Reversal of pancreatic desmoplasia by a tumour stroma-targeted nitric oxide nanogel overcomes TRAIL resistance in pancreatic tumours.

OBJECTIVE: Stromal barriers, such as the abundant desmoplastic stroma that is characteristic of pancreatic ductal adenocarcinoma (PDAC), can block the delivery and decrease the tumour-penetrating ability of therapeutics such as tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), which can selectively induce cancer cell apoptosis. This study aimed to develop a TRAIL-based nanotherapy that not only eliminated the extracellular matrix barrier to increase TRAIL delivery into tumours but also blocked antiapoptotic mechanisms to overcome TRAIL resistance in PDAC. DESIGN: Nitric oxide (NO) plays a role in preventing tissue desmoplasia and could thus be delivered to disrupt the stromal barrier and improve TRAIL delivery in PDAC. We applied an in vitro-in vivo combinatorial phage display technique to identify novel peptide ligands to target the desmoplastic stroma in both murine and human orthotopic PDAC. We then constructed a stroma-targeted nanogel modified with phage display-identified tumour stroma-targeting peptides to co-deliver NO and TRAIL to PDAC and examined the anticancer effect in three-dimensional spheroid cultures in vitro and in orthotopic PDAC models in vivo. RESULTS: The delivery of NO to the PDAC tumour stroma resulted in reprogramming of activated pancreatic stellate cells, alleviation of tumour desmoplasia and downregulation of antiapoptotic BCL-2 protein expression, thereby facilitating tumour penetration by TRAIL and substantially enhancing the antitumour efficacy of TRAIL therapy. CONCLUSION: The co-delivery of TRAIL and NO by a stroma-targeted nanogel that remodels the fibrotic tumour microenvironment and suppresses tumour growth has the potential to be translated into a safe and promising treatment for PDAC.

Inflammatory macrophages switch to CCL17-expressing phenotype and promote peritoneal fibrosis.

Peritoneal fibrosis remains a problem in kidney failure patients treated with peritoneal dialysis. Severe peritoneal fibrosis with encapsulation or encapsulating peritoneal sclerosis is devastating and life-threatening. Although submesothelial fibroblasts as the major precursor of scar-producing myofibroblasts in animal models and M2 macrophage (Mϕ)-derived chemokines in peritoneal effluents of patients before diagnosis of encapsulating peritoneal sclerosis have been identified, attenuation of peritoneal fibrosis is an unmet medical need partly because the mechanism for cross talk between Mϕs and fibroblasts remains unclear. We use a sodium hypochlorite-induced mouse model akin to clinical encapsulated peritoneal sclerosis to study how the peritoneal Mϕs activate fibroblasts and fibrosis. Sodium hypochlorite induces the disappearance of CD11bhigh F4/80high resident Mϕs but accumulation of CD11bint F4/80int inflammatory Mϕs (InfMϕs) through recruiting blood monocytes and activating local cell proliferation. InfMϕs switch to express chemokine (C-C motif) ligand 17 (CCL17), CCL22, and arginase-1 from day 2 after hypochlorite injury. More than 75% of InfMϕs undergo genetic recombination by Csf1r-driven Cre recombinase, providing the possibility to reduce myofibroblasts and fibrosis by diphtheria toxin-induced Mϕ ablation from day 2 after injury. Furthermore, administration of antibody against CCL17 can reduce Mϕs, myofibroblasts, fibrosis, and improve peritoneal function after injury. Mechanistically, CCL17 stimulates migration and collagen production of submesothelial fibroblasts in culture. By breeding mice that are induced to express red fluorescent protein in Mϕs and green fluorescence protein (GFP) in Col1a1-expressing cells, we confirmed that Mϕs do not produce collagen in peritoneum before and after injury. However, small numbers of fibrocytes are found in fibrotic peritoneum of chimeric mice with bone marrow from Col1a1-GFP reporter mice, but they do not contribute to myofibroblasts. These data demonstrate that InfMϕs switch to pro-fibrotic phenotype and activate peritoneal fibroblasts through CCL17 after injury. CCL17 blockade in patients with peritoneal fibrosis may provide a novel therapy. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Ferritin heavy chain mediates the protective effect of heme oxygenase-1 against oxidative stress.

