Energy-Based Devices for the Treatment of Cutaneous Verrucae: A Systematic Review.

BACKGROUND: Warts are one of the most common benign neoplasms caused by human papillomavirus infection and often pose a therapeutic challenge. OBJECTIVE: To summarize the current evidence on the safety and efficacy of laser and energy-based devices for the treatment of cutaneous verrucae. METHODS: A comprehensive systematic review of the literature on laser and energy-based devices for the treatment of cutaneous verrucae was performed. RESULTS: A total of 904 unique studies were identified, of which 109 were included in this review. The most commonly used lasers as a single treatment modality for verrucae included the long-pulsed Nd:Yag (n = 20) and pulsed dye (n = 18) lasers. Other modalities included the CO2 ablative laser (n = 10), photodynamic therapy (n = 11), local hyperthermia (n = 11), microwave therapy (n = 2), and nanopulse stimulation (n = 1). Other studies combined energy-based modalities with additional treatments, such as retinoids, imiquimod, and intralesional bleomycin. Overall, such devices were generally well-tolerated, with only a mild side effect profile. CONCLUSION: Overall, the use of laser and energy-based devices is a safe and well-tolerated option for cutaneous verrucae that is relatively less invasive than surgical interventions. Future studies using more consistent outcome assessment tools will be valuable to help clinicians develop device-specific protocols and treatment regimens to ensure replicable and effective outcomes.

An Overview on the Management of Atrophic Acne Scars: The Role of Trifarotene as an Adjunct.

Acne vulgaris is a common, often chronic inflammatory disease that can affect all ages and skin tones. Beyond acute lesions, the sequelae of acne - specifically scarring and dyspigmentation - can be long-lasting, challenging to treat and have substantial psychosocial impact on affected individuals. For acne scarring, treatment modalities include topical, physical, and laser and light therapies, with combination approaches typically yielding optimal outcomes. Trifarotene is a novel fourth generation retinoid with targeted action towards retinoid acid receptor gamma (RAR-γ), the most common isotype found in the epidermis, that has previously been approved for the management of moderate-to-severe facial and truncal acne in individuals over the age of 12 years. Recently, data on trifarotene supports its application in acne scarring. Herein, we provide a succinct review on various treatments for acne scarring and explore how trifarotene and its mechanism of action present an additional topical approach to target atrophic acne scarring.

A novel diagnostic approach for the classification of small B-cell lymphoid neoplasms based on the NanoString platform.

Small B-cell lymphoid neoplasms (SBCLNs) are a heterogeneous group of diseases characterized by malignant clonal proliferation of mature B-cells. However, the classification of SBCLNs remains a challenge, especially in cases where histopathological analysis is unavailable or those with atypical laboratory findings or equivocal pathologic data. In this study, gene expression profiling of 1039 samples from 27 gene expression omnibus (GEO) datasets was first investigated to select highly and differentially expressed genes among SBCLNs. Samples from 57 SBCLN cases and 102 nonmalignant control samples were used to train a classifier using the NanoString platform. The classifier was built by employing a cascade binary classification method based on the random forest algorithm with 35 refined gene signatures. Cases were successively classified as chronic lymphocytic leukemia/small lymphocytic lymphoma, conventional mantle cell lymphoma, follicular lymphoma, leukemic non-nodal mantle cell lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia, and other undetermined. The classifier algorithm was then validated using an independent cohort of 197 patients with SBCLNs. Under the distribution of our validation cohort, the overall sensitivity and specificity of proposed algorithm model were >95%, respectively, for all the cases with tumor cell content greater than 0.72. Combined with additional genetic aberrations including IGH-BCL2 translocation, MYD88 L265P mutation, and BRAF V600E mutation, the optimal sensitivity and specificity were respectively found at 0.88 and 0.98. In conclusion, the established algorithm demonstrated to be an effective and valuable ancillary diagnostic approach for the sub-classification and pathologic investigation of SBCLN in daily practice.

