The histone methyltransferase SETD2 regulates HIV expression and latency.

Understanding the mechanisms that drive HIV expression and latency is a key goal for achieving an HIV cure. Here we investigate the role of the SETD2 histone methyltransferase, which deposits H3K36 trimethylation (H3K36me3), in HIV infection. We show that prevention of H3K36me3 by a potent and selective inhibitor of SETD2 (EPZ-719) leads to reduced post-integration viral gene expression and accelerated emergence of latently infected cells. CRISPR/Cas9-mediated knockout of SETD2 in primary CD4 T cells confirmed the role of SETD2 in HIV expression. Transcriptomic profiling of EPZ-719-exposed HIV-infected cells identified numerous pathways impacted by EPZ-719. Notably, depletion of H3K36me3 prior to infection did not prevent HIV integration but resulted in a shift of integration sites from highly transcribed genes to quiescent chromatin regions and to polycomb repressed regions. We also observed that SETD2 inhibition did not apparently affect HIV RNA levels, indicating a post-transcriptional mechanism affecting HIV expression. Viral RNA splicing was modestly reduced in the presence of EPZ-719. Intriguingly, EPZ-719 exposure enhanced responsiveness of latent HIV to the HDAC inhibitor vorinostat, suggesting that H3K36me3 can contribute to a repressive chromatin state at the HIV locus. These results identify SETD2 and H3K36me3 as novel regulators of HIV integration, expression and latency.

Water Quenched and Acceptor-Doped Textured Piezoelectric Ceramics for Off-Resonance and On-Resonance Devices.

Piezoelectric materials should simultaneously possess the soft properties (high piezoelectric coefficient, d33 ; high voltage coefficient, g33 ; high electromechanical coupling factor, k) and hard properties (high mechanical quality factor, Qm ; low dielectric loss, tan δ) along with wide operation temperature (e.g., high rhombohedral-tetragonal phase transition temperature Tr-t ) for covering off-resonance (figure of merit (FOM), d33  × g33 ) and on-resonance (FOM, Qm  × k2 ) applications. However, achieving hard and soft piezoelectric properties simultaneously along with high transition temperature is quite challenging since these properties are inversely related to each other. Here, through a synergistic design strategy of combining composition/phase selection, crystallographic texturing, defect engineering, and water quenching technique, <001> textured 2 mol% MnO2 doped 0.19PIN-0.445PSN-0.365PT ceramics exhibiting giant FOM values of Qm  × k 31 2 $k_{31}^2$ (227-261) along with high d33  × g33 (28-35 × 10-12 m2 N-1 ), low tan δ (0.3-0.39%) and high Tr-t of 140-190 °C, which is far beyond the performance of the state-of-the-art piezoelectric materials, are fabricated. Further, a novel water quenching (WQ) room temperature poling technique, which results in enhanced piezoelectricity of textured MnO2 doped PIN-PSN-PT ceramics, is reported. Based upon the experiments and phase-field modeling, the enhanced piezoelectricity is explained in terms of the quenching-induced rhombohedral phase formation. These findings will have tremendous impact on development of high performance off-resonance and on-resonance piezoelectric devices with high stability.

Growth Kinetics and Atomistic Mechanisms of Native Oxidation of ZrSxSe2-x and MoS2 Crystals.

A thorough understanding of native oxides is essential for designing semiconductor devices. Here, we report a study of the rate and mechanisms of spontaneous oxidation of bulk single crystals of ZrSxSe2-x alloys and MoS2. ZrSxSe2-x alloys oxidize rapidly, and the oxidation rate increases with Se content. Oxidation of basal surfaces is initiated by favorable O2 adsorption and proceeds by a mechanism of Zr-O bond switching, that collapses the van der Waals gaps, and is facilitated by progressive redox transitions of the chalcogen. The rate-limiting process is the formation and out-diffusion of SO2. In contrast, MoS2 basal surfaces are stable due to unfavorable oxygen adsorption. Our results provide insight and quantitative guidance for designing and processing semiconductor devices based on ZrSxSe2-x and MoS2 and identify the atomistic-scale mechanisms of bonding and phase transformations in layered materials with competing anions.

