Rab25 suppresses colon cancer cell invasion through upregulating claudin­7 expression.

Ras­related protein 25 (Rab25) is a member of small GTPase and is implicated in cancer cell progression of various types of cancer. Growing evidence suggests the context­dependent role of Rab25 in cancer invasiveness. Claudin­7 is a tight junction protein and has been known to suppress cancer cell invasion. Although Rab25 was reported to repress cancer aggressiveness through recycling ß1 integrin to the plasma membrane, the detailed underlying mechanism remains to be elucidated. The present study identified the critical role of claudin­7 in Rab25­induced suppression of colon cancer invasion. 3D Matrigel system and modified Boyden chamber analysis showed that enforced expression of Rab25 attenuated colon cancer cell invasion. In addition, Rab25 inactivated epidermal growth factor receptor (EGFR) and increased E­cadherin expression. Unexpectedly, it was observed that Rab25 induces claudin­7 expression through protein stabilization. In addition, ectopic claudin­7 expression reduced EGFR activity and Snail expression as well as colon cancer cell invasion. However, silencing of claudin­7 expression reversed the tumor suppressive role of Rab25, thereby increasing colon cancer cell invasiveness. Collectively, the present data indicated that Rab25 inactivates EGFR and colon cancer cell invasion by upregulating claudin­7 expression.

Comparison of the association intensity of creatinine and cystatin C with hyperphosphatemia and hyperparathyroidism in patients with chronic kidney disease.

Herein, we compared the association intensity of estimated glomerular filtration rate (eGFR) equations using creatinine (Cr) or cystatin C (CysC) with hyperphosphatemia and secondary hyperparathyroidism occurrence, which reflect the physiological changes occurring during chronic kidney disease (CKD) progression. This study included 639 patients treated between January 2019 and February 2022. The patients were divided into low- and high-difference groups based on the median value of the difference between the Cr-based eGFR (eGFRCr) and CysC-based eGFR (eGFRCysC). Sociodemographic and laboratory factors underlying a high difference between eGFRCr and eGFRCysC were analyzed. The association intensity of eGFRCr, eGFRCysC and both Cr- and CysC-based eGFR (eGFRCr-CysC) was compared using the area under the receiver operating characteristic curve (AuROC) values for hyperphosphatemia and hyperparathyroidism occurrence in the overall cohort and the low- and high-difference groups. Age > 70 years and CKD grade 3 based on eGFRCr were significant factors affecting the high differences. eGFRCysC and eGFRCr-CysC showed higher AuROC values than that of eGFRCr, especially in the high-difference group and in patients with CKD grade 3. Our results show that CysC should be evaluated in patients with significant factors, including age > 70 years and CKD grade 3, to accurately assess kidney function to better determine the physiological changes in CKD progression and predict prognosis accurately.

Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation.

Introduction: Tacrolimus (TAC) has been widely used as an immunosuppressant after kidney transplantation (KT); however, the combined effects of intra-patient variability (IPV) and inter-patient variability of TAC-trough level (C0) in blood remain controversial. This study aimed to determine the combined impact of TAC-IPV and TAC inter-patient variability on allograft outcomes of KT. Methods: In total, 1,080 immunologically low-risk patients who were not sensitized to donor human leukocyte antigen (HLA) were enrolled. TAC-IPV was calculated using the time-weighted coefficient variation (TWCV) of TAC-C0, and values > 30% were classified as high IPV. Concentration-to-dose ratio (CDR) was used for calculating TAC inter-patient variability, and CDR < 1.05 ng•mg/mL was classified as rapid metabolizers (RM). TWCV was calculated based on TAC-C0 up to 1 year after KT, and CDR was calculated based on TAC-C0 up to 3 months after KT. Patients were classified into four groups according to TWCV and CDR: low IPV/non-rapid metabolizer (NRM), high IPV/NRM, low IPV/RM, and high IPV/RM. Subgroup analysis was performed for pre-transplant panel reactive antibody (PRA)-positive and -negative patients (presence or absence of non-donor-specific HLA-antibodies). Allograft outcomes, including deathcensored graft loss (DCGL) and biopsy-proven allograft rejection (BPAR), were compared. Results: The incidences of DCGL, BPAR, and overall graft loss were the highest in the high-IPV/RM group. In addition, a high IPV/RM was identified as an independent risk factor for DCGL. The hazard ratio of high IPV/RM for DCGL and the incidence of active antibody-mediated rejection were considerably increased in the PRA-positive subgroup. Discussion: High IPV combined with RM (inter-patient variability) was closely related to adverse allograft outcomes, and hence, more attention must be given to pre-transplant PRA-positive patients.

