ABSTRACT
Spur cell anemia is acquired hemolytic anemia seen in patients with advanced liver disease, particularly in the setting of alcoholism, and warrants urgent liver transplant evaluation. We describe the case of a 58-year-old female with alcoholic cirrhosis who presented with worsening liver disease, profound anemia poorly responsive to blood transfusions, and multiple spur cells on the peripheral smear. She underwent a liver transplant, which led to the resolution of hematologic abnormalities and the need for transfusions. Our case highlights the significance of spur cell anemia as a harbinger of poor prognosis in patients with advanced liver disease and its reversibility with liver transplantation.
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(1) We investigated the involvement of serum magnesium level in early alcoholic liver disease (ALD), gut barrier dysfunction, and inflammation in alcohol use disorder (AUD) patients; and lastly, the efficacy of 2-week abstinence and medical management to alleviate hypomagnesemia. (2) Forty-eight heavy drinking AUD patients (34 males (M)/14 females (F)) participated in this study. Patients were grouped by serum alanine aminotransferase (ALT) level (a marker of liver injury) as group 1 (Group 1 (Gr.1); ALT ≤ 40 U/L, 7M/8F, without any indication of early-stage ALD) and group 2 (Group 2 (Gr.2); ALT > 40 U/L, 27M/6F or early-stage ALD). These patients were sub-divided within each group into patients with normal magnesium (0.85 and more mmol/L) and deficient magnesium (less than 0.85 mmol/L) levels. All participants were assessed at baseline (BL) and received standard medical management for 2 weeks with reassessment at the treatment end (2w). (3) Female participants of this study showed a significantly lower baseline level of magnesium than their male counterparts. Gr.2 patients showed a greater propensity in the necrotic type of liver cell death, who reported higher chronic and recent heavy drinking. Magnesium level improved to the normal range in Gr.2 post-treatment, especially in the hypomagnesemia sub-group (0.77 ± 0.06 mmol/L (BL) vs. 0.85 ± 0.05 mmol/L (2w), p = 0.02). In Gr.2, both apoptotic (K18M30) and necrotic (K18M65) responses were significantly and independently associated with inflammasome activity comprising of LBP (Lipopolysaccharide binding-protein) and TNFα (Tumor necrosis factor -α), along with serum magnesium. (4) In AUD patients with liver injury, 2-week medical management seems to improve magnesium to a normal level. This group exhibited inflammatory activity (LBP and TNFα) contributing to clinically significant hypomagnesemia. In this group, the level of magnesium, along with the unique inflammatory activity, seems to significantly predict apoptotic and necrotic types of hepatocyte death.
Subject(s)
Alcoholism , Liver Diseases, Alcoholic , Alanine Transaminase , Alcoholism/complications , Female , Humans , Inflammasomes , Inflammation/complications , Lipopolysaccharides , Liver Diseases, Alcoholic/therapy , Magnesium , Male , Tumor Necrosis Factor-alphaABSTRACT
OBJECTIVES: Low molecular weight heparin and vitamin K antagonists are commonly used in cirrhotic patients requiring anticoagulation. However, their monitoring with anti-factor Xa and international normalized ratio (INR) may not be reliable in cirrhosis. Direct oral anticoagulants (DOACs) do not need laboratory monitoring, making these agents a favorable alternative. However, apixaban and rivaroxaban have been avoided in advanced liver disease due to their metabolism in the liver. The purpose of this medication use evaluation was to assess the use of DOACs, specifically apixaban and rivaroxaban, in patients with cirrhosis. METHODS: We performed a retrospective, single-center study. Inpatients who had a diagnosis of cirrhosis and received at least one dose of a DOAC (apixaban or rivaroxaban) from April 2016 through June 2020 at our hospital were included in the analysis. Data collected included the reason for admission, Child-Pugh classification, renal function, if this was a home medication or newly started as an inpatient medication, indication, and dosing. The clinical efficacy outcome (new venous thromboembolic event (VTE) or progression of old VTE), and clinical safety outcome (bleeding event) were analyzed. RESULTS: 41 patients with cirrhosis were treated with apixaban or rivaroxaban. Based on the Child-Pugh classification, 29.3% (n=12/41) were placed on a DOAC outside of the FDA prescribing recommendations. In this subpopulation, 8.3% (n=1/12) patients had venous thromboembolism (VTE) and 16.6% (n=2/12) had bleeding events. Overall, 7.3% patients (n=3/41) had VTE and 4.8% (n=2/41) had bleeding events. In the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial comparing the efficacy and safety profile of apixaban with enoxaparin/warfarin therapy in acute VTE, 2.3% of patients had VTE and 15% had bleeding events. CONCLUSION: Our study demonstrated that it may be possible to safely use DOACs in patients with advanced cirrhosis. Further studies are needed to evaluate the safety and efficacy of DOACs in this patient population, as our study was limited by the small sample size and its retrospective design.
