Evaluation of a Novel Dermal Cooling System for the Treatment of Benign Pigmented Lesions in Asians.

OBJECTIVE: Our study aimed to evaluate the efficacy of this novel dermal cooling system (DCS) in reducing pigmentation in benign pigmented lesions in Asian patients and its potential side effects. METHODS: It was a prospective open-label single-center study. Asian patients, with the presence of benign pigmented lesions mainly including lentigines, melasma, nevus spilus, ephelides, café au lait, and seborrheic keratosis were recruited for a novel DCS. The DCS provided localized cooling of the epidermal layer below freezing but was less intense than cryotherapy. Each patient received DCS at Week 0 and repeated at 4-week intervals up to 10 sessions. Global aesthetic improvement scores (GAIS) by blinded physicians and subjects were recorded at 2, 6, and 12 months posttreatment follow-up. RESULTS: Eighty-one patients were recruited with a total of 305 sessions performed and 1716 lesion sites treated. At 2-month posttreatment, 76.5% and 58.6% treatment sites showed obvious to marked improvement respectively and the improvement sustained at 6 and 12 months. Only minor adverse events were reported. Erythema and edema were the most commonly anticipated effects immediately after treatment. The pain was minimal. Postinflammatory hyperpigmentation was only reported in 2.2% (38/1716) treated sites. CONCLUSION: To our knowledge, this study was the first study to demonstrate that this novel DCS was an effective, safe, and well-tolerated treatment for benign pigmented lesions in Asians.

Discovery of Potent and Selective Covalent Inhibitors of HER2WT and HER2YVMA.

HER2 overexpression and amplification have been identified as oncogenic drivers, and the development of therapies to treat tumors harboring these markers has received considerable attention. Activation of HER2 signaling and subsequent cell growth can also be induced by HER2 mutations, including the common YVMA insertion in exon 20 within the kinase domain. Enhertu is currently the only approved treatment for HER2 mutant tumors in NSCLC. TKIs tested in this space have suffered from off-target activity, primarily due to EGFRWT inhibition or attenuated activity against HER2 mutants. The goal of this work was to identify a TKI that would provide robust inhibition of oncogenic HER2WT and HER2 mutants while sparing EGFRWT activity. Herein, we describe the development of a potent, covalent inhibitor of HER2WT and the YVMA insertion mutant while providing oral bioavailability and avoiding the inhibition of EGFRWT.

A simple and sensitive differential digestion method to analyze adeno-associated virus residual host cell proteins by LC-MS.

Many methods using liquid chromatography-mass spectrometry (LC-MS) have been established for identifying residual host cell proteins (HCPs) to aid in the process development and quality control of therapeutic proteins. However, the use of MS-based techniques for adeno-associated virus (AAV) is still in its infancy, with few methods reported and minimal information available on potentially problematic HCPs. In this study, we developed a highly sensitive and effective differential digestion method to profile residual HCPs in AAV. Unlike direct digestion, which completely digests both AAV and HCPs, our differential digestion method takes advantage of AAV's unique characteristics to maintain the integrity of AAV while preferentially digesting HCPs under denaturing and reducing conditions. This differential digestion method requires only several micrograms of sample and significantly enhances the identification of HCPs. Furthermore, this method can be applied to all five different AAV serotypes for comprehensive HCP profiling. Our work fills a gap in AAV HCP analysis by providing a sensitive and robust strategy for detecting, monitoring, and measuring HCPs.

The use of fractional radiofrequency in Asian patients to improve skin texture.

BACKGROUND AND OBJECTIVES: Fractional radiofrequency devices have been demonstrated to improve skin texture, such as smoothness, rhytides, brightness, and atrophic acne scars, by increasing dermal thickness, dermal collagen content, and dermal fibrillin content. The objective of the study is to assess the efficacy and adverse effects of this device on Asian patients of skin type III and IV with skin textural changes. MATERIALS AND METHODS: The study was designed as a prospective, open-labeled single-arm study, which was conducted with 20 Chinese patients aged 21-60 years and having irregularities in their skin texture, rhytides, and acne scars. The patients received six treatments at intervals of 4 weeks. Treatment was initiated with the maximum energy tolerated, which was then adjusted during the course of treatment if the patients felt excessive discomfort. A total of two passes were delivered in each session. Physician assessment results and standardized photographs were collected at the baseline, after all treatment visits, and at 1, 2, and 6 months after the final treatment visit. RESULTS: A total of 17 patients completed the study according to the established protocol. At the 6-month follow-up, 71% of patients were satisfied and 24% of patients were very satisfied with the received treatments, and the treatment physician reported varying degrees of improvement based on the global assessment scale in 60% of the subjects. While the anticipated side effects, such as erythema, edema, pinpoint bleeding, scab formation, and flare of acne, were noted in the patients, no serious adverse effects occurred. CONCLUSION: The use of fractional radiofrequency improves skin texture and is safe for use in Asian patients of skin type III and IV. No long-term serious adverse effects were noted.

