Stl1 transporter mediating the uptake of glycerol is not a weak point of Saccharomyces kudriavzevii's low osmotolerance.

Saccharomyces kudriavzevii is a nonconventional and rather osmosensitive yeast with a high potential of use in fermentation processes. To elucidate the basis of its relative osmosensitivity, the role of the STL1 gene encoding a putative glycerol uptake system was studied. Under higher osmotic pressure, the addition of a low amount of glycerol to the growth medium improved the growth of S. kudriavzevii and the expression of the STL1 gene was highly induced. Deletion of this gene decreased the strain's ability to grow in the presence of higher concentrations of salts and other solutes. Moreover, the mutant had a disturbed homeostasis of intracellular pH. Expression of the SkSTL1 gene in Saccharomyces cerevisiae complemented the osmosensitivity of the S. cerevisiae hog1Δ stl1Δ mutant, and the gene's tagging with GFP localized its product to the plasma membrane. Altogether, a deficiency in glycerol uptake did not seem to be the reason for S. kudriavzevii's low osmotolerance; its Stl1 transporter properly contributes to the regulation of intracellular pH and is crucial to its survival of osmotic stress. SIGNIFICANCE AND IMPACT OF THE STUDY: An increasing demand for food products with benefits for human health turns the attention to less-exploited nonconventional yeasts with interesting traits not found in Saccharomyces cerevisiae. Among them, Saccharomyces kudriavzevii has good potential for aroma-compound production, fermentations and other biotechnological applications, but it is less adapted to stressful industrial conditions. This report studied S. kudriavzevii relative osmosensitivity and its capacity for active glycerol uptake. The results obtained (on the activity and physiological function of S. kudriavzevii glycerol transporter) may contribute to a further engineering of this species aiming to improve its osmotolerance.

Adverse events associated with discontinuation of the biologics/classic systemic treatments for moderate-to-severe plaque psoriasis: data from the Spanish Biologics Registry, Biobadaderm.

BACKGROUND: Little is known about the adverse events (AEs) that lead to suspension of systemic treatments for psoriasis in clinical practice. OBJECTIVE: The study aimed to investigate AEs associated with discontinuation of systemic therapy in patients with psoriasis in a clinical setting (Biobadaderm). MATERIALS AND METHODS: Multicentre, prospective, cohort study of patients with moderate-to-severe plaque psoriasis receiving systemic therapies from January 2008 to November 2015, in 12 hospitals in Spain. The incidence rate (IR) was used to compare biologics and classic systemic therapies. RESULTS: A total of 4218 courses of treatment were given to 1938 patients. A total of 447 (11%) treatments were discontinued due to AEs. The IR of AE associated with discontinuation of systemic therapies was 13 events/100 patient-years (PY) (95% CI: 12.14-13.93), 9.34 events/100 PY (95% CI: 8.44-10.33) for biologics and 19.67 (95% CI: 17.9-21.6) events/100 PY for classics (P < 0.001). Of 810 discontinuation-related AEs, 117 (14%) were serious. The highest IRs were for cyclosporine [49.18/100 PY (95% CI: 41.91-57.72)] and infliximab [26.52/100 PY (95% CI: 20.98-33.51). Ustekinumab presented the lowest IR (2.6/100 PY (95% CI: 1.83-3.69). LIMITATIONS: Observational study with potential selection bias. CONCLUSION: Biologic therapies are associated with a lower rate of discontinuation-related AEs than are classic therapies in real clinical practice. Ustekinumab showed the lowest incidence.

Comparison of phenotype, comorbidities, therapy and adverse events between psoriatic patients with and without psoriatic arthritis. Biobadaderm registry.

