Integrated neural network and evolutionary algorithm approach for liver fibrosis staging: Can artificial intelligence reduce patient costs?

Background and Aim: Staging liver fibrosis is important, and liver biopsy is the gold standard diagnostic tool. We aim to design and evaluate an artificial neural network (ANN) method by taking advantage of the Teaching Learning-Based Optimization (TLBO) algorithm for the prediction of liver fibrosis stage in blood donors and hepatitis C patients. Methods: We propose a method based on a selection of machine learning classification methods including multilayer perceptron (MLP) neural network, Naive Bayesian (NB), decision tree, and deep learning. Initially, the synthetic minority oversampling technique (SMOTE) is performed to address the imbalance in the dataset. Afterward, the integration of MLP and TLBO is implemented. Results: We propose a novel algorithm that reduces the number of required patient features to seven inputs. The accuracy of MLP using 12 features is 0.903, while that of the proposed MLP with TLBO is 0.891. Besides, the diagnostic accuracy of all methods, except the model designed with the Bayesian network, increases when the SMOTE balancer is applied. Conclusion: The decision tree-based deep learning methods show the highest levels of accuracy with 12 features. Interestingly, with the use of TLBO and seven features, MLP reached an accuracy rate of 0.891, which is quite satisfactory when compared with those of similar studies. The proposed model provides high diagnostic accuracy, while reducing the required number of properties from the samples. The results of our study show that the recruited algorithm of our study is more straightforward, with a smaller number of required properties and similar accuracy.

Curcumin encapsulated in milk small extracellular vesicles as a nanotherapeutic alternative in experimental chronic liver disease.

Curcumin is a natural molecule widely tested in preclinical and clinical studies due to its antioxidant and anti-inflammatory activity. Nevertheless, its high hydrophobicity and low bioavailability limit in vivo applications. To overcome curcumin´s drawbacks, small extracellular vesicles (sEVs) have emerged as potential drug delivery systems due to their non-immunogenicity, nanometric size and amphiphilic composition. This work presents curcumin cargo into milk sEV structure and further in vitro and in vivo evaluation as a therapeutic nanoplatform. The encapsulation of curcumin into sEV was performed by two methodologies under physiological conditions: a passive incorporation and active cargo employing saponin. Loaded sEVs (sEVCurPas and sEVCurAc) were fully characterized by physicochemical techniques, confirming that neither methodology affects the morphology or size of the nanoparticles (sEV: 113.3±5.1 nm, sEVCurPas: 127.0±4.5 nm and sEVCurAc: 98.5±3.6 nm). Through the active approach with saponin (sEVCurAc), a three-fold higher cargo was obtained (433.5 µg/mL) in comparison with the passive approach (129.1 µg/mL). These sEVCurAc were further evaluated in vitro by metabolic activity assay (MTT), confocal microscopy, and flow cytometry, showing a higher cytotoxic effect in the tumoral cells RAW264.7 and HepG2 than in primary hepatocytes, specially at high doses of sEVCurAc (4%, 15% and 30% of viability). In vivo evaluation in an experimental model of liver fibrosis confirmed sEVCurAc therapeutic effects, leading to a significant decrease of serum markers of liver damage (ALT) (557 U/L to 338 U/L with sEVCurAc therapy) and a tendency towards decreased liver fibrogenesis and extracellular matrix (ECM) deposition.

Effectiveness and safety of direct oral anticoagulants among patients with non-valvular atrial fibrillation and liver disease: A multinational cohort study.

BACKGROUND AND AIMS: The effects of direct oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation (NVAF) and liver disease remain poorly understood. Our multinational cohort study assessed the effectiveness and safety of DOACs in this high-risk population. METHODS: We assembled two population-based cohorts in United Kingdom and in Québec of NVAF patients with liver disease initiating DOACs or vitamin K antagonists (VKAs) between 2011 and 2020. Using an as-treated exposure definition, we compared DOACs to VKAs and apixaban to rivaroxaban. After inverse probability of treatment weighting, Cox proportional hazards models estimated site-specific hazard ratios (HRs) and 95 % confidence intervals (CIs) of ischemic stroke and major bleeding. Site-specific estimates were pooled using random-effects models. Analyses were repeated among NVAF patients with cirrhosis. RESULTS: There were 11,881 NVAF patients with liver disease (2683 with cirrhosis). Among those, 8815 initiated DOACs (4414 apixaban, 2497 rivaroxaban) and 3696 VKAs. The HRs (95 % CIs) for DOACs compared to VKAs were 1.01 (0.76-1.34) for ischemic stroke and 0.87 (0.77-0.99) for major bleeding. Results were consistent among patients with cirrhosis. The HRs (95 % CIs) for apixaban compared to rivaroxaban were 0.85 (0.60-1.20) for ischemic stroke and 0.80 (0.68-0.95) for major bleeding. This decreased bleeding risk was not observed among patients with cirrhosis (HR, 1.01; 95 % CI 0.72-1.43). CONCLUSIONS: Among NVAF patients with liver disease, DOACs were as effective and slightly safer than VKAs, and apixaban was as effective but safer than rivaroxaban. The safety benefit with apixaban was not present among patients with cirrhosis.

