Effect of Sacubitril/Valsartan on Patients Having Heart Failure With Preserved Left Ventricular Ejection Fraction Undergoing Hemodialysis: A Long-term Observational Study.

BACKGROUND/AIM: Sacubitril/valsartan (SV), a novel pharmacological class of angiotensin receptor neprilysin inhibitors, is effective in treating heart failure (HF) by inhibiting the degradation of natriuretic peptides and the renin-angiotensin-aldosterone system. However, no studies have observed the long-term effects of SV on patients with HF and preserved left ventricular ejection fraction (LVEF) undergoing hemodialysis (HD) over a long period. PATIENTS AND METHODS: This single-center retrospective study of 21 months duration involved consecutive patients with HF and preserved LVEF undergoing HD, who received 50-200 mg/day. All patients were followed up regularly, and clinical, biochemical, and echocardiographic parameters were recorded at baseline and during follow-up. The efficacy and safety of SV were also analyzed. RESULTS: This longitudinal study included nine patients, with a median age of 76 years. The median HD duration was 7 years. At baseline, the mean brain natriuretic peptide (BNP) was 133±73.6 pg/ml and that of LVEF was 66%±9%. After SV therapy, the systolic blood pressure, diastolic blood pressure, and heart rate decreased, albeit without statistical significance. BNP levels, LVEF, left atrial anteroposterior dimension, and left ventricular mass index did not change, compared to baseline values. No adverse effects were observed in any of the patients. CONCLUSION: SV tended to decrease blood pressure and heart rate in patients with HF and preserved LVEF undergoing HD but did not alter cardiac function assessments, such as BNP or echocardiography.

Effects of Oral Semaglutide on Renal Function in Diabetic Kidney Disease: A Short-term Clinical Study.

BACKGROUND/AIM: In the SUSTAIN-6 trial, semaglutide reduced the risk of worsening nephropathy in patients with type 2 diabetes. The objective of this retrospective study was to elucidate the effect and safety of oral semaglutide (Rybelsus®) in patients with diabetic kidney disease (DKD). PATIENTS AND METHODS: Six patients with DKD received 3 mg/day semaglutide orally. The observation period was 9.0±5.0 months. Changes in estimated glomerular filtration rate (eGFR), urinary protein, fasting blood glucose, and hemoglobin A1c were studied from 6 months before the administration of oral semaglutide until 6 months after administration. RESULTS: The change in eGFR over the 6 months prior to semaglutide administration was -1.2±1.6 ml/min/1.73 m2, showing a trend for a decrease; although not statistically significant, the change at 6 months after oral semaglutide initiation showed improved eGFR (1-50.7±1.8 ml/min/1.73 m2). Proteinuria was not reduced after treatment with oral semaglutide. No significant adverse effects (including retinopathy) were observed in any patient during the study. CONCLUSION: Despite the small sample size and short observation period, oral semaglutide was found to be a relatively well-tolerated drug for patients with DKD.

Case Report: IgG4-related kidney disease complicated by interstitial pneumonia.

Immunoglobulin G4 (IgG4)-related disease is a systemic inflammatory disorder characterized by tubulointerstitial nephritis with IgG4-positive plasma cell infiltration. We report the case of an 84-year-old male who presented with a history of dyspnea on exertion and cough. The lymph nodes were palpated in the axilla. Urinalysis revealed mild proteinuria and increased levels of NAG and ß2-microglobulin. Blood tests showed hyperglobulinemia with a marked elevation of serum IgG4 levels. Chest computed tomography showed bilateral ground-glass and reticular opacities in the lower and peripheral portions of the lungs. Ga-67 scintigraphy showed kidney uptake. The patient was diagnosed with IgG4-related kidney disease based on the renal pathology indicative of typical tubulointerstitial nephritis with extensive IgG4-positive plasma cell infiltration. The patient was treated with prednisolone and showed a prompt response in his clinical condition. The patient achieved normalization of serum IgG4 levels 6 months after the initiation of treatment. Although IgG4-related disease is thought to be potentially associated with organ fibrosis, there are few reports on combination of interstitial pneumonia and IgG4-related kidney disease. Our case report presents a possible pattern of IgG4-related disease.