BACKGROUND: There are a limited number of studies comparing psoriasis patients without psoriatic arthritis (PsA) to those with arthritis. Previous results are controversial. OBJECTIVES: To perform a comparative analysis of the phenotype, baseline comorbidities, therapeutic profile and incidence of adverse events (particularly overall adverse events, infections and infestations, malignancies and psychiatric disorders) among psoriatic patients with/without PsA. METHODS: All the patients on the Biobadaderm registry, a prospective inception cohort of psoriasis patients on systemic therapy, were included. Patients were divided into two groups: those with psoriasis without arthritis at the time of entry into the cohort (Pso group) and those with psoriasis and psoriatic arthritis (PsA group) at entry. Patients were followed until the censorship date (last visit in a lost-to-follow-up patient, or 10 November 2015, whichever occurred first). We excluded all the patients who developed any kind of signs and/or symptoms of joint involvement during the follow-up. A descriptive analysis was performed. We estimated incidence ratios (IRR) of adverse events during systemic treatment using a mixed-effects Poisson regression. RESULTS: We included 2120 patients: 1871 (88%) patients with psoriasis without arthritis and 249 (12%) with psoriasis and PsA. The follow-up time was 5020 patients-year in the Pso group and 762 patients-year in the PsA group. Patients with PsA had more comorbidities, particularly hypertension and liver disease; used a higher number of systemic therapies, particularly anti-TNFα drugs and combination therapy; and presented more adverse events (IRR adjusted = 1.29; 95% CI: [1.05-1.58]), particularly serious adverse events (IRR adjusted = 1.51; 95% CI: [1.01-2.26]) and infections/infestations (IRR adjusted = 1.88; 95% CI: [1.27-2.79]), independently of the associated comorbidities and present/past therapies. CONCLUSIONS: Given the differences between patients with psoriasis alone or with psoriasis associated with PsA, patients with psoriasis and PsA should be followed and managed more closely and with specific attention.

Management of Biologic Therapy in Moderate to Severe Psoriasis in Surgical Patients: Data From the Spanish Biobadaderm Registry. / Manejo de los tratamientos biológicos en pacientes con psoriasis moderada-grave sometidos a intervenciones quirúrgicas en el registro español Biobadaderm.

BACKGROUND AND OBJECTIVE: We now have considerable experience in the use of biologic agents to treat psoriasis, but doubts about management arise in certain clinical settings. Surgery is one of them. Although treatment guidelines advise that biologics be suspended before major surgery, data about actual clinical practices and associated complications are lacking. We aimed to analyze current practice in the clinical management of these cases. METHODS: Retrospective study of cases in the Biobadaderm database. We analyzed the management of biologic therapy in patients with psoriasis who underwent surgical procedures. RESULTS: Forty-eight of the 2113 patients registered in Biobadaderm underwent surgery. The largest percentage of procedures (31%) involved skin lesions. Biologic treatment was interrupted in 42% of the cases. No postsurgical complications were significantly related to treatment interruption. Likewise we detected no associations between treatment interruption and other variables, such as sex, age, or duration or severity of psoriasis. CONCLUSION: Continuity of biologic treatment and the risk of postsurgical complications were not associated in this study, although conclusions are limited by the small sample size.

Survival of classic and biological systemic drugs in psoriasis: results of the BIOBADADERM registry and critical analysis.

BACKGROUND: Few reported studies compare drug survival in moderate-to-severe psoriasis vulgaris. OBJECTIVES: To describe and compare drug survival of systemic drugs, including biologic agents (infliximab, etanercept, adalimumab and ustekinumab) and classical drugs (acitretin, ciclosporin and methotrexate) in moderate-to-severe psoriasis. METHODS: This was a multicenter, prospective, cohort study of patients receiving systemic therapies between 2008 and 2013 in 12 hospitals in Spain. Baseline data and drug discontinuation were collected. Drug survival is presented using Kaplan-Meier survival curves. We compared adjusted risk ratios of serious adverse events (AEs) with results of survival analysis for AEs. RESULTS: A total of 1956 patients were included for analysis (1240 exposed to biologics during follow-up and 1076 to classic therapies). Median follow-up time was 3.3 years (0.0-5.1 years). There were 2209 discontinuations out of 3640 therapy cycles started. The main reason for discontinuation was lack of efficacy (36.4%) and remission (27.2%). Biologics showed a higher drug survival than classics and the pattern of survival results for all outcomes (positive or negative) were very similar. Adjusted risk ratios of serious AEs did not agree with results of survival analysis. LIMITATIONS: A limitation is that this is an observational study with potential selection bias. CONCLUSION: Survival as a proxy measure of drug safety in psoriasis is inadequate.

Risk of Reactivation of Hepatitis B Virus Infection in Psoriasis Patients Treated With Biologics: A Retrospective Analysis of 20 Cases From the BIOBADADERM Database.

