Lupus Low Disease Activity State and organ damage in relation to quality of life in systemic lupus erythematosus: a cohort study with up to 11 years of follow-up.

OBJECTIVES: Beyond prevention of organ damage, treatment goals in systemic lupus erythematosus (SLE) include optimisation of health-related quality of life (HRQoL). The Lupus Low Disease Activity State (LLDAS) has received increasing attention as a goal whenever remission cannot be achieved. How SLE disease activity, organ damage, and LLDAS attainment relate to patient-reported outcomes (PROs) is not fully explored, which formed the scope of this investigation. METHODS: We included 327 patients with SLE from a tertiary referral centre. Longitudinal registrations of disease activity using SLEDAI-2K and physician global assessment (PhGA), organ damage using the SLICC/ACR damage index (SDI), pharmacotherapies, EQ-5D-3L data, as well as visual analogue scale (VAS) scores for fatigue, pain, and overall SLE-related health state over a median follow-up time of 8.5 years were analysed. RESULTS: In the overall population, as well as subgroups of patients with recent-onset SLE and those with clinically active, autoantibody-positive disease, LLDAS attainment, lower PhGA, and lower clinical SLEDAI-2K scores were associated with favourable HRQoL by EQ-5D-3L and VAS assessments, while increasing SDI scores were associated with poor PROs yet not fatigue in the overall population. PROs were further enhanced by being in LLDAS sustainedly. In fully adjusted models of the entire study population, LLDAS attainment and lower disease activity were associated with favourable PROs, irrespective of SDI. CONCLUSION: In one of the longest to date observational studies, we demonstrated that low disease activity and being sustainedly in LLDAS were coupled with favourable HRQoL, pain, fatigue, and overall health experience, irrespective of organ damage.

Pigmentation control in pregnancy-induced melasma: Clinical assessment of a non-hydroquinone, non-retinol pigment-correcting serum.

BACKGROUND: Melasma is an acquired disorder that results in irregular brown patches on the skin that can occur due to hormonal changes. Although pregnancy-induced melasma is usually temporary, it can become a chronic condition, with significant negative impact on quality of life (QoL). AIMS: Determine the efficacy and tolerability of a topical, non-hydroquinone, non-retinol pigment-correcting serum (LYT2) for the treatment of pregnancy-induced melasma. METHODS: This 12-week, single-center clinical trial enrolled 34 non-pregnant women who developed mild to severe facial melasma following a previous pregnancy (mean age, 42 years). LYT2 was applied twice daily to facial skin for 12 weeks in addition to a basic skincare regimen. Outcomes included changes from baseline in skin physiology parameters, such as brightness (L*), using objective digital image analysis, investigator-rated Overall Hyperpigmentation scale, Global Improvement, and Melasma Area and Severity Index (MASI), as well as subject-assessed Melasma Quality of Life Scale. Subjects also completed a questionnaire on self-perceived efficacy and attributes of the study product. Tolerability was assessed by the investigators (erythema, scaling, and edema) and subjects (burning/stinging and itching). Clinical assessments were conducted at baseline and Weeks 4, 8, and 12. RESULTS: LYT2 provided statistically significant reductions in overall hyperpigmentation scores as early as Week 4 (-5.8% change from baseline) and continued through Week 12 (-14.6% change from baseline; all p < 0.001). Significant improvements in MASI scores and QoL were also achieved following LYT2 treatment, which was well tolerated. CONCLUSIONS: LYT2 represents a new efficacious alternative to hydroquinone-based treatments for pregnancy-induced melasma.

A Prospective Six-month Single-blind Study Evaluating Changes in Hair Growth and Quality Using a Nutraceutical Supplement in Men and Women of Diverse Ethnicities.