Effect of finerenone on diabetic kidney disease outcomes with estimated glomerular filtration rate below 25 mL/min/1.73 m2.

Background: In the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease trial, finerenone reduced the risk of cardiovascular events in patients with chronic kidney disease (CKD) and type 2 diabetes, while in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease trial, it improved renal and cardiovascular outcomes in patients with advanced CKD. However, no previous studies have assessed patients with CKD and type 2 diabetes with an estimated glomerular filtration rate (eGFR) below 25 mL/min/1.73 m2. Methods: Nine patients with CKD and type 2 diabetes who received finerenone 10 mg/day were analyzed retrospectively. Changes in eGFR, urinary protein, and serum potassium levels were studied from 1 year before administration of finerenone until 6 months after administration. Results: The mean baseline eGFR slope was -7.63 ± 9.84 (mL/min/1.73 m2/year). After finerenone treatment, the mean eGFR slope significantly improved -1.44 ± 3.17 (mL/min/1.73 m2/6 months, P=0.038). However, finerenone treatment did not significantly reduce proteinuria. Furthermore, finerenone did not increase serum potassium levels. Conclusions: Patients treated with finerenone showed a significantly slower decline in eGFR. Furthermore, aside from the present study, no reports have indicated the effectiveness of finerenone in patients with advanced CKD with an eGFR below 25 mL/min/1.73 m2. As confirmed in our clinical trials, the finding that finerenone is effective in a wide range of renal functions can be generalized to clinical practice. However, sample size in this study was small. Thus, further large-scale investigations will be needed.

Predictive significance of glomerular insulin receptor substrate-1 in patients with diabetic kidney disease.

Background: In rodents, glomerular expression of insulin receptor substrate 1 (IRS1) is decreased in diabetic kidney disease (DKD) and reduced associated functioning is involved in the development and progression of DKD. This study aimed to evaluate the significance of glomerular IRS1 expression in DKD patients, and investigated whether glomerular IRS1 expression can reflect renal pathology and predict renal outcomes. Methods: This study included 10 patients who underwent renal biopsy and were diagnosed with DKD or minor glomerular abnormality (MGA). IRS1-positive cells were determined based on renal biopsy and immunostaining, and the associations of the number of these cells with baseline and prognostic parameters were analyzed. Results: IRS1-positive cells were significantly decreased in DKD than in MGA. IRS1 positivity tended to be negatively correlated with global glomerulosclerosis and tubulointerstitial fibrosis. The rate of change in estimated glomerular filtration rate before and 12 months after renal biopsy was positively correlated to the number of IRS1-positive cells. Furthermore, a tendency towards negative correlation was observed between the number of glomerular IRS1-positive cells and the proteinuria. Conclusions: This study shows the glomerular IRS1-positive cell count was significantly decreased in DKD, and that the degree IRS1 positivity was partially correlated with renal pathology and function.

Effects of incretin-based therapeutic agents including tirzepatide on renal outcomes in patients with type 2 diabetes: A systemic review and meta-analysis.