ABSTRACT
(1) Background: Fibrosis in early-stage alcohol-associated liver disease (ALD) is commonly under-diagnosed in routine clinical practice. This study characterized the liver-injury and cell death response in alcohol use disorder (AUD) patients with ALD who also exhibited fibrosis and assessed the efficacy of standard of care (SOC) treatment in the improvement in liver injury. (2) Methods: Forty-eight heavy-drinking AUD patients aged 21−65 yrs. without clinical manifestations of liver injury were grouped by Fibrosis-4 (FIB-4) score, as negative (Gr.1 < 1.45, n = 21) or positive (Gr.2 ≥ 1.45, n = 27). Patients received 2-weeks (2 w) inpatient SOC. Data on demographics, drinking patterns, liver-injury, immune markers, and liver cell death (K18s) markers were analyzed at baseline (BL) and after 2 w SOC. (3) Results: Lifetime drinking (LTDH, yrs.) and acute heavy drinking (Heavy Drinking Days Past 90 Days [HDD90]) markers were significantly higher in Gr.2 vs. Gr.1. BL ALT, AST, AST:ALT and K18M65 were considerably higher in Gr.2. Dysregulated gut dysfunction and elevated immune activity were evident in Gr.2 characterized by TNF-α, IL-8 and LPS levels. After SOC, Gr.2 showed improvement in AST, ALT, AST/ALT ratio; and in the K18M65, K18M30 and K18M65/M30 ratio vs. Gr.1. The true positivity of BL IL-8 response to predict the improvement in K18M65 to normal levels among Gr.2 patients against those who did not have improvement after 2 w SOC was very high (AUROC = 0.830, p = 0.042). (4) Conclusions: Gut dysfunction, elevated cytokine response and necrotic liver cell death were elevated in AUD patients with early-stage ALD. K18 showed promise as a predictive theragnostic factor to differentiate among the AUD patients with early-stage ALD and baseline fibrosis who had improvement in liver injury against those who did not, by the levels of baseline IL-8.
Subject(s)
Liver Diseases, Alcoholic , Adult , Aged , Biomarkers/analysis , Humans , Interleukin-8/metabolism , Liver Cirrhosis, Alcoholic/diagnosis , Liver Cirrhosis, Alcoholic/metabolism , Liver Cirrhosis, Alcoholic/pathology , Liver Diseases, Alcoholic/diagnosis , Liver Diseases, Alcoholic/metabolism , Liver Diseases, Alcoholic/pathology , Middle Aged , Young AdultABSTRACT
Immunotherapy using monoclonal antibodies targeting the PD-1/PD-L1 interaction has shown enormous success for various cancers. Despite their encouraging results in clinics, antibody-based checkpoint inhibitors have several limitations, such as poor tumor penetration. To address these limitations of monoclonal antibodies, there is a growing interest in developing low-molecular-weight checkpoint inhibitors, such as antibody fragments. Several antibody fragments targeting PD-1/PD-L1 were recently discovered using phage libraries from camel or alpaca. However, animal-derived antibody fragments may elicit unwanted immune responses, which limit their therapeutic applications. For the first time, we used a human domain antibody phage library and discovered anti-human PD-L1 human single-domain antibodies (dAbs) that block the PD-1/PD-L1 interaction. Among them, the CLV3 dAb shows the highest affinity to PD-L1. The CLV3 dAb also exhibits the highest blocking efficacy of the PD-1/PD-L1 interaction. Moreover, the CLV3 dAb significantly inhibits tumor growth in mice implanted with CT26 colon carcinoma cells. These results suggest that CLV3 dAb can be potentially used as an anti-PD-L1 inhibitor for cancer immunotherapy.
