Comprehensive Review of Thermomechanical Fractional Injury Device: Applications in Medical and Cosmetic Dermatology.

Objective: Our aim was to review the current and emerging dermatological applications of the novel thermomechanical fractional injury (TMFI) device, Tixel® (Novoxel, Netanya, Israel). Methods: A systematic review of PubMed using the search terms of "Tixel", "thermomechanical fractional", ["thermomechanical ablation" and "skin"], and ["thermomechanical ablation" and "dermatology"]. Results: Thirty-six articles matched our inquiry. Fifteen articles did not meet inclusion criteria. Of the remaining 21 articles, eight were related to device-assisted drug delivery, seven related to photoaging, and seven related to scientific/ preclinical exploration. Preclinical studies have shown ablative and non-ablative microchannel formation similar to that of CO2 laser but without charring, with clinical studies demonstrating efficacy for a wide range of applications including rhytides, hypertrophic scarring, infantile hemangiomas, and acne/rosacea. The treatment is well tolerated with minimal discomfort and downtime, showing promise for pain-averse and pediatric populations. Few adverse events have been reported, with a high degree of safety demonstrated in all Fitzpatrick types. Limitations: Heterogeneous result reporting among studies. Limited number of randomized controlled trials. Conclusion: Tixel® is an emerging TMFI device with a wide range of current and potential applications, including device-assisted drug delivery and treatment of rhytides, photoaging, and scars among other conditions. The device has both ablative and non-ablative settings and has been safely used in all Fitzpatrick skin types. Larger and randomized controlled trials are needed to compare this device to current standard of care treatments.

Model-informed pediatric dose selection of marzeptacog alfa (activated): An exposure matching strategy.

Marzeptacog alfa (activated) (MarzAA) is an activated recombinant human rFVII variant intended for subcutaneous (s.c.) administration to treat or prevent bleeding in individuals with hemophilia A (HA) or B (HB) with inhibitors, and other rare bleeding disorders. The s.c. administration provides benefits over i.v. injections. The objective of the study was to support the first-in-pediatric dose selection for s.c. MarzAA to treat episodic bleeding episodes in children up through 11 years in a registrational phase III trial. Assuming the same exposure-response relationship as in adults, an exposure matching strategy was used with a population pharmacokinetics model. A sensitivity analysis evaluating the impact of doubling in absorption rate and age-dependent allometric exponents on dose selection was performed. Subsequently, the probability of trial success, defined as the number of successful trials for a given pediatric dose divided by the number of simulated trials (n = 1000) was studied. A successful trial was defined as outcome where four, three, or two out of 24 pediatric subjects per trial were allowed to fall outside the adult exposures after s.c. administration of 60 µg/kg. A dose of 60 µg/kg in children with HA/HB was supported by the clinical trial simulations to match exposures in adults. The sensitivity analyses further supported selection of the 60 µg/kg dose level in all age groups. Moreover, the probability of trial success evaluations given a plausible design confirmed the potential of a 60 µg/kg dose level. Taken together, this work demonstrates the utility of model-informed drug development and could be helpful for other pediatric development programs for rare diseases.

Diurnal variation in salivary progesterone in fertile Indian women.

Research question: Is there a diurnal variation in salivary progesterone levels during menstrual cycle among Indian women? Design: A longitudinal study was carried out to measure progesterone in saliva among small cross-sectional sample (n = 31) of fertile Indian women of reproductive age comprising young adults (18-25 years, n = 11), adults (26-38 years, n = 9) and middle aged (39-45 years, n = 11). Saliva samples were collected twice daily (morning and evening) across the entire menstrual cycle of 31 women. Results: Mean ages at enrolment and menarche were 30.6 years and 13.6 years respectively. Fifty-five percent of the women were married. The menstrual cycle range was 20-40 days. After controlling for age and menstrual cycle length, statistically significant diurnal variation in progesterone levels was observed across menstrual cycles with high levels in the morning. Conclusions: This is the first report on salivary progesterone in subjects with Indian ethnicity and could have clinical implications for designing point of care kits for menstrual cycle management, fertility and reproduction.