Lysophosphatidic acid-induced amphiregulin secretion by cancer-associated fibroblasts augments cancer cell invasion.

Cancer-associated fibroblasts (CAFs) are key structural components of the tumor microenvironment and are closely associated with tumor invasion and metastasis. Lysophosphatidic acid (LPA) is a biolipid produced extracellularly and involved in tumorigenesis and metastasis. LPA has recently been implicated in the education and transdifferentiation of normal fibroblasts (NFs) into CAFs. However, little is known about the effects of LPA on CAFs and their participation in cancer cell invasion. In the present study, we identified a critical role of LPA-induced amphiregulin (AREG) secreted from CAFs in cancer invasiveness. CAFs secrete higher amounts of AREG than NFs, and LPA induces AREG expression in CAFs to augment their invasiveness. Strikingly, knocking out the AREG gene in CAFs attenuates cancer invasiveness and metastasis. Mechanistically, LPA induces Yes-associated protein (YAP) activation and Zinc finger E-box binding homeobox 1 (Zeb1) expression through the LPAR1 and LPAR3/Gi/Rho signaling axes, leading to AREG expression. Furthermore, we provide evidence that metformin, a biguanide derivative, significantly inhibits LPA-induced AREG expression in CAFs to attenuate cancer cell invasiveness. Collectively, the present data show that LPA induces AREG expression through YAP and Zeb1 in CAFs to promote cancer cell invasiveness, with the process being inhibited by metformin, providing potential biomarkers and therapeutic avenues to interdict cancer cell invasion.

Ceria-Zirconia nanoparticles reduce intracellular globotriaosylceramide accumulation and attenuate kidney injury by enhancing the autophagy flux in cellular and animal models of Fabry disease.

BACKGROUND: Fabry disease (FD) is a lysosome storage disease (LSD) characterized by significantly reduced intracellular autophagy function. This contributes to the progression of intracellular pathologic signaling and can lead to organ injury. Phospholipid-polyethyleneglycol-capped Ceria-Zirconia antioxidant nanoparticles (PEG-CZNPs) have been reported to enhance autophagy flux. We analyzed whether they suppress globotriaosylceramide (Gb3) accumulation by enhancing autophagy flux and thereby attenuate kidney injury in both cellular and animal models of FD. RESULTS: Gb3 was significantly increased in cultured human renal proximal tubular epithelial cells (HK-2) and human podocytes following the siRNA silencing of α galactosidase A (α-GLA). PEG-CZNPs effectively reduced the intracellular accumulation of Gb3 in both cell models of FD and improved both intracellular inflammation and apoptosis in the HK-2 cell model of FD. Moreover these particles attenuated pro fibrotic cytokines in the human podocyte model of FD. This effect was revealed through an improvement of the intracellular autophagy flux function and a reduction in reactive oxygen species (ROS). An FD animal model was generated in which 4-week-old male B6;129-Glatm1Kul/J mice were treated for 8 weeks with 10 mg/kg of PEG-CZNPs (twice weekly via intraperitoneal injection). Gb3 levels were reduced in the kidney tissues of these animals, and their podocyte characteristics and autophagy flux functions were preserved. CONCLUSIONS: PEG-CZNPs alleviate FD associated kidney injury by enhancing autophagy function and thus provide a foundation for the development of new drugs to treat of storage disease.

Radiographic Predictors of Difficult McGrath MAC Videolaryngoscopy in Patient Undergoing Cervical Spine Surgery.

