-
PLoS Pathogens Mar 2022Intracellular transport via microtubule-based dynein and kinesin family motors plays a key role in viral reproduction and transmission. We show here that Kinesin Family...
Intracellular transport via microtubule-based dynein and kinesin family motors plays a key role in viral reproduction and transmission. We show here that Kinesin Family Member 4 (KIF4) plays an important role in HBV/HDV infection. We intended to explore host factors impacting the HBV life cycle that can be therapeutically addressed using siRNA library transfection and HBV/NLuc (HBV/NL) reporter virus infection in HepG2-hNTCP cells. KIF4 silencing resulted in a 3-fold reduction in luciferase activity following HBV/NL infection. KIF4 knockdown suppressed both HBV and HDV infection. Transient KIF4 depletion reduced surface and raised intracellular NTCP (HBV/HDV entry receptor) levels, according to both cellular fractionation and immunofluorescence analysis (IF). Overexpression of wild-type KIF4 but not ATPase-null KIF4 mutant regained the surface localization of NTCP and significantly restored HBV permissiveness in these cells. IF revealed KIF4 and NTCP colocalization across microtubule filaments, and a co-immunoprecipitation study revealed that KIF4 interacts with NTCP. KIF4 expression is regulated by FOXM1. Interestingly, we discovered that RXR agonists (Bexarotene, and Alitretinoin) down-regulated KIF4 expression via FOXM1-mediated suppression, resulting in a substantial decrease in HBV-Pre-S1 protein attachment to HepG2-hNTCP cell surface and subsequent HBV infection in both HepG2-hNTCP and primary human hepatocyte (PXB) (Bexarotene, IC50 1.89 ± 0.98 μM) cultures. Overall, our findings show that human KIF4 is a critical regulator of NTCP surface transport and localization, which is required for NTCP to function as a receptor for HBV/HDV entry. Furthermore, small molecules that suppress or alleviate KIF4 expression would be potential antiviral candidates targeting HBV and HDV entry.
Topics: Family; Hep G2 Cells; Hepatitis B virus; Hepatitis Delta Virus; Humans; Kinesins; Organic Anion Transporters, Sodium-Dependent; Retinoid X Receptors; Symporters; Virus Internalization
PubMed: 35312737
DOI: 10.1371/journal.ppat.1009983 -
BMJ Open Feb 2022Hand eczema (HE) is one of the most common skin disorders and an important cause for morbidity and occupational disability. The 1-year prevalence of HE is estimated to...
INTRODUCTION
Hand eczema (HE) is one of the most common skin disorders and an important cause for morbidity and occupational disability. The 1-year prevalence of HE is estimated to be up to 10% and it is estimated that 5%-7% of those develop severe chronic HE. However, current clinical evidence is not compelling enough to guide clinical practice. In a survey among 194 UK dermatologists the most frequent first choice approaches were psoralen combined with ultraviolet A (UVA) treatment (PUVA), oral steroids and alitretinoin (AL). When asked which strategy was most efficient for long-term outcome 20% of clinicians indicated they did not know; 43% of clinicians reported AL and 30% reported PUVA.
METHODS AND ANALYSIS
ALPHA is a multicentre, open, prospective, two-arm parallel group, randomised controlled trial comparing PUVA and AL with a planned sample size re-estimation. Between 500 and 780 participants will be randomised on a 1:1 basis. The physician's global assessment (PGA) will direct treatment after randomisation, non-responders will be treated according to usual clinical practice; providing valuable pilot data on second line therapeutic approaches to inform future trials.Assessments will be conducted up to 52 weeks post randomisation. The primary outcome measure is the Hand Eczema Severity Index at 12 weeks. Secondary outcome measures include modified Total Lesion Symptom Score, PGA, time to relapse, patient reported outcome measures and DNA extraction and assessment of genetic variants. A substudy on molecular inflammatory mediators will provide information on subgroup specific treatment responses. Photographs will be taken and HE severity assessed by a central review panel.
ETHICS AND DISSEMINATION
Ethics approval was obtained from Leeds West Research Ethics Committee (14/YH/1259).Trial results will be disseminated at relevant clinical conferences and societies, published in peer-reviewed journals and through relevant patient groups.