INTRODUCTION AND OBJECTIVES: A 5% risk of reactivation of hepatitis B virus (HBV) infection has been reported in patients with diseases other than psoriasis treated with tumor necrosis factor inhibitors. The aim of this study was to investigate the risk of HBV reactivation in patients with a past history of HBV infection who were receiving biologic therapy for psoriasis. MATERIAL AND METHODS: This was a multicenter study of 20 patients with psoriasis who were treated with at least 1 biologic agent. All the patients had serologic evidence of past HBV infection (positive total hepatitis B core antibody and negative hepatitis B surface antibody). We analyzed the clinical, serological, and liver function variables recorded before, during, and at the end of follow-up. The viral load at the end of follow-up was also analyzed for all patients. RESULTS: None of the patients fulfilled the criteria for HBV reactivation at the end of a median follow-up period of 40 months. Combining our data with data from other studies of psoriasis patients with a past history of HBV infection who were treated with a biologic, we calculated a maximum estimated risk of HBV reactivation for a mean follow-up period of 30 months of 2.7 reactivations per 100 patients. CONCLUSIONS: Biologic therapy did not cause HBV reactivation in our series of patients. Nonetheless, because of the potentially serious complications associated with HBV reactivation, it is important to measure viral load in patients with a history of HBV infection prior to initiation of biologic therapy to rule out occult carriage. These patients should also be monitored regularly in conjunction with a hepatologist.

Safety of classic and biologic systemic therapies for the treatment of psoriasis in elderly: an observational study from national BIOBADADERM registry.

BACKGROUND: Psoriasis patients over 65 years-old (elderly) constitute a growing group, underrepresented in clinical trials, and likely to be more prone to adverse events. OBJECTIVE: To describe safety of systemic psoriasis therapy in patients over 65 years-old compared to younger patients. METHODS: Patients registered in Biobadaderm, a Spanish national registry of psoriasis patients treated with systemic therapy, were grouped in elderly (≥ 65 years old) and younger patients. Rates of adverse events were described by severity and type, and the risks compared in both groups, taking into account exposure to classic or biologic drugs, using Cox regression. RESULTS: 175 (9.8%) of 1793 patients were elderly. Overall risk of adverse events was not higher in elderly (drug group adjusted HR 1.09 (95%CI: 0.93-1.3)). Serious adverse events were more common in elderly (drug group adjusted HR 3.2 (95%CI: 2.0-5.1)). Age adjusted HR of all adverse events was lower for patients exposed to biologics compared to classic drugs in the whole sample (HR 0.7 (95%CI: 0.6-0.7)). Age did not seem to modify the effect of therapy (biologic vs. classic) in the risk of adverse events (likelihood ratio test for interaction, p = 0.12 for all adverse events, p = 0-09 for serious adverse events). CONCLUSIONS: Serious adverse events are more common in elderly patients, although they may be related to other variants that are associated with this age group and not due to the treatment itself. Use of biologics was associated with lower risk of adverse events in the whole group. We found no differences in this association between young and elderly. These results are reassuring, although uncontrolled confounding could not be excluded as an explanation for these findings, and the power of the study to detect differences was low.

Risk of adverse events in psoriasis patients receiving classic systemic drugs and biologics in a 5-year observational study of clinical practice: 2008-2013 results of the Biobadaderm registry.

BACKGROUND: Biobadaderm is the Spanish registry of psoriasis patients receiving systemic treatment in clinical practice. OBJECTIVE: To compare the safety of biologics and classic systemic treatment. METHODS: Prospective cohort of patients receiving biologics and classic systemic therapies between 2008 and 2013 in 12 hospitals are included. We registered demographic data, diagnoses, comorbidities, treatments and adverse events (AE). We obtained raw relative risks (RR) for specific AE. Multivariate analysis consisted of Cox models adjusting for age, gender, chronic hepatic disease and previous cancer. RESULTS: A total of 1030 patients received biologics (2061 AE in 3681 person-years), 926 patients classic systemic drugs (1015 AE in 1517 person-years). Ninety-three per cent of AE in both groups were non-serious, 6% serious and 0.003% fatal. The age- and gender-adjusted hazard ratio of AE was lower in the biologics group [hazard ratio 0.6 (95% CI: 0.5-0.7)].We found no differences in rates of serious and mortal AE. Some system organ class AE rates differed between both groups. As limitations: Prescription bias might affect the incidence of AE in both groups. Association of drug and AE was based on timing: associations might not be causal. CONCLUSION: Patients receiving biologics had lower risk of AE. We did not find differences in the risk of serious or fatal AE.