Yin Yang 1 facilitates the activation, inflammation, and extracellular matrix deposition of hepatic stellate cells in hepatic fibrosis.

Chronic hepatic diseases often involve fibrosis as a pivotal factor in their progression. This study investigates the regulatory mechanisms of Yin Yang 1 (YY1) in hepatic fibrosis. Our data reveal that YY1 binds to the prolyl hydroxylase domain 1 (PHD1) promoter. Rats treated with carbon tetrachloride (CCl4) display heightened fibrosis in liver tissues, accompanied by increased levels of YY1, PHD1, and the fibrosis marker alpha-smooth muscle actin (α-SMA). Elevated levels of YY1, PHD1, and α-SMA are observed in the liver tissues of CCl4-treated rats, primary hepatic stellate cells (HSCs) isolated from fibrotic liver tissues, and transforming growth factor beta-1 (TGF-ß1)-induced HSCs. The human HSC cell line LX-2, upon YY1 overexpression, exhibits enhanced TGF-ß1-induced activation, leading to increased expression of extracellular matrix (ECM)-related proteins and inflammatory cytokines. YY1 silencing produces the opposite effect. YY1 exerts a positive regulatory effect on the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and PHD1 expression. PHD1 silencing rescues the promotion of YY1 in cell activation, ECM-related protein expression, and inflammatory cytokine production in TGF-ß1-treated LX-2 cells. Overall, our findings propose a model wherein YY1 facilitates TGF-ß1-induced HSC activation, ECM-related protein expression, and inflammatory cytokine production by promoting PHD1 expression and activating the PI3K/AKT signaling pathway. This study positions YY1 as a promising therapeutic target for hepatic fibrosis.

Albumin, an interesting and functionally diverse protein, varies from 'native' to 'effective' (Review).

Human serum albumins (HSAs) are synthesized in the liver and are the most abundant proteins in plasma of healthy human. They play an important role in the pathophysiological processes of the liver and even the whole organism. Previous studies have mainly focused on the regulation of HSAs' expression. However, with the progress of research in recent years, it has been found that the content of circulating albumin cannot fully reflect the biological function of albumin itself. Given the aforementioned fact, the concept of serum 'effective albumin concentration' has been proposed. It refers to the content of albumin that is structurally and functionally intact. Alterations in the molecular structure and function of albumin have been reported in a variety of diseases, including liver disease. Moreover, these changes have been verified to affect the progression of oxidative stress­related diseases. However, the link between albumin structure and function has not been fully elaborated, and the mechanisms by which different forms of albumin affect disease also need to be further investigated. In this context, the present review mainly expounded the biological characteristics and functions of albumin, summarized the different types of post­translational modification of albumin, and discussed their functional changes and possible mechanisms in non­alcoholic fatty liver disease, alcoholic hepatitis, viral hepatitis and different stages of cirrhosis. This will help to improve understanding of the role of albumin in disease development and provide a more comprehensive physiological basis for it in disease treatment.

Potential therapeutic implications of histidine catabolism by the gut microbiota in NAFLD patients with morbid obesity.

The gut microbiota contributes to the pathophysiology of non-alcoholic fatty liver disease (NAFLD). Histidine is a key energy source for the microbiota, scavenging it from the host. Its role in NAFLD is poorly known. Plasma metabolomics, liver transcriptomics, and fecal metagenomics were performed in three human cohorts coupled with hepatocyte, rodent, and Drosophila models. Machine learning analyses identified plasma histidine as being strongly inversely associated with steatosis and linked to a hepatic transcriptomic signature involved in insulin signaling, inflammation, and trace amine-associated receptor 1. Circulating histidine was inversely associated with Proteobacteria and positively with bacteria lacking the histidine utilization (Hut) system. Histidine supplementation improved NAFLD in different animal models (diet-induced NAFLD in mouse and flies, ob/ob mouse, and ovariectomized rats) and reduced de novo lipogenesis. Fecal microbiota transplantation (FMT) from low-histidine donors and mono-colonization of germ-free flies with Enterobacter cloacae increased triglyceride accumulation and reduced histidine content. The interplay among microbiota, histidine catabolism, and NAFLD opens therapeutic opportunities.

