Real-world effectiveness and safety of bimekizumab for hidradenitis suppurativa: An ambispective observational study.

In this original research, we present the results in terms of effectiveness and safety of bimekizumab for hidradenitis suppurativa in real clinical practice. Results indicated significant improvement in all activity scores and patient-reported outcomes at week 16, including a notable decrease in mean IHS4 from 27.1 to 15.6 (p < 0.001), HS-PGA from 5.1 to 3.2 (p < 0.001), VAS pain from 8.3 to 4.7 (p < 0.001) and DLQI from 21.6 to 12.6 (p < 0.001). Bimekizumab, administered every 2 or 4 weeks, was well-tolerated with no discontinuations and no new safety concerns identified. These findings corroborate the drug's effectiveness and favourable safety profile observed in phase 3 clinical trials, supporting its use in real-world clinical practice for treating HS.

Insights into the Window of Opportunity and Outcome Measures in Patients with Moderate to Severe Hidradenitis Suppurativa Treated with Secukinumab: A Real-World Study.

INTRODUCION: The concept of a window of opportunity in hidradenitis suppurativa (HS) management suggests that early initiation of biological therapy leads to better outcomes, though its timing remains uncertain. METHODS: We conducted a retrospective observational multicenter study, including consecutive patients with moderate to severe HS who initiated secukinumab treatment following prior failure with systemic antibiotics or adalimumab. Therapeutic burden was defined as the sum of previous systemic treatment cycles and previous major surgical interventions for HS. Patients were followed up for 24 weeks. Main outcomes were safety and effectiveness, assessed through the proportion of patients achieving HS Clinical Response (HiSCR) and a 55% reduction in International HS Severity Score System (IHS4-55). Additionally, potential predictors of response to secukinumab were studied. Analysis was performed on an intention-to-treat basis. RESULTS: A total of 67 patients (33 men, 34 women) were included, with a mean age of 41.55 (11.94) years and a mean baseline IHS4 of 17.88 (11.13). The mean therapeutic burden was 6.06 (3.49). At week 24, 10.45% (7/67) of patients experienced adverse events, with three leading to treatment discontinuation. At week 24, 41.79% (28/67) of patients achieved HiSCR, and 44.78% (30/67) of patients achieved IHS4-55. HiSCR could not be calculated in 12 patients with a baseline AN count < 3. A lower therapeutic burden was significantly associated with a higher likelihood of achieving HiSCR and IHS4-55 at week 24. CONCLUSIONS: Secukinumab showed safety and efficacy in real-world patients with HS, and the inverse correlation found between therapeutic burden and treatment response supports the concept of a window of opportunity, offering insights into its timing.

Intra-Individual Paired Mass Spectrometry Dataset for Decoding Solar-Induced Proteomic Changes in Facial Skin.

Photoaging is the premature aging of the skin caused by prolonged exposure to solar radiation. The visual alterations manifest as wrinkles, reduced skin elasticity, uneven skin tone, as well as other signs that surpass the expected outcomes of natural aging. Beyond these surface changes, there is a complex interplay of molecular alterations, encompassing shifts in cellular function, DNA damage, and protein composition disruptions. This data descriptor introduces a unique dataset derived from ten individuals, each with a minimum of 18 years of professional experience as a driver, who are asymmetrically and chronically exposed to solar radiation due to their driving orientation. Skin samples were independently collected from each side of the face using a microdermabrasion-like procedure and analyzed on an Exploris 240 mass spectrometer. Our adapted proteomic statistical framework leverages the sample pairing to provide robust insights. This dataset delves into the molecular differences in exposed skin and serves as a foundational resource for interdisciplinary research in photodermatology, targeted skincare treatments, and computational modelling of skin health.

Safety and Effectiveness of Percutaneous Ultrasound-Guided Galvanic Current in Tunnels of Patients with Hidradenitis Suppurativa: A Pilot Study.

INTRODUCTION: The recurrent nature of hidradenitis suppurativa (HS), even under maintained systemic treatment, makes it necessary to have effective local treatments; however, the response to these therapies is variable (44-81%). The application of galvanic current (GC) has demonstrated its utility in humans in treating lesions structurally similar to those of HS. With this background, the main objective of this study was to evaluate the efficacy and safety of ultrasound-guided percutaneous GC in inflamed and/or draining tunnels of HS. METHODS: This was an open study (one-way repeated measures design over time). Patients were evaluated at 4 and 12 weeks after receiving GC. A combined clinical response at week 12 (absence of suppuration/inflammation on examination and clinical interview) was considered the principal variable of efficacy. Adverse effects potentially associated with GC were reported by telephone and at each visit. RESULTS: Twenty-six patients were included, with a male/female ratio of 5:8. The mean age was 35.84 (13.14) years. At 12 weeks after the administration of GC, a complete response was achieved in 77% (20/26) of the treated lesions. No serious adverse effects were observed, and the mean procedural pain assessed by the numeric rating scale was 0.03 (0.2). CONCLUSION: GC has proven to be effective and well tolerated in inflamed and draining tunnels of patients with HS.

