Evidence-based update on rosacea comorbidities and their common physiologic pathways.

Rosacea is a common chronic inflammatory disease affecting the facial skin whose etiology and pathophysiology are the subject of much investigation. Risk factors include genetic and environmental elements that may predispose individuals to localized inflammation and abnormal neurovascular responses to stimuli. Recent studies have introduced an array of systemic rosacea comorbidities, such as inflammatory bowel disease and neurologic conditions, that can be challenging to synthesize. We critically review the current data behind reported rosacea comorbidities and identify and highlight underrecognized physiologic mediators shared among rosacea and associated comorbidities. This information may be helpful in addressing patient questions about potential systemic implications of rosacea and can serve as a candidate platform for future research to understand rosacea and improve treatments.

Integrative concepts of rosacea pathophysiology, clinical presentation and new therapeutics.

Rosacea is a chronic relapsing inflammatory skin disease with high prevalence worldwide. Recent research suggests that dysregulation of innate and adaptive immune pathways as well as neurovascular changes is present, with different degrees of importance in the various subtypes. Neither the aetiology, genetics nor pathophysiological basis of the vascular, inflammatory or fibrotic changes is well understood. The clinical spectrum comprises a huge variability from erythema (vasodilation) to papules/pustules (inflammatory infiltrate) to phymata (fibrosis, glandular hyperplasia) making it a valuable human disease model to understand the interplay between the neurovascular and immune systems as well as the progression from chronic inflammation to fibrosis in skin. The lack of appropriate animal models emphasizes the importance of further translational research validating observed molecular pathways under disease conditions. A wide spectrum of physical (UV, temperature), biological (microbiota, food) and endogenous (genetic, stress) stimuli has been discussed as "trigger factors" of rosacea. Novel findings implicate keratinocytes, smooth muscle cells, endothelial cells, macrophages, mast cells, fibroblasts, Th1/Th17 cells, antibody-producing B cells and neurons in the pathobiology of rosacea. So far, pattern recognition receptors like TLR2, transient receptor potential ion channels, cytokines, chemokines and proteases have been implicated as critical receptors/mediators. However, our understanding of the interactive networks on the molecular level is very limited. Identification of critical molecular components of the inflammatory cascade including antimicrobial peptides, the IL-1ß inflammasome, TNF, IFN-γ, proteases and neuropeptides may provide the basis for novel pathomechanism-based therapeutic approaches for this frequent and bothersome skin disease.

Improved clinical outcome and biomarkers in adults with papulopustular rosacea treated with doxycycline modified-release capsules in a randomized trial.

BACKGROUND: Patients with rosacea have increased amounts of cathelicidin and protease activity but their usefulness as disease biomarkers is unclear. OBJECTIVE: We sought to evaluate the effect of doxycycline treatment on cathelicidin expression, protease activity, and clinical response in rosacea. METHODS: In all, 170 adults with papulopustular rosacea were treated for 12 weeks with doxycycline 40-mg modified-release capsules or placebo in a multicenter, randomized, double-blind, placebo-controlled study. Clinical response was compared with cathelicidin and protease activity in stratum corneum samples obtained by tape strip and in skin biopsy specimens obtained from a random subset of patients. RESULTS: Treatment with doxycycline significantly reduced inflammatory lesions and improved investigator global assessment scores compared with placebo. Cathelicidin expression and protein levels decreased over the course of 12 weeks in patients treated with doxycycline. Low levels of protease activity and cathelicidin expression at 12 weeks correlated with treatment success. Low protease activity at baseline was a predictor of clinical response in the doxycycline treatment group. LIMITATIONS: Healthy control subjects were not studied. CONCLUSIONS: Improved clinical outcome correlated with reduced cathelicidin and protease activity, supporting both the mechanism of doxycycline and the potential of these molecules as biomarkers for rosacea.

High incidence of ErbB3, ErbB4, and MET expression in ovarian cancer.

