Inhibition of ß-catenin signaling attenuates arteriovenous fistula thickening in mice by suppressing myofibroblasts.

BACKGROUND: Arteriovenous fistula (AVF) is the most important vascular access for hemodialysis; however, preventive treatment to maintain the patency of AVFs has not been developed. In endothelium, ß-catenin functions in both the intercellular adherens complex and signaling pathways that induce the transition of endothelial cells to myofibroblasts in response to mechanical stimuli. We hypothesize that mechanical disturbances in the AVF activate ß-catenin signaling leading to the transition of endothelial cells to myofibroblasts, which cause AVF thickening. The present study aimed to test this hypothesis. METHODS: Chronic kidney disease in mice was induced by a 0.2% adenine diet. AVFs were created by aortocaval puncture. Human umbilical vein endothelial cells (HUVECs) were used in the cell experiments. A pressure-culture system was used to simulate mechanical disturbances of the AVF. RESULTS: Co-expression of CD31 and smooth muscle alpha-actin (αSMA), loss of cell-cell adhesions, and the expression of the myofibroblast marker, integrin subunit ß6 (ITGB6), indicated transition to myofibroblasts in mouse AVF. Nuclear translocation of ß-catenin, decreased axin2, and increased c-myc expression were also observed in the AVF, indicating activated ß-catenin signaling. To confirm that ß-catenin signaling contributes to AVF lesions, ß-catenin signaling was inhibited with pyrvinium pamoate; ß-catenin inhibition significantly attenuated AVF thickening and decreased myofibroblasts. In HUVECs, barometric pressure-induced nuclear localization of ß-catenin and increased expression of the myofibroblast markers, αSMA and ITGB6. These changes were attenuated via pretreatment with ß-catenin inhibition. CONCLUSIONS: The results of this study indicate that mechanical disturbance in AVF activates ß-catenin signaling to induce the transition of endothelial cells to myofibroblasts. This signaling cascade can be targeted to maintain AVF patency.

Enzalutamide Induces Apoptotic Insults to Human Drug-Resistant and -Sensitive Glioblastoma Cells via an Intrinsic Bax-Mitochondrion-Cytochrome C Caspase Cascade Activation Pathway.

Glioblastoma multiforme (GBM) is the most common and malignant brain tumor. Temozolomide (TMZ) is the first-line chemotherapeutic drug for treating GBM. However, drug resistance is still a challenging issue in GBM therapy. Our preliminary results showed upregulation of androgen receptor (AR) gene expression in human GBM tissues. This study was designed to evaluate the effects of enzalutamide, a specific inhibitor of the AR, on killing drug-resistant and -sensitive glioblastoma cells and the possible mechanisms. Data mining from The Cancer Genome Atlas (TCGA) database revealed upregulation of AR messenger (m)RNA and protein expressions in human GBM tissues, especially in male patients, compared to normal human brains. In addition, expressions of AR mRNA and protein in human TMZ-sensitive U87 MG and -resistant U87 MG-R glioblastoma cells were elevated compared to normal human astrocytes. Exposure of human U87 MG and U87 MG-R cells to enzalutamide concentration- and time-dependently decreased cell viability. As to the mechanism, enzalutamide killed these two types of glioblastoma cells via an apoptotic mechanism. Specifically, exposure to enzalutamide augmented enzyme activities of caspase-9 rather than those of caspase-8. Moreover, enzalutamide successively triggered an elevation in levels of the proapoptotic Bax protein, a reduction in the mitochondrial membrane potential, release of cytochrome c, cascade activation of caspases-3 and -6, DNA fragmentation, and cell apoptosis in human TMZ-sensitive and -resistant glioblastoma cells. Pretreatment with Z-VEID-FMK, an inhibitor of caspase-6, caused significant attenuations in enzalutamide-induced morphological shrinkage, DNA damage, and apoptotic death. Taken together, this study showed that enzalutamide could significantly induce apoptotic insults to human drug-resistant and -sensitive glioblastoma cells via an intrinsic Bax-mitochondrion-cytochrome c-caspase cascade activation pathway. Enzalutamide has the potential to be a drug candidate for treating GBM by targeting the AR signaling axis.