Background: This meta-analysis was conducted to investigate the effects of incretin-based therapeutic agents, including the latest agent tirzepatide, on renal outcomes in patients with type 2 diabetes. Methods: MEDLINE (via PubMed) and Cochrane databases were searched for studies involving incretin-based therapeutic agents up to July 2022. Randomized and controlled trials comparing incretin-based therapeutic agents with placebo or other antidiabetic agents, and reporting renal outcomes were selected. The inclusion criteria were items related to the effects on albuminuria and the kidney-specific composite outcomes. A network meta-analysis was conducted to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Twelve trials consisting of 75,346 participants were included in this meta-analysis. Glucagon-like peptide-1 (GLP-1) receptor agonists reduced the risk of the kidney-specific composite outcome by 21% (HR 0.79, 95% CI 0.75-0.85), and worsening albuminuria by 24% (HR 0.76, 95% CI 0.71-0.82). In particular, the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide remarkably reduced the risk of the kidney-specific composite outcome by 45% (HR 0.55, 95% CI 0.40-0.77), and worsening albuminuria by 62% (HR 0.38, 95% CI 0.24-0.61). Conclusions: Among incretin-based therapeutic agents, tirzepatide was associated with a significantly reduced risk of diabetic kidney disease.

Multicentric IL-5-positive Castleman Disease With Nephrotic Syndrome Relapsed After Rituximab Treatment.

BACKGROUND/AIM: To date, no reports of interleukin (IL)-5-producing Castleman disease with nephrotic syndrome and moreover no reports of relapse after remission with rituximab treatment, have been published. CASE REPORT: A 67-year-old male presented to the Osaka Medical and Pharmaceutical University Hospital with a history of low-grade fever, papules, and nephrotic syndrome. Lymph nodes were palpated in the inguinal region. The patient showed anemia, eosinophilia, polyclonal hypergammaglobulinemia, and elevated interleukin (IL)-6 levels. Patient's serum IL-5 and IL-6 levels were measured using ELISA and immunohistochemical staining of lymph nodes was performed with antibodies specific to CD134. Histological examination confirmed diagnosis of a plasma cell variant of Castleman disease. After a total of four weekly doses of rituximab, urinary protein disappeared, and skin symptoms improved. However, one month after rituximab treatment, the skin rash worsened again, and eosinophils and IL-5 were elevated significantly. CONCLUSION: This is the first report of recurrent Castleman disease with direct evidence of increased serum IL-5. It may be reasonable to use rituximab, an anti-CD20 antibody for treating the disease, however, for IL-5-producing cases the effect of rituximab may be partial.

Microfluidic system with light intensity filters facilitating the application of photodynamic therapy for high-throughput drug screening.

BACKGROUND: Photodynamic therapy utilizes light energy with a photosensitizer (a light-sensitive drug) to kill cancer cells through creation of singlet oxygen via light activation. When a photosensitizer is injected into the bloodstream and exposed to a specific wavelength of light, it generates oxygen to destroy or damage nearby cancer cells, while minimizing side effects on normal cells. Although photodynamic therapy is effective for treating cancer, various parameters, such as the optimum light intensity and photosensitizer dose, are currently poorly understood due to the complexity of conventional experimental schemes. METHODS: To effectively perform a simultaneous single parallel test for several different light irradiation conditions on each cell, a microfluidic device was developed to generate eight different intensities from a single light-emitting diode source, through eight different color dye concentrations functioning as light intensity filters. To show that this novel high-throughput microfluidic system can analyze the effects of various light intensities during photodynamic therapy, the optimum light intensities and photosensitizer doses were determined for two different cancer cell lines. RESULTS: Optimum light intensities and photosensitizer were determined for all cell lines. The photodynamic therapy effects in response to different irradiated light intensities were characterized by analyzing cell viability after photosensitizer treatment CONCLUSIONS: : The developed platform is capable of being used as a photodynamic therapy screening tool. The proposed platform provides a simple and robust way to optimize the combined parameters of light intensity and dosage for diverse types of cancer cells.

Identification of Lysine Histidine Transporter 2 as an 1-Aminocyclopropane Carboxylic Acid Transporter in Arabidopsis thaliana by Transgenic Complementation Approach.