Subject(s)
Antineoplastic Agents, Immunological , Colonic Neoplasms , Single-Domain Antibodies , Animals , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents, Immunological/pharmacology , B7-H1 Antigen , Colonic Neoplasms/therapy , Humans , Immunotherapy/methods , Mice , Programmed Cell Death 1 ReceptorABSTRACT
Cabazitaxel, a novel tubulin inhibitor with poor affinity for P-glycoprotein, is a second-generation taxane holding great promise for the treatment of metastatic castration-resistant prostate cancer. However, its poor solubility and lack of target-ability limit its therapeutic applications. Herein, we develop a biodegradable, enzyme-responsive, and targeted polymeric micelle for cabazitaxel. The micelle is formed from two amphiphilic block copolymers. The first block copolymer consists of PEG, an enzyme-responsive peptide, and cholesterol; whereas the second block copolymer consists of a targeting ligand, PEG and cholesterol. The enzyme-responsive peptide is cleavable in the presence of matrixmetaloproteinase-2 (MMP-2), which is overexpressed in the tumor microenvironment of prostate cancer. The micelle showed a very low critical micelle concentration (CMC), high drug loading, and high entrapment efficiency. Release of cabazitaxel from the micelle is dependent on the cleavage of the enzyme-responsive peptide. Moreover, the micelle showed dramatically higher cellular uptake in prostate cancer cells compared to free cabazitaxel. Importantly, the ligand-coupled polymeric micelle demonstrated better inhibition of tumor growth in mice bearing prostate cancer xenografts compared to unmodified micelle and free cabazitaxel. Taken together, these findings suggest that the enzyme-responsive cabazitaxel micelle is a potent and promising drug delivery system for advanced prostate cancer therapy. STATEMENT OF SIGNIFICANCE: Herein, we develop a biodegradable, enzyme-responsive, and actively targeted polymer micelle for cabazitaxel, which is a novel tubulin inhibitor with poor affinity for P-glycoprotein. Despite cabazitaxel's great promise for metastatic castration-resistant prostate cancer, its poor solubility, lack of target-ability, and high systemic toxicity limit its therapeutic applications, and therefore a targeted delivery system is highly needed for cabazitaxel. Our results demonstrate the importance of active targeting in targeted prostate cancer therapy. Encapsulating cabazitaxel in the micelle increases its activity and is expected to reduce its systemic toxicity, which is a major hurdle in its clinical applications. Moreover, the polymeric micelle may servers as a promising nanoscale platform for the targeted delivery of other chemotherapeutic agents to prostate cancer.
Subject(s)
Micelles , Prostatic Neoplasms , Animals , Cell Line, Tumor , Humans , Male , Mice , Polymers , Prostatic Neoplasms/drug therapy , Taxoids/pharmacology , Taxoids/therapeutic use , Tumor MicroenvironmentABSTRACT
BACKGROUND: Immunotherapy using checkpoint inhibitors, especially PD-1/PD-L1 inhibitors, has now evolved into the most promising therapy for cancer patients. However, most of these inhibitors are monoclonal antibodies, and their large size may limit their tumor penetration, leading to suboptimal efficacy. As a result, there has been a growing interest in developing low-molecular-weight checkpoint inhibitors. METHODS: We developed a novel biopanning strategy to discover small peptide-based anti-PD-L1 inhibitors. The affinity and specificity of the peptides to PD-L1 were examined using various assays. Three-dimensional (3D) spheroid penetration study was performed to determine the tumor penetration capability of the peptides. Anti-tumor activity of the peptides was evaluated in mice bearing CT26 tumor cells. RESULTS: We discover several anti-PD-L1 peptide inhibitors to block PD-1/PD-L1 interaction. The peptides exhibit high affinity and specificity to human PD-L1 protein as well as PD-L1-overexpressing human cancer cells MDA-MB-231 and DU-145. Molecular docking studies indicate that the peptide CLP002 specifically binds to PD-L1 at the residues where PD-L1 interacts with PD-1. The peptide also blocks the CD80/PD-L1 interaction, which may further enhance the immune response of tumor-infiltrating T cells. Compared to antibody, the peptide CLP002 exhibits better tumor penetration in a 3D tumor spheroid model. The peptide CLP002 restores proliferation and prevents apoptosis of T cells that are co-cultured with cancer cells. The peptide CLP002 also inhibits tumor growth and increases survival of CT26 tumor-bearing mice. CONCLUSIONS: This study demonstrated the feasibility of using phage display to discover small peptide-based checkpoint inhibitors. Our results also suggested that the anti-PD-L1 peptide represents a promising low-molecular-weight checkpoint inhibitor for cancer immunotherapy.