Mitofusin 1 silencing decreases the senescent associated secretory phenotype, promotes immune cell recruitment and delays melanoma tumor growth after chemotherapy.

Cellular senescence is a therapy endpoint in melanoma, and the senescence-associated secretory phenotype (SASP) can affect tumor growth and microenvironment, influencing treatment outcomes. Metabolic interventions can modulate the SASP, and mitochondrial energy metabolism supports resistance to therapy in melanoma. In a previous report we showed that senescence, induced by the DNA methylating agent temozolomide, increased the level of fusion proteins mitofusin 1 and 2 in melanoma, and silencing Mfn1 or Mfn2 expression reduced interleukin-6 secretion by senescent cells. Here we expanded these observations evaluating the secretome of senescent melanoma cells using shotgun proteomics, and explored the impact of silencing Mfn1 on the SASP. A significant increase in proteins reported to reduce the immune response towards the tumor was found in the media of senescent cells. The secretion of several of these immunomodulatory proteins was affected by Mfn1 silencing, among them was galectin-9. In agreement, tumors lacking mitofusin 1 responded better to treatment with the methylating agent dacarbazine, tumor size was reduced and a higher immune cell infiltration was detected in the tumor. Our results highlight mitochondrial dynamic proteins as potential pharmacological targets to modulate the SASP in the context of melanoma treatment.

4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification.

BACKGROUND AND AIMS: Developing novel therapies to battle the global public health burden of heart failure remains challenging. This study investigates the underlying mechanisms and potential treatment for 4-hydroxynonenal (4-HNE) deleterious effects in heart failure. METHODS: Biochemical, functional, and histochemical measurements were applied to identify 4-HNE adducts in rat and human failing hearts. In vitro studies were performed to validate 4-HNE targets. RESULTS: 4-HNE, a reactive aldehyde by-product of mitochondrial dysfunction in heart failure, covalently inhibits Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis. 4-HNE inhibition of Dicer impairs miRNA processing. Mechanistically, 4-HNE binds to recombinant human Dicer through an intermolecular interaction that disrupts both activity and stability of Dicer in a concentration- and time-dependent manner. Dithiothreitol neutralization of 4-HNE or replacing 4-HNE-targeted residues in Dicer prevents 4-HNE inhibition of Dicer in vitro. Interestingly, end-stage human failing hearts from three different heart failure aetiologies display defective 4-HNE clearance, decreased Dicer activity, and miRNA biogenesis impairment. Notably, boosting 4-HNE clearance through pharmacological re-activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) using Alda-1 or its improved orally bioavailable derivative AD-9308 restores Dicer activity. ALDH2 is a major enzyme responsible for 4-HNE removal. Importantly, this response is accompanied by improved miRNA maturation and cardiac function/remodelling in a pre-clinical model of heart failure. CONCLUSIONS: 4-HNE inhibition of Dicer directly impairs miRNA biogenesis in heart failure. Strikingly, decreasing cardiac 4-HNE levels through pharmacological ALDH2 activation is sufficient to re-establish Dicer activity and miRNA biogenesis; thereby representing potential treatment for patients with heart failure.

The impact of photodynamic therapy on skin homeostasis in patients with actinic keratosis: A prospective observational study.

BACKGROUND: Photodynamic therapy (PDT) is an effective treatment for actinic keratosis (AKs), but there is little information on how PDT affects skin barrier function. The objectives of this study are: To compare skin barrier function between skin with AKs and healthy skin and to evaluate the impact of PDT on skin homeostasis in patients with AKs. METHODS: A prospective observational study was conducted in patients with AKs to evaluate epidermal barrier function and skin homeostasis before and 1 ek after receiving PDT. RESULTS: A total of 21 subjects were included in the study, male/female ratio was 17:4, mean age was 75.86 years. The number of AKS observed before starting treatment was reduced with respect to those diagnosed 1 month after starting PDT (14.83 vs. 1.91, p < 0.0001). Application of PDT for treating AKs modifies epidermal barrier function. Immediately after the first session temperature, transepidermal water loss (TEWL), stratum corneum hydration (SCH) and total antioxidant capacity (TAC) increased while pH decreased on lesional skin. After 1-month follow-up, the only remained change was the increased in SCH. Higher increases in temperature were observed when using occlusive PDT compared to mixed modality. 5-ALA and M-ALA seem to have a similar impact on skin barrier. CONCLUSIONS: PDT can improve skin barrier function in patients with AKs. Skin homeostasis parameters can be used to assess efficacy and optimize dosing.