TRIAL REGISTRATION NUMBER
ISRCTN80206075.
Topics: Humans; Alitretinoin; Eczema; Multicenter Studies as Topic; Patient Reported Outcome Measures; Prospective Studies; Randomized Controlled Trials as Topic
PubMed: 35197358
DOI: 10.1136/bmjopen-2021-060029 -
Bioengineered Feb 2022The relevant metabolite biomarkers for risk prediction of early onset of ventricular fibrillation (VF) after ST-segment elevation myocardial infarction (STEMI) remain... (Clinical Trial)
Clinical Trial
Human Plasma Metabolomics Identify 9-cis-retinoic Acid and Dehydrophytosphingosine Levels as Novel biomarkers for Early Ventricular Fibrillation after ST-elevated Myocardial Infarction.
The relevant metabolite biomarkers for risk prediction of early onset of ventricular fibrillation (VF) after ST-segment elevation myocardial infarction (STEMI) remain unstudied. Here, we aimed to identify these imetabolites and the important metabolic pathways involved, and explore whether these metabolites could be used as predictors for the phenotype. Plasma samples were obtained retrospectively from a propensity-score matched cohort including 42 STEMI patients (21 consecutive VF and 21 non-VF). Ultra-performance liquid chromatography and mass spectrometry in combination with a comprehensive analysis of metabolomic data using Metaboanalyst 5.0 version were performed. As a result, the retinal metabolism pathway proved to be the most discriminative for the VF phenotype. Furthermore, 9-cis-Retinoic acid (9cRA) and dehydrophytosphingosine proved to be the most discriminative biomarkers. Biomarker analysis through receiver operating characteristic (ROC) curve showed the 2-metabolite biomarker panel yielding an area under the curve (AUC) of 0.836. The model based on Monte Carlo cross-validation found that 9cRA had the greatest probability of appearing in the predictive panel of biomarkers in the model. Validation of model efficiency based on an ROC curve showed that the combination model constructed by 9cRA and dehydrophytosphingosine had a good predictive value for early-onset VF after STEMI, and the AUC was 0.884 (95% CI 0.714-1). Conclusively, the retinol metabolism pathway was the most powerful pathway for differentiating the post-STEMI VF phenotype. 9cRA was the most important predictive biomarker of VF, and a plasma biomarker panel made up of two metabolites, may help to build a potent predictive model for VF.
Topics: Adolescent; Adult; Aged; Alitretinoin; Biomarkers; Female; Humans; Male; Middle Aged; ST Elevation Myocardial Infarction; Sphingosine; Ventricular Fibrillation
PubMed: 35094641
DOI: 10.1080/21655979.2022.2027067 -
Journal of Cutaneous Medicine and... 2022Chronic hand dermatitis (CHD) is difficult to treat and has high individual and societal burdens. Phototherapy and oral alitretinoin are safe monotherapies for CHD, but...
BACKGROUND
Chronic hand dermatitis (CHD) is difficult to treat and has high individual and societal burdens. Phototherapy and oral alitretinoin are safe monotherapies for CHD, but their combination has not been assessed.
OBJECTIVE
To assess the effectiveness and safety of low dose oral alitretinoin combined with phototherapy versus high dose oral alitretinoin for CHD refractory to topical corticosteroids.
METHODS
This retrospective study of adult patients with CHD refractory to topical corticosteroid therapy compared low dose oral alitretinoin (10 mg three times weekly) combined with narrowband ultraviolet B therapy (three times weekly; LDA-UVB) to high dose oral alitretinoin (30 mg daily; HDA) for 16 weeks. Outcomes were improvement in disease severity measured by the Physician's Global Assessment and quality of life measured with the Dermatology Life Quality Index.
RESULTS
The mean age of the study population ( = 64) was 41.25 years and 57.8% were male. Both cohorts experienced improvements in disease severity and quality of life after 16 weeks, however, significantly more participants who received LDA-UVB ( = 21/33, 63.6%) achieved "clear" or "almost clear" assessments compared to those who received HDA ( = 12/31, 38.7%; < .05). Adverse effects were significantly more prevalent in the HDA group ( < .0001) and included headache, elevated cholesterol, and dry lips.