The phenomenon that heme oxygenase-1 (HO-1) protects cell from injury yet its enzymatic product, iron, may facilitate generation of free radical has been long puzzling. Here we establish a functional connection between ferritin heavy chain (FHC) and HO-1. In human lupus nephritis HO-1 and FHC are colocalized within the glomeruli. In rodent anti-Thy1 (thymocyte antigen 1) induced glomerulonephritis, heme oxygenase blockade lowers the expression of FHC and accelerates mesangial cell death. Stimulation of heme oxygenase in cultured rat mesangial cell enhances its resistance to hydrogen peroxide, whereas FHC knockdown by RNA interference compromises this salutary effect. RNA interference of HO-1 makes the cell more susceptible to hydrogen peroxide, which can be rescued by forced expression of wild-type FHC but not mutants that lose the capacity of iron storage and ferroxidase activity. Phosphorylation of JunD was not sustained in these cells. Microarray analysis identifies four candidate transcriptional factors that may regulate the HO-1-induced transcription of FHC. Our results support the role of FHC in neutralizing the iron toxicity as well as mediating the protective effect of HO-1 in response to oxidative stress.

A quantitative review of nanotechnology-based therapeutics for kidney diseases.

Kidney-specific nanocarriers offer a targeted approach to enhance therapeutic efficacy and reduce off-target effects in renal treatments. The nanocarriers can achieve organ or cell specificity via passive targeting and active targeting mechanisms. Passive targeting capitalizes on the unique physiological traits of the kidney, with factors like particle size, charge, shape, and material properties enhancing organ specificity. Active targeting, on the other hand, achieves renal specificity through ligand-receptor interactions, modifying nanocarriers with molecules, peptides, or antibodies for receptor-mediated delivery. Nanotechnology-enabled therapy targets diseased kidney tissue by modulating podocytes and immune cells to reduce inflammation and enhance tissue repair, or by inhibiting myofibroblast differentiation to mitigate renal fibrosis. This review summarizes the current reports of the drug delivery systems that have been tested in vivo, identifies the nanocarriers that may preferentially accumulate in the kidney, and quantitatively compares the efficacy of various cargo-carrier combinations to outline optimal strategies and future research directions. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Metabolic syndrome and abdominal fat are associated with inflammation, but not with clinical outcomes, in peritoneal dialysis patients.

BACKGROUND: In the general population, metabolic syndrome (MetS) is correlated with visceral fat and a risk factor for cardiovascular disease (CVD); however, little is known about the significance of abdominal fat and its association with inflammation and medication use in peritoneal dialysis (PD) patients. We investigated the relationship of visceral fat area (VFA) with C-reactive protein (CRP) levels and medication use in PD patients and followed their clinical outcomes. METHODS: In a prospective study from February 2009 to February 2012, we assessed diabetes mellitus (DM) status, clinical and PD-associated characteristics, medication use, CRP levels, components of MetS, and VFA in 183 PD patients. These patients were categorized into 3 groups based on MetS and DM status: non-MetS (group 1, n = 73), MetS (group 2, n = 65), and DM (group 3, n = 45). VFA was evaluated by computed tomography (CT) and corrected for body mass index (BMI). RESULTS: Patients in group 1 had smaller VFAs than patients in groups 2 and 3 (3.2 ± 1.8, 4.6 ± 1.9, and 4.9 ± 2.0 cm2/[kg/m2], respectively, P < 0.05) and lower CRP levels (0.97 ± 2.31, 1.27 ± 2.57, and 1.11 ± 1.35 mg/dL, respectively, P < 0.05). VFA increased with the number of criteria met for MetS. After adjusting for age, body weight, and sex, CRP and albumin levels functioned as independent positive predictors of VFA; on other hand, the use of renin-angiotensin system blockers was inversely correlated with VFA in PD patients without DM. In the survival analysis, DM patients (group 3) had the poorest survival among the 3 groups, but no significant differences were found between groups 1 and 2. CONCLUSION: This study showed that VFA and MetS are associated with CRP levels but cannot predict survival in PD patients without DM. The complex relationship of nutritional parameters to VFA and MetS may explain these results. The type of antihypertensive medication used was also associated with the VFA. The mechanisms behind these findings warrant further investigation.

Delivery of nitric oxide with a pH-responsive nanocarrier for the treatment of renal fibrosis.