Factors Influencing Major Life-Changing Decisions in Patients with Psoriasis: A Cross-sectional Study.

Psoriasis is a chronic inflammatory disease associated with significant impairment in quality of life. Although quality of life in patients with psoriasis has been widely studied, there is little evidence regarding the impact of psoriasis on major life-changing decisions (MLCD). The aims of this study are to describe the impact of psoriasis on MLCD and to explore the potential clinical factors associated with MLCD. This cross-sectional study included 113 patients with psoriasis, regardless of disease severity, duration, or current treatment. The impact of the disease on different MLCD, including those related to professional career, decision of having children, choice of clothing, and leisure activities, was explored using Likert scales. Mean age was 51 years old and female to male ratio was 1.08 (54/50). The mean Psoriasis Area Severity Index was 3.75, and 30% (35/113) of the patients had psoriatic arthropathy. The most affected MLCD were career choice (median (interquartile range) score 3 (2-4)), social relationships (2 (1-3)), choice of clothing (2 (1-3)), job performance, absenteeism, and choice of holiday destination (1 (0-2)). Female sex, early age of onset and psoriatic arthropathy were associated with a greater impact of the disease on MLCD (p < 0.05). The results showed that a range of MLCD are affected in patients with psoriasis, such as career choice, job performance, absenteeism, or choice of clothing. Female sex,  psoriatic arthritis and early age of onset are factors associated with a greater impact on MLCD. In order to limit the long-term negative effects of psoriasis on patients, special attention should be paid to detection of psoriatic arthritis, and to patients with early disease onset.

Pilonidal Sinus Disease is Associated with Severe Hidradenitis Suppurativa in a Spanish Cohort.

Hidradenitis suppurativa is a chronic inflammatory disorder of the hair follicle with a high level of morbidity. Pilonidal sinus disease is a comorbid disorder and may be the reason for first contact with the healthcare system of patients with hidradenitis suppurativa. The aim of this study was to evaluate the frequency of association of pilonidal sinus disease and hidradenitis suppurativa and to explore whether pilonidal sinus disease defines a different clinical profile for patients with hidradenitis suppurativa. A cross-sectional study in which data regarding past history of pilonidal sinus disease, clinical and sociodemographic information were recorded during the first visit to the Hidradenitis Suppurativa Clinic of 2 tertiary hospitals. A total of 839 patients were included in the study. Of these, 51.7% (434/839) were male and mean age was 37.3 ± 13.6 years. Pilonidal sinus disease was present in 32.6% (269/839) of the patients and was associated with an early debut of hidradenitis suppurativa, a higher Hurley stage, inflammatory phenotype and a greater number of fistulas and perianal involvement. Elapsed time between pilonidal sinus disease and diagnosis of hidradenitis suppurativa was associated with higher disease severity. Pilonidal sinus disease is a frequent comorbidity and risk marker for hidradenitis suppurativa disease severity. Pilonidal sinus disease could be a sentinel event to identify patients who would benefit from close treatment and follow-up.

Eukaryotic-like gephyrin and cognate membrane receptor coordinate corynebacterial cell division and polar elongation.

The order Corynebacteriales includes major industrial and pathogenic Actinobacteria such as Corynebacterium glutamicum or Mycobacterium tuberculosis. These bacteria have multi-layered cell walls composed of the mycolyl-arabinogalactan-peptidoglycan complex and a polar growth mode, thus requiring tight coordination between the septal divisome, organized around the tubulin-like protein FtsZ, and the polar elongasome, assembled around the coiled-coil protein Wag31. Here, using C. glutamicum, we report the discovery of two divisome members: a gephyrin-like repurposed molybdotransferase (Glp) and its membrane receptor (GlpR). Our results show how cell cycle progression requires interplay between Glp/GlpR, FtsZ and Wag31, showcasing a crucial crosstalk between the divisome and elongasome machineries that might be targeted for anti-mycobacterial drug discovery. Further, our work reveals that Corynebacteriales have evolved a protein scaffold to control cell division and morphogenesis, similar to the gephyrin/GlyR system that mediates synaptic signalling in higher eukaryotes through network organization of membrane receptors and the microtubule cytoskeleton.