Objective: The goal of this study was to assess the perceived efficacy of a standardized nutraceutical to improve hair growth and quality in men and women of various ethnicities with self-perceived hair thinning. Methods: This prospective, single-blind study enrolled healthy men aged 20 to 55 years (n=47) and premenopausal women aged 20 to 45 years (n=51) with self-perceived, mild-to-moderate hair thinning and included African American, Asian, Hispanic Caucasian and Non-Hispanic Caucasian participants. The nutraceutical supplement (Nutrafol® Men or Women Capsules, Nutraceutical Wellness Inc., New York, New York) was taken daily for six months. Subjects were evaluated in the clinic at baseline and Weeks 12 and 24 with two self-assessments at Weeks 4 and 8. Study endpoints were standardized digital imaging and investigator rated assessments. Self-assessment questionnaires rated hair growth, hair satisfaction, and lifestyle factors. Results: Investigator ratings for baseline hair growth, coverage, density, and volume were significant at Weeks 12 and 24 for all subjects (for each, p<0.001). These significant improvements were seen in 83.7 percent of men and 79.5 percent of women at Week 24. Results were similar across ethnic subgroups with significant benefit at Weeks 12 and 24 (for each, p<0.05). All subjects reported significant improvements in baseline hair appearance/quality, volume/fullness, scalp coverage, thickness, and shedding at Weeks 4, 8, 12 and 24 (for each, p<0.01). Conclusion: A standardized nutraceutical supplement improved visible hair growth with less notable shedding based on subjects' and investigators' overall perception of treatment benefit for men and women of various ethnic backgrounds.

Novel Rotational Combination Regimen of Skin Topicals Improves Facial Photoaging: Efficacy Demonstrated in Double-Blinded Clinical Trials and Laboratory Validation.

Topical antiaging products are often a first-line intervention to counter visible signs of facial photoaging, aiming for sustained cosmetic improvement. However, prolonged application of a single active topical compound was observed clinically to lead to a plateau effect in improving facial photoaging. In view of this, we set out to reduce this effect systematically using a multi-tiered approach with laboratory evidence and clinical trials. The objective of the study was to evaluate the effects of active topical ingredients applied either alone, in combination, or in a rotational manner on modulation of facial photoaging. The study methodology included in vitro, organotypic, and ex vivo skin explants; in vivo biopsy study; as well as clinical trials. We demonstrate for the first time that a pair of known antiaging ingredients applied rotationally, on human dermal fibroblasts, maximized pro-collagen I production. Indeed, rotational treatment with retinol and phytol/glycolic acid (PGA) resulted in better efficacy than application of each active ingredient alone as shown by explants and in vivo biopsy study, with penetration of active ingredients confirmed by Raman spectroscopy. Furthermore, two split-face, randomized, double-blinded clinical trials were conducted, one for 12 months to compare treated vs. untreated and the other for 6 months followed by a 2-month regression to compare treated vs. commercially marketed products. In both studies, rotational regimen showed superior results to its matching comparison as assessed by clinical grading and image analysis of crow's feet wrinkles. In conclusion, rotational regimen using retinol and PGA is effective in treating facial photoaging signs with long-lasting benefits.

Molecular Regulation of Lysophosphatidic Acid Receptor 1 Maturation and Desensitization.

Lysophosphatidic acid receptor 1 (LPA1) belongs to the G protein-coupled receptor family. The ligand for LPA1 is LPA, the simplest lysophospholipid. LPA is considered a growth factor and induces cell proliferation, anti-apoptosis, and cell migration. The pro-inflammatory and pro-fibrotic roles of LPA have also been well-demonstrated. Most of the biological functions of LPA are mostly executed through LPA1. The mature form of LPA1 is glycosylated and localized on the plasma membrane. LPA1 is bound to heterotrimetric G proteins and transduces intracellular signaling in response to ligation to LPA. Desensitization of LPA1 negatively regulates LPA1-mediated signaling and the resulting biological functions. Phosphorylation and ubiquitination are well-demonstrated posttranslational modifications of GPCR. In this review, we will discuss our knowledge of LPA1 glycosylation, maturation, and trafficking from the endoplasmic reticulum (ER)/Golgi to the plasma membrane. Moreover, in light of recent findings, we will also discuss molecular regulation of LPA1 internalization and stability.