Discovery of 5-Azaquinoxaline Derivatives as Potent and Orally Bioavailable Allosteric SHP2 Inhibitors.

SHP2 has emerged as an important target for oncology small-molecule drug discovery. As a nonreceptor tyrosine phosphatase within the MAPK pathway, it has been shown to control cell growth, differentiation, and oncogenic transformation. We used structure-based design to find a novel class of potent and orally bioavailable SHP2 inhibitors. Our efforts led to the discovery of the 5-azaquinoxaline as a new core for developing this class of compounds. Optimization of the potency and properties of this scaffold generated compound 30, that exhibited potent in vitro SHP2 inhibition and showed excellent in vivo efficacy and pharmacokinetic profile.

SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy.

Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion-positive lung cancer, BRAFV600E-mutant colorectal cancer, KRASG12D-mutant ovarian cancer, and ROS1 fusion-positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial. After progression on PF-07284892 monotherapy, a novel study design allowed the addition of oncogene-directed targeted therapy that had previously failed. Combination therapy led to rapid tumor and circulating tumor DNA (ctDNA) responses and extended the duration of overall clinical benefit. SIGNIFICANCE: PF-07284892-targeted therapy combinations overcame bypass-signaling-mediated resistance in a clinical setting in which neither component was active on its own. This provides proof of concept of the utility of SHP2 inhibitors in overcoming resistance to diverse targeted therapies and provides a paradigm for accelerated testing of novel drug combinations early in clinical development. See related commentary by Hernando-Calvo and Garralda, p. 1762. This article is highlighted in the In This Issue feature, p. 1749.

Risk Factors for Adjacent Segment Disease Following Anterior Cervical Discectomy and Fusion with Plate Fixation: A Systematic Review and Meta-Analysis.

BACKGROUND: Adjacent segment disease (ASD) following anterior cervical discectomy and fusion with plating (ACDF-P) may yield a poor prognosis or reoperation. This review aimed to summarize risk factors for radiographic ASD (RASD) and clinical ASD (CASD) after ACDF-P. METHODS: Six electronic databases were searched from inception to October 30, 2021. Four reviewers independently screened titles, abstracts, and full-text articles to identify relevant studies. Methodological quality of the included studies was evaluated. Meta-analyses for risk factors were conducted, if possible. RESULTS: Sixteen cohort and 3 case-control studies (3,563 participants) were included. These studies showed low (n = 2), moderate (n = 9), and high (n = 8) risk of bias. One risk factor for RASD was pooled for 2 meta-analyses based on the follow-up period. Four different risk factors for CASD at ≥4 years were pooled for meta-analyses. Limited evidence showed that multi-level fusion, greater asymmetry in total or functional cross-sectional area of the cervical paraspinal muscle, and preoperative degeneration in a greater number of segments were associated with a higher RASD incidence <4 years after ACDF-P. In contrast, no significant risk factors were identified for CASD <4 years after ACDF-P. At ≥4 years after ACDF-P, limited evidence supported that both cephalad and caudal plate-to-disc distances of <5 mm were associated with a higher RASD incidence, and very limited evidence supported that developmental canal stenosis, preoperative RASD, unfused C5-C6 or C6-C7 adjacent segments, use of autogenous bone graft, and spondylosis-related ACDF-P were associated with a higher CASD incidence. CONCLUSIONS: Although several risk factors for RASD and CASD development after ACDF-P were identified, the supporting evidence was very limited to limited. Future prospective studies should extend the existing knowledge by more robustly identifying risk factors for RASD and CASD after ACDF-P to inform clinical practice. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

A Multimetric Readability Analysis of Online Patient Educational Materials for Submental Fat Reduction.