Needs and Gaps in Resident Trainee Education, Clinical Patient Care, and Clinical Research in Cosmetic Dermatology: Position Statement of the Association of Academic Cosmetic Dermatology.

Cosmetic dermatology is a key subspecialty of academic dermatology. As such, academic centers are expected to demonstrate excellence in the teaching of cosmetic dermatology skills to trainees, the clinical delivery of cosmetic dermatology services to patients, and the performance of clinical research that advances knowledge and uncovers new therapies in cosmetic dermatology. The Association of Academic Cosmetic Dermatology (AACD), a newly formed medical professional society, includes as its principal aims the support of all of these areas. AACD is comprised of group of board-certified dermatologists who teach cosmetic and laser dermatology at US dermatology residency programs. An expert panel constituted by the AACD recently convened a workshop to review gaps pertaining to academic cosmetic dermatology. This panel considered needs and potential corrective initiatives in three domains: resident education, patient experience, and clinical research. The work of the panel was used to develop a roadmap, which was adopted by consensus, and which will serve to guide the AACD moving forward.

The Association of Academic Cosmetic Dermatology: improving cosmetic dermatology education through collaboration, research, and advocacy.

Cosmetic and laser procedures are increasingly popular among patients and are skills in which dermatologists are regarded as well trained. Most dermatology residents intend to incorporate cosmetic procedures into their practice and prefer to learn such procedures during residency through direct patient care. However, there are notable challenges in optimizing how residents are trained in cosmetic and laser dermatology. To address these barriers and elevate the practice of cosmetic dermatology in academic medicine, the Association of Academic Cosmetic Dermatology (AACD) was founded in 2021 as the lead professional society for dermatologists who direct the education of resident trainees in cosmetic and laser dermatology. The AACD, a group of board-certified dermatologists who teach cosmetic and laser dermatology to residents, aims to improve cosmetic dermatology education through collaboration, research, and advocacy.

Phase III dose selection of marzeptacog alfa (activated) informed by population pharmacokinetic modeling: A novel hemostatic drug.

Marzeptacog alfa (activated) (MarzAA) is an activated recombinant human FVII (rFVIIa) variant developed as subcutaneous (s.c.) administration for the treatment or prevention of bleeding episodes in patients with hemophilia A (HA) or hemophilia B (HB) with inhibitors and other rare bleeding disorders. Population pharmacokinetic (PK) modeling was applied for dose selection for a pivotal phase III clinical trial evaluating s.c. MarzAA for episodic treatment of spontaneous or traumatic bleeding episodes. The population PK model used MarzAA intravenous and s.c. data from previously completed clinical trials in patients with HA/HB with or without inhibitors. Based on the model, clinical trial simulations were performed to predict MarzAA exposure after different dosing regimens. The exposure target was identified using an exposure-matching strategy with a wild-type rFVIIa but adjusting for the difference in potency between the two compounds. Simulations demonstrated a sufficient absorption rate and prolonged exposure following a single 60 µg/kg dose leading to 51% and 70% of the population reaching levels above the target after 3 and 6 h, respectively. According to the phase III protocol, if a second dose was required after 3 h because of a lack of efficacy, 90% of the population was observed to be above target 6 h after the initial dose. The model-informed drug development approach integrated information from several trials and guided dose selection in the pivotal phase III clinical trial for episodic treatment of an acute bleeding event in individuals with HA or HB with inhibitors without the execution of a phase II trial for that indication.

Picosecond laser with specialized optic for facial rejuvenation using a compressed treatment interval.