Inadequate dietary energy intake associates with higher prevalence of metabolic syndrome in different groups of hemodialysis patients: a clinical observational study in multiple dialysis centers.

BACKGROUND: Metabolic syndrome (MetS) has been established as a risk for cardiovascular diseases and mortality in hemodialysis patients. Energy intake (EI) is an important nutritional therapy for preventing MetS. We examined the association of self-reported dietary EI with metabolic abnormalities and MetS among hemodialysis patients. METHODS: A cross-sectional study design was carried out from September 2013 to April 2017 in seven hemodialysis centers. Data were collected from 228 hemodialysis patients with acceptable EI report, 20 years old and above, underwent three hemodialysis sessions a week for at least past 3 months. Dietary EI was evaluated by a three-day dietary record, and confirmed by 24-h dietary recall. Body compositions were measured by bioelectrical impedance analysis. Biochemical data were analyzed using standard laboratory tests. The cut-off values of daily EI were 30 kcal/kg, and 35 kcal/kg for age ≥ 60 years and < 60 years, respectively. MetS was defined by the American Association of Clinical Endocrinologists (AACE-MetS), and Harmonizing Metabolic Syndrome (HMetS). Logistic regression models were utilized for examining the association between EI and MetS. Age, gender, physical activity, hemodialysis vintage, Charlson comorbidity index, high sensitive C-reactive protein, and interdialytic weight gains were adjusted in the multivariate analysis. RESULTS: The prevalence of inadequate EI, AACE-MetS, and HMetS were 60.5%, 63.2%, and 53.9%, respectively. Inadequate EI was related to higher proportion of metabolic abnormalities and MetS (p <  0.05). Results of the multivariate analysis shows that inadequate EI was significantly linked with higher prevalence of impaired fasting glucose (OR = 2.42, p <  0.01), overweight/obese (OR = 6.70, p <  0.001), elevated waist circumference (OR = 8.17, p <  0.001), AACE-MetS (OR = 2.26, p <  0.01), and HMetS (OR = 3.52, p <  0.01). In subgroup anslysis, inadequate EI strongly associated with AACE-MetS in groups of non-hypertension (OR = 4.09, p = 0.004), and non-cardiovascular diseases (OR = 2.59, p = 0.012), and with HMetS in all sub-groups of hypertension (OR = 2.59~ 5.33, p <  0.05), diabetic group (OR = 8.33, p = 0.003), and non-cardiovascular diseases (OR = 3.79, p <  0.001). CONCLUSIONS: Inadequate EI and MetS prevalence was high. Energy intake strongly determined MetS in different groups of hemodialysis patients.

Peroxisome Proliferator-Activated Receptor α Protects Renal Tubular Cells from Gentamicin-Induced Apoptosis via Upregulating Na+/H+ Exchanger NHE1.

Peroxisome proliferator-activated receptor (PPAR)-α is a transcription factor that has been reported to inhibit gentamicin-induced apoptosis in renal tubular cells. However, the antiapoptotic mechanism of PPARα is still unknown. In this study, we found that PPARα overexpression induced Na+/H+ exchanger-1 (NHE1) expression in the rat renal tubular cells NRK-52E. Beraprost, a PPARα ligand, also increased NHE1 expression in the renal tubules in normal mice, but not in PPARα knockout mice. Chromatin immunoprecipitation assays revealed that two PPARα binding elements were located in the rat NHE1 promoter region. Na+/H+ exchanger activity also increased in the PPARα-overexpressed cells. Flow cytometry showed that the PPARα-overexpressed cells were resistant to apoptosis-induced shrinkage. Cariporide, a selective NHE1 inhibitor, inhibited the antiapoptotic effect of PPARα in the gentamicin-treated cells. The interaction between NHE1 and ezrin/radixin/moesin (ERM) and between ERM and phosphatidylinositol 4,5-bisphosphate in the PPARα-overexpressed cells was more than in the control cells. ERM short interfering RNA (siRNA) transfection inhibited the PPARα-induced antiapoptotic effect. PPARα overexpression also increased the phosphoinositide 3-kinase (PI3K) expression, which is dependent on NHE1 activity. Increased PI3K further increased the phosphorylation of the prosurvival kinase Akt in the PPARα-overexpressed cells. Wortmannin, a PI3K inhibitor, inhibited PPARα-induced Akt activity and the antiapoptotic effect. We conclude that PPARα induces NHE1 expression and then recruits ERM to promote PI3K/Akt-mediated cell survival in renal tubular cells. The application of PPARα activation reduces the nephrotoxicity of gentamicin and may expand the clinical use of gentamicin.