Ovarian cancer is the leading cause of death from gynecologic cancers in the United States. Failure may be due to variable expression and/or complex interactions of growth factor receptors in individual tumors. As ErbB3-MET cooperativity is implicated in solid tumor resistance to EGFR/ErbB2 inhibitors, we evaluated expression of MET and all 4 ErbB family members in ovarian cancers. Tissue arrays were prepared from archival formalin-fixed paraffin-embedded tumor samples, including 202 ovarian carcinomas (Stage I-IV) and controls. Of 202 patient samples, only 25% were positive for EGFR and 35% for ErbB2 expression. ErbB3, ErbB4, and MET showed marked expression in 76%, 98%, and 96% of cases. Consistent with high incidence, there was no significant correlation for expression of ErbB3, ErbB4, or MET with outcome. On the basis of their high expression in the majority of cases, inhibitors targeting ErbB3, ErbB4, and/or MET may be broadly applicable as therapeutic agents in this disease.

The genome sequence of the cut surfclam, Spisula subtruncata (da Costa, 1778).

We present a genome assembly from a specimen of Spisula subtruncata (the cut surfclam; Mollusca; Bivalvia; Venerida; Mactridae). The genome sequence is 930.8 megabases in span. Most of the assembly is scaffolded into 19 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 19.64 kilobases in length.

The genome sequence of a segmented worm, Terebella lapidaria Linnaeus, 1767.

We present a genome assembly from an individual Terebella lapidaria (segmented worm; Annelida; Polychaeta; Terebellida; Terebellidae). The genome sequence spans 765.20 megabases. Most of the assembly is scaffolded into 16 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 15.97 kilobases in length.

Potential role of microorganisms in the pathogenesis of rosacea.

Rosacea is a skin condition of abnormal inflammation and vascular dysfunction. The active contribution of a microbial agent in the development or progression of rosacea continues to be debated. Research supports the presence of commensal Demodex folliculorum mites at increased density in the skin and associates Helicobacter pylori infection of the gut with rosacea. Fewer studies implicate Staphylococcus epidermidis, Chlamydophila pneumoniae, and the Demodex-associated bacteria Bacillus oleronius. No research, however, provides a mechanism by which colonization by a microorganism translates to manifestation of the condition. Prevailing and emerging principles in the biology of the microbiome and the pathophysiology of rosacea may help to reconcile these lingering questions. Here the microorganisms implicated in rosacea are reviewed and the reaction of the microbiome to inflammation and to changes in microenvironments and macroenvironments are discussed to explain potential roles for microorganisms in rosacea pathophysiology.

The genome sequence of the surf clam, Spisula solida (Linnaeus, 1758).

We present a genome assembly from an individual Spisula solida (the surf clam; Mollusca; Bivalvia; Venerida; Mactridae). The genome sequence is 932.1 megabases in span. Most of the assembly is scaffolded into 19 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 19.3 kilobases in length. Gene annotation of this assembly on Ensembl identified 13,833 protein coding genes.

The genome sequence of the turban top shell, Gibbula magus (Linnaeus, 1758).

We present a genome assembly from an individual Gibbula magus (the turban top shell; Mollusca; Gastropoda; Trochida; Trochidae). The genome sequence is 1,470 megabases in span. Most of the assembly is scaffolded into 18 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 16.1 kilobases in length. Gene annotation of this assembly on Ensembl identified 41,167 protein coding genes.

Prevention of COVID-19 Following a Single Intramuscular Administration of Adintrevimab: Results From a Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Trial (EVADE).