Studies using a 755 nm picosecond laser with a focus lens array have been reported to be effective for facial wrinkles and pigmentation. This study reports the safety and efficacy using a shorter interval of 2-3 weeks between treatments. Nineteen female subjects and one male subject, primarily Fitzpatrick skin types II and III (one skin type I), who had mild to moderate wrinkles and sun-induced pigmentation were enrolled and treated using the 755 nm PicoSure Laser with focus lens array. The skin was cleansed then wiped with an alcohol wipe prior to treatment. Lidocaine 30% ointment and/or forced air cooling could be used to increase subject comfort. Adjacent pulses, with minimal overlap (10% or less), were delivered to the full face. Subjects received four treatments, performed at 2-3-week intervals. The laser energy used was 0.71 J/cm2 . The physician administered 3-7 passes with an average total of 6,253 pulses per treatment. Follow-up visits occurred at 1 and 3 months post-last treatment at which the physician scored satisfaction and improvement and subjects scored satisfaction and likelihood to recommend to others. The most common side effects were mild swelling, pain, redness, and crusting, most of which subsided within hours of the treatment, with the latest resolving within 48 hours. This is similar to a previous reported study (Weiss et al. ASLMS 2015) where treatments were performed every 6 weeks with side effects resolving within 24 hours. At the 1 and 3 month follow-up visits, 94% (n = 19) and 93% (n = 15) of subjects scored themselves as satisfied or extremely satisfied with their overall results and 81% and 93% were likely to recommend the treatment based on global assessment, respectively. The treating physician was satisfied with 93% of subject's overall results. Three blinded evaluators were able to correctly identify the baseline from post-treatment photographs in 77% of the subjects at the 1 month follow-up and 69% of the subjects at the 3 month follow-up, on average. The average treatment pain score was 4.2 on a 1-10 scale. A compressed treatment interval expedites results without increasing side effects and resulted in a high physician and subject satisfaction rate. Lasers Surg. Med. 48:723-726, 2016. © 2016 Wiley Periodicals, Inc.

Fluoxetine induces cytotoxic endoplasmic reticulum stress and autophagy in triple negative breast cancer.

AIM: To investigate the mechanism of action of lipophilic antidepressant fluoxetine (FLX) in representative molecular subtypes of breast cancer. METHODS: The anti-proliferative effects and mechanistic action of FLX in triple-negative (SUM149PT) and luminal (T47D and Au565) cancer cells and non-transformed MCF10A were investigated. Reverse phase protein microarray (RPPM) was performed with and without 10 µmol/L FLX for 24 and 48 h to determine which proteins are significantly changed. Viability and cell cycle analysis were also performed to determine drug effects on cell growth. Western blotting was used to confirm the change in protein expression examined by RPPM or pursue other signaling proteins. RESULTS: The FLX-induced cell growth inhibition in all cell lines was concentration- and time-dependent but less pronounced in early passage MCF10A. In comparison to the other lines, cell growth reduction in SUM149PT coincided with significant induction of endoplasmic reticulum (ER) stress and autophagy after 24 and 48 h of 10 µmol/L FLX, resulting in decreased translation of proteins along the receptor tyrosine kinase/Akt/mammalian target of rapamycin pathways. The increase in autophagy marker, cleaved microtubule-associated protein 1 light chain 3, in SUM149PT after 24 h of FLX was likely due to increased metabolic demands of rapidly dividing cells and ER stress. Consequently, the unfolded protein response mediated by double-stranded RNA-dependent protein kinase-like ER kinase resulted in inhibition of protein synthesis, growth arrest at the G1 phase, autophagy, and caspase-7-mediated cell death. CONCLUSION: Our study suggests a new role for FLX as an inducer of ER stress and autophagy, resulting in death of aggressive triple negative breast cancer SUM149PT.

Light-emitting Diodes: A Brief Review and Clinical Experience.

BACKGROUND: In the early 1990s, the biological significance of light-emitting diodes was realized. Since this discovery, various light sources have been investigated for their cutaneous effects. STUDY DESIGN: A Medline search was performed on light-emitting diode lights and their therapeutic effects between 1996 and 2010. Additionally, an open-label, investigator-blinded study was performed using a yellow light-emitting diode device to treat acne, rosacea, photoaging, alopecia areata, and androgenetic alopecia. RESULTS: The authors identified several case-based reports, small case series, and a few randomized controlled trials evaluating the use of four different wavelengths of light-emitting diodes. These devices were classified as red, blue, yellow, or infrared, and covered a wide range of clinical applications. The 21 patients the authors treated had mixed results regarding patient satisfaction and pre- and post-treatment evaluation of improvement in clinical appearance. CONCLUSION: Review of the literature revealed that differing wavelengths of light-emitting diode devices have many beneficial effects, including wound healing, acne treatment, sunburn prevention, phototherapy for facial rhytides, and skin rejuvenation. The authors' clinical experience with a specific yellow light-emitting diode device was mixed, depending on the condition being treated, and was likely influenced by the device parameters.