BACKGROUND: McGrath MAC videolaryngoscopy is a useful technique for successful intubation in cervical spine-injured patients with manual in-line stabilization of the neck during intubation. We aimed to identify radiographic predictors of difficult McGrath MAC videolaryngoscopy in patient undergoing cervical spine surgery. METHODS: Patients undergoing cervical spine surgery who were intubated with a McGrath MAC videolaryngoscope under manual in-line stabilization of the neck between June 2016 and August 2018 were included in this study. Data on airway-related variables and radiographic indices obtained from preoperative lateral cervical spine x-ray, magnetic resonance imaging, and computed tomography (CT) scans were retrospectively collected. Patients were divided into difficult and easy McGrath MAC videolaryngoscopic intubation groups on the basis of intubation time and the number of intubation attempts. RESULTS: In total, 183 patients were included in the study of which 33 (18%) showed difficult videolaryngoscopic intubation. In multivariate logistic regression analysis, atlanto-occipital distance (odds ratio [OR], 0.74; 95% confidence interval [CI], 0.62-0.89; P=0.001) on lateral cervical spine x-ray, incisor-C1-C6 angle in neck extension on lateral cervical spine x-ray (OR, 1.12; 95% CI, 1.02-1.22; P=0.015), tongue area/oral cavity area ratio in the mid-sagittal plane of cervical magnetic resonance imaging or computed tomography (OR, 1.12; 95% CI, 1.05-1.19; P<0.001), and interincisor gap (OR, 0.92; 95% CI, 0.86-0.98; P=0.015) were independent risk factors for difficult videolaryngoscopic intubation. CONCLUSIONS: Radiographic variables indicating enlarged tongue relative to the oral cavity and limited neck extension were associated with difficult McGrath MAC videolaryngoscopy in patients undergoing cervical spine surgery with manual in-line cervical stabilization during intubation.

Discoidin Domain Receptor 2 Mediates Lysophosphatidic Acid-Induced Ovarian Cancer Aggressiveness.

Lysophosphatidic acid (LPA), a bioactive lipid produced extracellularly by autotaxin (ATX), has been known to induce various pathophysiological events, including cancer cell invasion and metastasis. Discoidin domain receptor 2 (DDR2) expression is upregulated in ovarian cancer tissues, and is closely associated with poor clinical outcomes in ovarian cancer patients. In the present study, we determined a critical role and signaling cascade for the expression of DDR2 in LPA-induced ovarian cancer cell invasion. We also found ectopic expression of ATX or stimulation of ovarian cancer cells with LPA-induced DDR2 expression. However, the silencing of DDR2 expression significantly inhibited ATX- and LPA-induced ovarian cancer cell invasion. In addition, treatment of the cells with pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), Akt, and mTOR abrogated LPA-induced DDR2 expression. Moreover, we observed that HIF-1α, located downstream of the mTOR, is implicated in LPA-induced DDR2 expression and ovarian cancer cell invasion. Finally, we provide evidence that LPA-induced HIF-1α expression mediates Twist1 expression to upregulate DDR2 expression. Collectively, the present study demonstrates that ATX, and thereby LPA, induces DDR2 expression through the activation of the PI3K/Akt/mTOR/HIF-1α/Twist1 signaling axes, aggravating ovarian cancer cell invasion.

Microvolt T-wave alternans at the end of surgery is associated with postoperative mortality in cardiac surgery patients.

Microvolt T-wave alternans (MTWA), which reflects electrical dispersion of repolarization, is known to be associated with arrhythmia or sudden cardiac death in high risk patients. In this study we investigated the relationship between MTWA and postoperative mortality in 330 cardiac surgery patients. Electrocardiogram, official national data and electric chart were analysed to provide in-hospital and mid-term outcome. MTWA at the end of surgery was significantly associated with in-hospital mortality in both univariate analysis (OR = 27.378, 95% CI 5.616-133.466, p < 0.001) and multivariate analysis (OR = 59.225, 95% CI 6.061-578.748, p < 0.001). Cox proportional hazards model revealed MTWA at the end of surgery was independently associated with mid-term mortality (HR = 4.337, 95% CI 1.594-11.795). The area under the curve of the model evaluating MTWA at the end of surgery was 0.764 (95% CI, 0.715-0.809) and it increased to 0.929 (95% CI, 0.896-0.954) when combined with the EuroSCORE II. MTWA positive at the end of surgery had a 60-fold increase in in-hospital mortality and a 4-fold increase in mid-term mortality. Moreover, MTWA at the end of surgery could predict in-hospital mortality and this predictability is more robust when combined with the EuroSCORE II.