Subject(s)
Antineoplastic Agents, Immunological/chemistry , B7-H1 Antigen/chemistry , Drug Discovery , Peptides/chemistry , Antibody Specificity , Antineoplastic Agents, Immunological/pharmacology , Apoptosis/drug effects , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Weight , Peptide Library , Peptides/antagonists & inhibitors , Programmed Cell Death 1 Receptor/metabolism , Protein Binding/drug effects , Structure-Activity RelationshipABSTRACT
Triple negative breast cancer (TNBC) is the most difficult breast cancer subtype to treat. TNBC patients have significantly higher expression of vascular endothelial growth factor (VEGF) in tumors compared to non-TNBC patients. VEGF not only exerts its pro-angiogenic effects on endothelial cells but also acts as a survival and autocrine growth factor for VEGF receptor (VEGFR) expressing cancer cells. Silencing the expression of VEGF is therefore a potential therapy for TNBC. Methods: A novel biocompatible linear copolymer poly[bis(ε-Lys-PEI)Glut-PEG] (PLEGP) was developed to deliver VEGF siRNA for TNBC therapy. The copolymer is composed of lysine and glutaric acid, a natural metabolite of amino acids in the body. Low-molecular weight polyethyleneimine (PEI) was grafted to the copolymer to efficiently condense siRNA into nanocomplex without inducing cytotoxicity. Various in vitro studies were performed to evaluate the stability, cellular uptake, tumor penetration, and biological activities of the VEGF siRNA nanocomplex. The anti-tumor activities of the nanocomplex was also evaluated in an orthotopic TNBC mouse model. Results: PEIs with different molecular weights were evaluated, and the copolymer PLEGP1800 was able to easily form a stable nanocomplex with siRNAs and protect them from serum degradation. The siRNA/PLEGP1800 nanocomplex exhibited negligible cytotoxicity but showed high cellular uptake, high transfection efficiency, and high tumor penetration. In vitro activity studies showed that the siRNA nanocomplex significantly inhibited migration and invasion of TNBC cells. Moreover, the VEGF siRNA nanocomplex efficiently inhibited tumor growth in an orthotopic TNBC mouse model and down-regulated VEGF expression in the tumor. Conclusion: PLEGP1800 is a safe and efficient copolymer to deliver siRNAs for TNBC therapy. It could potentially be applied to other cancers by changing the cargo and incorporating tumor-specific ligands.
Subject(s)
Biocompatible Materials/chemistry , Nanoparticles/chemistry , RNA, Small Interfering/administration & dosage , Triple Negative Breast Neoplasms/therapy , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/pharmacokinetics , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Cell Death , Cell Line, Tumor , Cell Movement , Cell Proliferation , Endocytosis , Female , Gene Silencing , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Luciferases/metabolism , Mice, Nude , Neoplasm Invasiveness , Neovascularization, Physiologic , Polyethylene Glycols/chemistry , Polyethyleneimine/chemistry , Spheroids, Cellular/cytology , Tissue Distribution , Triple Negative Breast Neoplasms/pathologyABSTRACT
Severe reactions to modern iodinated contrasts are uncommon. Breakthrough reactions in the setting of pretreatment with corticosteroids are even rarer. Patients with a history of these refractory reactions can create challenging situations in the diagnostic and therapeutic process. Here, we present a case of an 83-year-old male with hepatocellular carcinoma and a history of multiple severe reactions to iodinated contrast. The patient required a transarterial chemoembolization but the conventional technique was unavailable due to the allergy. Gadolinium-based contrast was substituted and used in conjunction with C-arm CT and a percutaneous ethanol injection to treat the tumor. After nearly 3 years, there is no evidence of residual or recurrent hepatocellular carcinoma.