Magnolol Inhibits RANKL-induced osteoclast differentiation of raw 264.7 macrophages through heme oxygenase-1-dependent inhibition of NFATc1 expression.

Magnolol (1) isolated from Magnolia officinalis exhibits many beneficial effects such as anti-inflammatory and antioxidant activity. The aim of this study was to evaluate the effects of magnolol (1) on RANKL-induced osteoclast differentiation and investigate the underlying molecular mechanisms. Treatment with magnolol (1) significantly inhibited osteoclast differentiation of RAW 264.7 macrophages and bone-resorbing activity of osteoclasts in the RANKL-induced system. Moreover, RANKL-activated JNK/ERK/AP-1 and NF-κB signaling, ROS formation, and NFATc1 activation were attenuated by magnolol (1). A novel finding of this study is that magnolol (1) can increase heme oxygenase-1 (HO-1) expression and Nrf2 activation in RANKL-stimulated cells. Blocking HO-1 activity with tin protoporphyrin IX markedly reversed magnolol (1)-mediated inhibition of osteoclast differentiation, NFATc1 nuclear translocation, and MMP-9 activity, suggesting that HO-1 contributes to the attenuation of NFATc1-mediated osteoclastogenesis by magnolol (1). Therefore, the inhibitory effect of magnolol (1) on osteoclast differentiation is due to inhibition of MAPK/c-fos/AP-1 and NF-κB signaling as well as ROS production and up-regulation of HO-1 expression, which ultimately suppresses NFATc1 induction. These findings indicate that magnolol (1) may have potential to treat bone diseases associated with excessive osteoclastogenesis.

High-volume plasma exchange in a patient with acute liver failure due to non-exertional heat stroke in a sauna.

Heat stroke is a life-threatening condition characterized by an increased core body temperature (over 40°C) and a systemic inflammatory response, which may lead to a syndrome of multiple organ dysfunction. Heat stroke may be due to either strenuous exercise or non-exercise-induced exposure to a high environmental temperature. Current management of heat stroke is mostly supportive, with an emphasis on cooling the core body temperature and preventing the development of multiple organ dysfunction. Prognosis of heat stroke depends on the severity of organ involvement. Here, we report a rare case of non-exercise-induced heat stroke in a 73-year-old male patient who was suffering from acute liver failure after prolonged exposure in a hot sauna room. We successfully managed this patient by administering high-volume plasma exchange, and the patient recovered completely after treatment.

Association between the hemodialysis eating index and risk factors of cardiovascular disease in hemodialysis patients.

