive linear correlation with ICA PSV (p = 0.016) but an inverse correlation with the heart rate (p = 0.009). There was a significant decline in PSV (p = 0.002), resistance index (p < 0.001), and flow volume (p = 0.0121) of the ICA as well as cerebral blood flow (p = 0.009) as the heart rate increased. Conclusion: Cerebral blood flow is markedly reduced in ischemic stroke patients with AF as compared with that in patients with small vessel disease but without AF

Omega-3 fatty acids and acute neurological trauma: a perspective on clinical translation

Acute neurological trauma remains one of the clinical areas with the most significant unmet needs worldwide. In the central nervous system, acute trauma has two stages: the primary injury and the secondary injury. The former is irreversible, and is a direct consequence of the impact. In the aftermath of the injury, a complex series of processes exacerbate the injury and amplify tissue damage. Some of these processes are local, others involve a systemic response. It is these processes which ultimately determine the clinical outcome. The aim of the treatments is a) to confer neuroprotection and b) to promote neuroregeneration. The results reported so far with omega-3 fatty acids in animal models of neurotrauma suggest that these compounds have the potential to offer a novel therapeutic approach and target both protection and regeneration. They lead to increased neuronal and glial survival, they can limit the damaging neuroinflammation and they can also protect neurites. Long chain omega-3 fatty acids such as eicosapentaenoic acid and docosahexaenoic acid have a complex pharmacodynamics, which leads potentially to the activation of a multitude of targets, including voltage and ligand-gated ion channels, transcription factors and G-protein coupled receptors. They can produce tissue-specific metabolites which have intrinsic activity, either on the same or on different cellular targets. The apparent large therapeutic window of omega-3 fatty acids is an advantage in the context of trauma, with patients in an unstable state, with multiple injuries. The specific use of omega-3 fatty acids in spinal cord injury and peripheral nerve injury will be discussed, focusing on issues which need to be addressed in order to translate successfully to the clinic the efficacy reported in the initial proof of concept animal studies

Omega-3 fatty acids and acute neurological trauma: a perspective on clinical translation*

Acute neurological trauma remains one of the clinical areas with the most significant unmet needs worldwide. In the central nervous system, acute trauma has two stages: the primary injury and the secondary injury. The former is irreversible, and is a direct consequence of the impact. In the aftermath of the injury, a complex series of processes exacerbate the injury and amplify tissue damage. Some of these processes are local, others involve a systemic response. It is these processes which ultimately determine the clinical outcome. The aim of the treatments is a) to confer neuroprotection and b) to promote neuroregeneration. The results reported so far with omega-3 fatty acids in animal models of neurotrauma suggest that these compounds have the potential to offer a novel therapeutic approach and target both protection and regeneration. They lead to increased neuronal and glial survival, they can limit the damaging neuroinflammation and they can also protect neurites. Long chain omega-3 fatty acids such as eicosapentaenoic acid and docosahexaenoic acid have a complex pharmacodynamics, which leads potentially to the activation of a multitude of targets, including voltage and ligand-gated ion channels, transcription factors and G-protein coupled receptors. They can produce tissue-specific metabolites which have intrinsic activity, either on the same or on different cellular targets. The apparent large therapeutic window of omega-3 fatty acids is an advantage in the context of trauma, with patients in an unstable state, with multiple injuries. The specific use of omega-3 fatty acids in spinal cord injury and peripheral nerve injury will be discussed, focusing on issues which need to be addressed in order to translate successfully to the clinic the efficacy reported in the initial proof of concept animal studies

Impact of an MT-RNR1 Gene Polymorphism on Hepatocellular Carcinoma Progression and Clinical Characteristics

Mitochondrial DNA (mtDNA) mutations are highly associated with cancer progression. The poor prognosis of hepatocellular carcinoma (HCC) is largely due to high rates of tumor metastasis. This emphasizes the urgency of identifying these patients in advance and developing new therapeutic targets for successful intervention. However, the issue of whether mtDNA influences tumor metastasis in hepatoma remains unclear. In the current study, multiple mutations in mtDNA were identified by sequencing HCC samples. Among these mutations, mitochondrially encoded 12S rRNA (MT-RNR1) G709A was identified as a novel potential candidate. The MT-RNR1 G709A polymorphism was an independent risk factor for overall survival and distant metastasis-free survival. Subgroup analysis showed that in patients with cirrhosis, HBV-related HCC, α-fetoprotein ≥ 400 ng/mL, aspartate transaminase ≥ 31 IU/L, tumor number > 1, tumor size ≥ 5 cm, and histology grade 3-4, MT-RNR1 G709A was associated with both shorter overall survival and distant metastasis-free survival. Mechanistically, MT-RNR1 G709A was clearly associated with hexokinase 2 (HK2) expression and unfavorable prognosis in HCC patients. Our data collectively highlight that novel associations among MT-RNR1 G709A and HK2 are an important risk factor in HCC patients

Optimizing treatment persistence in epilepsy: a comparative analysis of combined antiseizure medications with different mechanisms of action

Background: Combination therapy with antiseizure medications (ASMs) is a rational strategy if monotherapy cannot effectively control seizures, thereby aiming to improve tolerance and treatment persistence. Objectives: To compare the efficacy of different ASM combinations among patients. Design: Patients with epilepsy on monotherapy who had a second ASM added as concomitant two-drug therapy from January 2009 to May 2019 in the Chang Gung Research Database, Taiwan, were included in the analysis. Methods: ASM combinations were compared based on their primary mechanism of action (MoA) which are as follows: gamma-aminobutyric acid receptor (G), sodium channel blocker (SC), synaptic vesicle protein 2A (SV2), calcium channel blocker (C), and multiple mechanisms (M). Treatment persistence was compared, and the predictors of persistence were analyzed. Results: In total, 3033 patients were enrolled in this study. Combined ASMs with different MoAs had significantly longer treatment persistence than ASMs with similar MoAs, specifically SC and M combinations. Patients receiving combined ASMs with different MoAs were less likely to discontinue treatment [adjusted hazards ratio: 0.83 (95% CI: 0.75–0.93), p  < 0.001]. Among all combinations, the SC + SV2 combination had the longest treatment persistence (mean ± SD: 912.7 ± 841.6 days). Meanwhile, patients receiving the G combination had a higher risk of treatment discontinuation than those receiving the SC + SV2 combination. Underlying malignancies were associated with an increased risk of treatment discontinuation across all MoA categories. Male patients receiving the SC, SV2, and M combinations were more likely to discontinue treatment than female patients. Moreover, patients with renal disease were more likely to discontinue treatment with the SV2 combinations. Conclusion: ASM combinations with different MoAs had superior efficacy and tolerability to ASM combinations with similar MoAs, particularly SC and M combinations. In our cohort, factors associated with treatment discontinuation included underlying malignancy, male sex, and renal disease. These findings may provide valuable insights into the use of ASM combinations if monotherapy cannot adequately control seizures