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Heterogeneous adaptation of cysteine reactivity to a covalent oncometabolite.

An important context in which metabolism influences tumorigenesis is the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a disease in which mutation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) causes hyperaccumulation of fumarate. This electrophilic oncometabolite can alter gene activity at the level of transcription, via reversible inhibition of epigenetic dioxygenases, as well as posttranslationally, via covalent modification of cysteine residues. To better understand the potential for metabolites to influence posttranslational modificat

Metabolically based liver damage pathophysiology in patients with urea cycle disorders - A new hypothesis.

UNLABELLED: The underlying pathophysiology of liver dysfunction in urea cycle disorders (UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle (UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients sufferi

Rapid Initiation of Antiretroviral Therapy With Coformulated Bictegravir, Emtricitabine, and Tenofovir Alafenamide Versus Efavirenz, Lamivudine, and Tenofovir Disoproxil Fumarate in HIV-Positive Men Who Have Sex With Men in China: Week 48 Results of the Multicenter, Randomized Clinical Trial.

BACKGROUND: Most international treatment guidelines recommend rapid initiation of antiretroviral therapy (ART) for people newly diagnosed with human immunodeficiency virus (HIV)-1 infection, but experiences with rapid ART initiation remain limited in China. We aimed to evaluate the efficacy and safety of efavirenz (400 mg) plus lamivudine and tenofovir disoproxil fumarate (EFV + 3TC + TDF) versus coformulated bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) in rapid ART initiation among men who have sex with men (MSM) who have been diagnosed with HIV. METHODS: This multicen

A phase III study of triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler 320/18/9.6 μg and 160/18/9.6 μg using co-suspension delivery technology in moderate-to-very severe COPD: The ETHOS study protocol.

BACKGROUND: Single inhaler triple therapies providing an inhaled corticosteroid, a long-acting muscarinic antagonist, and a long-acting β2-agonist (ICS/LAMA/LABAs) are an emerging treatment option for chronic obstructive pulmonary disease (COPD). Nevertheless, questions remain regarding the optimal patient population for triple therapy as well as the benefit:risk ratio of ICS treatment. METHODS: ETHOS is an ongoing, randomized, double-blind, multicenter, parallel-group, 52-week study in symptomatic patients with moderate-to-very severe COPD and a history of exacerbation(s) in the previous yea

Prevention of mother-to-child transmission of hepatitis B virus: a phase III, placebo-controlled, double-blind, randomized clinical trial to assess the efficacy and safety of a short course of tenofovir disoproxil fumarate in women with hepatitis B virus e-antigen.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is complicated by cirrhosis and liver cancer. In Thailand, 6-7 % of adults are chronically infected with HBV. The risk of mother-to-child transmission (MTCT) of HBV has been estimated to be about 12 % when mothers have a high hepatitis B viral load, even if infants receive passive-active prophylaxis with HBV immunoglobulin (HBIg) and initiate the hepatitis B vaccine series at birth. We designed a study to assess the efficacy and safety of a short course of maternal tenofovir disoproxil fumarate (TDF) among women with a marker of high viral

Metabolic flexibility of a prospective bioremediator: Desulfitobacterium hafniense Y51 challenged in chemostats.

Desulfitobacterium hafniense Y51 has been widely used in investigations of perchloroethylene (PCE) biodegradation, but limited information exists on its other physiological capabilities. We investigated how D. hafniense Y51 confronts the debilitating limitations of not having enough electron donor (lactate), or electron acceptor (fumarate) during cultivation in chemostats. The residual concentrations of the substrates supplied in excess were much lower than expected. Transcriptomics, proteomics and fluxomics were integrated to investigate how this phenomenon was regulated. Through diverse regu

[Immunomodulating therapy of psoriasis vulgaris].

BACKGROUND: Newest studies have shown that psoriasis is not primarily a skin disorder but an immunological disturbance under the skin. The skin manifestations are a result of overstimulation of superficial skin cells (Langerhans cells) due to increased production of interleukin 2, 6 and 8 as well as transforming growth-factor-alpha. Interleucin-10 production is diminished. In a recent study (11 German University Skin Clinics) fumaric acid was shown to improve the skin leasons in 80% of treated patients. OWN EXPERIENCES: Our own studies on 54 patients which where treated in addition with intra

Mitochondrial stress and glycoxidation increase with decreased kidney function.