ABSTRACT
Liver fibrosis is a wound healing process with excessive accumulation of extracellular matrix in the liver. We recently discovered a PCBP2 siRNA that reverses fibrogenesis in activated hepatic stellate cells (HSCs), which are the key players in liver fibrogenesis. However, targeted delivery of siRNAs to HSCs still remains a challenge. Herein, we developed a new strategy to fabricate a multicomponent nanocomplex using siRNA/PNA hybrid instead of chemically conjugated siRNA, thus increasing the scalability and feasibility of the siRNA nanocomplex for animal studies. We modified the nanocomplex with an insulin growth factor 2 receptor (IGF2R)-specific peptide, which specifically binds to activated HSCs. The siRNA nanocomplex shows a controllable size and high serum stability. The nanocomplex also demonstrates high cellular uptake in activated HSCs in vitro and in vivo. Anti-fibrotic activity of the siRNA nanocomplex was evaluated in rats with carbon tetrachloride-induced liver fibrosis. Treatment with the PCBP2 siRNA nanocomplex significantly inhibits the mRNA expressions of PCBP2 and type I collagen in fibrotic liver. Histology study revealed that the siRNA nanocomplex efficiently reduces the protein level of type I collagen and reverses liver fibrosis. Our data suggest that the nanocomplex efficiently delivers the siRNA to fibrotic liver and produces a potent anti-fibrotic effect.
ABSTRACT
BACKGROUND AND AIM: α-complex protein-2 (αCP2) encoded by the poly (rC) binding protein 2(PCBP2) gene is responsible for the accumulation of type I collagen in fibrotic livers. In this study, we silenced the PCBP2 gene using a small interfering RNA (siRNA) to reverse alcohol-and cytokine-induced profibrogenic effects on hepatic stellate cells (HSCs). METHODS: Primary rat HSCs and the HSC-T6 cell line were used as fibrogenic models to mimic the initiation and perpetuation stages of fibrogenesis, respectively. We previously found that a PCBP2 siRNA, which efficiently silences expression of αCP2, reduces the stability of type I collagen mRNA. We investigated the effects of the PCBP2 siRNA on cell proliferation and migration. Expression of type I collagen in HSCs was analyzed by quantitative real-time PCR and western blotting. In addition, we evaluated the effects of the PCBP2 siRNA on apoptosis and the cell cycle. RESULTS: PCBP2 siRNA reversed multiple alcohol- and cytokine-induced profibrogenic effects on primary rat HSCs and HSC-T6 cells. The PCBP2 siRNA also reversed alcohol- and cytokine-induced accumulation of type I collagen as well as cell proliferation and migration. Moreover, the combination of LY2109761, a transforming growth factor-ß1 inhibitor, and the PCBP2 siRNA exerted a synergistic inhibitive effect on the accumulation of type I collagen in HSCs. CONCLUSIONS: Silencing of PCBP2 using siRNA could be a potential therapeutic strategy for alcoholic liver fibrosis.
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Protein-based drug delivery carrier has been one of the most employed modalities in biopharmaceuticals. In this study, we have compared avidin and its two analogues, neutravidin and streptavidin, as nanocarriers for the delivery of biotin-labeled siRNA with the help of biotinylated cholesterol (targeting ligand) and protamine (condensing agent). These proteins have similar binding affinity to biotin but substantial difference in their physical and chemical characteristics. Here, we have shown how these characteristics affect the size, cellular uptake, and activity of the avidin-based siRNA nanocomplex. In contrast to avidin and streptavidin nanocomplexes, neutravidin-based nanocomplex shows very low endosome entrapment and high cytoplasmic localization at extended times. High amount of the siRNA released in the cytoplasm by neutravidin-based nanocomplex at extended times (24 h) results in extensive and sustained PCBP2 gene silencing activity in HSC-T6 rat hepatic stellate cells. Neutravidin-based nanocomplex shows significantly low exocytosis in comparison to the streptavidin-based nanocomplex. Avidin-, neutravidin-, and streptavidin-based nanocomplexes are similar in size and had no significant cytotoxicity in transfected HSC-T6 cells or inflammatory cytokine induction in a whole blood assay. Compared to free siRNA, the neutravidin-based siRNA nanocomplex exhibits higher accumulation at 2 h in the liver of the rats with CCl4-induced liver fibrosis. Neutravidin has therefore been shown to be the most promising avidin analogue for the delivery of siRNA.