PKHD1L1, A Gene Involved in the Stereocilia Coat, Causes Autosomal Recessive Nonsyndromic Hearing Loss.

Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modelling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modelling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild-moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild-moderate hearing loss may identify further affected families.

Intestinal Microbiome in Dogs with Chronic Hepatobiliary Disease: Can We Talk about the Gut-Liver Axis?

The gut-liver axis represents a current topic in human medicine. Extensive research investigates the gut microbiome (GM) modifications in relation to various kinds of chronic hepatobiliary diseases (CHD), with many mechanisms and therapeutical implications recognized. Those aspects in veterinary medicine are still quite unexplored. The aim of the present study was to evaluate GM in dogs diagnosed with CD. Comparison among CHD dogs were made considering some clinical and biochemical variables (lipemia and alanine-aminotransferase activities), presence of cholestasis or endocrine disorders, diet). Sixty-five dogs were prospectively enrolled with clinical and hematobiochemical evaluation and 16S-RNA GM sequencing assessed. Dogs that received antibiotics and/or pre/pro/symbiotics administration were excluded. Deeper GM alteration was observed between dogs with or without ultrasonographic and biochemical cholestatic CHD. Cholestasis was associated with a decrease in several bacterial taxa, including Clostridium hiranonis, Fusobacterium, Megamonas, Ruminococcus faecis, Turicibacter, and higher levels of Escherichia/Shigella and Serratia. Thus, the alteration in bile flow and composition, typical of cholestasis, may directly affect the local intestinal microbial environment. For the management of dogs with CHD and especially cholestatic CHD, clinicians should be aware that gut-liver interaction may lead to dysbiosis.

Mycophenolate mofetil as a treatment for presumed idiopathic chronic hepatitis in dogs: Six cases (2010-2022).

OBJECTIVES: The objectives of this study were to describe the clinical findings, treatment and outcomes of six dogs with presumed idiopathic chronic hepatitis treated with mycophenolate mofetil (MMF). MATERIALS AND METHODS: Medical records were retrospectively searched to identify dogs in which idiopathic chronic hepatitis was diagnosed on histopathology between January 2010 and June 2022 that were treated with MMF for at least two weeks with >2 follow-up examinations. Data recorded from each dog included signalment, clinical signs, diagnostic test results and treatment. RESULTS: Six dogs were treated with MMF at a median initial dosage of 9.6 mg/kg PO q 12 h. Reported adverse effects from MMF included decreased appetite, vomiting and diarrhoea. In all six dogs, MMF was used successfully long term for the treatment of idiopathic chronic hepatitis as determined by 46% or greater improvement of alanine aminotransferase (ALT) between 4 and 18 weeks of starting MMF. Three dogs were also temporarily treated for 4-6 months on a tapering dose of prednisone. In two dogs, ALT remained within the reference interval, and in one dog, it was very mildly elevated when on MMF alone. In all six dogs, owners reported that the medication was well tolerated. CLINICAL SIGNIFICANCE: To the authors' knowledge, this is the first report describing the use of MMF with and without a tapering dose of prednisone for the treatment of idiopathic chronic hepatitis in six dogs. Based on the outcomes of the dogs in this report, MMF can be effective for the long-term treatment of idiopathic chronic hepatitis as measured by reduction in ALT and improvement of clinical signs.

Repeated specific canine pancreatic lipase measurements do not identify multiple acquired portosystemic shunts in dogs after extrahepatic portosystemic shunt attenuation.