A rare case of lues maligna in an HIV-negative woman.

We describe an HIV-negative 43-year-old woman presenting with a diffuse ulceronodular eruption and positive serological tests for syphilis consistent with lues maligna. Lues maligna is a severe and rare variant of secondary syphilis characterized by prodromal constitutional symptoms followed by the formation of multiple well-circumscribed nodules with ulceration and crust. This case depicts a particularly rare presentation as lues maligna usually involves HIV-positive men. The clinical presentation of lues maligna can pose a diagnostic challenge, with infections, sarcoidosis, and cutaneous lymphoma as just a few entities in its broad differential diagnosis. However, with a high index of suspicion, clinicians can diagnose and treat this entity earlier and reduce morbidity.

Alternative Cosmetic and Medical Applications of Injectable Deoxycholic Acid: A Systematic Review.

BACKGROUND: Beyond submental fat reduction, injectable deoxycholic acid (DCA) has gained popularity in recent years for various minimally invasive lipolysis applications. OBJECTIVE: To summarize and evaluate the evidence of off-label uses of injectable DCA. METHODS: MEDLINE, Embase, CINAHL, Web of Science, and CENTRAL were searched. The outcomes measured included applications of DCA, treatment regimen, and its efficacy. An overall success rate for each condition was calculated based on the improvement defined in the included studies. RESULTS: Eleven studies evaluated the cosmetic use of DCA for excess adipose tissue on various anatomical locations. The outcomes were evaluated at time points ranging from 1 to 21 months post-treatment, with overall success rates over 85%. Eight case reports and series reported the success of using DCA treating lipomas, xanthelasmas, paradoxical adipose hyperplasia, fibrofatty residue of infantile hemangioma, piezogenic pedal papules, and HIV-associated lipohypertrophy. Although the preliminary efficacies were high, the overall recommendations for off-label uses are weak because of the lack of high-level studies. CONCLUSION: The review emphasizes the diversity of injectable DCA as a minimally invasive technique for lipolysis. Further high-level studies demonstrating consistent treatment regimens and methods of evaluation are warranted to make more definitive recommendations regarding off-label DCA use.

Microneedling Treatment of Striae Distensae in Light and Dark Skin With Long-Term Follow-Up.

BACKGROUND: Striae distensae have notoriously been difficult to treat due to their extensive involvement of nonfacial skin. Microneedling with its lack of thermal injury during microneedling treatment renders it a viable treatment option in darker skin tones and nonfacial regions due to the reduced risk of postinflammatory hyperpigmentation. OBJECTIVE: To describe the clinical results and side effects of microneedling in a series of 25 individuals with striae distensae. MATERIALS AND METHODS: Twenty-five consecutive adults (SPT I-V) with striae distensae involving the trunk and extremities were treated using a microneedling device. No additional treatments (topical or intralesional) were applied. Two assessors blinded to treatment protocol rated clinical improvement of striae on a 5-point scale. Side effects were monitored and tabulated. RESULTS: Patients received 1 to 3 consecutive monthly treatments. All striae improved at least 50% after an average of 1.8 treatments, and 28% of patients demonstrated more than 75% clinical improvement. Striae in thicker skin regions (e.g., buttocks/thighs) showed comparable clinical improvement than those in thinner skin areas (e.g., breasts) and did not require additional treatment sessions. Side effects were limited to transient erythema in all skin phototypes. No infections or dyspigmentation were observed. CONCLUSION: The clinical results obtained in this study support the safe and effective treatment of striae distensae with microneedling in light and dark skin tones in various body locations. Standardization of treatment protocols are anticipated with further (ongoing) studies.

Skin Surface pH

The role of skin surface pH, also referred to as "acid mantle," was described more than 90 years ago and due to developing insights has now returned into focus.1

Clinical Insights About the Role of pH in Acne

Acne vulgaris is the most common dermatological disorder globally.1,2 Psychological and emotional distress due to acne, including poor self-esteem, social anxiety, depression, and suicidal ideation have been reported in various studies.3,4, Acne is a complex multifactorial disease with its pathophysiology incompletely elucidated.