The velocity curve of the clotting waveform of rotational thromboelastometry predicts bleeding after cardiac surgery but conventional rotational thromboelastometric parameters do not.

BACKGROUND: Early detection of a risk of postoperative bleeding is essential in cardiac surgery patients. The aim of the present study was to evaluate the utility of the first derivative curve (the V-curve) of the clotting waveform of rotational thromboelastometry (ROTEM) in terms of predicting bleeding after cardiac surgery. METHODS: We retrospectively analysed 534 cardiac surgery patients. We used the chest tube output during the stay in the intensive care unit to divide patients into a higher blood loss group (HBL group; the fourth quartile) and a lower blood loss group (LBL group; the lower quartiles). We performed multivariable logistic regression using the V-curve parameters and potential confounders including conventional ROTEM parameters. RESULTS: In the multivariable model, the adjusted odds ratios for HBL of patients with a lower maximum clotting velocity (MaxVel ≤9 mm*100 s-1) as revealed by extrinsically activated ROTEM (EXTEM), and the area under the velocity curve (AUC ≤988 mm*100) of the fibrin-based extrinsically activated ROTEM (FIBTEM), both measured at skin closure in the end of surgery, were 1.78 (95% CI 1.03 to 3.07) and 2.14 (95% CI 1.20 to 3.82), respectively. However, conventional ROTEM parameters were not included in the final model. Additionally, lower EXTEM MaxVel and FIBTEM AUC values were associated with the need for a higher transfusion volume, longer postoperative intensive care unit and hospital stays, and more frequent re-exploration to control bleeding. CONCLUSIONS: The ROTEM V-curve parameters can predict postoperative bleeding and clinical outcomes after cardiac surgery.

Exceptional mucocutaneous manifestations with amyloid nephropathy: a case report.

BACKGROUND: Amyloidosis is a very rare disease that is difficult to diagnose because of the unspecific early clinical manifestations of the disease. Accurate and early diagnosis is extremely important because the effect of treatment is dependent on the extent of disease progression. Sicca syndrome and nail dystrophy are very rare symptoms of amyloidosis. We report here a case of sicca syndrome and nail dystrophy with renal dysfunction in a 52-year-old Korean woman who was diagnosed as having systemic amyloidosis. CASE PRESENTATION: We present the case of a 52-year-old Korean woman complaining of dry mouth and nail dystrophy for 4 months as an initial symptom. A slit lamp examination revealed superficial keratoconjunctival erosion in both eyes. A laboratory test showed anemia, azotemia, and proteinuria. Urine protein electrophoresis showed increased gamma globulin excretion. Serum free light chain of kappa and lambda were increased. Histopathological studies of biopsy specimens of minor salivary glands and kidney revealed deposits of amyloid fibrils. A bone marrow aspiration biopsy showed hypercellular marrow with 5% plasma cells. She was diagnosed as having primary systemic amyloidosis then started on chemotherapy. CONCLUSION: Such atypical mucocutaneous manifestations of amyloidosis can serve as important early diagnostic signs with less invasive biopsy confirmation in patients with systemic amyloidosis.

Risk Factors of Postoperative Delirium in the Intensive Care Unit After Liver Transplantation.

BACKGROUND: Postoperative delirium after liver transplantation is relatively common, especially due to preexisting conditions such as hepatic encephalopathy. Most studies of delirium after liver transplantation were based on ICU practices using deep hypnosedation. Therefore, risk factors and consequences of postoperative delirium after liver transplantation were evaluated in the light sedation era. METHODS: A total of 253 liver transplantation patients were evaluated for postoperative delirium. Clinical outcomes including mortality were compared between patients who suffered delirium and those who did not. Risk factors for postoperative delirium were analyzed with subgroup analysis depending on MELD scores and type of liver transplantation. RESULTS: Post-liver transplant delirium developed in 17% of the patients, 88% of which occurred within the first postoperative day. Alcoholic liver cirrhosis, class C Child-Pugh score, higher MELD scores, higher proportion of deceased donor liver transplantation, and reintubation were more frequent in patients who developed delirium, but there was no difference in mortality. Higher preoperative MELD group (15-24 vs. <15; OR 4.10, 95% Cl [1.67-10.09], P = 0.002, ≥25 vs. <15; OR 5.59, 95% CI [2.06-15.19], P < 0.01), higher APACHE II scores (OR 5.59, 95% CI [2.06-15.19], P < 0.01), and reintubation (OR 6.46, 95% CI [2.10-19.88], P < 0.01) were identified as significant risk factors for postoperative delirium. CONCLUSION: Postoperative delirium after liver transplantation was associated with worse clinical outcomes. MELD scores greater than 15 were predictive of postoperative delirium in both living and deceased donor liver transplantation.