Background: The prevention of coronavirus disease 2019 (COVID-19) in vulnerable populations is a global health priority. EVADE was a phase 2/3 multicenter, double-blind, randomized, placebo-controlled trial of adintrevimab, an extended-half-life monoclonal antibody, for postexposure (PEP) and pre-exposure prophylaxis (PrEP) of symptomatic COVID-19. Methods: Eligible participants (vaccine-naive, aged ≥12 years) were randomized 1:1 to receive a single 300-mg intramuscular injection of adintrevimab or placebo. Primary efficacy end points were reverse transcription polymerase chain reaction (RT-PCR)-confirmed symptomatic COVID-19 through day 28 in the PEP cohort (RT-PCR-negative at baseline) and through month 3 in the PrEP cohort (RT-PCR-negative and seronegative at baseline) among participants randomized before emergence of the severe acute respiratory syndrome coronavirus 2 Omicron variant (November 30, 2021). Safety was assessed through 6 months. Results: Between April 27, 2021, and January 11, 2022, 2582 participants were randomized. In the primary efficacy analysis, RT-PCR-confirmed symptomatic COVID-19 occurred in 3/175 (1.7%) vs 12/176 (6.8%) adintrevimab- and placebo-treated PEP participants, respectively (74.9% relative risk reduction [RRR]; standardized risk difference, -5.0%; 95% CI, -8.87% to -1.08%; P = .0123) and in 12/752 (1.6%) vs 40/728 (5.5%) adintrevimab- and placebo-treated PrEP participants, respectively (71.0% RRR; standardized risk difference, -3.9%; 95% CI, -5.75% to -2.01%; P < .0001). In a prespecified exploratory analysis of 428 PrEP participants randomized after the emergence of Omicron, adintrevimab reduced RT-PCR-confirmed symptomatic COVID-19 by 40.6% (standardized risk difference -8.4%; 95% CI, -15.35% to -1.46%; nominal P = .0177) vs placebo. Adintrevimab was well tolerated, with no serious drug-related adverse events reported. Conclusions: A single intramuscular injection of adintrevimab provided prophylactic efficacy against COVID-19 due to susceptible variants without safety concerns. Clinical trial registration. NCT04859517.

The genome sequence of Gari tellinella (Lamarck, 1818), a sunset clam.

We present a genome assembly from an individual Gari tellinella (Mollusca; Bivalvia; Cardiida; Psammobiidae). The genome sequence is 1,598 megabases in span. The majority of the assembly (99.85%) is scaffolded into 19 chromosomal pseudomolecules. The complete mitochondrial genome was also assembled and is 18.5 kilobases in length.

The genome sequence of the scale worm, Lepidonotus clava (Montagu, 1808).

We present a genome assembly from an individual Lepidonotus clava (scale worm; Annelida; Polychaeta; Phyllodocida; Polynoidae). The genome sequence is 1,044 megabases in span. Most of the assembly is scaffolded into 18 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 15.6 kilobases in length.

Acute nicotine enhances strategy-based semantic processing in Parkinson's disease.

Nicotinic mechanisms may play a role in the cognitive deficits of Parkinson's disease (PD). Recently, on a cognitively demanding strategy-based priming task, nicotine selectively affected controlled semantic processing in young adult non-smokers as reported by Holmes et al. (International Journal of Neuropsychopharmacology 11, 389-399, 2008). Such controlled semantic processing is compromised in PD. This study investigated the effects of acute transdermal nicotine on controlled semantic processing in non-smokers with PD (n = 10) and non-smoking matched controls (n = 16) using a strategy-based semantic priming paradigm. Transdermal nicotine patches (7 mg/24 h) were administered in a double-blind, placebo-controlled, crossover design. Participants were instructed to expect target words from specified semantic categories based on the primes, while unexpected targets were also presented. Priming conditions included those concurring with trained expectations (expected-related and expected-unrelated), those which did not (unexpected-related and unexpected-unrelated), and neutral-baseline conditions. Controls evidenced significant expectancy effects (i.e. reaction-time differences for expected vs. unexpected conditions) under both drug states. An expectancy effect was not evident for PD under placebo due to a lack of reaction-time slowing for unexpected conditions. However, under nicotine an expectancy effect was present for PD at a level comparable to controls. Overall the findings indicate that nicotine can improve impaired controlled semantic processing in PD possibly via enhanced expectancy or inhibitory mechanisms.

HSP72 protects against obesity-induced insulin resistance.

Patients with type 2 diabetes have reduced gene expression of heat shock protein (HSP) 72, which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signaling proteins such as c-jun amino terminal kinase (JNK), inhibitor of kappaB kinase, and tumor necrosis factor-alpha, can induce insulin resistance, but HSP 72 can block the induction of these molecules in vitro. Accordingly, we examined whether activation of HSP72 can protect against the development of insulin resistance. First, we show that obese, insulin resistant humans have reduced HSP72 protein expression and increased JNK phosphorylation in skeletal muscle. We next used heat shock therapy, transgenic overexpression, and pharmacologic means to overexpress HSP72 either specifically in skeletal muscle or globally in mice. Herein, we show that regardless of the means used to achieve an elevation in HSP72 protein, protection against diet- or obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance was observed. This protection was tightly associated with the prevention of JNK phosphorylation. These findings identify an essential role for HSP72 in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding.

Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase.

Although interleukin-6 (IL-6) has been associated with insulin resistance, little is known regarding the effects of IL-6 on insulin sensitivity in humans in vivo. Here, we show that IL-6 infusion increases glucose disposal without affecting the complete suppression of endogenous glucose production during a hyperinsulinemic-euglycemic clamp in healthy humans. Because skeletal muscle accounts for most of the insulin-stimulated glucose disposal in vivo, we examined the mechanism(s) by which IL-6 may affect muscle metabolism using L6 myotubes. IL-6 treatment increased fatty acid oxidation, basal and insulin-stimulated glucose uptake, and translocation of GLUT4 to the plasma membrane. Furthermore, IL-6 rapidly and markedly increased AMP-activated protein kinase (AMPK). To determine whether the activation of AMPK mediated cellular metabolic events, we conducted experiments using L6 myotubes infected with dominant-negative AMPK alpha-subunit. The effects described above were abrogated in AMPK dominant-negative-infected cells. Our results demonstrate that acute IL-6 treatment enhances insulin-stimulated glucose disposal in humans in vivo, while the effects of IL-6 on glucose and fatty acid metabolism in vitro appear to be mediated by AMPK.

A potential synergistic anticancer effect of paclitaxel and amifostine on endometrial cancer.

Although paclitaxel is one of the most effective chemotherapeutic agents, its usefulness is still limited in advanced and recurrent endometrial cancer. Amifostine protection of normal tissues against the side effects of chemotherapeutic agents has been clinically proven in cancer patients; however, its application in endometrial cancer has not been fully evaluated. We have investigated the use of paclitaxel and amifostine in controlling the growth of poorly differentiated endometrial cancer cells, Hec50co, in vitro and in vivo. Our studies show that amifostine had direct anticancer effects on endometrial cancer cells in vitro by arresting the cell cycle at the G1 phase and inducing apoptosis. Amifostine also inhibited s.c. tumor growth in athymic mice. Paclitaxel IC50 value was reduced from 14 to 2 nmol/L with pretreatment of a single dose of 178 micromol/L of amifostine for 72 hours. Amifostine also synergized with paclitaxel in the arrest of the cell cycle at the G2-M phase and in the induction of apoptosis. This two-drug regimen inhibited s.c. tumor growth as well as improved mouse survival significantly more than paclitaxel alone. Amifostine also significantly improved paclitaxel-induced cytotoxic effects on peripheral blood profiles. Our studies show that amifostine has direct anticancer effects on endometrial cancer. Our data have also shown a potential anticancer synergy between amifostine and paclitaxel in vitro and in vivo, whereas amifostine maintained a protective role in peripheral blood profiles. The dual specificity of amifostine action should be further investigated.

Multidisciplinary Consideration of Potential Pathophysiologic Mechanisms of Paradoxical Erythema with Topical Brimonidine Therapy.

Rosacea is a chronic inflammatory disease with transient and non-transient redness as key characteristics. Brimonidine is a selective α2-adrenergic receptor (AR) agonist approved for persistent facial erythema of rosacea based on significant efficacy and good safety data. The majority of patients treated with brimonidine report a benefit; however, there have been sporadic reports of worsening erythema after the initial response. A group of dermatologists, receptor physiology, and neuroimmunology scientists met to explore potential mechanisms contributing to side effects as well as differences in efficacy. We propose the following could contribute to erythema after application: (1) local inflammation and perivascular inflammatory cells with abnormally functioning ARs may lead to vasodilatation; (2) abnormal saturation and cells expressing different AR subtypes with varying ligand affinity; (3) barrier dysfunction and increased skin concentrations of brimonidine with increased actions at endothelial and presynaptic receptors, resulting in increased vasodilation; and (4) genetic predisposition and receptor polymorphism(s) leading to different smooth muscle responses. Approximately 80% of patients treated with brimonidine experience a significant improvement without erythema worsening as an adverse event. Attention to optimizing skin barrier function, setting patient expectations, and strategies to minimize potential problems may possibly reduce further the number of patients who experience side effects. FUNDING: Galderma International S.A.S., Paris, France.