A nitroalkene derivative of salicylate alleviates diet-induced obesity by activating creatine metabolism and non-shivering thermogenesis.

Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.

Risk Factors of Quality-Of-Life and Sexual Function Impairment in Chronic Spontaneous Urticaria Patients: Cross-Sectional Study.

BACKGROUND: Chronic spontaneous urticaria (CSU) has been associated with poor quality of life and mood disturbances. However, factors associated with these dimensions have not been properly assessed. Moreover, there is a lack of studies regarding sexual dysfunction (SxD) and CSU. Therefore, the aims of this study were to assess quality of life associated factors and to evaluate the prevalence and potential impact of SxD in patients with CSU. METHOD: Cross-sectional study of patients suffering from CSU. Sociodemographic and disease activity variables, quality of life, sleep, SxD, anxiety, and depression were collected using validated questionnaires. RESULTS: Seventy-five patients were included, with a female-to-male ratio of 2.40. Female sex, worse disease control, and sexual dysfunction were associated with poor quality-of-life indexes (p < 0.001). SxD was detected in 52% of female and 63% of male patients. SxD was associated with poor disease control (p < 0.001). Female SxD, but not male, was associated with poorer quality of life (p = 0.02) and an increased risk for anxiety 85% and depression 90% (p < 0.05). CONCLUSIONS: Female patients and those with an inadequate control of CSU are in higher risk of having poorer quality of life. SxD seems to be frequent in patients with CSU. Moreover, female SxD seems to have a more profound impact on quality of life and mood disturbances when compared to males. Assessment of SxD in Urticaria Clinic might be of benefit to identify patients at a higher risk of poor quality of life.

Short-Term Effectiveness, Safety, and Potential Predictors of Response of Secukinumab in Patients with Severe Hidradenitis Suppurativa Refractory to Biologic Therapy: A Multicenter Observational Retrospective Study.

INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. Biologic drugs have a key role in the long-term anti-inflammatory treatment of moderate to severe patients due to their immunomodulatory properties. The aim of this study is to evaluate the effectiveness and safety of secukinumab in patients with moderate to severe HS after 16 weeks of treatment, and to explore potential predictors of clinical response to the drug. METHODS: Multicenter observational retrospective study. Patients treated with secukinumab 300 mg every 2 or 4 weeks who had completed at least 16 weeks of follow-up from nine hospitals based in southern Spain (Andalusia) were included in this study. Treatment effectiveness was assessed using the Hidradenitis Suppurativa Clinical Response (HiSCR). Information about adverse events was collected, the therapeutic burden of the patients was calculated as the summation of systemic medical treatments and surgical interventions (excluding incision and drainage) experienced until the start of secukinumab treatment. RESULTS: Forty-seven patients with severe HS were included for analysis. At week 16, 48.9% (23/47) of patients achieved HiSCR. Adverse events were present in 6.4% (3/47) of the patients. The multivariate analysis showed that female sex and, to a lesser extent, lower body mass index (BMI) and a lower therapeutic burden were potentially associated with a higher probability of HiSCR achievement. CONCLUSIONS: Favorable short-term effectiveness and safety of secukinumab in the treatment of severe HS patients were observed. Female sex, lower BMI and a lower therapeutic burden may be associated with a higher probability of achieving HiSCR.

The impact of dupilumab on skin barrier function: A systematic review.

Skin barrier dysfunction plays an important role in atopic dermatitis (AD) aetiopathogenesis. Dupilumab, a drug that inhibits IL-4 and IL-13, is an effective treatment for AD but there is scarce evidence about its impact on epidermal barrier. The objective of this systematic review is to evaluate the influence of dupilumab on skin barrier in patients with AD using non-invasive tools. A systematic review was designed following PRISMA guidelines. The literature search identified 73 references and, finally, only 6 were selected, including a total of 233 participants. All the studies were prospective observational studies. Dupilumab improved clinical scores in all the research. Skin barrier function parameters were mainly measured on the volar forearm. Transepidermal water loss (TEWL) was the parameter most frequently measured, evaluated in all the studies. Dupilumab decreased TEWL on eczematous lesions and non-involved skin. About 33.6% (2/6) studies reported that dupilumab also increased stratum corneum hydration (SCH) on eczematous lesions while one study did not report any changes in this parameter. This drug also decreased temperature and improved ceramide composition. In conclusion, dupilumab improved skin barrier function in AD patients, mainly reflected in a decreased in TEWL values.