BACKGROUND: Patients often utilize the Internet to seek information related to their care. This study assesses the readability of online patient educational materials for submental fat reduction. METHODS: Patient educational materials from the 12 most popular websites related to submental fat reduction were downloaded and assessed for readability grade level using 10 unique scales. RESULTS: Analysis of the 12 most popular websites (and corresponding 47 articles) revealed that patient educational materials were written, on average, at an 11th grade reading level. The Flesch Reading Ease score was 48.9 (range 39.8-59.2), representing a "difficult" level of reading. Mean readability grade levels (range 9-13th grade for individual websites) were as follows: Coleman-Liau, 11.1; Flesch-Kincaid, 10.8; FORCAST, 10.8; Fry Graph, 10.1; Gunning Fog, 12.7; New Dale-Chall, 10.1; New Fog Count, 11.8; Simple Measure of Gobbledygook, 11.7; Raygor, 6.7. No website was at the 6th grade reading level for patient educational materials recommended by the American Medical Association and National Institutes of Health. CONCLUSIONS: Online patient educational materials for submental fat reduction are written well above the recommended reading level. Recognition of disparities in health literacy is necessary to enable patients to make informed decisions and become active participants in their own care. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors   www.springer.com/00266.

AutoCAT: automated cancer-associated TCRs discovery from TCR-seq data.

SUMMARY: T cells participate directly in the body's immune response to cancer, allowing immunotherapy treatments to effectively recognize and target cancer cells. We previously developed DeepCAT to demonstrate that T cells serve as a biomarker of immune response in cancer patients and can be utilized as a diagnostic tool to differentiate healthy and cancer patient samples. However, DeepCAT's reliance on tumor bulk RNA-seq samples as training data limited its further performance improvement. Here, we benchmarked a new approach, AutoCAT, to predict tumor-associated TCRs from targeted TCR-seq data as a new form of input for DeepCAT, and observed the same level of predictive accuracy. AVAILABILITY AND IMPLEMENTATION: Source code is freely available at https://github.com/cew88/AutoCAT, and data is available at 10.5281/zenodo.5176884. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

HLA-B*58:01 screening to prevent allopurinol-induced severe cutaneous adverse reactions in Chinese patients with chronic kidney disease.

Human leukocyte antigen (HLA)-B*58:01 allele is a significant risk factor for allopurinol-induced severe cutaneous adverse reactions (SCARs) which is potentially fatal. In some studies, chronic kidney disease (CKD) was also implicated to compound the risk of SCARs. We aim to investigate if pre-treatment HLA-B*58:01 screening can prevent allopurinol-induced SCARs in Chinese patients with CKD and its cost-effectiveness. We prospectively recruited Chinese CKD patients who required allopurinol during 2011-2015 and performed pre-treatment HLA testing (HLA screening group). Patients tested positive for HLA-B*58:01 were refrained from allopurinol while those tested negative were prescribed allopurinol. The incidence of SCARs in the HLA screening group was compared with the historical control in previous 5 years and the cost-effectiveness of HLA testing was analyzed. In the historical control (2006-2010), 3605 patients on allopurinol were screened, 22 out of 1027 (2.14%) CKD Chinese patients newly started on allopurinol developed SCARs, including 6 SJS/TEN. In the HLA screening group, 28 out of 192 patients (14.6%) tested HLA-B*58:01 positive were advised to avoid allopurinol; 156 out of 164 HLA-B*58:01-negative patients received allopurinol and none developed SCARs. The incidence rate of SCARs was significantly lower in the HLA screening group compared with controls (0% vs 2.14% respectively, p = 0.037*). The targeted HLA screening approach was associated with lower healthcare costs compared with no HLA screening (US$ 92,430 vs US$ 281,226). Pre-treatment HLA-B*58:01 screening is cost-effective to target on patients with CKD in Chinese to prevent allopurinol-induced SCARs.

Cosmetic dermatologic surgery fellowship websites and social media presence: Opportunities for improved applicant recruitment.