Megakaryocyte TGFß1 partitions erythropoiesis into immature progenitor/stem cells and maturing precursors.

Erythropoietin (EPO) provides the major survival signal to maturing erythroid precursors (EPs) and is essential for terminal erythropoiesis. Nonetheless, progenitor cells can irreversibly commit to an erythroid fate well before EPO acts, risking inefficiency if these progenitors are unneeded to maintain red blood cell (RBC) counts. We identified a new modular organization of erythropoiesis and, for the first time, demonstrate that the pre-EPO module is coupled to late EPO-dependent erythropoiesis by megakaryocyte (Mk) signals. Disrupting megakaryocytic transforming growth factor ß1 (Tgfb1) disorganized hematopoiesis by expanding the pre-EPO pool of progenitor cells and consequently triggering significant apoptosis of EPO-dependent EPs. Similarly, pharmacologic blockade of TGFß signaling in normal mice boosted the pre-EPO module, leading to apoptosis of EPO-sensitive EPs. Subsequent treatment with low-dose EPO triggered robust RBC production in both models. This work reveals modular regulation of erythropoiesis and offers a new strategy for overcoming chronic anemias.

Evaluating the Viability of Successive Ring-Expansions Based on Amino Acid and Hydroxyacid Side-Chain Insertion.

The outcome of ring-expansion reactions based on amino/hydroxyacid side-chain insertion is strongly dependent on ring size. This manuscript, which builds upon our previous work on Successive Ring Expansion (SuRE) methods, details efforts to better define the scope and limitations of these reactions on lactam and ß-ketoester ring systems with respect to ring size and additional functionality. The synthetic results provide clear guidelines as to which substrate classes are more likely to be successful and are supported by computational results, using a density functional theory (DFT) approach. Calculating the relative Gibbs free energies of the three isomeric species that are formed reversibly during ring expansion enables the viability of new synthetic reactions to be correctly predicted in most cases. The new synthetic and computational results are expected to support the design of new lactam- and ß-ketoester-based ring-expansion reactions.

Gold-Catalyzed Cycloisomerization of Sulfur Ylides to Dihydrobenzothiepines.

The metal-promoted nucleophilic addition of sulfur ylides to π-systems is a well-established reactivity. However, the driving force of such transformations, elimination of a sulfide moiety, entails stoichiometric byproducts making them unfavorable in terms of atom economy. In this work, a new take on sulfur ylide chemistry is reported, an atom-economical gold(I)-catalyzed synthesis of dihydrobenzo[b]thiepines. The reaction proceeds under mild conditions at room temperature.

Cost-effectiveness of tacrolimus for the treatment of moderate-to-severe lupus nephritis in China.

Aim: Therapy for lupus nephritis (LN) requires treatment with immunosuppressive regimens, often including intravenous cyclophosphamide (IVCY), mycophenolate mofetil (MMF) or azathioprine. Additionally, tacrolimus (original form or generic) is recommended to treat LN patients in Asia, including China. However, the cost-effectiveness of tacrolimus therapy has not previously been assessed. We aimed to estimate the cost-effectiveness of tacrolimus in the treatment of moderate-to-severe LN versus standard therapies in China. Materials & methods: This cost-effectiveness model combined a decision-tree/Markov-model structure to map transitions between health states during induction and maintenance treatment phases. Induction with tacrolimus, IVCY or MMF, was followed by tacrolimus, MMF or azathioprine maintenance. Results: According to the model, during induction, complete remission rates were higher with tacrolimus versus IVCY (relative risk 1.40 vs IVCY [deterministic sensitivity analysis minimum 0.92, maximum 2.13]) and time to response was shorter. Relapse rates were lower with tacrolimus versus azathioprine or MMF during maintenance. Tacrolimus induction and maintenance was the most cost-effective regimen, incurring the lowest total costs (CN¥180,448) with the highest quality-adjusted life-years. Conclusion: The model demonstrated that tacrolimus use in both induction and maintenance therapy may be an efficacious and cost-effective treatment for LN in China.