OBJECTIVE: In this study, a Hemodialysis Eating Index (HDEI) suitable for hemodialysis (HD) patients in Taiwan was developed based on the dietary recommendations of the U.S. National Kidney Foundation for HD patients and the Taiwanese 2011 Daily Food Guide. The HDEI was used to explore HD-associated cardiovascular disease (CVD) risk factors. METHODS: In this prospective study, 108 HD patients from 2 HD centers in Taiwan were recruited as participants in 2010. All participants were older than 20 years. Patient CVD risk factor and 3-day dietary data were collected, and their HDEI scores were calculated. The HDEI scores comprise 12 food-related factors: the consumption of vegetables, fruits, total grains, whole grains, high-protein foods, high biological values, red and white meat, fish, oils, saturated fatty acids or trans fatty acids, nuts, and the duration of multivitamin use. The scores ranged from 5 to 100, and SAS software version 9.3 was used to perform statistical analyses. A P value less than .05 was considered statistically significant. RESULTS: The HDEI scores and serum albumin (Alb) levels were significantly and positively correlated. The participants were divided into 2 groups on the basis of the median HDEI score of 72.2. Two months after HDEI evaluation, the high-HDEI scoring group exhibited significantly decreased levels of serum total cholesterol and increased hemoglobin (Hb) levels. CONCLUSION: The HDEI can be used to reflect selected nutritional status markers, such as Alb and Hb levels and CVD risk factors, for HD patients. The HDEI can also serve as an eating index for HD patients in Taiwan to facilitate CVD prevention.

The Ratio of Plasma Amyloid-ß 1-42 over Serum Albumin Can Be a Novel Biomarker Signature for Diagnosing End-Stage Renal Disease-Associated Cognitive Impairment.

BACKGROUND: Cognitive impairment (CI) is one of the major complications in chronic kidney disease patients, especially those with end-stage renal disease (ESRD). Limited biomarkers have been found that can significantly predict ESRD-associated cognitive decline. OBJECTIVE: This cohort study aimed to investigate de novo biomarkers for diagnosis of the ESRD-associated CI. METHODS: In this cohort study, qualified samples were divided into control (with an estimated glomerular filtration rate (eGFR) of≥60 mL/min and a Mini-Mental State Examination (MMSE) score of > 27), ESRD without CI (eGFR < 15 and MMSE > 27), and ESRD with CI (eGFR < 15 and MMSE < 27) groups. Levels of plasma amyloid-ß (Aß)1 - 42, serum indoxyl sulfate, and hematologic and biochemical parameters were measured. RESULTS: Compared to the control group, levels of blood urea nitrogen, creatinine, and indoxyl sulfate were elevated in ESRD patients both without and with CI. Interestingly, ESRD patients with CI had the lowest levels of serum albumin. In contrast, levels of plasma Aß1 - 42 were significantly higher in the ESRD with CI group than in the control and ESRD without CI groups. In addition, the ratio of plasma Aß1 - 42 over serum albumin was significantly higher in the ESRD with CI group than in the control or ESRD without CI groups. Importantly, the area under the receiver operating characteristic curve (AUROC) for CI in the total population by the ratio of Aß1 - 42 over albumin was 0.785 and significant (p < 0.05). CONCLUSIONS: This cohort study has shown that the ratio of plasma Aß1 - 42 over serum albumin can be a de novo biomarker for the diagnosis and prognosis of ESRD-associated cognitive decline.

Successful treatment of drug-induced acute liver failure with high-volume plasma exchange.

We report two patients with drug-induced liver injury (DILI)-related acute liver failure (ALF) who were successfully treated with high-volume plasma exchange without liver transplantation. The first patient was a 66-year-old man admitted because of a perforated duodenal ulcer complicated with peritonitis and septic shock. After treatment with multiple antibiotics, the patient developed DILI and ALF. Grade 3 hepatic encephalopathy and profound jaundice were present. Symptoms and signs of ALF improved dramatically after initiation of plasma exchange. The patient was discharged uneventfully. The second patient was a 94-year-old man admitted for treatment of newly diagnosed pulmonary tuberculosis. DILI and ALF developed 5 days after initiation of anti-tuberculosis treatment. Grade 4 hepatic encephalopathy was present. After plasma exchange, the patient's level of consciousness improved dramatically, and he recovered from ALF. These 2 cases show the potential of plasma exchange in the treatment of DILI despite occurrence acute liver failure.

Exploring the Relevance between Gut Microbiota-Metabolites Profile and Chronic Kidney Disease with Distinct Pathogenic Factor.