1-Aminocyclopropane-1-carboxylic acid (ACC), a biosynthetic precursor of ethylene, has long been proposed to act as a mobile messenger in higher plants. However, little is known about the transport system of ACC. Recently, our genetic characterization of an ACC-resistant mutant with normal ethylene sensitivity revealed that lysine histidine transporter 1 (LHT1) functions as a transporter of ACC. As amino acid transporters might have broad substrate specificity, we hypothesized that other amino acid transporters including LHT1 paralogs might have the ACC-transporter activity. Here, we took a gain-of-function approach by transgenic complementation of lht1 mutant with a selected set of amino acid transporters. When we introduced transgene into the lht1 mutant, the transgenic expression of LHT2, but not of LHT3 or amino acid permease 5 (AAP5), restored the ACC resistance phenotype of the lht1 mutant. The result provides genetic evidence that some, if not all, amino acid transporters in Arabidopsis can function as ACC transporters. In support, when expressed in Xenopus laevis oocytes, both LHT1 and LHT2 exhibited ACC-transporting activity, inducing inward current upon addition of ACC. Interestingly, the transgenic expression of LHT2, but not of LHT3 or AAP5, could also suppress the early senescence phenotypes of the lht1 mutant. Taking together, we propose that plants have evolved a multitude of ACC transporters based on amino acid transporters, which would contribute to the differential distribution of ACC under various spatiotemporal contexts.

Exposure to ambient PM2.5 during pregnancy and preterm birth in metropolitan areas of the state of Georgia.

A number of studies has pointed to air pollution as an additional factor that could be associated with preterm birth. We assessed in this study the association between exposure to PM2.5 in ambient air during pregnancy and preterm birth in metropolitan areas of the state of Georgia, where the rate of preterm birth has been among the highest in the nation over the years. Birth data were obtained from the National Center for Health Statistics natality dataset. The study population consisted of 53,094 singleton live births between January 1 and December 31, 2004 in nine metropolitan counties of Georgia. Preterm birth was defined as birth, which occurs before 37 weeks of gestation. County-level daily air quality index (AQI) data obtained from the US Environmental Protection Agency (EPA) was used to estimate individual exposure levels of PM2.5 for each study participant based on the county of residence for the duration of the pregnancy. A multivariate logistic regression analysis was conducted to assess the association, adjusting for potential confounders. Of the infants whose mothers resided in the nine metropolitan counties of Georgia, 4543 (8.6%) were born preterm. A higher rate of preterm birth (9.8%) was observed in infants whose mothers were exposed to ambient PM2.5 with AQI values > 50 than the ones with AQI ≤ 50 (EPA standard for good air quality conditions). Mothers with exposure to PM2.5 at average AQI values greater than 50 during the entire pregnancy were at increased risk of preterm birth (odds ratio 1.15; 95% CI 1.07, 1.25), after adjusting for sex of infant, mother's age, race/ethnicity, education, marital status, prenatal care, cigarette smoking, alcohol consumption, and season of conception. The study provides more evidence on the role of PM2.5 in preterm birth. Reducing exposure to ambient particulate matter, especially in urban areas, for pregnant women would be necessary to improve the health of infants.

A missense allele of KARRIKIN-INSENSITIVE2 impairs ligand-binding and downstream signaling in Arabidopsis thaliana.

A smoke-derived compound, karrikin (KAR), and an endogenous but as yet unidentified KARRIKIN INSENSITIVE2 (KAI2) ligand (KL) have been identified as chemical cues in higher plants that impact on multiple aspects of growth and development. Genetic screening of light-signaling mutants in Arabidopsis thaliana has identified a mutant designated as ply2 (pleiotropic long hypocotyl2) that has pleiotropic light-response defects. In this study, we used positional cloning to identify the molecular lesion of ply2 as a missense mutation of KAI2/HYPOSENSITIVE TO LIGHT, which causes a single amino acid substitution, Ala219Val. Physiological analysis and genetic epistasis analysis with the KL-signaling components MORE AXILLARY GROWTH2 (MAX2) and SUPPRESSOR OF MAX2 1 suggested that the pleiotropic phenotypes of the ply2 mutant can be ascribed to a defect in KL-signaling. Molecular and biochemical analyses revealed that the mutant KAI2ply2 protein is impaired in its ligand-binding activity. In support of this conclusion, X-ray crystallography studies suggested that the KAI2ply2 mutation not only results in a narrowed entrance gate for the ligand but also alters the structural flexibility of the helical lid domains. We discuss the structural implications of the Ala219 residue with regard to ligand-specific binding and signaling of KAI2, together with potential functions of KL-signaling in the context of the light-regulatory network in Arabidopsis thaliana.