BACKGROUND: In dogs with portal hypertension (PH), spec cPL is suggested to be increased despite normal pancreatic histology. After attenuation of congenital extrahepatic portosystemic shunts (cEHPSS), multiple acquired portosystemic shunt (MAPSS) can develop as consequence of sustained PH. Presence of MAPSS affects future therapeutic options and prognosis. OBJECTIVE: Evaluate if spec cPL concentrations increase postoperatively in dogs that develop MAPSS and can thus serve as an indicator of PH. ANIMALS: Twenty-four dogs with cEHPSS. METHODS: Dogs classified according to surgical outcome after cEHPSS attenuation (8 with MAPSS [group M], 9 with closed cEHPSS [group C] and 7 with patent blood flow through the original cEHPSS, without evidence of MAPSS [group P]). Spec cPL was measured in preoperative samples (T0), 4 days (T1) and 1 (T2) and 3- to 6-months (T3) after surgery. RESULTS: Spec cPL was within reference interval (<200 µg/L) at all timepoints except at T1. At T1, 2 dogs in group M (321 and >2000 µg/L) and also 1 in group C (688 µg/L) and 1 in group P (839 µg/L) had increased spec cPL concentrations. No differences in spec cPL concentrations between groups or changes over time were identified. CONCLUSIONS AND CLINICAL IMPORTANCE: Spec cPL is not consistently increased in dogs that develop MAPSS after cEHPSS attenuation and has no potential as a biomarker for the identification of MAPSS after cEHPSS attenuation.

The genetic spectrum of polycystic kidney disease in children

SUMMARY OBJECTIVE: Autosomal dominant polycystic kidney disease is an inherited kidney disorder with mutations in polycystin-1 or polycystin-2. Autosomal recessive polycystic kidney disease is a severe form of polycystic kidney disease that is characterized by enlarged kidneys and congenital hepatic fibrosis. Mutations at PKHD1 are responsible for all typical forms of autosomal recessive polycystic kidney disease. METHODS: We evaluated the children diagnosed with polycystic kidney disease between October 2020 and May 2022. The diagnosis was established by family history, ultrasound findings, and/or genetic analysis. The demographic, clinical, and laboratory findings were evaluated retrospectively. RESULTS: There were 28 children (male/female: 11:17) evaluated in this study. Genetic analysis was performed in all patients (polycystin-1 variants in 13, polycystin-2 variants in 7, and no variants in 8 patients). A total of 18 variants in polycystin-1 and polycystin-2 were identified and 9 (50%) of them were not reported before. A total of eight novel variants were identified as definite pathogenic or likely pathogenic mutations. There was no variant detected in the PKDH1 gene. CONCLUSION: Our results highlighted molecular features of Turkish children with polycystic kidney disease and demonstrated novel variations that can be utilized in clinical diagnosis and prognosis.

Systematic Multiomic Analysis of PKHD1L1 Gene Expression and Its Role as a Predicting Biomarker for Immune Cell Infiltration in Skin Cutaneous Melanoma and Lung Adenocarcinoma.

The identification of genetic factors that regulate the cancer immune microenvironment is important for understanding the mechanism of tumor progression and establishing an effective treatment strategy. Polycystic kidney and hepatic disease 1-like protein 1 (PKHD1L1) is a large transmembrane protein that is highly expressed in immune cells; however, its association with tumor progression remains unclear. Here, we systematically analyzed the clinical relevance of PKHD1L1 in the tumor microenvironment in multiple cancer types using various bioinformatic tools. We found that the PKHD1L1 mRNA expression levels were significantly lower in skin cutaneous melanoma (SKCM) and lung adenocarcinoma (LUAD) than in normal tissues. The decreased expression of PKHD1L1 was significantly associated with unfavorable overall survival (OS) in SKCM and LUAD. Additionally, PKHD1L1 expression was positively correlated with the levels of infiltrating B cells, cluster of differentiation (CD)-8+ T cells, and natural killer (NK) cells, suggesting that the infiltration of immune cells could be associated with a good prognosis due to increased PKHD1L1 expression. Gene ontology (GO) analysis also revealed the relationship between PKHD1L1-co-altered genes and the activation of lymphocytes, including B and T cells. Collectively, this study shows that PKHD1L1 expression is positively correlated with a good prognosis via the induction of immune infiltration, suggesting that PKHD1L1 has potential prognostic value in SKCM and LUAD.

Corrigendum: Epidemiological, clinical, and laboratory features of patients infected with Elizabethkingia meningoseptica at a tertiary hospital in Hefei City, China.

[This corrects the article DOI: 10.3389/fpubh.2022.964046.].

Development and Evaluation of a Physiologically Based Pharmacokinetic Model of Labetalol in Healthy and Diseased Populations.