Internal Nucleophilic Catalyst Mediated Cyclisation/Ring Expansion Cascades for the Synthesis of Medium-Sized Lactones and Lactams.

A strategy for the synthesis of medium-sized lactones and lactams from linear precursors is described in which an amine acts as an internal nucleophilic catalyst to facilitate a novel cyclisation/ring expansion cascade sequence. This method obviates the need for the high-dilution conditions usually associated with medium-ring cyclisation protocols, as the reactions operate exclusively via kinetically favourable "normal"-sized cyclic transition states. This same feature also enables biaryl-containing medium-sized rings to be prepared with complete atroposelectivity by point-to-axial chirality transfer.

Evaluation of the Antioxidant Capacity and Protective Effects of a Comprehensive Topical Antioxidant Containing Water-soluble, Enzymatic, and Lipid-soluble Antioxidants.

Objectives: Investigators sought to evaluate the antioxidant capacity of a comprehensive topical antioxidant (WEL-DS), its ability to protect skin against the oxidizing effects of UVA/UVB radiation, and to assess the effectiveness and tolerability of WEL-DS for visible improvements in facial photodamage. Study Designs: In-vitro testing utilized a hydrogen peroxide assay to detect activity in human skin explants following application with WEL-DS, a leading antioxidant serum (L-AOX), and a saline control. Clinical studies included a minimal erythema dose (MED) trial in female subjects, aged 35 to 60 years. Skin was initially irradiated to determine each subject's MED. WEL-DS was applied for four days to one site on the lower back of subjects; the other site remained untreated. Both sites were irradiated with 1X, 2X and 3X each subject's MED, digital images were obtained, and punch biopsies were collected from the 3X MED irradiated areas for histological analysis. A second clinical study evaluated efficacy and tolerability of twice daily application of WEL-DS in female subjects, aged 25 to 65 years with mild-to-moderate photodamage. Changes in fine lines/ wrinkles, dyschromia, erythema, skin tone, pores, and tolerability were assessed at baseline and Weeks 4, 8, and 12. A subset of subjects were evaluated through Week 16. Results: Skin treated with WEL-DS neutralized up to 53 percent more oxidative stress relative to L-AOX. WEL-DS-treated skin demonstrated significantly less UV-induced erythema at 1X, 2X, and 3X MED and demonstrated cellular protective effects versus untreated irradiated skin (N=5). WEL-DS demonstrated average improvements from baseline of 37 percent, fine lines/ wrinkles; 17 percent, skin tone; 13 percent, dyschromia; 18 percent, erythema; and four percent, pores (N=21; Week 12). Continued improvements were demonstrated in all parameters in an extension study (n=14; week 16). WEL-DS was well-tolerated. Conclusion: These studies demonstrate WEL-DS's innate ability to quench free radicals, protect skin from the oxidizing effects of UV radiation, and reduce the visible effects of facial photodamage.

Split-face Evaluation of a Multi-ingredient Brightening Foam Versus a Reference Control in Women with Photodamaged Facial Skin.

Background: The gold standard for the treatment of hyperpigmentation is hydroquinone (HQ), which has been available as a skin lightener for more than 50 years. Numerous clinical studies have proven its efficacy in various topical formulations. In the United States, HQ is available as a nonprescription product in 2% formulations and as a 4% prescription product. Objective: This study compared the safety and efficacy of a 2% hydroquinone multi-ingredient foam with a standard 4% hydroquinone cream on photodamaged facial skin. Methods: A 12-week, investigator-blinded, randomized trial with a split-face design was conducted in women with moderate photodamaged facial skin. Results: Both products improved the appearance of photodamaged facial skin and were well-tolerated. No statistically significant changes were seen between treatments during the efficacy or tolerability evaluations. Conclusion: Both treatments (2% HQ Brighten and 4% HQ) improved the appearance of photodamaged facial skin and were well-tolerated and results well-perceived by subjects over the 12-week treatment period, compared with baseline grading scores.