Body mass index in patients with moderate-to-severe psoriasis in Spain and its impact as an independent risk factor for therapy withdrawal: results of the Biobadaderm Registry.

BACKGROUND: There are few data on the prevalence of obesity in the general psoriasis population and on the real impact of obesity on the management of psoriasis patients in the clinical setting. OBJECTIVES: To evaluate the prevalence of overweight and obesity in patients with moderate-to-severe psoriasis compared to the general population and to assess the relationship between Body Mass Index (BMI) and the risk of discontinuing treatment. METHODS: Patients registered on Biobadaderm, a prospective registry, were grouped according the different categories of BMI and compared to the general Spanish population. Drug survival was analysed considering only drug withdrawal due to lack of effectiveness, remission and adverse events. RESULTS: A total of 1162 moderate-to-severe psoriasis patients on systemic conventional or biological treatment were recruited. The prevalence of obesity was found to be significantly higher in psoriasis patients than in the general Spanish population (P < 0.001). In multivariate analysis a 5-unit increase in BMI, similar to a change in BMI category from normal weight to overweight and from overweight to obesity, was associated with a 12% increased risk of discontinuing therapy due to lack of effectiveness (HR 1.12, 95% CI: 1.01-1.24) and with a 17% increased risk of having an adverse event (HR 1.17, 95% CI: 1.02-1.36), both independently of the drug used. CONCLUSIONS: Patients with moderate-to-severe psoriasis had a higher prevalence of obesity than the general population. Increased BMI was associated with an increased risk of treatment discontinuation due to lack of effectiveness and a higher risk of adverse events.

The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4.

HIPK2 is a eukaryotic Serine-Threonine kinase that controls cellular proliferation and survival in response to exogenous signals. Here, we show that the human transcription factor ZBTB4 is a new target of HIPK2. The two proteins interact in vitro, colocalize and associate in vivo, and HIPK2 phosphorylates several conserved residues of ZBTB4. Overexpressing HIPK2 causes the degradation of ZBTB4, whereas overexpressing a kinase-deficient mutant of HIPK2 has no effect. The chemical activation of HIPK2 also decreases the amount of ZBTB4 in cells. Conversely, the inhibition of HIPK2 by drugs or by RNA interference causes a large increase in ZBTB4 levels. This negative regulation of ZBTB4 by HIPK2 occurs under normal conditions of cell growth. In addition, the degradation is increased by DNA damage. These findings have two consequences. First, we have recently shown that ZBTB4 inhibits the transcription of p21. Therefore, the activation of p21 by HIPK2 is two-pronged: stimulation of the activator p53, and simultaneous repression of the inhibitor ZBTB4. Second, ZBTB4 is also known to bind methylated DNA and repress methylated sequences. Consequently, our findings raise the possibility that HIPK2 might influence the epigenetic regulation of gene expression at loci that remain to be identified.

Wine yeast strains engineered for glycogen overproduction display enhanced viability under glucose deprivation conditions.

We used metabolic engineering to produce wine yeasts with enhanced resistance to glucose deprivation conditions. Glycogen metabolism was genetically modified to overproduce glycogen by increasing the glycogen synthase activity and eliminating glycogen phosphorylase activity. All of the modified strains had a higher glycogen content at the stationary phase, but accumulation was still regulated during growth. Strains lacking GPH1, which encodes glycogen phosphorylase, are unable to mobilize glycogen. Enhanced viability under glucose deprivation conditions occurs when glycogen accumulates in the strain that overexpresses GSY2, which encodes glycogen synthase and maintains normal glycogen phosphorylase activity. This enhanced viability is observed under laboratory growth conditions and under vinification conditions in synthetic and natural musts. Wines obtained from this modified strain and from the parental wild-type strain don't differ significantly in the analyzed enological parameters. The engineered strain might better resist some stages of nutrient depletion during industrial use.