Subject(s)
Avidin/chemistry , Drug Delivery Systems/methods , Streptavidin/chemistry , Animals , Apoptosis/genetics , Apoptosis/physiology , Cell Line , Exocytosis/genetics , Exocytosis/physiology , Gene Silencing , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/chemistry , RatsABSTRACT
Prostate-specific membrane antigen (PSMA) has been widely used as a biomarker and targeting receptor for prostate cancer therapy because of its overexpression in most prostate cancer cells. In this study, a novel combinatorial phage biopanning procedure was developed to discover PSMA-specific peptides that can be potentially used as ligands for targeted drug delivery to prostate cancer cells. Five rounds of biopanning against recombinant human PSMA extracellular domain (ECD), PSMA-positive LNCaP cells, and LNCaP xenografts in nude mice were conducted. Various affinity assays were conducted to identify high-affinity peptides for PSMA ECD and PSMA-positive prostate cancer cells. Among them, the GTI peptide shows the highest affinity as well as specificity to PSMA in prostate cancer cells. The apparent Kd values of the GTI peptide to PSMA-positive LNCaP and C4-2 cells are 8.22µM and 8.91µM, respectively. The GTI peptide can specifically deliver the proapoptotic peptide D(KLAKLAK)2 to LNCaP cells to induce cell death. In the biodistribution study, the GTI peptide shows the highest uptake in C4-2 xenografts, while its uptake in other major organs, such as the liver and spleen, are either low or negligible. Compared to its scrambled control (random permutation of the GTI peptide), the GTI peptide exhibits higher and more specific uptake in C4-2 xenografts. All the results suggest that the GTI peptide is a potentially promising ligand for PSMA-targeted drug delivery for prostate cancer therapy.
Subject(s)
Antigens, Surface/metabolism , Drug Delivery Systems , Glutamate Carboxypeptidase II/metabolism , Peptides/administration & dosage , Prostatic Neoplasms/drug therapy , Proteins/administration & dosage , Animals , Antineoplastic Agents/administration & dosage , Apoptosis/drug effects , Cell Line, Tumor , Humans , Ligands , Male , Mice , Mice, Nude , Myosin Light Chains , Peptides/pharmacology , Proteins/metabolism , Tissue Distribution , Xenograft Model Antitumor AssaysABSTRACT
An enzyme-responsive peptide drug conjugate was developed for TGX-D1, a promising PI3K inhibitor for prostate cancer therapy. LNCaP-specific KYL peptide was used as the targeting ligand and the prostate specific antigen (PSA) cleavable peptide (SSKYQSL) was used as the enzyme-responsive linker. SSKYQSL is cleaved by recombinant human PSA at 10-250 µg/mL. By contrast, the linker is stable in the serum of prostate cancer patients with high PSA levels (>500 ng/mL), indicating that this linker can survive the systemic circulation in prostate cancer patients but be cleaved in the tumor microenvironment. Cellular uptake of the peptide drug conjugate in prostate cancer cells is improved by about nine times. Biodistribution study reveals significant tumor accumulation of the peptide drug conjugate in nude mice bearing C4-2 tumor xenografts. Meanwhile, distribution of the conjugate in other major tissues is the same as the parent drug, indicating a high specificity of the conjugate to prostate cancers in vivo.