Iterative Assembly of Macrocyclic Lactones using Successive Ring Expansion Reactions.

Macrocyclic lactones can be prepared from lactams and hydroxyacid derivatives via an efficient 3- or 4-atom iterative ring expansion protocol. The products can also be expanded using amino acid-based linear fragments, meaning that macrocycles with precise sequences of hydroxy- and amino acids can be assembled in high yields by "growing" them from smaller rings, using a simple procedure in which high dilution is not required. The method should significantly expedite the practical synthesis of diverse nitrogen containing macrolide frameworks.

Efficacy and Tolerability of an Acne Treatment Regimen with Antiaging Benefits in Adult Women: A Pilot Study.

Objective: The objective of this study was to assess clinical safety and efficacy of a novel acne treatment regimen in adult women. Methods: Participants in the study included an ethnically diverse group of adult women (n=24) with mild-to-moderate acne who were treated twice daily with a topical regimen (cleanser, acne cream, and rebalancing gel) for eight weeks. Following baseline assessments, subjects returned to clinic at Weeks 2, 4, and 8 for clinical assessments and self-assessment questionnaires. Results: Twenty-one of the 24 enrolled women completed the eight-week clinical trial. Statistically significant clinical improvements were seen in both acne and aging parameters over time. The product regimen was well tolerated without adverse reactions commonly seen with topical acne products. Conclusion: The regimen demonstrated efficacy and tolerability in adult women with acne and signs of skin aging.

NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension.

Germline mutations involving small mothers against decapentaplegic-transforming growth factor-ß (SMAD-TGF-ß) signaling are an important but rare cause of pulmonary arterial hypertension (PAH), which is a disease characterized, in part, by vascular fibrosis and hyperaldosteronism (ALDO). We developed and analyzed a fibrosis protein-protein network (fibrosome) in silico, which predicted that the SMAD3 target neural precursor cell expressed developmentally down-regulated 9 (NEDD9) is a critical ALDO-regulated node underpinning pathogenic vascular fibrosis. Bioinformatics and microscale thermophoresis demonstrated that oxidation of Cys18 in the SMAD3 docking region of NEDD9 impairs SMAD3-NEDD9 protein-protein interactions in vitro. This effect was reproduced by ALDO-induced oxidant stress in cultured human pulmonary artery endothelial cells (HPAECs), resulting in impaired NEDD9 proteolytic degradation, increased NEDD9 complex formation with Nk2 homeobox 5 (NKX2-5), and increased NKX2-5 binding to COL3A1 Up-regulation of NEDD9-dependent collagen III expression corresponded to changes in cell stiffness measured by atomic force microscopy. HPAEC-derived exosomal signaling targeted NEDD9 to increase collagen I/III expression in human pulmonary artery smooth muscle cells, identifying a second endothelial mechanism regulating vascular fibrosis. ALDO-NEDD9 signaling was not affected by treatment with a TGF-ß ligand trap and, thus, was not contingent on TGF-ß signaling. Colocalization of NEDD9 with collagen III in HPAECs was observed in fibrotic pulmonary arterioles from PAH patients. Furthermore, NEDD9 ablation or inhibition prevented fibrotic vascular remodeling and pulmonary hypertension in animal models of PAH in vivo. These data identify a critical TGF-ß-independent posttranslational modification that impairs SMAD3-NEDD9 binding in HPAECs to modulate vascular fibrosis and promote PAH.

A Coupling Approach for the Generation of α,α-Bis(enolate) Equivalents: Regioselective Synthesis of gem-Difunctionalized Ketones.