Tumor mechanics and metabolic dysfunction.

Desmosplasia is a characteristic of most solid tumors and leads to fibrosis through abnormal extracellular matrix (ECM) deposition, remodeling, and posttranslational modifications. The resulting stiff tumor stroma not only compromises vascular integrity to induce hypoxia and impede drug delivery, but also promotes aggressiveness by potentiating the activity of key growth, invasion, and survival pathways. Intriguingly, many of the protumorigenic signaling pathways that are mechanically activated by ECM stiffness also promote glucose uptake and aerobic glycolysis, and an altered metabolism is a recognized hallmark of cancer. Indeed, emerging evidence suggests that metabolic alterations and an abnormal ECM may cooperatively drive cancer cell aggression and treatment resistance. Accordingly, improved methods to monitor tissue mechanics and metabolism promise to improve diagnostics and treatments to ameliorate ECM stiffening and elevated mechanosignaling may improve patient outcome. Here we discuss the interplay between ECM mechanics and metabolism in tumor biology and suggest that monitoring these processes and targeting their regulatory pathways may improve diagnostics, therapy, and the prevention of malignant transformation.

The interruption of PKC-ι signaling and TRAIL combination therapy against glioblastoma cells.

Glioblastoma is a highly aggressive type of brain cancer which currently has limited options for treatment. It is imperative to develop combination therapies that could cause apoptosis in glioblastoma. The aim of this study was to characterize the affect of modified ICA-1, a PKC-iota inhibitor, on the growth pattern of various glioblastoma cell lines. T98G and U87 glioblastoma cells were treated with ICA-1 alone and the absolute cell numbers of each group were determined for cell growth expansion analysis, cell viability analysis, and cell death analysis. Low dose ICA-1 treatment alone significantly inhibited cell growth expansion of high density glioblastoma cells without inducing cell death. However, the high dose ICA-1 treatment regimen provided significant apoptosis for glioblastoma cells. Furthermore, this study was conducted to use a two layer molecular level approach for treating glioblastoma cells with ICA-1 plus an apoptosis agent, tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL), to induce apoptosis in such chemo-refractory cancer cells. Following ICA-1 plus TRAIL treatment, apoptosis was detected in glioblastoma cells via the TUNEL assay and via flow cytometric analysis using Annexin-V FITC/PI. This study offers the first evidence for ICA-1 alone to inhibit glioblastoma cell proliferation as well as the novel combination of ICA-1 with TRAIL to cause robust apoptosis in a caspase-3 mediated mechanism. Furthermore, ICA-1 plus TRAIL simultaneously modulates down-regulation of PKC-iota and c-Jun.

Special requirements for electronic health records in dermatology.

Government incentives and mandates to increase the meaningful use of electronic health records (EHR), with subsequent disincentives by Medicare, have made a significant push for dermatologists to adopt this technology into their practices. EHRs were originally developed for primary care physicians; however, owing to the unique features of dermatology, specialty-specific systems are a must. In this article, we discuss the special needs of dermatologists when choosing an EHR system.

Regulation of Cdk7 activity through a phosphatidylinositol (3)-kinase/PKC-ι-mediated signaling cascade in glioblastoma.