Lithium inhibits tumor lymphangiogenesis and metastasis through the inhibition of TGFBIp expression in cancer cells.

Metastasis is the main cause of mortality in cancer patients. Although there are many anti-cancer drugs targeting tumor growth, anti-metastatic agents are rarely developed. Angiogenesis and lymphangiogenesis are crucial for cancer progression; in particular, lymphangiogenesis is pivotal for metastasis in cancer. Here we report that lithium inhibits colon cancer metastasis by blocking lymphangiogenesis. Lithium reduces the expression of transforming growth factor-ß-induced protein (TGFBIp) in colon cancer cells by inhibiting Smad3 phosphorylation via GSK3ß inactivation. Moreover, lithium inhibits lymphatic endothelial cell migration, which is increased upon TGFBIp expression in tumor cells. Lithium had no significant effect on SW620 tumor growth in vitro and in vivo; however, it inhibited lymphangiogenesis in tumors. In tumor xenografts model, lithium was found to prevent metastasis to the lungs, liver, and lymph nodes by inhibiting TGFBIp-induced tumor lymphangiogenesis. Collectively, our findings demonstrate a novel role of lithium in the inhibition of colon cancer metastasis by blocking TGFBIp expression, and thereby TGFBIp-induced lymphangiogenesis, in primary tumors.

Genetic identification of ACC-RESISTANT2 reveals involvement of LYSINE HISTIDINE TRANSPORTER1 in the uptake of 1-aminocyclopropane-1-carboxylic acid in Arabidopsis thaliana.

1-Aminocyclopropane-1-carboxylic acid (ACC) is a biosynthetic precursor of ethylene, a gaseous plant hormone which controls a myriad of aspects of development and stress adaptation in higher plants. Here, we identified a mutant in Arabidopsis thaliana, designated as ACC-resistant2 (are2), displaying a dose-dependent resistance to exogenously applied ACC. Physiological analyses revealed that mutation of are2 impaired various aspects of exogenous ACC-induced ethylene responses, while not affecting sensitivity to other plant hormones during seedling development. Interestingly, the are2 mutant was normally sensitive to gaseous ethylene, compared with the wild type. Double mutant analysis showed that the ethylene-overproducing mutations, eto1 or eto3, and the constitutive ethylene signaling mutation, ctr1 were epistatic to the are2 mutation. These results suggest that the are2 mutant is not defective in ethylene biosynthesis or ethylene signaling per se. Map-based cloning of ARE2 demonstrated that LYSINE HISTIDINE TRANSPORTER1 (LHT1), encoding an amino acid transporter, is the gene responsible. An uptake experiment with radiolabeled ACC indicated that mutations of LHT1 reduced, albeit not completely, uptake of ACC. Further, we performed an amino acid competition assay and found that two amino acids, alanine and glycine, known as substrates of LHT1, could suppress the ACC-induced triple response in a LHT1-dependent way. Taken together, these results provide the first molecular genetic evidence supporting that a class of amino acid transporters including LHT1 takes part in transport of ACC, thereby influencing exogenous ACC-induced ethylene responses in A. thaliana.

Hrq1 facilitates nucleotide excision repair of DNA damage induced by 4-nitroquinoline-1-oxide and cisplatin in Saccharomyces cerevisiae.