The importance of caveolins and caveolae to dermatology: Lessons from the caves and beyond.

Caveolae are flask-shaped invaginations of the cell membrane rich in cholesterol and sphingomyelin, with caveolin proteins acting as their primary structural components that allow compartmentalization and orchestration of various signalling molecules. In this review, we discuss how pleiotropic functions of caveolin-1 (Cav1) and its intricate roles in numerous cellular functions including lipid trafficking, signalling, cell migration and proliferation, as well as cellular senescence, infection and inflammation, are integral for normal development and functioning of skin and its appendages. We then examine how disruption of the homeostatic levels of Cav1 can lead to development of various cutaneous pathophysiologies including skin cancers, cutaneous fibroses, psoriasis, alopecia, age-related changes in skin and aberrant wound healing and propose how levels of Cav1 may have theragnostic value in skin physiology/pathophysiology.

Patients' prediction of their wound healing time.

Understanding and managing patients' expectations can help improve their adherence to treatment for chronic wounds; however, little is known concerning about their expectations regarding healing time. Recruited subjects were asked to predict how long their wounds would take to heal and their charts were reviewed to retrieve real time of healing. We recruited 100 subjects from which 77% have healed. Fifty-three subjects (68.8%) had a longer healing time than they predicted (underestimated), and 17 (22.1%) had a shorter healing time than they predicted (overestimated). Subjects with shorter wound duration history tended to predict shorter healing time than subjects with longer wound duration (p < 0.01). However, wound duration did not affect prediction accuracy (p = 0.65). Subjects with chronic wounds seem more often to underestimate their time of healing. Wound duration significantly influenced patients' prediction time, although it did not make their prediction more accurate. Patient education about expectations may be important as patients often expect their wounds to heal faster than they actually do.

Widespread Skin Necrosis Secondary to Gemcitabine Therapy.

Gemcitabine, a pyrimidine nucleoside analogue, is an oncologic agent used in the treatment of cutaneous T-cell lymphoma (CTCL). Common dermatologic reactions associated with gemcitabine include alopecia, mild skin rash, and mucositis but skin necrosis is exceptional. Herein we present an unusual case of widespread skin necrosis mimicking toxic epidermal necrolysis in a 45-year-old woman receiving gemcitabine therapy for stage IIIA cutaneous T-cell lymphoma. This is the first reported case of a TEN-like reaction subsequent to gemcitabine treatment. J Drugs Dermatol. 2018;17(5):582-585.

Primary Cribriform Carcinoma of the Eyelid With Neuroendocrine Features: A Case Report.

A variety of tumors may involve the eyelid, most of which are primary, but rarely can be metastatic. Previously reported eyelid primary carcinomas with neuroendocrine features include Merkel cell carcinoma, apocrine and eccrine gland carcinoma, sebaceous gland carcinoma, and one report of primary "well-differentiated neuroendocrine tumor." Herein we report the first case of primary cribriform carcinoma of the eyelid with neuroendocrine features. The patient is a 75-year-old black man who presented to the clinic with a 5-year history of a slowly growing, non-painful, non-exudative lesion of his left lower eyelid. Examination disclosed a non-tender 8 mm by 9 mm ovoid, firm, euchromic subdermal non-adherent nodule involving the left lower eyelid with no madarosis or loss of lid margin architecture, but with overlying induration. An incisional biopsy demonstrated nodules and aggregates of tumor composed of cuboidal hyperchromatic basoloid cells with occasional mitotic figures within sheets in a mostly cribriform and occasionally papillary pattern. The tumor was diffusely positive for cytokeratin, Epithelial Membrane Antigen, and p40 and focally positive for synaptophysin. The tumor was negative with antibodies for Cytokeratin 20 (CK20), p63, CD10, Thyroid Transcription Factor-1, Cytokeratin 7, Prostate Specific Antigen, and Epithelial Specific Antigen. Oncologic evaluation was negative for metastases. The patient underwent a complete excision of his eyelid tumor with 5 mm margins using Mohs surgery, with subsequent reconstruction using a Hughes tarsoconjunctival flap, myocutaneous advancement flap, and lateral canthal tendon plication.