CONCLUSIONS
The combination of low dose oral alitretinoin with narrowband-UVB therapy was more effective and had fewer adverse effects compared to high dose oral alitretinoin for participants with CHD refractory to topical corticosteroid therapy.
Topics: Adrenal Cortex Hormones; Adult; Alitretinoin; Chronic Disease; Eczema; Female; Humans; Male; Quality of Life; Retrospective Studies; Treatment Outcome; Ultraviolet Therapy
PubMed: 35067082
DOI: 10.1177/12034754211071123 -
Frontiers in Immunology 2021The retinoid X receptor agonist bexarotene promotes remyelination in patients with multiple sclerosis. Murine studies have also demonstrated that RXR agonists have...
The retinoid X receptor agonist bexarotene promotes remyelination in patients with multiple sclerosis. Murine studies have also demonstrated that RXR agonists have anti-inflammatory effects by enhancing the ability of all-trans-retinoic acid (RA) to promote T-regulatory cell (Treg) induction and reduce Th17 differentiation By stimulating human naïve CD4 T-cells in the presence of Treg or Th17 skewing cytokines, we show that bexarotene also tips the human Treg/Th17 axis in favor of Treg induction, but unlike murine cells this occurs independently of RA and retinoic acid receptor signaling. Tregs induced in the presence of bexarotene express canonical markers of T-regulation and are functionally suppressive Circulating Treg numbers did not increase in the blood of trial patients receiving bexarotene; we believe this is because Treg induction is likely to occur within tissues. These findings lend support to developing RXR agonists as treatments of autoimmune diseases, in particular multiple sclerosis.
Topics: Adult; Alitretinoin; Bexarotene; CD4-Positive T-Lymphocytes; Cells, Cultured; Clinical Trials as Topic; Fatty Acids, Unsaturated; Female; Forkhead Transcription Factors; Humans; Leukocytes, Mononuclear; Lymphopoiesis; Middle Aged; Remyelination; Retinoid X Receptors; T-Lymphocytes, Regulatory; Tetrahydronaphthalenes; Th17 Cells
PubMed: 34447379
DOI: 10.3389/fimmu.2021.712241 -
Cancer Medicine Oct 2021In this survey, we analyzed data from patients suffering from the most common cutaneous T-cell lymphomas (CTCLs) subtypes mycosis fungoides (MF) and Sézary syndrome...
INTRODUCTION
In this survey, we analyzed data from patients suffering from the most common cutaneous T-cell lymphomas (CTCLs) subtypes mycosis fungoides (MF) and Sézary syndrome (SS), treated with the retinoid alitretinoin during a 7-year period at our outpatient department between 2015 and 2020.
MATERIALS AND METHODS
We analyzed patient medical records including TNMB stage, side effects under therapy with alitretinoin, time to next treatment (TTNT), and previous photo documentation.
RESULTS
A total of 35 patients with MF (n = 28) and SS (n = 7) were included in the study, of whom 69% were male and 31% were female. The mean age of onset was 56 ± 15 years in MF and 65.4 ± 10.8 years in SS with 51.4% having early stage (IA-IIA) and 48.6% having advanced stage (IIB-IVA) CTCL. Of these patients 37.2% responded to alitretinoin, 28.6% had a stable course, and 34.3% experienced progression. Alitretinoin was administered as a monotherapy (25.7%) or combined with five concomitant therapies (74.2%), most frequently with ECP (31.4%) and PUVA (11.4%). 63% did not report any side effects, most often hypertriglyceridemia (20%) was described.
CONCLUSION
Considering that nearly two thirds of the CTCL patients treated with alitretinoin showed a response or stable disease, together with a low number of side effects and low cost compared to bexarotene, alitretinoin may be a potential alternative in the treatment of less advanced CTCLs. This survey represents the largest number of recorded therapies with the retinoid alitretinoin in CTCLs in a European patient collective.