Hrq1 helicase is a novel member of the RecQ family. Among the five human RecQ helicases, Hrq1 is most homologous to RECQL4 and is conserved in fungal genomes. Recent genetic and biochemical studies have shown that it is a functional gene, involved in the maintenance of genome stability. To better define the roles of Hrq1 in yeast cells, we investigated genetic interactions between HRQ1 and several DNA repair genes. Based on DNA damage sensitivities induced by 4-nitroquinoline-1-oxide (4-NQO) or cisplatin, RAD4 was found to be epistatic to HRQ1. On the other hand, mutant strains defective in either homologous recombination (HR) or post-replication repair (PRR) became more sensitive by additional deletion of HRQ1, indicating that HRQ1 functions in the RAD4-dependent nucleotide excision repair (NER) pathway independent of HR or PRR. In support of this, yeast two-hybrid analysis showed that Hrq1 interacted with Rad4, which was enhanced by DNA damage. Overexpression of Hrq1K318A helicase-deficient protein rendered mutant cells more sensitive to 4-NQO and cisplatin, suggesting that helicase activity is required for the proper function of Hrq1 in NER.

Genetic identification of a second site modifier of ctr1-1 that controls ethylene-responsive and gravitropic root growth in Arabidopsis thaliana.

Ethylene controls myriad aspects of plant growth throughout developmental stages in higher plants. It has been well established that ethylene-responsive growth entails extensive crosstalk with other plant hormones, particularly auxin. Here, we report a genetic mutation, named 1-aminocyclopropane carboxylic acid (ACC) resistant root1-1 (are1-1) in Arabidopsis thaliana (L.) Heynh. The CONSTITUTIVE TRIPLE RESPONSE1 (CTR1) encodes a Raf-related protein, functioning as an upstream negative regulator of ethylene signaling in Arabidopsis thaliana. We found that the ctr1-1, a kinase-inactive allele exhibited slightly, but significantly, longer root length, compared to ACC-treated wild-type or ctr1-3, a null allele. Our genetic studies unveiled the existence of are1-1 mutation in the ctr1-1 mutant, as a second-site modifier which confers root-specific ethylene-resistance. Based on well-characterized crosstalk between ethylene and auxin during ethylene-responsive root growth, we performed various physiological analyses. Whereas are1-1 displayed normal sensitivity to synthetic auxins, it showed modest resistance to an auxin transport inhibitor, 1-Nnaphthylphthalamic acid. In addition, are1-1 mutant exhibited ectopically altered DR5:GUS activity upon ethylenetreatment. The results implicated the involvement of are1-1 in auxin-distribution, but not in auxin-biosynthesis, -uptake, or -sensitivity. In agreement, are1-1 mutant exhibited reduced gravitropic root growth and defective redistribution of DR5:GUS activity upon gravi-stimulation. Taken together with genetic and molecular analysis, our results suggest that ARE1 defines a novel locus to control ethylene-responsive root growth as well as gravitropic root growth presumably through auxin distribution in Arabidopsis thaliana.

Genetic identification of a novel locus, ACCELERATED FLOWERING 1 that controls chromatin modification associated with histone H3 lysine 27 trimethylation in Arabidopsis thaliana.

Flowering on time is a critically important for successful reproduction of plants. Here we report an early-flowering mutant in Arabidopsis thaliana, accelerated flowering 1-1D (afl1-1D) that exhibited pleiotropic developmental defects including semi-dwarfism, curly leaf, and increased branching. Genetic analysis showed that afl1-1D mutant is a single, dominant mutant. Chromosomal mapping indicates that AFL1 resides at the middle of chromosome 4, around which no known flowering-related genes have been characterized. Expression analysis and double mutant studies with late flowering mutants in various floral pathways indicated that elevated FT is responsible for the early-flowering of afl1-1D mutant. Interestingly, not only flowering-related genes, but also several floral homeotic genes were ectopically overexpressed in the afl1-1D mutants in both FT-dependent and -independent manner. The degree of histone H3 Lys27-trimethylation (H3K27me3) was reduced in several chromatin including FT, FLC, AG and SEP3 in the afl1-1D, suggesting that afl1-1D might be involved in chromatin modification. In support, double mutant analysis of afl1-1D and lhp1-4 revealed epistatic interaction between afl1-1D and lhp1-4 in regard to flowering control. Taken together, we propose that AFL1 regulate various aspect of development through chromatin modification, particularly associated with H3K27me3 in A. thaliana.