INTRODUCTION: The American Society for Dermatologic Surgery (ASDS) established a cosmetic dermatologic surgery fellowship in 2013. Programs often outline details of fellowships on their websites to help prospective applicants make informed decisions. Our primary goal was to evaluate the content quality of online information for all ASDS-accredited cosmetic dermatologic surgery fellowships on program websites and the ASDS website. Our secondary goal was to describe program activity on social media platforms as another avenue for applicant recruitment. METHODS: Program websites were assessed using an aggregate score from twenty-one standardized content quality variables. Social media activity on Facebook and Instagram from January 6 2021, to March 6, 2021, was categorized. RESULTS: Among 24 cosmetic dermatologic surgery fellowship programs, 23 had websites. Basic information was provided across most websites or the ASDS website (eg, address, 95.8%), but more qualitative variables like research opportunities or didactic schedule were not consistently reported. Most programs had highly active social media accounts (91.7% on Facebook and 79.2% on Instagram). CONCLUSION: There is a gap of information availability between the ASDS website and individual cosmetic dermatologic surgery fellowship websites. Increasing information availability may enhance the applicant recruitment process and serve as a low-cost intervention to ensure optimal fit.

Treatment Options and Outcomes for Squamous Cell Carcinoma of the Nail Unit: A Systematic Review.

BACKGROUND: Nail squamous cell carcinoma (nSCC) is the most common nail unit malignancy. However, no studies to date have evaluated treatment options for nSCC based on recurrence data while controlling for invasion. OBJECTIVE: To identify temporal trends in nSCC treatment modalities and compare treatment outcomes based on invasion. METHODS AND MATERIALS: The authors performed a systematic review of articles published on PubMed, MEDLINE, and Scopus from inception to April 2020 reporting treatment of nSCC. The primary outcome was disease recurrence. RESULTS: Reports of nSCC treatments have increased in the past decade. Mohs micrographic surgery (MMS) is the most common treatment reported overall. The lowest recurrence rates for in situ nSCC were seen with wide surgical excision (WSE) and MMS. For invasive disease, the recurrence rates were lowest with amputation, MMS, and WSE. CONCLUSION: Complete surgical excision of nSCC with either WSE or MMS is associated with lower recurrence rates than limited excision and nonsurgical therapies, regardless of degree of invasion. The prognostic significance of in situ versus invasive disease remains unclear. Confirmation of complete excision may improve outcomes. Digital amputation is indicated for nSCC with bone invasion. Prospective studies and randomized controlled trials are needed to directly compare surgical modalities for nSCC.

Tardive Dyskinesia in a Postoperative Gynecological Patient After Single Dose Administration of Metoclopramide.

Metoclopramide is a dopamine D2-receptor blocking agent commonly used to treat nausea, vomiting, and gastroparesis. Due to their mechanism of action, these drugs can lead to extrapyramidal side effects such as tardive dyskinesia. In this article, we report a case of a nulliparous gynecology patient who developed dyskinetic movements after intraoperative administration of metoclopramide. During further workup after stabilization, she was found to have several risk factors for tardive dyskinesia. As the occurrence of this phenomenon is somewhat rare, this case report aims to discuss the condition, associated risk factors, and differentiation from other diagnoses.

Uptake of oral fluid-based HIV self-testing among men who have sex with men and transgender women in Thailand.

BACKGROUND: Suboptimal uptake of HIV testing remains a primary bottleneck to HIV prevention and treatment for men who have sex with men (MSM) and transgender women (TGW) in Thailand. The World Health Organization has recommended HIV self-testing (HIVST) as an additional strategic HIV service. However, HIVST has not been fully endorsed and implemented in many countries in Southeast Asia. The aim of this study was to assess the uptake of oral fluid-based HIVST in MSM and TGW populations in Thailand. METHODS: During 2017 and 2018, we conducted a cross-sectional study using convenience sampling to enroll 2,524 participants from three major urban areas. Participants were recruited during outreach and online activities and were offered unassisted or assisted HIVST, or referral to HIV testing services. A descriptive analysis was performed for summarizing data. RESULTS: A total of 2,502 participants (1,422 MSM and 1,082 TGW) were included in the analysis with about one-third (36.1%) of them being first-time testers. Among all participants enrolled in the study, a total of 2,486 participants (99.3%) selected HIVST versus referral to HIV testing services. Of those who selected HIVST, 2,095 (84.3%) opted for assisted HIVST while the rest opted for unassisted HIVST: 1,148 of 1,411 MSM (81.4%) and 947 of 1,075 TGW (88.1%) selected assisted HIVST. While no serious adverse events were reported during the study, we found that among 179 participants who needed a confirmatory test and were referred to HIV testing services, 108 (60.3.4%) accessed these later services. CONCLUSIONS: This study demonstrated a high uptake of oral fluid-based HIVST among MSM and TGW populations in Thailand and that HIVST could be scaled up through the national epidemic control program. However, a better understanding of HIV testing-seeking behavior and innovative follow-up solutions are needed to improve and monitor linkages to services for people who undertake HIVST.

Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas.

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM. The reprogrammed GBM-infiltrating Treg cells express genes associated with a Th1 response signature, produce IFNγ, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. αGITR and αPD1 antibodies increase survival benefit in three experimental GBM models, with a fraction of cohorts exhibiting complete tumor eradication and immune memory upon tumor re-challenge. Moreover, αGITR and αPD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.

Fractional 1064 nm Picosecond Laser in Treatment of Melasma and Skin Rejuvenation in Asians, A Prospective Study.

BACKGROUND AND OBJECTIVES: Facial melasma is a disfiguring pigmentation and occurs frequently with aging skin. Topical treatment alone was often suboptimal. A recent study showed that fractional picosecond laser has promising result in benign pigmentary lesions. This study aims to investigate the efficacy and safety of 1064 nm picosecond laser in treatment of facial melasma and skin rejuvenation in Asian skin. STUDY DESIGN/MATERIALS AND METHODS: Patients of Asian descent seeking treatment for facial melasma and skin rejuvenation were screened and recruited. Each patient received up to nine laser treatments at 4-6 weeks intervals with a fractionated nonablative 1064 nm picosecond laser. Baseline and posttreatment modified Melasma Area Severity Index (mMASI) and Global Aesthetic Improvement Scale (IGAS) were assessed by blinded investigators based on the clinical photographs. Subject overall satisfaction was assessed by the questionnaires after treatment. All adverse events were documented. RESULTS: Twenty patients were recruited with a median age of 52.7 ± 8.2 years. Three subjects had Fitzpatrick skin type III and 17 had skin type IV. All subjects received nine laser sessions. Over 70% of patients were satisfied with the treatment outcomes. There was a statistically significant improvement in mMASI which reduced from 10.8 at baseline to 2.7 and 3.6 at 6 and 12 weeks post-treatment, respectively (both P < 0.01). For skin rejuvenation, 70% reported at least a moderate improvement at 6 weeks of post-treatment. No major side-effect was reported. Erythema was the most frequent transient response, while some reported edema (1.1%). Both resolved spontaneously. None reported hypo- or hyperpigmentation after treatment. The overall mean pain scare (VAS) was 1.92. CONCLUSION: Fractionated non-ablative 1064 nm picosecond laser was effective in treatment of melasma and skin rejuvenation. It was also safe and well tolerated. Importantly, there was no hypo or hyperpigmentation reported. Lasers Surg. Med. 00:00-00, 2021. © 2021 Wiley Periodicals LLC.

Inflammatory cytokine levels implicated in Alzheimer's disease moderate the effects of sex on verbal memory performance.

Despite having an initial verbal memory advantage over men, women have greater rates of Alzheimer's disease and more rapid cognitive decline once diagnosed. Moreover, although Alzheimer's disease is influenced by inflammation, which itself has known sex differences, no study has investigated whether sex differences in memory are moderated by peripheral inflammatory activity. To address this issue, we analyzed data from 109 individuals (50 women, Mage = 71.62, range = 55-87) diagnosed as cognitively normal, or having mild cognitive impairment or Alzheimer's disease dementia. We then followed the sample for 12 months, as part of a longitudinal study of aging and Alzheimer's disease. At baseline, we assessed levels of the inflammatory cytokines interleukin (IL)-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α) in plasma. At baseline and 12 months, we assessed verbal memory using the Rey Auditory Verbal Learning Test and nonverbal memory using the Brief Visuospatial Memory Test-Revised. As hypothesized, for the full sample, women exhibited stronger verbal (but not nonverbal) memory than men. In women, but not men, higher IL-1ß at baseline related to poorer verbal learning across both time points and delayed recall at 12 months. The effect of sex on memory also differed by IL-1ß level, with women exhibiting a memory advantage both at baseline and 12 months, but only for those with low-to-moderate IL-1ß levels. Therefore, high peripheral inflammation levels may lead to a sex-specific memory vulnerability relevant for Alzheimer's disease.