The objective of this research was to study the potential function of protein kinase C (PKC)-ι in cell cycle progression and proliferation in glioblastoma. PKC-ι is highly overexpressed in human glioma and benign and malignant meningioma; however, little is understood about its role in regulating cell proliferation of glioblastoma. Several upstream molecular aberrations and/or loss of PTEN have been implicated to constitutively activate the phosphatidylinositol (PI) (3)-kinase pathway. PKC-ι is a targeted mediator in the PI (3)-kinase signal transduction repertoire. Results showed that PKC-ι was highly activated and overexpressed in glioma cells. PKC-ι directly associated and phosphorylated Cdk7 at T170 in a cell cycle-dependent manner, phosphorylating its downstream target, cdk2 at T160. Cdk2 has a major role in inducing G(1)-S phase progression of cells. Purified PKC-ι phosphorylated both endogenous and exogenous Cdk7. PKC-ι downregulation reduced Cdk7 and cdk2 phosphorylation following PI (3)-kinase inhibition, phosphotidylinositol-dependent kinase 1 knockdown as well as PKC-ι silencing (by siRNA treatment). It also diminished cdk2 activity. PKC-ι knockdown inhibited overall proliferation rates and induced apoptosis in glioma cells. These findings suggest that glioma cells may be proliferating through a novel PI (3)-kinase-/PKC-ι/Cdk7/cdk2-mediated pathway.

A novel PKC-ι inhibitor abrogates cell proliferation and induces apoptosis in neuroblastoma.

Protein Kinase C-iota (PKC-ι), an atypical protein kinase C isoform manifests its potential as an oncogene by targeting various aspects of cancer cells such as growth, invasion and survival. PKC-ι confers resistance to drug-induced apoptosis in cancer cells. The acquisition of drug resistance is a major obstacle to good prognosis in neuroblastoma. The focus of this research was to identify the efficacy of [4-(5-amino-4-carbamoylimidazol-1-yl)-2,3-dihydroxycyclopentyl] methyl dihydrogen phosphate (ICA-1) as a novel PKC-ι inhibitor in neuroblastoma cell proliferation and apoptosis. ICA-1 specifically inhibits the activity of PKC-ι but not that of PKC-zeta (PKC-ζ), the closely related atypical PKC family member. The IC(50) for the kinase activity assay was approximately 0.1µM which is 1000 times less than that of aurothiomalate, a known PKC-ι inhibitor. Cyclin dependent kinase 7 (Cdk7) phosphorylates cyclin dependent kinases (cdks) and promotes cell proliferation. Our data shows that PKC-ι is an in vitro Cdk7 kinase and the phosphorylation of Cdk7 by PKC-ι was potently inhibited by ICA-1. Furthermore, our data shows that neuroblastoma cells proliferate via a PKC-ι/Cdk7/cdk2 cell signaling pathway and ICA-1 mediates its antiproliferative effects by inhibiting this pathway. ICA-1 (0.1µM) inhibited the in vitro proliferation of BE(2)-C neuroblastoma cells by 58% (P=0.01). Additionally, ICA-1 also induced apoptosis in neuroblastoma cells. Interestingly, ICA-1 did not affect the proliferation of normal neuronal cells suggesting its potential as chemotherapeutic with low toxicity. Hence, our results emphasize the potential of ICA-1 as a novel PKC-ι inhibitor and chemotherapeutic agent for neuroblastoma.

Paradoxical hypertrichosis after laser therapy: a review.

BACKGROUND: Laser hair removal is a safe and effective procedure for the treatment of unwanted body hair but is not exempt from side effects. A rare but significant adverse effect with this treatment modality is paradoxical hypertrichosis. OBJECTIVE: To evaluate the potential etiologies, risk factors, related laser types, and treatment options for the development of excess hair after laser therapy. MATERIALS AND METHODS: An analysis of previously published case studies and review articles along with our own experience was used to gather information regarding this phenomenon. RESULTS: Paradoxical hypertrichosis has a low incidence, ranging from 0.6% to 10%, and most commonly occurs on the face and neck. All laser and light sources have the potential to cause hair induction, especially in individuals with darker skin types (III-VI); with dark, thick hair; and with underlying hormonal conditions. Possible causes include the effect of inflammatory mediators and subtherapeutic thermal injury causing induction of the hair cycle. Treatment for paradoxical hypertrichosis is laser therapy of the affected area. CONCLUSIONS: Paradoxical hypertrichosis is a rare side effect of laser hair removal; the pathogenesis of this event remains widely unknown. We recommend further large-scale studies to investigate this effect. The authors have indicated no significant interest with commercial supporters.