J Drugs Dermatol. 2017;16(2):173-174.

Development of a Flipped Medical School Dermatology Module.

OBJECTIVES: The flipped classroom module incorporates independent study in advance of in-class instructional sessions. It is unproven whether this methodology is effective within a medical school second-year organ system module. We report the development, implementation, and effectiveness of the flipped classroom methodology in a second-year medical student dermatology module at the University of Miami Leonard M. Miller School of Medicine. METHODS: In a retrospective cohort analysis, we compared attitudinal survey data and mean scores for a 50-item multiple-choice final examination of the second-year medical students who participated in this 1-week flipped course with those of the previous year's traditional, lecture-based course. RESULTS: Each group comprised nearly 200 students. Students' age, sex, Medical College Admission Test scores, and undergraduate grade point averages were comparable between the flipped and traditional classroom students. The flipped module students' mean final examination score of 92.71% ± 5.03% was greater than that of the traditional module students' 90.92% ± 5.51% (P < 0.001) score. Three of the five most commonly missed questions were identical between the two cohorts. The majority of students preferred the flipped methodology to attending live lectures or watching previously recorded lectures. CONCLUSIONS: The flipped classroom can be an effective instructional methodology for a medical school second-year organ system module.

Statins may be associated with six-week diabetic foot ulcer healing.

Diabetic foot ulcers (DFUs) affect 1.5 million Americans annually, of which only a minority heal with standard care, and they commonly lead to amputation. To improve care, investigations are underway to better understand DFU pathogenesis and develop more effective therapies. Some currently used medications may improve healing. One small, randomized clinical trial found statins improve DFU healing. In this secondary analysis of a large multisite prospective observational cohort of 139 patients with DFUs receiving standard care, we investigated whether there was an association between 6-week DFU wound size reduction and use of a variety of medications including alpha-blockers, beta-blockers, angiotensin converting enzyme inhibitors (ACEi) and statins. We found no significant (p < 0.05) association between six-week wound reduction and use of any of the evaluated drugs; however, statins did trend toward an association (p = 0.057). This suggests a potential benefit of statins on DFU healing, and larger, targeted studies are warranted.

Adalimumab treatment leads to reduction of tissue tumor necrosis factor-alpha correlated with venous leg ulcer improvement: a pilot study.

Venous leg ulcers (VLUs) have higher tumor necrosis factor-α (TNF-α) levels compared with normal skin. Refractory VLUs of long duration have higher TNF-α levels compared with VLUs of shorter duration. As up to 75% of VLUs fail to heal with standard care, we sought to evaluate the role of anti-TNF-α therapy for patients with refractory VLUs. Evaluable data were obtained in four of five subjects with recalcitrant VLUs treated with 80 mg of subcutaneous adalimumab at week 0 and with 40 mg at week 2 along with compression therapy and were followed-up for 6 weeks. Wound biopsies taken at weeks 0 and 4 were stained with anti-TNF-α antibodies. Average 4-week percent wound size reduction was 20.5% ± 6.4%. Two patients had wound size reduction more than 25%, and their percent wound size reduction correlated to percent TNF-α staining score reductions (P = 0.02, R(2) = 0.999). VLU TNF-α level decrease 4 weeks post-adalimumab treatment correlated with wound healing.

Cryo-Induced Thermal Wounds: A Human Acute Wound Model.