Structures reveal details of small molecule binding to cardiac troponin.

In cardiac and skeletal muscle, the troponin complex turns muscle contraction on and off in a calcium-dependent manner. Many small molecules are known to bind to the troponin complex to modulate its calcium binding affinity, and this may be useful in a broad range of conditions in which striated muscle function is compromised, such as congestive heart failure. As a tool for developing drugs specific for the cardiac isoform of troponin, we have designed a chimeric construct (cChimera) consisting of the regulatory N-terminal domain of cardiac troponin C (cNTnC) fused to the switch region of cardiac troponin I (cTnI), mimicking the key binding event that turns on muscle contraction. We demonstrate by solution NMR spectroscopy that cChimera faithfully reproduces the native interface between cTnI and cNTnC. We determined that small molecules based on diphenylamine can bind to cChimera with a KD as low as 10µM. Solution NMR structures show that minimal structural perturbations in cChimera are needed to accommodate 3-methyldiphenylamine (3-mDPA), which is probably why it binds with higher affinity than previously studied compounds like bepridil, despite its significantly smaller size. The unsubstituted aromatic ring of 3-mDPA binds to an inner hydrophobic pocket adjacent to the central beta sheet of cNTnC. However, the methyl-substituted ring is able to bind in two different orientations, either inserting into the cNTnC-cTnI interface or "flipping out" to form contacts primarily with helix C of cNTnC. Our work suggests that preservation of the native interaction between cNTnC and cTnI is key to the development of a high affinity cardiac troponin-specific drug.

The structural and functional effects of the familial hypertrophic cardiomyopathy-linked cardiac troponin C mutation, L29Q.

Familial hypertrophic cardiomyopathy (FHC) is characterized by severe abnormal cardiac muscle growth. The traditional view of disease progression in FHC is that an increase in the Ca(2+)-sensitivity of cardiac muscle contraction ultimately leads to pathogenic myocardial remodeling, though recent studies suggest this may be an oversimplification. For example, FHC may be developed through altered signaling that prevents downstream regulation of contraction. The mutation L29Q, found in the Ca(2+)-binding regulatory protein in heart muscle, cardiac troponin C (cTnC), has been linked to cardiac hypertrophy. However, reports on the functional effects of this mutation are conflicting, and our goal was to combine in vitro and in situ structural and functional data to elucidate its mechanism of action. We used nuclear magnetic resonance and circular dichroism to solve the structure and characterize the backbone dynamics and stability of the regulatory domain of cTnC with the L29Q mutation. The overall structure and dynamics of cTnC were unperturbed, although a slight rearrangement of site 1, an increase in backbone flexibility, and a small decrease in protein stability were observed. The structure and function of cTnC was also assessed in demembranated ventricular trabeculae using fluorescence for in situ structure. L29Q reduced the cooperativity of the Ca(2+)-dependent structural change in cTnC in trabeculae under basal conditions and abolished the effect of force-generating myosin cross-bridges on this structural change. These effects could contribute to the pathogenesis of this mutation.

microRNA-449a functions as a tumor suppressor in neuroblastoma through inducing cell differentiation and cell cycle arrest.