Topics: Adult; Aged; Alitretinoin; Antineoplastic Agents; Bexarotene; Combined Modality Therapy; Disease Progression; Female; Humans; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Mycosis Fungoides; PUVA Therapy; Sezary Syndrome; Skin Neoplasms
PubMed: 34435474
DOI: 10.1002/cam4.4237 -
Scientific Reports Jul 2021Retinoids play a pivotal role in adrenal development and differentiation. Recent clinical trials revealed therapeutic potential of both all-trans and 9-cis retinoic acid...
Retinoids play a pivotal role in adrenal development and differentiation. Recent clinical trials revealed therapeutic potential of both all-trans and 9-cis retinoic acid in patients with cortisol excess due to a pituitary ACTH-secreting adenoma and indicated that retinoids might act also on the adrenal. Aim of the present study was to evaluate the effect of 9-cis retinoic acid on adrenals from patients with ACTH-dependent Cushing's syndrome. Adrenal specimens from six patients with Cushing's disease were incubated with 10 nM-1 µM 9-cis retinoic acid with and without 10 nM ACTH. Cortisol secretion was measured by immunoassay and expression of genes involved in steroidogenesis as well as retinoic acid action were evaluated by real-time RT-PCR. Incubation with 10-100 nM 9-cis retinoic acid increased spontaneous cortisol secretion and expression of STAR and CYP17A. On the other hand, in wells treated with ACTH, 9-cis retinoic acid markedly diminished ACTH receptor upregulation and no stimulatory effect on cortisol secretion or steroidogenic enzyme synthesis was observed. ACTH itself increased ligand-induced retinoic acid receptor expression, possibly enhancing sensitivity to retinoic acid. Our findings indicate that the effect of 9-cis retinoic acid in presence of ACTH is distinct from unchallenged wells and support the hypothesis of a direct adrenal action in patients with Cushing's disease.
Topics: Adrenal Glands; Adrenocorticotropic Hormone; Alitretinoin; Cushing Syndrome; Humans; Hydrocortisone; Pituitary ACTH Hypersecretion; Receptors, Retinoic Acid; Translational Research, Biomedical; Tretinoin
PubMed: 34253781
DOI: 10.1038/s41598-021-93672-0 -
Annals of Dermatology Feb 2021Oral alitretinoin is effective in the treatment of chronic hand eczema (CHE), and ≥12 weeks of alitretinoin treatment has been shown to be effective in Korean...
BACKGROUND
Oral alitretinoin is effective in the treatment of chronic hand eczema (CHE), and ≥12 weeks of alitretinoin treatment has been shown to be effective in Korean patients. However, in the real world, a considerable number of patients discontinue alitretinoin, which leads to treatment failure.
OBJECTIVE
To evaluate the compliance rate of alitretinoin treatment and explore common reasons for poor compliance in patients with CHE in the real world.
METHODS
We retrospectively reviewed the electronic medical records of CHE patients treated with alitretinoin. We defined 'poor-compliance' as subjects who were treated with alitretinoin for <12 weeks and 'good-compliance' as subjects who were treated with alitretinoin for ≥12 weeks. We reviewed the demographics, dose, and duration of alitretinoin usage, efficacy, and reasons for poor compliance.
RESULTS
A total of 137 subjects were enrolled, and 77 (56.2%) did not complete the 12-week treatment with alitretinoin. Among them, the non-improvement rate was significantly higher in the poor-compliance group than in the good-compliance group (<0.01). The main reasons for the alitretinoin cessation in the poor-compliance group were insufficient response (40.8%), followed by high cost (34.7%), and adverse events (24.5%).
CONCLUSION
Alitretinoin appears the preferred long-term treatment option for CHE. Although there are complaints about late efficacy, cost, and side effects, following proper explanation, these should not justify discontinuation. Physicians need to recognize the reasons for poor compliance with alitretinoin for each patient and suggest continuing alitretinoin for the successful treatment of CHE.
PubMed: 33911811
DOI: 10.5021/ad.2021.33.1.46 -
Cureus Feb 2021Kaposi sarcoma (KS) is a vascular neoplasm caused by human gammaherpesvirus 8 (HHV-8). Four subtypes of KS are described: classic (Mediterranean), epidemic (acquired...