Hrq1 functions independently of Sgs1 to preserve genome integrity in Saccharomyces cerevisiae.

Maintenance of genome stability in eukaryotes involves a number of conserved proteins, including RecQ helicases, which play multiple roles at various steps in homologous recombination and DNA repair pathways. Sgs1 has been described as the only RecQ helicase in lower eukaryotes. However, recent studies revealed the presence of a second RecQ helicase, Hrq1, which is most homologous to human RECQL4. Here we show that hrq1Δ mutation resulted in increased mitotic recombination and spontaneous mutation in Saccharomyces cerevisiae, and sgs1Δ mutation had additive effects on the phenotypes of hrq1Δ. We also observed that the hrq1Δ mutant was sensitive to 4-nitroquinoline 1-oxide and cisplatin, which was not complemented by overexpression of Sgs1. In addition, the hrq1Δ sgs1Δ double mutant displayed synthetic growth defect as well as a shortened chronological life span compared with the respective single mutants. Analysis of the type of age-dependent Can(r) mutations revealed that only point mutations were found in hrq1Δ, whereas significant numbers of gross deletion mutations were found in sgs1Δ. Our results suggest that Hrq1 is involved in recombination and DNA repair pathways in S. cerevisiae independent of Sgs1.

Determination of the Potential of Drug Candidates to Cause Severe Skin Disorders Using Computational Modeling.

Efficient and accurate prediction for drugs' potential to cause rare and severe adverse drug reactions (ADRs) is needed to facilitate the evaluation of risk-benefit ratio of drug candidates during drug development. Severe skin disorders like the Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are life-threatening dermatological conditions, are such ADRs that have not received sufficient attention so far. In this study, a total of 1127 marketed drugs were screened for their potential to cause SJS/TEN, of which 255 were found to cause SJS/TEN and 239 were unlikely to cause SJS/TEN. One-class classification method was used to develop multiple prediction models. An applicability domain was determined to define the applicability of the model. Ensemble method was used to develop ensemble models to improve prediction ability. The final ensemble model achieved a sensitivity and specificity of 81 % and 67.4 %, respectively, when estimated using the external 5-fold cross validation method, and a sensitivity of 66.7 % when assessed using an external positive set. The results suggest the methods used in this study are potentially useful for facilitating the prediction of rare and severe ADRs.

Saccharomyces cerevisiae Hrq1 requires a long 3'-tailed DNA substrate for helicase activity.

RecQ helicases are well conserved proteins from bacteria to human and function in various DNA metabolism for maintenance of genome stability. Five RecQ helicases are found in humans, whereas only one RecQ helicase has been described in lower eukaryotes. However, recent studies predicted the presence of a second RecQ helicase, Hrq1, in fungal genomes and verified it as a functional gene in fission yeast. Here we show that 3'-5' helicase activity is intrinsically associated with Hrq1 of Saccharomyces cerevisiae. We also determined several biochemical properties of Hrq1 helicase distinguishable from those of other RecQ helicase members. Hrq1 is able to unwind relatively long duplex DNA up to 120-bp and is significantly stimulated by a preexisting fork structure. Further, the most striking feature of Hrq1 is its absolute requirement for a long 3'-tail (⩾70-nt) for efficient unwinding of duplex DNA. We also found that Hrq1 has potent DNA strand annealing activity. Our results indicate that Hrq1 has vigorous helicase activity that deserves further characterization to expand our understanding of RecQ helicases.