microRNA-449a (miR-449a) has been identified to function as a tumor suppressor in several types of cancers. However, the role of miR-449a in neuroblastoma has not been intensively investigated. We recently found that the overexpression of miR-449a significantly induces neuroblastoma cell differentiation, suggesting its potential tumor suppressor function in neuroblastoma. In this study, we further investigated the mechanisms underlying the tumor suppressive function of miR-449a in neuroblastoma. We observed that miR-449a inhibits neuroblastoma cell survival and growth through 2 mechanisms--inducing cell differentiation and cell cycle arrest. Our comprehensive investigations on the dissection of the target genes of miR-449a revealed that 3 novel targets- MFAP4, PKP4 and TSEN15 -play important roles in mediating its differentiation-inducing function. In addition, we further found that its function in inducing cell cycle arrest involves down-regulating its direct targets CDK6 and LEF1. To determine the clinical significance of the miR-449a-mediated tumor suppressive mechanism, we examined the correlation between the expression of these 5 target genes in neuroblastoma tumor specimens and the survival of neuroblastoma patients. Remarkably, we noted that high tumor expression levels of all the 3 miR-449a target genes involved in regulating cell differentiation, but not the target genes involved in regulating cell cycle, are significantly correlated with poor survival of neuroblastoma patients. These results suggest the critical role of the differentiation-inducing function of miR-449a in determining neuroblastoma progression. Overall, our study provides the first comprehensive characterization of the tumor-suppressive function of miR-449a in neuroblastoma, and reveals the potential clinical significance of the miR-449a-mediated tumor suppressive pathway in neuroblastoma prognosis.

AcousTac: Tactile Sensing with Acoustic Resonance for Electronics-Free Soft Skin.

Sound is a rich information medium that transmits through air; people communicate through speech and can even discern material through tapping and listening. To capture frequencies in the human hearing range, commercial microphones typically have a sampling rate of over 40 kHz. These accessible acoustic technologies are not yet widely adopted for the explicit purpose of giving robots a sense of touch. Some researchers have used sound to sense tactile information, both monitoring ambient soundscape and with embedded speakers and microphones to measure sounds within structures. However, these options commonly do not provide a direct measure of steady state force or require electronics integrated somewhere near the contact location. In this work, we present AcousTac, an acoustic tactile sensor for electronics-free, force-sensitive soft skin. Compliant silicone caps and plastic tubes compose the resonant chambers that emit pneumatic-driven sound measurable with a conventional off-board microphone. The resulting frequency changes depend on the external loads on the compliant endcaps. The compliant cap vibrates with the resonant pressure waves and is a nonidealized boundary condition, initially producing a nonmonotonic force response. We characterize two solutions-adding a distal hole and mass to the cap-resulting in monotonic and nonhysteretic force readings with this technology. We can tune each AcousTac taxel to specific force and frequency ranges, based on geometric parameters including tube length, and thus uniquely sense each taxel simultaneously in an array. We demonstrate AcousTac's functionality on two robotic systems: a 4-taxel array and a 3-taxel astrictive gripper. Simple to implement with off-the-shelf parts, AcousTac is a promising concept for force sensing on soft robotic surfaces, especially in situations where electronics near the contact are not suitable. Equipping robots with tactile sensing and soft skin provides them with a sense of touch and the ability to safely interact with their surroundings.

Elucidation of isoform-dependent pH sensitivity of troponin i by NMR spectroscopy.

Myocardial ischemia is characterized by reduced blood flow to cardiomyocytes, which can lead to acidosis. Acidosis decreases the calcium sensitivity and contractile efficiency of cardiac muscle. By contrast, skeletal and neonatal muscles are much less sensitive to changes in pH. The pH sensitivity of cardiac muscle can be reduced by replacing cardiac troponin I with its skeletal or neonatal counterparts. The isoform-specific response of troponin I is dictated by a single histidine, which is replaced by an alanine in cardiac troponin I. The decreased pH sensitivity may stem from the protonation of this histidine at low pH, which would promote the formation of electrostatic interactions with negatively charged residues on troponin C. In this study, we measured acid dissociation constants of glutamate residues on troponin C and of histidine on skeletal troponin I (His-130). The results indicate that Glu-19 comes in close contact with an ionizable group that has a pK(a) of ∼6.7 when it is in complex with skeletal troponin I but not when it is bound to cardiac troponin I. The pK(a) of Glu-19 is decreased when troponin C is bound to skeletal troponin I and the pK(a) of His-130 is shifted upward. These results strongly suggest that these residues form an electrostatic interaction. Furthermore, we found that skeletal troponin I bound to troponin C tighter at pH 6.1 than at pH 7.5. The data presented here provide insights into the molecular mechanism for the pH sensitivity of different muscle types.