Fibrosis is an excessive accumulation of extracellular matrix (ECM) that may cause severe organ dysfunction. Nitric oxide (NO), a multifunctional gaseous signaling molecule, may inhibit fibrosis, and delivery of NO may serve as a potential antifibrotic strategy. However, major limitations in the application of NO to treat fibrotic diseases include its nonspecificity, short half-life and low availability in fibrotic tissue. Herein, we aimed to develop a stimuli-responsive drug carrier to deliver NO to halt kidney fibrosis. We manufactured a nanoparticle (NP) composed of pH-sensitive poly[2-(diisopropylamino)ethyl methacrylate (PDPA) polymers to encapsulate a NO donor, a dinitrosyl iron complex (DNIC; [Fe2(µ-SEt)2(NO)4]). The NPs were stable at physiological pH 7.4 but disintegrated at pH 4.0-6.0. The NPs showed significant cytotoxicity to cultured human myofibroblasts and were able to inhibit the activation of myofibroblasts, as indicated by a lower expression level of α-smooth muscle actin and the synthesis of a major ECM component, collagen I, in cultured human myofibroblasts. When given to mice treated with unilateral ureteral ligation/obstruction (UUO) to induce kidney fibrosis, these NPs remained in blood at a stable concentration for as long as 24 h and might enter the fibrotic kidneys to suppress myofibroblast activation and collagen I production, leading to a 70% reduction in the fibrotic area. In summary, our strategy to assemble a NO donor, the iron nitrosyl complex DNIC, into pH-responsive NPs proves effective in treating renal fibrosis and warrants further investigation for its therapeutic potential.

Canonical Notch signaling in the developing lung is required for determination of arterial smooth muscle cells and selection of Clara versus ciliated cell fate.

Lung development is the result of complex interactions between four tissues: epithelium, mesenchyme, mesothelium and endothelium. We marked the lineages experiencing Notch1 activation in these four cellular compartments during lung development and complemented this analysis by comparing the cell fate choices made in the absence of RBPjkappa, the essential DNA binding partner of all Notch receptors. In the mesenchyme, RBPjkappa was required for the recruitment and specification of arterial vascular smooth muscle cells (vSMC) and for regulating mesothelial epithelial-mesenchymal transition (EMT), but no adverse affects were observed in mice lacking mesenchymal RBPjkappa. We provide indirect evidence that this is due to vSMC rescue by endothelial-mesenchymal transition (EnMT). In the epithelium, we show that Notch1 activation was most probably induced by Foxj1-expressing cells, which suggests that Notch1-mediated lateral inhibition regulates the selection of Clara cells at the expense of ciliated cells. Unexpectedly, and in contrast to Pofut1-null epithelium, Hes1 expression was only marginally reduced in RBPjkappa-null epithelium, with a corresponding minimal effect on pulmonary neuroendocrine cell fate selection. Collectively, the primary roles for canonical Notch signaling in lung development are in selection of Clara cell fate and in vSMC recruitment. These analyses suggest that the impact of gamma-secretase inhibitors on branching in vitro reflect a non-cell autonomous contribution from endothelial or vSMC-derived signals.

A rare cause of childhood-onset nephrotic syndrome: lipoprotein glomerulopathy.

We report on a 12-year-old female patient with lipoprotein glomerulopathy (LPG) who was proven to be heterozygous for ApoE2 Kyoto (Arg25Cys). Her family members have the same variant but do not have obvious signs of renal function impairment. Six months of treatment with a statin caused significant clinical improvement in the lipid profile, proteinuria, and renal function. Our case suggests that administration of a statin is a potential therapeutic strategy for improving nephrotic syndrome in patients with LPG.

Impending cardiac tamponade caused by salt supplement in a hyponatremic patient with chronic kidney disease.

We documented a hyponatremic patient who developed imminent cardiac tamponade upon oral salt supplement. A 72-year-old diabetic woman had hemorrhagic stroke; pericardial effusion; and chronic kidney disease, stage IV. She developed hyponatremia (serum sodium level, 125 mmol/L), compatible with the syndrome of inappropriate antidiuretic hormone, and received oral salt supplement 9 g/d for 4 days. Shortness of breathing and increasing heart rate ensued, and the echocardiography found accumulation of pericardial effusion with signs of impending cardiac tamponade. Pig-tail drainage through pericardiocentesis was done, and the vital signs were stabilized. We found the production of pericardial effusion increased from 100 to 220 mL/d after oral salt supplement at 3 g/d was reassumed. We discuss the relationship between serum sodium levels, the dose of salt supplement and the accumulation of pericardial effusion.