Labetalol is a drug that exhibits both alpha and beta-adrenergic receptor-blocking properties. The American Heart Association/American Stroke Association (AHA/ASA) has recommended labetalol as an initial treatment option for the management of severe hypertension. The physiologically based pharmacokinetic (PBPK) model is an in silico approach to determining the pharmacokinetics (PK) of a drug by incorporating blood flow and tissue composition of the organs. This study was conducted to evaluate the primary reasons for the difference in PK after intravenous (IV) and oral administration in healthy and diseased (renal and hepatic) populations. A comprehensive literature search was done using two databases, PubMed and Google Scholar. Various PK parameters were screened for the development of the PBPK model utilizing a population-based PK-Sim simulator. Simulations were performed after creating building blocks firstly in healthy individuals and then in diseased patients after IV and oral administration. The disposition of labetalol after IV and oral administration occurring in patients with the hepatic and renal disease was predicted. The model was evaluated by calculating the Robs/pred ratio and average fold error (AFE), which was in the two-fold error range. Moreover, Box-whisker plots were made to compare the overall concentration of the drug in the body at various stages of disease severity. The presented model provides useful quantitative estimates of drug dosing in patients fighting against severe chronic diseases.

Epidemiological, clinical, and laboratory features of patients infected with Elizabethkingia meningoseptica at a tertiary hospital in Hefei City, China.

Background: Elizabethkingia meningoseptica is a bacterium causing potential nosocomial infections and is associated with a high mortality rate; however, the date of patients in the Hefei population who have been diagnosed with this infection is generally limited. Purpose: The clinical and laboratory data of patients from a tertiary hospital in Hefei City who had E. meningoseptica infection were evaluated in this retrospective analysis. Patients and methods: From May 2017 to November 2021, there were 24 patients infected with E. meningoseptica in the First Affiliated Hospital of Anhui Medical University. Data were gathered from the hospital's electronic medical records for all patients. Results: The most prevalent symptom among the 24 patients was fever (83.3%), followed by edema (41.7%), cough (37.5%), altered consciousness (41.7%), and sputum (37.5%), and laboratory results presented with anemia (75%), hypoproteinemia (75%), elevated C-reactive protein (CRP) (66.7%), neutrophilia (54.2%), and leukocytosis (50.0%). Hepatic disease (1 vs. 7, P = 0.009) was the only significant risk factor for underlying diseases. The mean value of lymphocyte (LYMPH#) (1.4 vs. 0.83 × 109/L, P = 0.033) counts was higher in the survival group than death group, while both anemia (8 vs. 10, P = 0.024) and hypoproteinemia (8 vs. 10, P = 0.024) occurred more frequently in the death group compared with the survival one. Conclusion: Fever was the most common symptom and the only significant factor of underlying diseases was hepatic disease (P = 0.009) that often occurred in death groups. In this investigation, the risk factors for death in patients were anemia, hypoproteinemia, and lymphocyte count. The susceptibility of some quinolones, piperacillin-tazobactam, and cotrimoxazole was relatively high, suggesting that they may be the preferred drugs for the treatment of E. meningoseptica infection. As E. meningoseptica can produce biofilm to pollute the hospital environment and cause infection in patients, the disinfection of the hospital environment should be strengthened and medical staff should pay attention to aseptic operations.

Maternal deaths due to indirect causes: Report from a tertiary care center of a developing country.

Objective: To assess the causes of indirect maternal deaths. Setting: The Department of Obstetrics & Gynecology, of a tertiary referral center in Karachi, Pakistan, from January 2018 to December 2020. Maternal deaths were categorized according to World Health Organization guidelines into direct and indirect deaths. Result: The total maternal deaths during the study period were 96, with 26 (27%) due to indirect causes. The mean age in the indirect group was 27 (range: 20-35) years, with only eight (31%) registered (attending for three of more antenatal visits). The mean gestational age was 33 (range: 22-39) weeks. Cesarean section was the main mode of delivery, in 13 (50%). Perinatal mortality was 68%. Cardiac and hepatic diseases (each six deaths, 23%) were the main causes of indirect maternal deaths. The majority of women (20; 76%) died during the postpartum period. Delays in seeking medical help, referral, and appropriate treatment were observed in 10, 9, and 7 cases, respectively. Conclusion: Indirect maternal deaths are an important cause of maternal mortality.

Comparison of the Efficacy and Safety of Single-Session OK-432 and Multiple-Session 99% Ethanol Sclerotherapy for Symptomatic Simple Hepatic Cysts.