Mitochondrial stress increases the production of fumarate, an intermediate of the Krebs cycle. Fumarate non-enzymatically reacts with the thiol group of cysteine, leading to the production of S-(2-succinyl)cysteine. Here, we quantified the concentration of fumarate, the free form of S-(2-succinyl)cysteine, and advanced glycation end-products, including N ε-(carboxymethyl)lysine and N δ-(5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine, in the serum of chronic kidney disease patients, using liquid chromatography-tandem mass spectrometry and an enzymatic assay. In a cross-sectional study, we evalu

Rifampicin effect on intracellular and plasma pharmacokinetics of tenofovir alafenamide.

OBJECTIVES: Tenofovir alafenamide produces lower plasma tenofovir and higher intracellular tenofovir diphosphate (DP) concentrations than tenofovir disoproxil fumarate but it is likely a victim of interactions with rifampicin. We aimed to investigate the pharmacokinetics of tenofovir alafenamide/emtricitabine with rifampicin. PATIENTS AND METHODS: Healthy volunteers received tenofovir alafenamide/emtricitabine at 25/200 mg once daily, followed by tenofovir alafenamide/emtricitabine + rifampicin daily followed by tenofovir disoproxil fumarate. Plasma tenofovir alafenamide, tenofovir, emtricita

Guselkumab demonstrates long-term efficacy and maintenance of treatment response postwithdrawal in systemic treatment-naïve patients and nonresponders to fumaric acid esters: results from parts II and III of a randomized active-comparator-controlled phase IIIb trial (POLARIS).

BACKGROUND: The anti-interleukin-23 antibody guselkumab (GUS) demonstrated favourable week 24 efficacy and safety over fumaric acid esters (FAE) in systemic treatment-naïve patients with moderate-to-severe plaque psoriasis (study part I). OBJECTIVES: To compare, in study part II, the sustainability of treatment responses (weeks 24-32) in GUS- and FAE-treated patients and treatment responses (weeks 32-56) in patients treated with GUS and FAE and in FAE nonresponders switching to GUS; and, in part III, to investigate the maintenance of response through week 100 in patients withdrawn from GUS at

Hereditary leiomyomatosis and renal cell cancer without cutaneous manifestations in two Japanese siblings.

Hereditary leiomyomatosis and renal cell cancer is a rare genetic disorder characterized by cutaneous and uterine leiomyomatosis, and an aggressive type 2 papillary renal cell carcinoma. The disease is caused by a germline mutation in the fumarate hydratase gene. We report a familial hereditary leiomyomatosis and renal cell cancer in two siblings. A 34-year-old woman underwent nephrectomy for treatment of a renal cell carcinoma. The patient's sister had been diagnosed with renal cell carcinoma at 28 years-of-age and died of the disease. Neither sister had apparent skin tumors. Histopathology o

Изменяющиеся схемы первоначальной обработки RRMS в Финляндии (2013 - 2022 годы): Понимание из общенационального регистра множественных склерозов.

ОКРУЖАЮЩАЯ СЛЕДУЮЩАЯ ДЕЯТЕЛЬНОСТЬ: Изменяется лечение повторно излучаемого склероза (RRMS). В Финляндии имеется ограниченный объем данных о первоначальной обработке ОРУО. ЦЕЛЬ: Наши цели заключались в изучении тенденций в области первоначального лечения с целью модификации болезней (ДМТ) для пациентов, страдающих ОРМС в период с 2013 по 2022 год, задержек с лечением, факторов, связанных с выбором ДРМ, схем переключения ОРМ и последствий пандемии COVID-19. МЕТОДЫ: В этом ретроспективном исследовании регистра использовались вторичные данные из финского регистра MS. DMT были классифицированы в ка

Совпадение в аннотации оригинала
BACKGROUND: The treatment of relapsing-remitting multiple sclerosis (RRMS) is changing. There are limited data about initial treatment of RR … . The DMTs were classified into medium-efficacy DMTs (meDMTs; beta interferons, glatiramer acetate, fumarates, and teriflunomide) and high-efficacy DMTs (heDMTs; alemtuzumab, cladribine, daclizumab, natalizumab, ocrelizumab, ofatumumab, and rituximab). RESULTS: The inclusion criteria were fulfilled by 2479 individuals. From 2013 to 2022, the proportion of …

[Psoriasis capitis and seborrhoic eczema of scalp diseases].

The scalp may be affected by various diseases with equally varying manifestations. Erythema and scaling is often accompanied by agonizing it … psoriatic disease, systemic treatment may be necessary, including the classic agents methotrexate, fumarates and ciclosporin as well as biologicals. Systemic treatment of seborrheic eczema is rarely necessary and resides on corticosteroids, antimycotic agents and vitamin A derivatives. In addition, intensive counseling of patients on the necessity of conse …

Изосорбидные дистеры: механистическое понимание и терапевтическое применение кожных и нейроинфламативных расстройств.