Delivery of sorafenib by myofibroblast-targeted nanoparticles for the treatment of renal fibrosis.

Fibrosis is an excessive accumulation of the extracellular matrix within solid organs in response to injury and a common pathway that leads functional failure. No clinically approved agent is available to reverse or even prevent this process. Herein, we report a nanotechnology-based approach that utilizes a drug carrier to deliver a therapeutic cargo specifically to fibrotic kidneys, thereby improving the antifibrotic effect of the drug and reducing systemic toxicity. We first adopted in vitro-in vivo combinatorial phage display technology to identify peptide ligands that target myofibroblasts in mouse unilateral ureteral obstruction (UUO)-induced fibrotic kidneys. We then engineered lipid-coated poly(lactic-co-glycolic acid) nanoparticles (NPs) with fibrotic kidney-homing peptides on the surface and sorafenib, a potent antineoplastic multikinase inhibitor, encapsulated in the core. Sorafenib loaded in the myofibroblast-targeted NPs significantly reduced the infiltration of α-smooth muscle actin-expressing myofibroblasts and deposition of collagen I in UUO-treated kidneys and enhanced renal plasma flow measured by Technetium-99m mercaptoacetyltriglycine scintigraphy. This study demonstrates the therapeutic potential of the newly identified peptide fragments as anchors to target myofibroblasts and represents a strategic advance for selective delivery of sorafenib to treat renal fibrosis. SIGNIFICANCE STATEMENT: Renal fibrosis is a pathological feature accounting for the majority of issues in chronic kidney disease (CKD), which may progress to end-stage renal disease (ESRD). This manuscript describes a myofibroblast-targeting drug delivery system modified with phage-displayed fibrotic kidney-homing peptides. By loading the myofibroblast-targeting nanoparticles (NPs) with sorafenib, a multikinase inhibitor, the NPs could suppress collagen synthesis in cultured human myofibroblasts. When given intravenously to mice with UUO-induced renal fibrosis, sorafenib loaded in myofibroblast-targeting NPs significantly ameliorated renal fibrosis. This approach provides an efficient therapeutic option to renal fibrosis. The myofibroblast-targeting peptide ligands and nanoscale drug carriers may be translated into clinical application in the future.

Endoplasmic reticulum stress implicated in the development of renal fibrosis.

Endoplasmic reticulum (ER) stress-associated apoptosis plays a role in organ remodeling after insult. The effect of ER stress on renal tubular damage and fibrosis remains controversial. This study aims to investigate whether ER stress is involved in tubular destruction and interstitial fibrosis in vivo. Renal cell apoptosis was proven by terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) stain and poly-ADP ribose polymerase expression in the unilateral ureteral obstruction (UUO) kidney. ER stress was evoked and confirmed by the upregulation of glucose-regulated protein 78 (GRP78) and the common Lys-Asp-Glu-Leu (KDEL) motif of ER retention proteins after UUO. ER stress-associated proapoptotic signals, including B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2-associated × protein (BAX) expression, caspase-12 and c-Jun N-terminal kinase (JNK) phosphorylation, were activated in the UUO kidney. Prolonged ER stress attenuated both unsplicing and splicing X-box binding protein 1 (XBP-1) protein expression, but continued to activate inositol-requiring 1α (IRE1α)-JNK phosphorylation, protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2α subunit (eIF2α), activating transcription factor (ATF)-4, CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) and cleavage activating transcription factor 6 (cATF6)-CHOP signals, which induce ER stress-related apoptosis but attenuate adaptive unfolded protein responses in UUO kidneys. However, renal apoptosis and fibrosis were attenuated in candesartan-treated UUO kidney. Candesartan was associated with maintenance of XBP-1 expression and attenuated ATF4, cATF6 and CHOP protein expression. Taken together, results show that overwhelming ER stress leads to renal cell apoptosis and subsequent fibrosis; and candesartan, at least in part, restores renal integrity by blocking ER stress-related apoptosis. Reducing ER stress may present a way to attenuate renal fibrosis.