The intimate correlation of chronic kidney disease (CKD) with structural alteration in gut microbiota or metabolite profile has been documented in a growing body of studies. Nevertheless, a paucity of demonstrated knowledge regarding the impact and underlying mechanism of gut microbiota or metabolite on occurrence or progression of CKD is unclarified thus far. In this study, a liquid chromatography coupled-mass spectrometry and long-read sequencing were applied to identify gut metabolites and microbiome with statistically-discriminative abundance in diabetic CKD patients (n = 39), hypertensive CKD patients (n = 26), or CKD patients without comorbidity (n = 40) compared to those of healthy participants (n = 60). The association between CKD-related species and metabolite was evaluated by using zero-inflated negative binomial (ZINB) regression. The predictive utility of identified operational taxonomic units (OTUs), metabolite, or species-metabolite association toward the diagnosis of incident chronic kidney disease with distinct pathogenic factor was assessed using the random forest regression model and the receiver operating characteristic (ROC) curve. The results of statistical analyses indicated alterations in the relative abundances of 26 OTUs and 41 metabolites that were specifically relevant to each CKD-patient group. The random forest regression model with only species, metabolites, or its association differentially distinguished the hypertensive, diabetic CKD patients, or enrolled CKD patients without comorbidity from the healthy participants. IMPORTANCE Gut dysbiosis-altered metabolite association exhibits specific and convincing utility to differentiate CKD associated with distinct pathogenic factor. These results present the validity of pathogenesis-associated markers across healthy participants and high-risk population toward the early screening, prevention, diagnosis, or personalized treatment of CKD.

Resveratrol triggers the ER stress-mediated intrinsic apoptosis of neuroblastoma cells coupled with suppression of Rho-dependent migration and consequently prolongs mouse survival.

Neuroblastoma, the most common childhood tumor, are highly malignant and fatal because neuroblastoma cells extremely defend against apoptotic targeting. Traditional treatments for neuroblastomas are usually ineffective and lead to serious side effects and poor prognoses. In this study, we investigated the molecular mechanisms of resveratrol-induced insults to neuroblastoma cells and survival extension of nude mice with neuroblastomas, especially in the endoplasmic reticular (ER) stress-intracellular reactive oxygen species (iROS) axis-mediated signals. Resveratrol specifically killed neuroblastoma cells mainly via apoptosis and autophagy rather than necrosis. As to the mechanisms, resveratrol time-dependently triggered productions of Grp78 protein and iROS in neuroblastoma cells. Attenuating the ER stress-iROS signaling axis significantly suppressed resveratrol-induced autophagy, DNA damage, and cell apoptosis. Successively, resveratrol decreased phosphorylation of retinoblastoma protein and induced cell cycle arrest at the S phase, translocation of Bak protein to mitochondria, a reduction in the mitochondrial membrane potential, cascade activation of caspases-9, -3, and -6, and DNA fragmentation. Moreover, weakening the ER stress-iROS axis concomitantly overcome resveratrol-induced decreases in translocation of Rho protein to membranes and succeeding cell migration. Interestingly, administration of resveratrol did not cause significant side effects but could protect the neuroblastoma-bearing nude mice from body weight loss and consequently extended the animal survival. In parallel, resveratrol elevated levels of Grp78 and then induced cell apoptosis in neuroblastoma tissues. This study has shown that resveratrol could kill neuroblastoma cells and extend survival of animals with neuroblastomas by triggering the ER stress-iROS-involved intrinsic apoptosis and suppression of Rho-dependent cell migration. Our results imply the potential of resveratrol as a drug candidate for chemotherapy of neuroblastoma patients.

Intestinal paragonimiasis with colonic ulcer and hematochezia in an elderly Taiwanese woman.

A 94-year-old female with end-stage renal disease presents with fever, fatigue, and hematochezia. She had previously resided in Hunan Province, China, and Myanmar, and she immigrated to Taiwan 30 years ago. Colonoscopy revealed a colonic ulcer. Biopsy of the colonic ulcer showed ulceration of the colonic mucosa, and many Paragonimus westermani-like eggs were noted. Serum IgG antibody levels showed strong reactivity with P. westermani excretory-secretory antigens by ELISA. Intestinal paragonimiasis was thus diagnosed according to the morphology of the eggs and serologic finding. After treatment with praziquantel, hematochezia resolved. The present case illustrates the extreme manifestations encountered in severe intestinal paragonimiasis.