TGF-ß-mediated NADPH oxidase 4-dependent oxidative stress promotes colistin-induced acute kidney injury.

Background: Colistin (polymyxin E) is an important constituent of the polymyxin class of cationic polypeptide antibiotics. Intrarenal oxidative stress can contribute to colistin-induced nephrotoxicity. Nicotinamide adenine dinucleotide 3-phosphate oxidases (Noxs) are important sources of reactive oxygen species. Among the various types of Noxs, Nox4 is predominantly expressed in the kidney. Objectives: We investigated the role of Nox4 and benefit of Nox4 inhibition in colistin-induced acute kidney injury using in vivo and in vitro models. Methods: Human proximal tubular epithelial (HK-2) cells were treated with colistin with or without NOX4 knockdown, or GKT137831 (most specific Nox1/4 inhibitor). Effects of Nox4 inhibition on colistin-induced acute kidney injury model in Sprague-Dawley rats were examined. Results: Nox4 expression in HK-2 cells significantly increased following colistin exposure. SB4315432 (transforming growth factor-ß1 receptor I inhibitor) significantly inhibited Nox4 expression in HK-2 cells. Knockdown of NOX4 transcription reduced reactive oxygen species production, lowered the levels of pro-inflammatory markers (notably mitogen-activated protein kinases) implicated in colistin-induced nephrotoxicity and attenuated apoptosis by altering Bax and caspase 3/7 activity. Pretreatment with GKT137831 replicated these effects mediated by downregulation of mitogen-activated protein kinase activities. In a rat colistin-induced acute kidney injury model, administration of GKT137831 resulted in attenuated colistin-induced acute kidney injury as indicated by attenuated impairment of glomerulus function, preserved renal structures, reduced expression of 8-hydroxyguanosine and fewer apoptotic cells. Conclusions: Collectively, these findings identify Nox4 as a key source of reactive oxygen species responsible for kidney injury in colistin-induced nephrotoxicity and highlight a novel potential way to treat drug-related nephrotoxicity.

Effects of calcium chloride coadministered with neostigmine on neuromuscular blockade recovery: A double-blind randomised study.

BACKGROUND: Ionised calcium plays an important role in neuromuscular transmission, but its effects on the reversal of nondepolarising neuromuscular blockade have not been fully evaluated. OBJECTIVE: We examined whether calcium chloride coadministered with neostigmine could enhance the rate of neuromuscular recovery. DESIGN: Randomised double-blind trial. SETTING: A tertiary teaching hospital. PATIENTS: In total, 53 patients undergoing elective surgery under general anaesthesia with neuromuscular monitoring by acceleromyography using a TOF-Watch SX monitor. INTERVENTIONS: Patients were randomly allocated to receive either 5 mg kg of calcium chloride (calcium group, n = 26) or the same volume of normal saline (control group, n = 27) coadministered with 25 µg kg of neostigmine and 15 µg kg of atropine at the end of surgery. MAIN OUTCOME MEASURES: The primary end point was the neuromuscular recovery time [time from neostigmine administration to recovery of the TOF ratio (TOFr) to 0.9]. Secondary end points included the TOFr at 5, 10 and 20 min after neostigmine administration and the incidence of postoperative residual curarisation (PORC), defined as a TOFr less than 0.9 at each time point. RESULTS: The neuromuscular recovery time was significantly faster in the calcium group than in the control group (median [Q1 to Q3]; 5.0 [3.0 to 7.0] vs. 6.7 [5.7 to 10.0] min, respectively; P = 0.007). At 5 min after neostigmine administration, the TOFr was higher [87 (74 to 100) vs. 68 (51 to 81)%, respectively; P = 0.002] and the incidence of PORC was lower (50.0 vs. 81.5%, respectively; P = 0.016) in the calcium group than in the control group. There were no differences between the two groups with respect to the TOFr or incidence of PORC at 10 and 20 min after neostigmine administration. CONCLUSION: Calcium chloride coadministered with neostigmine enhanced neuromuscular recovery in the early period of nondepolarising neuromuscular blockade reversal.