Tamoxifen downregulates connective tissue growth factor to ameliorate peritoneal fibrosis.

Peritoneal fibrosis (PF), including simple sclerosis and encapsulating peritoneal sclerosis (EPS), is a serious complication in patients on long-term peritoneal dialysis. Tamoxifen has successfully been used in treating EPS; however, the mechanism of tamoxifen in treating EPS fibrosis disorders remains unclear. This study demonstrates a possible antifibrotic mechanism of tamoxifen. A bleach-induced PF rat model was applied as the in vivo treatment target. Tamoxifen was intraperitoneally injected daily to treat PF. The PF scores and thickness of the submesothelial zone over the liver surface were measured as indicators for the severity of PF. Human peritoneal mesothelial cells (HPMC) were used as an in vitro model to test the antifibrotic effect of tamoxifen. Gene expressions of transforming growth factors-ß (TGF-ß), connective tissue growth factor (CTGF) and collagen were investigated using quantitative polymerase chain reactions. In HPMC, tamoxifen showed paradoxical effects between collagen I and TGF-ß. Tamoxifen also inhibited TGF-ß-induced collagen and CTGF. The possible antifibrotic effect of tamoxifen is through inhibiting CTGF to block collagen synthesis, although it enhances TGF-ß which increases fibrosis. These results provide a possible molecular mechanism for tamoxifen.

Worldwide Epidemiology of Diabetes-Related End-Stage Renal Disease, 2000-2015.

OBJECTIVE: The annual risk among patients with diabetes of reaching end-stage renal disease (ESRD) is largely unknown worldwide. This study aimed to compare the incidence of diabetes-related ESRD by creating a global atlas during 2000-2015. RESEARCH DESIGN AND METHODS: The annual incidence of ESRD among patients with diabetes was calculated as the quotient of the number of incident ESRD patients with diabetes divided by the total number of patients with diabetes after subtraction of the number with existing ESRD. The estimated ESRD prevalence and annual incidence were validated with use of the data provided by Fresenius Medical Care, Germany, and previously reported data, respectively. RESULTS: Data were obtained from 142 countries, covering 97.3% of the world population. The global percentage of the prevalent ESRD patients with diabetes increased from 19.0% in 2000 to 29.7% in 2015 worldwide, while the percentage of incident ESRD patients due to diabetes increased from 22.1% to 31.3%. The global annual incidence of ESRD among patients with diabetes increased from 375.8 to 1,016.0/million with diabetes during 2000-2015. The highest average rates were observed in the Western Pacific Region. Comparatively, the rates of incident ESRD among European patients with diabetes ranged from one-half (309.2 vs. 544.6) to one-third (419.4 vs. 1,245.2) of the rates of the Western Pacific population during 2000-2015. CONCLUSIONS: Great and nonrandom geographic variation in the annual rates among patients with diabetes of reaching ESRD suggests that distinct health care, environmental, and/or genetic factors contribute to the progression of diabetic kidney disease. Measures to prevent and treat diabetes-related ESRD require better patient susceptibility stratification.

Correlation between breath ammonia and blood urea nitrogen levels in chronic kidney disease and dialysis patients.

Previous studies have shown that breath ammonia (breath-NH3) concentration is associated with blood urea nitrogen (BUN) levels. However, interindividual variations in breath-NH3 concentrations were observed. Thus, the present study aimed to assess the effect of oral cavity conditions on breath-NH3 concentration and to validate whether the measurement of breath-NH3 concentration is feasible in clinical settings. A total of 125 individuals, including patients with stage 3 to 5 chronic kidney disease (CKD3-5), those on dialysis, and healthy participants, were recruited. A nanostructured sensor was used to detect breath-NH3 concentrations. Pre- and post-gargling as well as pre- and post-hemodialysis (HD) breath-NH3, salivary pH, and salivary urea levels were measured. Breath-NH3, salivary urea, salivary pH, and BUN levels were positively correlated to each other. Breath-NH3 concentrations were associated with BUN levels (r = 0.43, p < 0.001) and were significantly higher in CKD3-5 (p < 0.005) and dialysis patients (p < 0.001) than in healthy participants. Higher correlation coefficients were noted between breath-NH3 concentrations and BUN levels during follow-up (r = 0.59-0.94, p < 0.05). When the cutoff value of breath-NH3 was set at 523.65 ppb, its sensitivity and specificity in predicting CKD (BUN level >24 mg dl-1) were 87.6% and 80.9%, respectively. Breath-NH3 concentrations decreased after HD (p < 0.001) and immediately after gargling (p < 0.01). Breath-NH3 concentration, which was affected by gargling, was correlated to BUN level. The measurement of breath-NH3 concentration using the nanostructured device may be used as a tool for CKD detection and personalized point-of-care for CKD and dialysis patients. The current study had a small sample size. Thus, further studies with a larger cohort must be conducted to validate the effect of oral factors on breath-NH3 concentration and to validate the benefit of breath-NH3 measurement.

gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis.

The role of Notch signaling during skin development was analyzed using Msx2-Cre to create mosaic loss-of-function alleles with precise temporal and spatial resolution. We find that gamma-secretase is not involved in skin patterning or cell fate acquisition within the hair follicle. In its absence, however, inner root sheath cells fail to maintain their fates and by the end of the first growth phase, the epidermal differentiation program is activated in outer root sheath cells. This results in complete conversion of hair follicles to epidermal cysts that bears a striking resemblance to Nevus Comedonicus. Sebaceous glands also fail to form in gamma-secretase-deficient mice. Importantly, mice with compound loss of Notch genes in their skin phenocopy loss of gamma-secretase in all three lineages, demonstrating that Notch proteolysis accounts for the major signaling function of this enzyme in this organ and that both autonomous and nonautonomous Notch-dependent signals are involved.

Affective and cognitive rather than somatic symptoms of depression predict 3-year mortality in patients on chronic hemodialysis.

Depression is more common in many medical conditions than among the general population and is associated with an increased risk of mortality. We aimed to determine whether somatic symptoms of depression were more predictive of mortality than affective and cognitive symptoms in hemodialysis patients. We conducted a prospective cohort study in which the survival outcomes of 151 subjects were followed for more than 3 years. Depression was assessed with the Taiwanese Depression Questionnaire (TDQ). Subjects with TDQ scores 19-54 (correlated with clinically significant depressive symptoms) and those with scores 15-18 had higher 3-year mortality rates than the two groups with lower scores (40.0%, 46.7%, 16.0% and 19.6%, p = 0.021, ANOVA). Affective and cognitive symptoms, including sadness, tenseness, indecisiveness and low self-confidence, and one somatic item (bodily discomfort) were associated with mortality. Affective and cognitive symptoms affected quality of life more than somatic symptoms. The somatic subscale was associated with female gender, low income and education, dialysis vintage, and low serum creatinine and albumin levels, whereas the affective and cognitive subscale was associated with less education and a low serum albumin level. In conclusion, affective and cognitive symptoms of depression may better predict long-term mortality in patients undergoing chronic hemodialysis than somatic symptoms.

Docetaxel-carboxymethylcellulose nanoparticles ameliorate CCl4-induced hepatic fibrosis in mice.

Chronic liver diseases have recently garnered substantial attention as a leading cause of death around the world. During the progression of liver fibrosis/cirrhosis induced by chronic liver injury, hepatic stellate cells (HSCs) play key roles in the regulation of liver fibrogenesis and can even accelerate the progression of hepatocellular carcinoma (HCC). Thus, inhibition of HSC activation or suppression of inflammatory cytokine secretion by HSCs may be an efficient therapeutic strategy to ameliorate liver fibrosis/cirrhosis. In this study, we demonstrated that Cellax NPs (Carboxymethylcellulose - docetaxel-conjugated nanoparticles), which are nanoscale Pegylated carboxymethylcellulose - DTX conjugates, selectively target activated HSCs and abrogate their fibrogenic properties in vitro. Furthermore, Cellax NPs alleviated CCl4-induced hepatic fibrosis and suppressed HCC progression in a clinically relevant HCC model associated with underlying liver fibrosis in vivo. Taken together, Cellax NPs demonstrate great therapeutic promise as a treatment for liver fibrosis and cancer.

Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development.