Regioselective α,α-difunctionalization adjacent to a ketone is a significant synthetic challenge. Here, we present a solution to this problem through the transition-metal-free coupling of esters with geminal bis(boron) compounds. This forms an α,α-bis(enolate) equivalent which can be trapped with electrophiles including alkyl halides and fluorinating agents. This presents an efficient, convergent synthetic strategy for the synthesis of unsymmetrical blocked ketones.

Efficacy of Trifecting® Night Cream, a Novel Triple acting Skin Brightening Product: A Double-blind, Placebo-controlled Clinical Study.

Background: Melasma is a common, persistent disorder of hyperpigmented facial skin predominantly attributed to ultraviolet light exposure, hormonal influences, and genetic predisposition. Objectives: This double-blind, placebo-controlled, randomized clinical trial was conducted to assess the efficacy and tolerance of a multimodality night cream when used over a course of 24 weeks followed by a four-week regression in female subjects with moderate to severe melasma, presence of solar lentigines, and periocular lines and wrinkles. Methods: Subjects were randomized into one of two groups: Cell 1 received Trifecting® Night Cream (Envy Medical, Long Beach, California) 1.0 and Cell 2 did not. All subjects were supplied with a two-product regimen comprising a cleanser and sunscreen to use during the trial. Clinical grading, tolerability assessments, and Chroma Meter measurements (Konica Minolta, Tokyo, Japan) were performed at baseline and at Weeks 8, 16, 24, and 28 (regression). Standardized digital photographs were taken and self-assessment questionnaires were completed. Results: Twenty-five subjects completed the 28-week study, with 14 subjects in Cell 1 and 11 subjects in Cell 2. Subjects in both groups showed improvements in facial conditions. Cell 1 outperformed Cell 2 in improving fine lines, solar lentigines, and melasma conditions. These improvements were sustained during regression period. Conclusions: Trifecting® Night Cream 1.0, is effective for the treatment of moderate to severe melasma, solar lentigines, and periocular lines and wrinkles over 24 weeks of usage, with its benefits sustained for at least four weeks after treatment.

Synthesis of Cyclic Peptide Mimetics by the Successive Ring Expansion of Lactams.

A successive ring-expansion protocol is reported that enables the controlled insertion of natural and non-natural amino acid fragments into lactams. Amino acids can be installed into macrocycles via an operationally simple and scalable iterative procedure, without the need for high dilution. This method is expected to be of broad utility, especially for the synthesis of medicinally important cyclic peptide mimetics.

Transition-Metal-Free Homologative Cross-Coupling of Aldehydes and Ketones with Geminal Bis(boron) Compounds.

We report a transition-metal-free coupling of aldehydes and ketones with geminal bis(boron) building blocks which provides the coupled, homologated carbonyl compound upon oxidation. This reaction not only extends an alkyl chain containing a carbonyl group, it also simultaneously introduces a new carbonyl substituent. We demonstrate that enantiopure aldehydes with an enolizable stereogenic center undergo this reaction with complete retention of stereochemistry.

Mechanics of post-fusion exocytotic vesicle.

Exocytosis is an important cellular process controlled by metabolic signaling. It involves vesicle fusion to the plasma membrane, followed by the opening of a fusion pore, and the subsequent release of the vesicular lumen content into the extracellular space. While most modeling efforts focus on the events leading to membrane fusion, how the vesicular membrane remodels after fusing to plasma membrane remains unclear. This latter event dictates the nature and the efficiency of exocytotic vesicular secretions, and is thus critical for exocytotic function. We provide a generic membrane mechanical model to systematically study the fate of post-fusion vesicles. We show that while membrane stiffness favors full-collapse vesicle fusion into the plasma membrane, the intravesicular pressure swells the vesicle and causes the fusion pore to shrink. Dimensions of the vesicle and its associated fusion pore further modulate this mechanical antagonism. We systematically define the mechanical conditions that account for the full spectrum of the observed vesicular secretion modes. Our model therefore can serve as a unified theoretical framework that sheds light on the elaborate control mechanism of exocytosis.