End stage renal disease caused by thromboangiitis obliterans: a case report.

INTRODUCTION: Thromboangiitis obliterans or Buerger's disease is a nonatherosclerotic, segmental, inflammatory vasculitis that is strongly associated with tobacco products and commonly affects the small- and medium-sized arteries of the upper and lower extremities. However, the disease can, rarely, involve large central or visceral arteries. We report here the case of end stage renal disease due to renal artery thrombosis caused by thromboangiitis obliterans. CASE PRESENTATION: A 51-year-old Korean man who had previously required amputation of both great toes due to thromboangiitis obliterans presented with left flank pain and oliguria. Both his renal arteries were occluded on contrast-enhanced abdominal computed tomography and abdominal angiography. He also had abdominal angina. He had no risk factor of thromboembolism from cardiac origin, atherosclerosis except for tobacco abuse, collagen diseases or hypercoagulable disorders. Renal failure and mesenteric ischemia associated with thromboangiitis obliterans progression was diagnosed. CONCLUSIONS: Renal failure due to renal artery thrombosis and mesenteric ischemia represents an unusual manifestation of thromboangiitis obliterans. But once it occurs, it can be life-threatening. When we care for a patient with thromboangiitis obliterans, we should pay attention to this rare disease course, and encourage cessation of the smoking of tobacco products.

A case of transient central diabetes insipidus after aorto-coronary bypass operation.

Diabetes insipidus (DI) is characterized by excessive urination and thirst. This disease results from inadequate output of antidiuretic hormone (ADH) from the pituitary gland or the absence of the normal response to ADH in the kidney. We present a case of transient central DI in a patient who underwent a cardiopulmonary bypass (CPB) for coronary artery bypass grafting (CABG). A 44-yr-old male underwent a CABG operation. An hour after the operation, the patient developed polyuria and was diagnosed with central DI. The patient responded to desmopressin and completely recovered five days after surgery. It is probable that transient cerebral ischemia resulted in the dysfunction of osmotic receptors in the hypothalamus or hypothalamus-pituitary axis during CPB. It is also possible that cardiac standstill altered the left atrial non-osmotic receptor function and suppressed ADH release. Therefore, we suggest that central DI is a possible cause of polyuria after CPB.

Impact of gene polymorphisms of interleukin-18, transforming growth factor-ß, and vascular endothelial growth factor on development of IgA nephropathy and thin glomerular basement membrane disease.

BACKGROUND: We investigated the effects of gene polymorphisms on the development of IgA nephropathy and thin glomerular basement membrane (GBM) disease by analyzing polymorphisms in the interleukin (IL)-18, transforming growth factor (TGF)-ß, and vascular endothelial growth factor (VEGF) genes in Korean patients. METHODS: This study included 146 normal individuals and 69 biopsy-proven IgA nephropathy and 44 thin GBM disease patients. The gene polymorphisms -607 A/C and -137 G/C in IL-18, -509C/T and T869C in TGF-ß, and -2578C/A and 405C/G in VEGF were investigated in DNA extracted from peripheral blood. RESULTS: The frequencies of the IL-18 -607CC genotype (43.5% vs. 21.2%, P=0.002, P corrected=0.012) and the VEGF 405 GG genotype (37.7% vs. 21.2%, P=0.002, P corrected=0.012) were significantly increased in the IgA nephropathy group compared with the control group, whereas no significant differences in genotype frequency were observed between the thin GBM disease and control groups. However, there were no significant differences in genotype and allele frequencies between the IgA nephropathy and thin GBM disease groups. CONCLUSION: This study did not show any statistically significant differences of six selected gene polymorphisms of the IL-18, TGF-ß, and VEGF genes between IgA nephropathy and thin GBM disease. Additional extensive studies are required to clarify the potential role of gene polymorphism to discriminate IgA nephropathy and thin GBM disease without renal biopsy.