Oligosaccharides Ameliorate Acute Kidney Injury by Alleviating Cluster of Differentiation 44-Mediated Immune Responses in Renal Tubular Cells.

Acute kidney injury (AKI) is a sudden episode of kidney damage that commonly occurs in patients admitted to hospitals. To date, no ideal treatment has been developed to reduce AKI severity. Oligo-fucoidan (FC) interferes with renal tubular cell surface protein cluster of differentiation 44 (CD44) to prevent renal interstitial fibrosis; however, the influence of oligosaccharides on AKI remains unknown. In this study, FC, galacto-oligosaccharide (GOS), and fructo-oligosaccharide (FOS) were selected to investigate the influence of oligosaccharides on AKI. All three oligosaccharides have been proven to be partially absorbed by the intestine. We found that the oligosaccharides dose-dependently reduced CD44 antigenicity and suppressed the hypoxia-induced expression of CD44, phospho-JNK, MCP-1, IL-1ß, and TNF-α in NRK-52E renal tubular cells. Meanwhile, CD44 siRNA transfection and JNK inhibitor SP600125 reduced the hypoxia-induced expression of phospho-JNK and cytokines. The ligand of CD44, hyaluronan, counteracted the influence of oligosaccharides on CD44 and phospho-JNK. At 2 days post-surgery for ischemia-reperfusion injury, oligosaccharides reduced kidney inflammation, serum creatine, MCP-1, IL-1ß, and TNF-α in AKI mice. At 7 days post-surgery, kidney recovery was promoted. These results indicate that FC, GOS, and FOS inhibit the hypoxia-induced CD44/JNK cascade and cytokines in renal tubular cells, thereby ameliorating AKI and kidney inflammation in AKI mice. Therefore, oligosaccharide supplementation is a potential healthcare strategy for patients with AKI.

Effect of Different Nutritional Education Based on Healthy Eating Index for HemoDialysis Patients on Dietary Quality and Muscle Mass.

BACKGROUND: Hemodialysis patients are at high risk of muscle loss as a result of aging and disease, and combined with inadequate dietary intake. The Healthy Eating Index for HemoDialysis patients (HEI-HD) was developed to assess the dietary quality of hemodialysis patients. The purposes of this study were to examine the effects of different nutritional education models using HEI-HD-based education on dietary quality and muscle mass in hemodialysis patients. METHODS: A quasi-experimental study was conducted from May 2019 to April 2021, with four groups, including no course for patients and nurses (Non-C), course for nurses (CN), course for patients (CP), and course for patients and nurses (CPN). The courses were delivered by registered dietitians. The data of 94 patients were collected and analyzed at baseline, after 2 months of intervention, and 2 months follow-up, including demographics, body composition, 3-day dietary records, and hemodialysis dietary knowledge. The HEI-HD index score was calculated. RESULTS: Patients aged 58.3 ± 10.1 years. The dietary quality change in the CPN group was improved as compared with the Non-C group (-3.4 ± 9.5 vs. 3.0 ± 5.5, 0.04). The skeletal muscle mass of the Non-C group at intervention was also significantly lower than baseline, but the CPN group was not. CONCLUSIONS: The HEI-HD-based nutritional education for both patients and nurses showed a positive effect on improving the dietary quality and maintaining muscle mass in hemodialysis patients.

The Effect of Different Nutritional Education Models on Reducing Cardiovascular Disease Risk Factors by Improving Dietary Fat Quality in Hemodialysis Patients.