Combined Use of Morphological and Molecular Tools to Resolve Species Mis-Identifications in the Bivalvia The Case of Glycymeris glycymeris and G. pilosa.

Morphological and molecular tools were combined to resolve the misidentification between Glycymeris glycymeris and Glycymeris pilosa from Atlantic and Mediterranean populations. The ambiguous literature on the taxonomic status of these species requires this confirmation as a baseline to studies on their ecology and sclerochronology. We used classical and landmark-based morphometric approaches and performed bivariate and multivariate analyses to test for shell character interactions at the individual and population level. Both approaches generated complementary information. The former showed the shell width to length ratio and the valve asymmetry to be the main discriminant characters between Atlantic and Mediterranean populations. Additionally, the external microsculpture of additional and finer secondary ribs in G. glycymeris discriminates it from G. pilosa. Likewise, landmark-based geometric morphometrics revealed a stronger opisthogyrate beak and prosodetic ligament in G. pilosa than G. glycymeris. Our Bayesian and maximum likelihood phylogenetic analyses based on COI and ITS2 genes identified that G. glycymeris and G. pilosa form two separate monophyletic clades with mean interspecific divergence of 11% and 0.9% for COI and ITS2, respectively. The congruent patterns of morphometric analysis together with mitochondrial and nuclear phylogenetic reconstructions indicated the separation of the two coexisting species. The intraspecific divergence occurred during the Eocene and accelerated during the late Pliocene and Pleistocene. Glycymeris pilosa showed a high level of genetic diversity, appearing as a more robust species whose tolerance of environmental conditions allowed its expansion throughout the Mediterranean.

Dermatological Adverse Events Associated with Topical Brimonidine Gel 0.33% in Subjects with Erythema of Rosacea: A Retrospective Review of Clinical Studies.

BACKGROUND: The topical α2 adrenergic receptor agonist brimonidine gel 0.33% is an effective and safe pharmacological treatment for the facial erythema of rosacea. However, adverse events of worsened redness have occasionally been reported with its use. OBJECTIVE: A detailed analysis of adverse events is needed to accurately define worsening erythema and the adverse-events profile associated with brimonidine gel treatment. METHODS AND MEASUREMENTS: A retrospective review of related dermatological adverse events occurring in subjects enrolled in the two pivotal four-week Phase 3 studies and the 52-week long-term safety study for brimonidine gel was conducted. Measurements included total adverse-event incidences; number of subjects experiencing adverse events; study discontinuation due to adverse events, severity, onset, episodic duration period; and correlation of adverse events to subject disposition, and rosacea profile. RESULTS: Flushing and erythema were the most commonly reported adverse events, occurring in a total of 5.4 percent of subjects in the Phase 3 studies and in 15.4 percent in the long-term study. Most adverse events were mild or moderate in severity, transient, and intermittent. Adverse events occurred early in treatment, and duration was short-lived in the majority of cases. Adverse-event patterns were not remarkably altered with regard to subject disposition in the long-term study. CONCLUSION: Adverse events of worsening redness are not frequent, are transient in nature, and occur early in the course of treatment with brimonidine gel.

Mast cells and dendritic cells form synapses that facilitate antigen transfer for T cell activation.

Mast cells (MCs) produce soluble mediators such as histamine and prostaglandins that are known to influence dendritic cell (DC) function by stimulating maturation and antigen processing. Whether direct cell-cell interactions are important in modulating MC/DC function is unclear. In this paper, we show that direct contact between MCs and DCs occurs and plays an important role in modulating the immune response. Activation of MCs through FcεRI cross-linking triggers the formation of stable cell-cell interactions with immature DCs that are reminiscent of the immunological synapse. Direct cellular contact differentially regulates the secreted cytokine profile, indicating that MC modulation of DC populations is influenced by the nature of their interaction. Synapse formation requires integrin engagement and facilitates the transfer of internalized MC-specific antigen from MCs to DCs. The transferred material is ultimately processed and presented by DCs and can activate T cells. The physiological outcomes of the MC-DC synapse suggest a new role for intercellular crosstalk in defining the immune response.