Liver damage and fibrosis are precursors of hepatocellular carcinoma (HCC). In HCC patients, sorafenib-a multikinase inhibitor drug-has been reported to exert anti-fibrotic activity. However, incomplete inhibition of RAF activity by sorafenib may also induce paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in malignant cells. The consequence of this effect in non-malignant disease (hepatic fibrosis) remains unknown. This study aimed to examine the effects of sorafenib on activated hepatic stellate cells (HSCs), and develop effective therapeutic approaches to treat liver fibrosis and prevent cancer development. Methods: We first examined the effects of sorafenib in combination with MEK inhibitors on fibrosis pathogenesis in vitro and in vivo. To improve the bioavailability and absorption by activated HSCs, we developed CXCR4-targeted nanoparticles (NPs) to co-deliver sorafenib and a MEK inhibitor to mice with liver damage. Results: We found that sorafenib induced MAPK activation in HSCs, and promoted their myofibroblast differentiation. Combining sorafenib with a MEK inhibitor suppressed both paradoxical MAPK activation and HSC activation in vitro, and alleviated liver fibrosis in a CCl4-induced murine model of liver damage. Furthermore, treatment with sorafenib/MEK inhibitor-loaded CXCR4-targeted NPs significantly suppressed hepatic fibrosis progression and further prevented fibrosis-associated HCC development and liver metastasis. Conclusions: Our results show that combined delivery of sorafenib and a MEK inhibitor via CXCR4-targeted NPs can prevent activation of ERK in activated HSCs and has anti-fibrotic effects in the CCl4-induced murine model. Targeting HSCs represents a promising strategy to prevent the development and progression of fibrosis-associated HCC.

A single question regarding mobility in the World Health Organization quality of life questionnaire predicts 3-year mortality in patients receiving chronic hemodialysis.

Low quality of life, depression and poor quality of sleep are associated with increased mortality in hemodialysis patients. It is not clear which factor has the highest predictive power and what the core element is to explain the predictability. We thus conducted a prospective cohort study that included 151 hemodialysis adults. Three traits of interest were assessed by World Health Organization Quality of Life questionnaire, an abbreviated version (WHOQOL-BREF), Taiwanese Depression Questionnaire, and Athens Insomnia Scale, respectively. They were followed for more than 3 years and the all-cause mortality was 30.5%. The prevalence of quality of life at the lowest tertile, depression and poor quality of sleep was 19.9%, 43.0% and 74.2%, respectively. Discriminant analysis showed the standardized coefficient of each factor as 0.813, -0.289 and 0.066, indicating the highest discriminating power by quality of life to predict mortality. Question 15 "how well are you able to get around?" in the physical health domain of WHOQOL-BREF independently associated a hazard ratio of mortality 0.623 (95% confidence interval 0.423-0.918). Subjective perception of overall quality of life was more related to psycho-social-environmental factors. In conclusion, mobility is an independent and powerful predictor to long term mortality in patients on chronic hemodialysis.

The effectiveness and safety of angiotensin-converting enzyme inhibition or receptor blockade in vascular diseases in patients with hemodialysis.

Patients with end-stage renal disease (ESRD) who are on hemodialysis have high risk of vascular diseases. Our study sought to examine whether angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin type 1 receptor blockers (ARBs) could reduce the frequencies of cardiovascular and cerebrovascular events in patients receiving hemodialysis using the medication possession ratio (MPR) method of analysis.This retrospective cohort study identified cases of ESRD with dialysis from the National Health Insurance Research Database between 1999 and 2006, and used Cox-regression methods to evaluate risk of poor outcomes. Primary outcomes, including death from any cause, and secondary outcomes, including admission for stroke, myocardial infarction, and heart failure, were examined.Compared to the nonuser group, the adjusted HRs for mortality of the nonadherence group and the adherence group were 0.81 (95% CI: 0.76-0.86) and 0.98 (95% CI: 0.86-1.13), respectively. Cardiovascular events were more frequent in patients with ESRD receiving ACEIs /ARBs than in nonusers. Compared with nonusers, the hazard of secondary outcome significantly increased in the nonadherence group or adherence group in 10 years follow-up.Compared with patients with diabetes or chronic kidney disease, patients on hemodialysis may not experience the same cardiovascular and cerebrovascular benefits from ACEIs/ARBs use.