Purpose: This retrospective study aimed to compare the efficacy and safety of single-session OK-432 and multiple-session 99% ethanol sclerotherapy for symptomatic simple hepatic cysts. Methods: We reviewed patients who received aspiration sclerotherapy with OK-432 (group A) or 99% ethanol (group B) for symptomatic simple hepatic cysts at Guangdong Provincial People's Hospital from January 2013 to November 2019. Results: We included 42 patients in group A and 39 patients in group B. No significant difference was found in the mean volume of hepatic cysts between the two groups. The overall success rates were 92.9% (39 of 42 patients) in group A and 79.5% (31 of 39 patients) in group B (P = 0.08). The treatment success for cyst volumes <200 ml, 200-500 ml, and >500 ml was 100, 93.3, and 88.2% in group A, and 100, 84.6, and 57.1% in group B, respectively. The symptomatic relief rate in group A was higher than that in group B for cysts ≥500 ml (P = 0.049) and cysts <500 ml. For treatment-related complications, the incidence of pain at the injection site in group A was lower than that in group B. Conclusion: Single-session OK-432 sclerotherapy was safer and more effective than multiple-session 99% ethanol sclerotherapy for treating large cysts, although both treatments had similar effects on small cysts.

Pharmacokinetic study comparing doxorubicin concentrations after chemoembolization or intravenous administration in dogs with naturally occurring nonresectable hepatic carcinoma.

BACKGROUND: Chemoembolization is a viable treatment option for patients with nonresectable hepatic carcinoma (HC) and may allow delivery of chemotherapeutic drugs with decreased systemic toxicity. HYPOTHESIS/OBJECTIVE: Compare the serum concentrations of doxorubicin after chemoembolization or IV administration in the same patient. We hypothesized that locoregional delivery may result in increased tumor chemotherapeutic drug concentrations, reflected by decreased measurable serum drug concentrations. Adverse hematological events were hypothesized to be decreased after locoregional delivery. ANIMALS: Seventeen client-owned dogs with incompletely resectable HC. METHODS: Prospective, single-arm clinical trial. Drug-eluting bead transarterial chemoembolization was performed to varying levels of blood flow stasis (NO STASIS, STASIS). Intravenous doxorubicin (IVC) subsequently was administered in selected patients. Systemic exposure was quantified by area under the serum doxorubicin concentration time curve (AUC), maximum serum doxorubicin concentration (Cmax ), and time doxorubicin was last above the limit of quantitation (Tlast ). Nadir test results after treatments were used to evaluate adverse hematological events. RESULTS: Thirteen NO STASIS treatments, 15 STASIS treatments, and 9 IVC treatments were performed. Maximum serum doxorubicin concentration, AUC, and Tlast were significantly lower when comparing NO STASIS or STASIS to IVC treatments. Of the patients with nadir results available, no adverse hematological events were observed after NO STASIS or STASIS treatments. Two patients developed adverse hematological events after IVC treatment. CONCLUSIONS/CLINICAL RELEVANCE: Drug-eluting bead transarterial chemoembolization offers a viable treatment option for patients with incompletely resectable HC with the potential for increased local tumor doxorubicin concentrations, decreased systemic chemotherapeutic exposure, and fewer adverse hematological events.

Investigation of a relationship between serum concentrations of microRNA-122 and alanine aminotransferase activity in hospitalised cats.

OBJECTIVES: Current blood tests to diagnose feline liver diseases are suboptimal. Serum concentrations of microRNA (miR)-122 have been shown in humans, dogs and rodents to be a sensitive and specific biomarker for liver injury. To explore the potential diagnostic utility of measuring serum concentrations of miR-122 in cats, miR-122 was measured in a cohort of ill, hospitalised cats with known serum alanine aminotransferase (ALT) activity. METHODS: In this retrospective study, cats were grouped into those with an ALT activity within the reference interval (0-83 U/l; n = 38) and those with an abnormal ALT activity (>84 U/l; n = 25). Serum concentrations of miR-122 were measured by real-time quantitative PCR and the relationship between miR-122 and ALT was examined. RESULTS: miR-122 was significantly higher in the group with high ALT activity than the ALT group, within normal reference limits (P <0.0004). There was also a moderately positive correlation between serum ALT activity and miR-122 concentrations (P <0.001; r = 0.52). CONCLUSIONS AND RELEVANCE: Concentrations of miR-122 were reliably quantified in feline serum and were higher in a cohort of cats with increased ALT activity than in cats with normal ALT activity. This work highlights the potential diagnostic utility of miR-122 as a biomarker of liver damage in cats and encourages further investigation to determine the sensitivity and specificity of miR-122 as a biomarker of hepatocellular injury in this species.