Kaposi sarcoma (KS) is a vascular neoplasm caused by human gammaherpesvirus 8 (HHV-8). Four subtypes of KS are described: classic (Mediterranean), epidemic (acquired immunodeficiency syndrome (AIDS)-associated), endemic (sub-Saharan Africa), and iatrogenic. Iatrogenic KS due to tumor necrosis factor-alpha (TNF-α) inhibitor therapy is particularly rare. A 66-year-old female with a history of seropositive rheumatoid arthritis (RA) presented with a skin lesion on her right second toe. Diagnosed with RA four years prior, she failed to respond to methotrexate, hydroxychloroquine, and etanercept. As a result, she was started on adalimumab. Approximately two months into therapy, she presented to the emergency room with a dark brown skin lesion on her right second toe. She underwent excisional biopsy of the mass, which demonstrated a tumor composed of spindle cells forming slit-like spaces with extravasated red blood cells. The tumor was positive for cluster of differentiation 31 (CD31), CD34, and HHV-8 immunostains and negative for smooth muscle antibody (SMA) and desmin immunostains, consistent with Kaposi sarcoma. Human immunodeficiency virus (HIV) serology was negative. The patient was diagnosed with iatrogenic KS. Adalimumab was discontinued. The patient was started on alitretinoin and underwent adjuvant radiation therapy to minimize recurrence. TNF-α is a pro-inflammatory cytokine that has been implicated in many inflammatory diseases and in cell apoptosis. While anti-TNF-α agents have improved outcomes in many immune-mediated diseases, higher rates of infections and malignancy have also been reported. The incidence of KS with anti-TNF-α therapy remains a rare entity. Therefore, it is extremely important for patients receiving biologic agents, including TNF-α inhibitors, to have a close follow-up and receive routine skin evaluation for malignancy. Clinicians should have a high index of suspicion for KS in such non-HIV patients started on immunosuppressive agents.
PubMed: 33754107
DOI: 10.7759/cureus.13384 -
The British Journal of Dermatology Oct 2021Oral alitretinoin is a retinoid used for severe chronic hand eczema. Although caution is recommended for patients with uncontrolled dyslipidaemia or cardiovascular risk...
BACKGROUND
Oral alitretinoin is a retinoid used for severe chronic hand eczema. Although caution is recommended for patients with uncontrolled dyslipidaemia or cardiovascular risk factors, the actual atherothrombotic risk has not been investigated thus far.
OBJECTIVES
To detect any excess of atherothrombotic events among patients exposed to alitretinoin, during treatment or in the 2 years following initiation.
METHODS
Using the French Health Insurance database, we compared the number of patients who had an atherothrombotic event (coronary artery disease, ischaemic stroke or peripheral artery disease requiring revascularization) in the population exposed to oral alitretinoin vs. the general population of the same age, sex and baseline cardiovascular risk, using standardized morbidity ratios (SMRs).
RESULTS
Between 2009 and 2017, 19 513 patients were exposed to oral alitretinoin in France. Sixty-four (0·3%) patients had an atherothrombotic event while on alitretinoin. Patients receiving alitretinoin experienced no more atherothrombotic events than the general population: patients without cardiovascular risk factors or previous atherothrombotic events had a SMR of 0·65 [95% confidence interval (CI) 0·26-1·34] during alitretinoin treatment, and 1·21 (95% CI 0·90-1·59) in the 2 years following initiation; patients with cardiovascular risk factors or previous atherothrombotic events had a SMR of 0·82 (95% CI 0·60-1·08) during alitretinoin treatment and 0·95 (95% CI 0·82-1·09) in the 2 years following initiation. Taken separately, SMRs for each outcome did not increase either.
CONCLUSIONS
These data from an exhaustive nationwide population-based study do not support an increase in the incidence of atherothrombotic events with alitretinoin use, regardless of the baseline cardiovascular risk of the patient.
Topics: Alitretinoin; Brain Ischemia; Cohort Studies; Dermatologic Agents; Humans; Stroke; Tretinoin
PubMed: 33735442
DOI: 10.1111/bjd.20069