Family income and cardiovascular disease risk in American adults.

Socioeconomic status is an overlooked risk factor for cardiovascular disease (CVD). Low family income is a measure of socioeconomic status and may portend greater CVD risk. Therefore, we assessed the association of family income with cardiovascular risk factor and disease burden in American adults. This retrospective analysis included data from participants aged ≥ 20 years from the National Health and Nutrition Examination Survey (NHANES) cycles between 2005 and 2018. Family income to poverty ratio (PIR) was calculated by dividing family (or individual) income by poverty guidelines specific to the survey year and used as a measure of socioeconomic status. The association of PIR with the presence of cardiovascular risk factors and CVD as well as cardiac mortality and all-cause mortality was examined. We included 35,932 unweighted participants corresponding to 207,073,472 weighted, nationally representative participants. Participants with lower PIR were often female and more likely to belong to race/ethnic minorities (non-Hispanic Black, Mexican American, other Hispanic). In addition, they were less likely to be married/living with a partner, to attain college graduation or higher, or to have health insurance. In adjusted analyses, the prevalence odds of diabetes mellitus, hypertension, coronary artery disease (CAD), congestive heart failure (CHF), and stroke largely decreased in a step-wise manner from highest (≥ 5) to lowest PIR (< 1). In adjusted analysis, we also noted a mostly dose-dependent association of PIR with the risk of all-cause and cardiac mortality during a mean 5.7 and 5.8 years of follow up, respectively. Our study demonstrates a largely dose-dependent association of PIR with hypertension, diabetes mellitus, CHF, CAD and stroke prevalence as well as incident all-cause mortality and cardiac mortality in a nationally representative sample of American adults. Public policy efforts should be directed to alleviate these disparities to help improve cardiovascular outcomes in vulnerable groups with low family income.

Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss.

The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate 23. Introduction of a spirocyclic conformational constraint allowed for simultaneous optimization of MC4R potency and ADME attributes while avoiding the production of hERG active metabolites observed in early series leads. Compound 23 is a potent and selective MC4R antagonist with robust efficacy in an aged rat model of cachexia and has progressed into clinical trials.

Structural and functional consequences of the cardiac troponin C L48Q Ca(2+)-sensitizing mutation.

Calcium binding to the regulatory domain of cardiac troponin C (cNTnC) causes a conformational change that exposes a hydrophobic surface to which troponin I (cTnI) binds, prompting a series of protein-protein interactions that culminate in muscle contraction. A number of cTnC variants that alter the Ca(2+) sensitivity of the thin filament have been linked to disease. Tikunova and Davis engineered a series of cNTnC mutations that altered Ca(2+) binding properties and studied the effects on the Ca(2+) sensitivity of the thin filament and contraction [Tikunova, S. B., and Davis, J. P. (2004) J. Biol. Chem. 279, 35341-35352]. One of the mutations they engineered, the L48Q variant, resulted in a pronounced increase in the cNTnC Ca(2+) binding affinity and Ca(2+) sensitivity of cardiac muscle force development. In this work, we sought structural and mechanistic explanations for the increased Ca(2+) sensitivity of contraction for the L48Q cNTnC variant, using an array of biophysical techniques. We found that the L48Q mutation enhanced binding of both Ca(2+) and cTnI to cTnC. Nuclear magnetic resonance chemical shift and relaxation data provided evidence that the cNTnC hydrophobic core is more exposed with the L48Q variant. Molecular dynamics simulations suggest that the mutation disrupts a network of crucial hydrophobic interactions so that the closed form of cNTnC is destabilized. The findings emphasize the importance of cNTnC's conformation in the regulation of contraction and suggest that mutations in cNTnC that alter myofilament Ca(2+) sensitivity can do so by modulating Ca(2+) and cTnI binding.