Изосорбиды жирных кислотных диестеров представляют собой новый класс биоактивных соединений с возникающими терапевтическими видами применения при воспалительных и бескомпромиссных расстройствах. В частности, изосорбид дикаприлат (ИДК) и изосорбид дилинолат/олеат (ИДЛ) синергически укрепляют целостность эпидермального барьера, усиливают стратум роговиум гидрацию, регулируют дифференциацию кератиноцитов, подавляют проинфламационную сигнализацию и выгодно модифицируют микробиом кожи. Случайные, двойные клинические испытания как в педиатрии, так и во взрослом населении с дерматитом (AD) показывают

Совпадение в аннотации оригинала
Isosorbide fatty acid diesters constitute a novel class of bioactive compounds with emerging therapeutic applications in inflammatory and ba … stress and immune pathways with improved safety and mechanistic precision compared to conventional fumarates, although its systemic use remains exploratory and requires clinical validation. Collectively, isosorbide diesters emerge as multifunctional therapeutic agents offering barrier repair, immune modulation, and inflammation control, representing promis …

Safety and Monitoring of the Treatment with Disease-Modifying Therapies (DMTs) for Multiple Sclerosis (MS).

BACKGROUND: Disease-Modifying Therapies (DMTs) for Multiple Sclerosis (MS) are widely used given their proven efficacy in the relapsing form … monitoring of DMTs. CONCLUSION: Data for oral (Sphingosine 1-phosphate (S1P) receptor modulators, Fumarates, Teriflunomide, Cladribine), injectables (Interferons, Glatiramer acetate, Ofatumumab), and infusion therapies (Natalizumab, Ocrelizumab, Alemtuzumab) are presented.

Management of Nail Disease in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations.

OBJECTIVE: Nail psoriasis is common, impairs fine motor finger functioning, affects cosmesis, and is associated with a lower quality of life … f topical corticosteroids, topical calcipotriol, topical tazarotene, topical cyclosporine, dimethyl fumarates/fumaric acid esters, phototherapy, and alitretinoin. There is a low strength of evidence to support the use of calcipotriol and corticosteroid preparations, topical tacrolimus, oral cyclosporine, oral methotrexate, intralesional corticosteroids, pul …

Novel Cocrystals of Vonoprazan: Machine Learning-Assisted Discovery.

Vonoprazan (VPZ) is the first-in-class potassium-competitive acid blocker (P-CAB), and has many advantages over proton pump inhibitors (PPIs … ution at pH 6.8. In addition, novel VPZ cocrystals had superior stability in aqueous media than VPZ fumarates, demonstrating their potential for improved pharmaceutical performance.

[Children and adolescents with psoriasis. What therapy is recommended?].

Juvenile psoriasis shows a cumulative incidence of 1.76% until the 18th year of life and thus is important for both pediatricians and dermat … emic treatment with classical immunomodulatory agents like methotrexate, cyclosporin, retinoids and fumarates may be initiated but all usage is off-label. The only agent licensed for the treatment of psoriasis in patients above the age of 8 years is etanercept if classical treatment has failed. Rehabilitative measures in mountain and seaside areas are reaso …

Elevated levels of prostaglandin E2 in the tears of patients with severe allergic conjunctivitis and primary cultured conjunctival cells are suppressed by ketotifen and dexamethasone.

OBJECTIVE: We examined the production of prostaglandin E2 (PGE2), which is the key prostaglandin involved in inflammatory disorders of the ocular surface. Tears and conjunctival fibroblasts were evaluated in order to assess allergic inflammation and the effect of specific drugs. METHODS AND ANALYSIS: PGE2 was measured in tears from both patients and normal volunteers. Primary cultures of human conjunctival fibroblasts were incubated with interleukin (IL)-4 and tumour necrosis factor (TNF)-α with or without ketotifen fumarate or dexamethasone. The culture supernatants were removed 24 hours aft

Evaluation of the Leishmania Inositol Phosphorylceramide Synthase as a Drug Target Using a Chemical and Genetic Approach.

The lack of effective vaccines and the development of resistance to the current treatments highlight the urgent need for new anti-leishmanials. Sphingolipid metabolism has been proposed as a promising source of Leishmania-specific targets as these lipids are key structural components of the eukaryotic plasma membrane and are involved in distinct cellular events. Inositol phosphorylceramide (IPC) is the primary sphingolipid in the Leishmania species and is the product of a reaction mediated by IPC synthase (IPCS). The antihistamine clemastine fumarate has been identified as an inhibitor of IPCS