INTRODUCTION: Clinical models are invaluable in studying wound healing. Challenges in studying human wounds include heterogeneity of patients and wounds, as well as prolonged study time, resulting in high costs. Animal models are an efficient method to study wound healing, but often lack correlation with human acute wound healing. Human wound models can be created using sharp instruments, suction, acids, heat and cold. In this observational study, we propose a practical human acute wound model where partial thickness wounds are induced by cryosurgery to create wounds that could facilitate wound healing research and development. METHODS: On forearms of 8 healthy adult volunteers, freeze injuries were induced using liquid nitrogen spray delivered onto a target area of a 1 cm circular opening at a distance from the cryo-device to the skin of 0.5-1 cm. Several freeze-thaw time cycles were implemented by administering pulses ranging from 3 to 12 seconds. Clinical evaluation was performed at a 24-hour follow-up period. Blister roofs were histologically analyzed by a blinded dermatophathologist. Clinical assessment of time to heal was determined. RESULTS: Freeze-times greater than 5 seconds caused a majority of subjects to develop blisters, and freeze-times greater than 8 seconds resulted in uniform blister formation. Consistent histology of full thickness necrotic epidermis with intact detached basement membrane with minimal acute neutrophilic inflammatory infiltrate was observed in all blister specimens examined. The 8-second freeze-time group had a time to heal of 13-14 days, while the 12-second freeze-time group required 3 weeks to heal. After healing, an area of hypopigmented skin and slightly hypertrophic scarring remained. DISCUSSION: This novel cryo-induced wound model is a potential simple, efficient and reliable model for studying the dynamic processes involved in acute wound healing and to aid in the development of new wound healing therapies. Clinicaltrials.gov identifier: NCT01253135.

Estrogen prevents cardiac and vascular failure in the 'listless' zebrafish (Danio rerio) developmental model.

The presence of a robust estrogen (E2) response system throughout heart and blood vessel tissues of vertebrates, including humans, has led to the speculation that this ubiquitous hormone may play a prominent role in the health and maintenance of the adult cardiovascular system (CVS). We previously established an embryonic zebrafish model called 'listless', which results from the inhibition of E2 synthesis by treatment with aromatase enzyme inhibitors (AI). These fish have outward symptoms similar to the human condition of congestive heart failure and tamponade. E2 replacement therapy (1) reduced the severity of cardiac sac abnormalities, (2) protected heart function, (3) prevented reduction in heart size, and (4) reduced blood vessel deterioration. Nitric oxide may be a critical downstream mediator of these events. We also demonstrate that removal of fluid around the heart increases survival of AI-treated fish. These results strongly indicate the importance of E2 in the developing CVS of the zebrafish and offer a potential model for the study of its role in CVS development, maintenance, and disease conditions.

Evidence-based best practice advice for patients treated with systemic immunosuppressants in relation to COVID-19.

The emergence of the COVID-19 pandemic has led to significant uncertainty among physicians and patients about the safety of immunosuppressive medications used for the management of dermatologic conditions. We review available data on commonly used immunosuppressants and their effect on viral infections beyond COVID-19. Notably, the effect of some immunosuppressants on viruses related to SARS-CoV2, including SARS and MERS, has been previously investigated. In the absence of data on the effect of immunosuppressants on COVID-19, these data could be used to make clinical decisions on initiation and continuation of immunosuppressive medications during this pandemic. In summary, we recommend considering the discontinuation of oral Janus kinase (JAK) inhibitors and prednisone; considering the delay of rituximab infusion; and suggesting the careful continuation of cyclosporine, mycophenolate, azathioprine, methotrexate, and biologics in patients currently benefitting from such treatments.

Denial of Illness in a Patient with Infiltrative Basal Cell Carcinoma.

A 73-year-old Caucasian man presented with a pink, pearly papule anterior to his right ear. He was a well-educated, retired stockbroker. Biopsy revealed an infiltrating basal cell carcinoma (BCC). The dermatologist repeatedly attempted to contact the patient encouraging treatment. After ignoring calls and letters, he was lost to contact with dermatology for 10 years. In the interim, the patient presented to the emergency room after discovering maggots in his ear. He subsequently consulted a head and neck surgeon but refused the recommended surgical excision. Although still operable, by this time the patient had developed significant erosion (Figure 1), nerve damage with loss of taste, facial muscle control, and hearing loss. One year after surgical consultation, he returned to dermatology due to ear discharge and pain while chewing. Multiple clinicians urged him to reconsider surgery. The patient stated that he had avoided treatment for the previous 10 years, because he had felt "stronger than the cancer." He had been convinced that cancer "can't hurt me." Despite this, he conceded that denying treatments earlier was "probably the worst decision of my life." By then the cancer was inoperable and required chemotherapy. The patient again refused treatment and later expired.