Cardiovascular disease (CVD) is the most common complication in hemodialysis patients. Nutritional education provided by dietitians could improve overall dietary quality and dietary fat quality to reduce the risk of CVD. However, no studies have investigated the relationship between dietary fat quality (using the hypocholesterolemic/hypercholesterolemic ratio, or the h/H) and CVD risk factors in hemodialysis patients. The aim of this study was to examine the association between the h/H and CVD risk factors, and further explore how nutritional education intervention models could improve dietary fat quality and CVD risk factors in hemodialysis patients. A quasi-experimental design was conducted from May 2019 to April 2021 on four groups, including 'no course for patients and nurses' as the non-C group, a "course for nurses" as the CN group, a "course for patients" as the CP group, and a "course for patients and nurses" as the CPN group. Nutritional education booklets based on a healthy eating index for hemodialysis patients were developed and provided to patients and nurses. Data of 119 patients were collected at baseline, intervention, and follow-up periods, including patients' basic information, blood biochemical data, dietary content, and calculated h/H. The results showed that the h/H was negatively correlated with body mass index (BMI) and positively correlated with high-density lipoprotein cholesterol (HDL-C). Compared with the non-C group, the CPN group was significantly higher in the h/H as well as HDL-C, and significantly lower in serum total cholesterol. In conclusion, the h/H was found to predict CVD risk factors, which helps in improving dyslipidemia. Nutritional education for both patients and nurses showed a beneficial impact on reducing CVD risks in hemodialysis patients.

The Humoral Immune Response of the ChAdOx1 nCoV-19 Vaccine in Maintenance Dialysis Patients without Prior COVID-19 Infection.

BACKGROUND: Chronic kidney disease (CKD) patients tend to have a reduced immune response to infection and vaccination. The efficacy of current available COVID-19 vaccines in CKD patients has not been widely evaluated. METHODS: In the present study, three hundred and eight chronic dialysis patients received ChAdOx1 nCoV-19 (Oxford-AstraZeneca, AZ). Blood tests using an antibody against the receptor-binding domain (RBD) of the S1 subunit of the SARS-CoV-2 spike protein had performed at four designed time points before and after the first and second vaccine. RESULTS: The mean age of patients was 65.5 ± 12.38 years, and the male/female ratio was 61.4%:38.6% (189/119). Two weeks after the first vaccination, only 37.66% of patients had a positive antibody response (>50 AU/mL). However, 65.58% of the participants showed a delayed antibody response ten weeks after the first vaccine. Four weeks after the second vaccine, 94.16% of participants had positive antibody levels. Age was the most significant factor associated with antibody response. Flow cytometry analysis revealed that immune-naïve patients had significantly lower early active B cells and proliferative B cells than the age- and sex-matched immune responders. CONCLUSION: Despite a delayed response, 94.16% of chronic dialysis patients achieved a positive antibody response after two doses of the AZ vaccine. Age is the most significant factor associated with antibody response.

Luminal pressure gradient and risk of arteriovenous fistula nonmaturation.

While arteriovenous fistula (AVF) nonmaturation is a major issue of hemodialysis care, an effective treatment to improve AVF maturation remains lacking. AVF introduces pulsatile arterial blood flow into its venous limb and produces high luminal pressure gradient, which may have adverse effect on vascular remodeling. As such, the aim of the present study is to investigate effect of luminal pressure gradient on AVF nonmaturation. This single-center, prospective observational study includes patients receiving autologous AVF creation. Participants received early postoperative ultrasound 5-7 days after surgery to collect parameters including diameters, flow rates, and volume at inflow and outflow sites. Luminal pressure gradient was estimated by using modified Bernoulli equation. The outcome was spontaneous AVF maturation within 8 weeks after surgery without intervention. Thirty patients were included, of which the mean age was 66.9 years and 70% were male. At the end of study, 13 (43.3%) patients had spontaneous AVF maturation. All demographic and laboratory characteristics were similar between patients with mature and nonmature AVF. Regarding ultrasonographic parameters, nonmature AVF showed significantly higher inflow/outflow diameter ratio, inflow velocity, and luminal pressure gradient. While these 3 parameters were significantly correlated, multivariate logistic regression showed their significant association with AVF nonmaturation. Receiver operating characteristic curve exhibited their high predictive value for AVF nonmaturation. Our findings showed that higher inflow/outflow ratio, inflow velocity, and AVF luminal pressure gradient in early postoperative ultrasound predicted risk of AVF nonmaturation. Reducing inflow/outflow diameter ratio or inflow rate may be an approach to improve AVF maturation. The predictive value of this early assessment might have impact on the clinical practice of AVF care.