Subject(s)
Enzyme Inhibitors/administration & dosage , Phosphatidylinositol 3-Kinases , Prostatic Neoplasms/drug therapy , Animals , Humans , Male , Mice , Mice, Nude , Tissue Distribution , Tumor Cells, CulturedABSTRACT
Although combination simeprevir (SIM) plus sofosbuvir (SOF) is an approved regimen for genotype 1 chronic hepatitis C virus (HCV), data regarding its safety and efficacy in liver transplant recipients remain limited. A multicenter retrospective study was performed to determine the efficacy and tolerability of a 12-week regimen of SIM/SOF with or without ribavirin (RBV) in 56 consecutive liver transplant recipients in 2014; 79% of patients had genotype 1a, 14% had cirrhosis, and 73% were treatment experienced. Sustained virological response at 12 weeks (SVR12) was 88% by intention to treat analysis (95% confidence interval, 84%-90%). Four patients relapsed, but no on-treatment virological failures occurred. The Q80K polymorphism did not impact SVR12, but there was a trend toward decreased sustained virological response with advanced fibrosis (P = 0.18). HCV RNA was detectable at treatment week 4 in 21% of patients, and those who had detectable levels were less likely to achieve SVR12 (58% versus 95%; P = 0.003). Five patients had baseline Child-Pugh class B cirrhosis, and 2 of them died (1 following early discontinuation of therapy). An additional discontinuation resulted from a severe photosensitivity reaction in a patient on concomitant cyclosporine. Seven patients receiving RBV developed progressive anemia requiring intervention. Immunosuppression dose modifications were minimal. SIM/SOF for 12 weeks was effective and well tolerated by compensated liver transplant recipients especially when administered without concomitant RBV or cyclosporine. SIM/SOF appears to have a niche as the only 12-week RBV-free treatment regimen currently recommended by guidelines for compensated transplant recipients. However, 12 weeks may not be the optimal duration of therapy for those with detectable virus at week 4 or possibly for those with cirrhosis. These data require confirmation by prospective randomized clinical trials. Liver Transplantation 22 635-643 2016 AASLD.
Subject(s)
Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/surgery , Liver Transplantation , Ribavirin/administration & dosage , Simeprevir/administration & dosage , Sofosbuvir/administration & dosage , Aged , Antiviral Agents/administration & dosage , Drug Therapy, Combination , Female , Genotype , Hepacivirus/genetics , Humans , Immunosuppression Therapy , Liver Cirrhosis , Male , Middle Aged , Patient Safety , Polymorphism, Genetic , Recurrence , Retrospective Studies , Transplant Recipients , Treatment OutcomeABSTRACT
Chemotherapy is one of the most widely used approaches in combating advanced prostate cancer, but its therapeutic efficacy is usually insufficient due to poor specificity and associated toxicity. Lack of targeted delivery to prostate cancer cells is also the primary obstacles in achieving feasible therapeutic effect of other promising agents including peptide, protein, and nucleic acid. Consequently, there remains a critical need for strategies to increase the selectivity of anti-prostate cancer agents. This review will focus on various prostate cancer-relevant antigens and enzymes that could be exploited for prostate cancer targeted drug delivery. Among various targeting strategies, active targeting is the most advanced approach to specifically deliver drugs to their designated cancer cells. In this approach, drug carriers are modified with targeting ligands that can specifically bind to prostate cancer-specific antigens. Moreover, there are several specific enzymes in the tumor microenvironment of prostate cancer that can be exploited for stimulus-responsive drug delivery systems. These systems can specifically release the active drug in the tumor microenvironment of prostate cancer, leading to enhanced tumor penetration efficiency.
Subject(s)
Antigens, Neoplasm/immunology , Drug Delivery Systems , Prostatic Neoplasms/enzymology , Prostatic Neoplasms/immunology , Animals , Biomarkers, Tumor/immunology , Biomarkers, Tumor/metabolism , Humans , MaleABSTRACT
PURPOSE: Rapamycin has demonstrated potent anti-tumor activity in preclinical and clinical studies. However, the clinical development of its formulations was hampered due to its poor solubility and undesirable distribution in vivo. Chemical modification of rapamycin presents an opportunity for overcoming the obstacles and improving its therapeutic index. The objective of this study is to develop a drug-polymer conjugate to increase the solubility and cellular uptake of rapamycin. METHODS: We developed the rapamycin-polymer conjugate using a novel, linear, poly(ethylene glycol) (PEG) based multiblock copolymer. Cytotoxicity and cellular uptake of the rapamycin-polymer conjugate were evaluated in various cancer cells. RESULTS: The rapamycin-polymer conjugate provides enhanced solubility in water compared with free rapamycin and shows profound activity against a panel of human cancer cell lines. The rapamycin-polymer conjugate also presents high drug loading capacity (wt% ~ 26%) when GlyGlyGly is used as a linker. Cellular uptake of the conjugate was confirmed by confocal microscopic examination of PC-3 cells that were cultured in the presence of FITC-labled polymer (FITC-polymer). CONCLUSION: This study suggests that the rapamycin-polymer conjugate is a novel anti-cancer agent that may provide an attractive strategy for treatment of a wide variety of tumors.
Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Drug Carriers/chemistry , Polyethylene Glycols/chemistry , Polymers/chemistry , Sirolimus/administration & dosage , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacokinetics , Antibiotics, Antineoplastic/pharmacology , Cell Line, Tumor , Humans , Neoplasms/drug therapy , Sirolimus/chemistry , Sirolimus/pharmacokinetics , Sirolimus/pharmacology , SolubilityABSTRACT
Zinc is an essential trace element required for normal cell growth, development, and differentiation. It is involved in DNA synthesis, RNA transcription, and cell division and activation. It is a critical component in many zinc protein/enzymes, including critical zinc transcription factors. Zinc deficiency/altered metabolism is observed in many types of liver disease, including alcoholic liver disease (ALD) and viral liver disease. Some of the mechanisms for zinc deficiency/altered metabolism include decreased dietary intake, increased urinary excretion, activation of certain zinc transporters, and induction of hepatic metallothionein. Zinc deficiency may manifest itself in many ways in liver disease, including skin lesions, poor wound healing/liver regeneration, altered mental status, or altered immune function. Zinc supplementation has been documented to block/attenuate experimental ALD through multiple processes, including stabilization of gut-barrier function, decreasing endotoxemia, decreasing proinflammatory cytokine production, decreasing oxidative stress, and attenuating apoptotic hepatocyte death. Clinical trials in human liver disease are limited in size and quality, but it is clear that zinc supplementation reverses clinical signs of zinc deficiency in patients with liver disease. Some studies suggest improvement in liver function in both ALD and hepatitis C following zinc supplementation, and 1 study suggested improved fibrosis markers in hepatitis C patients. The dose of zinc used for treatment of liver disease is usually 50 mg of elemental zinc taken with a meal to decrease the potential side effect of nausea.
Subject(s)
Deficiency Diseases/complications , Dietary Supplements , Liver Diseases/etiology , Trace Elements/deficiency , Zinc/deficiency , Animals , Deficiency Diseases/drug therapy , Deficiency Diseases/metabolism , Hepatitis C/drug therapy , Hepatitis C/etiology , Hepatitis C/metabolism , Humans , Liver Diseases/drug therapy , Liver Diseases/metabolism , Liver Diseases, Alcoholic/drug therapy , Liver Diseases, Alcoholic/etiology , Liver Diseases, Alcoholic/metabolism , Trace Elements/metabolism , Trace Elements/therapeutic use , Zinc/metabolism , Zinc/therapeutic useABSTRACT
Malnutrition, both protein energy malnutrition (PEM) and deficiencies in individual nutrients, is a frequent complication of alcoholic liver disease (ALD). Severity of malnutrition correlates with severity of ALD. Malnutrition also occurs in patients with cirrhosis due to etiologies other than alcohol. The mechanisms for malnutrition are multifactorial, and malnutrition frequently worsens in the hospital due to fasting for procedures and metabolic complications of liver disease, such as hepatic encephalopathy. Aggressive nutritional support is indicated in inpatients with ALD, and patients often need to be fed through an enteral feeding tube to achieve protein and calorie goals. Enteral nutritional support clearly improves nutrition status and may improve clinical outcome. Moreover, late-night snacks in outpatient cirrhotics improve nutritional status and lean body mass. Thus, with no FDA-approved therapy for ALD, careful nutritional intervention should be considered as frontline therapy.
Subject(s)
Liver Diseases, Alcoholic/complications , Liver Diseases, Alcoholic/metabolism , Malnutrition/complications , Malnutrition/metabolism , Animals , Energy Intake/physiology , Humans , Liver Diseases, Alcoholic/therapy , Malnutrition/therapy , Nutritional Status/physiology , Nutritional Support/methodsABSTRACT
Drug-induced hepatotoxicity is underreported and underestimated in the United States. It is an important cause of acute liver failure. Common classes of drugs causing drug-induced hepatotoxicity include antibiotics, lipid lowering agents, oral hypoglycemics, psychotropics, antiretrovirals, acetaminophen, and complementary and alternative medications. Hepatotoxic drugs often have a signature or pattern of liver injury including patterns of liver test abnormalities, latency of symptom onset, presence or absence of immune hypersensitivity, and the course of the reaction after drug withdrawal.