Podocalyxin EBP50 ezrin molecular complex enhances the metastatic potential of renal cell carcinoma through recruiting Rac1 guanine nucleotide exchange factor ARHGEF7.

Podocalyxin was initially identified in glomerular podocytes to critically maintain the structural and functional integrity of the glomerular ultrafiltrative apparatus. Lately, it has emerged as a malignant marker in tumors arising from a variety of tissue origins. By immunohistochemistry, we identified that 9.6% of renal cell carcinoma patients overexpress this protein. This subset of patients had significantly shorter disease-specific and overall survivals, and, importantly, we established podocalyxin overexpression as an independent prognostic factor for latent distant metastasis with multivariate analysis. Podocalyxin down-regulation by small interfering RNA led to defective migration in model renal tubular cells, which was corrected by re-expression of podocalyxin. The activity of the small GTPase Rac1, a well-characterized modulator of cell migration, was diminished by podocalyxin knock-down. Conversely, podocalyxin overexpression in human embryonic kidney cells up-regulated Rac1 activity, which depended on a complex formed by podocalyxin, ERM-binding phosphoprotein 50, ezrin, and ARHGEF7, a Rac1 activator. Therefore, podocalyxin can serve as a biomarker to identify renal cell carcinoma patients with higher metastatic potential for more aggressive intervention at earlier clinical stages.

Nephrotoxicity of vancomycin in patients with methicillin-resistant Staphylococcus aureus bacteraemia.

AIM: Vancomycin and teicoplanin are the two most used glycopeptides for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin is suspected to have more nephrotoxicity but this has not been clearly established. The aim of this study was to assess its nephrotoxicity by a consensus definition of acute kidney injury (AKI): the risk (R), injury (I), failure (F), loss and end-stage renal disease (RIFLE) classification. METHODS: Patients with MRSA bacteraemia who were prescribed either vancomycin or teicoplanin between 2003 and 2008 were classified. Patients who developed AKI were classified by RIFLE criteria. Variables such as comorbidities, laboratory data and medical cost information were also obtained from the database. Outcomes determined were: (i) the rate of nephrotoxicity and mortality; and (ii) the association of nephrotoxicity with the length of hospital stay and costs. RESULTS: The study included 190 patients (vancomycin 33, teicoplanin 157). Fifteen patients on vancomycin and 27 patients on teicoplanin developed AKI (P = 0.0004). In the vancomycin group, four, eight and three patients were classified to RIFLE criteria R, I and F, respectively. In the teicoplanin group, 17, nine and one patient were classified to RIFLE criteria R, I and F, respectively. Kaplan-Meier analysis showed significant difference in time to nephrotoxicity for the vancomycin group compared to the teicoplanin group. No significant differences were found between the groups in terms of total mortality, length of hospital stay and costs. CONCLUSION: The study data suggest that vancomycin is associated with a higher likelihood of nephrotoxicity using the RIFLE classification.

Involvement of microRNA in Solid Cancer: Role and Regulatory Mechanisms.

MicroRNAs (miRNAs) function as the post-transcriptional factor that finetunes the gene expression by targeting to the specific candidate. Mis-regulated expression of miRNAs consequently disturbs gene expression profile, which serves as the pivotal mechanism involved in initiation or progression of human malignancy. Cancer-relevant miRNA is potentially considered the therapeutic target or biomarker toward the precise treatment of cancer. Nevertheless, the regulatory mechanism underlying the altered expression of miRNA in cancer is largely uncovered. Detailed knowledge regarding the influence of miRNAs on solid cancer is critical for exploring its potential of clinical application. Herein, we elucidate the regulatory mechanism regarding how miRNA expression is manipulated and its impact on the pathogenesis of distinct solid cancer.