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1.
Annu Rev Neurosci ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33556251

RESUMO

During the approximately 5 days of Drosophila neurogenesis (late embryogenesis to the beginning of pupation), a limited number of neural stem cells produce approximately 200,000 neurons comprising hundreds of cell types. To build a functional nervous system, neuronal types need to be produced in the proper places, appropriate numbers, and correct times. We discuss how neural stem cells (neuroblasts) obtain so-called area codes for their positions in the nervous system (spatial patterning) and how they keep time to sequentially produce neurons with unique fates (temporal patterning). We focus on specific examples that demonstrate how a relatively simple patterning system (Notch) can be used reiteratively to generate different neuronal types. We also speculate on how different modes of temporal patterning that operate over short versus long time periods might be linked. We end by discussing how specification programs are integrated and lead to the terminal features of different neuronal types. Expected final online publication date for the Annual Review of Neuroscience, Volume 44 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

3.
J Cutan Pathol ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33576022

RESUMO

BACKGROUND: Novel solutions are needed for expediting margin assessment to guide BCC surgeries. Ex-vivo fluorescence confocal microscopy (FCM) is starting to be used in freshly-excised surgical specimens to examine BCC margins in real-time. Training and educational process are needed for this novel technology to be implemented into clinic. OBJECTIVE: To test a training and reading process, and measure diagnostic accuracy of clinicians with varying expertise level in reading ex-vivo FCM images. METHODS: An international 3-center study was designed for training and reading to assess BCC surgical margins and residual subtypes. Each center included a lead dermatologic/Mohs surgeon (clinical developer of FCM), and 3 additional readers (dermatologist, dermatopathologist, dermatologic/Mohs surgeon), who use confocal in clinical practice. Testing was conducted on 30 samples. RESULTS: Overall, the readers achieved 90% average sensitivity, 78% average specificity in detecting residual BCC margins, showing high and consistent diagnostic reading accuracy. Those with expertise in dermatologic surgery and dermatopathology showed the strongest potential for learning to assess FCM images. LIMITATIONS: Small dataset, variability in mosaic quality between centers. CONCLUSION: Suggested process is feasible and effective. This process is proposed for wider implementation, to facilitate wider adoption of FCM to potentially expedite BCC margin assessment to guide surgery in real-time. This article is protected by copyright. All rights reserved.

4.
Dermatol Surg ; 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33625139

RESUMO

BACKGROUND: Extramammary Paget disease (EMPD) poses treatment challenges. Invasive and noninvasive treatment modalities exist with variable success reported. Reflectance confocal microscopy (RCM) is emerging as an adjuvant diagnostic tool. OBJECTIVE: To evaluate the treatment of EMPD patients and the role of RCM. METHODS: Prospective study. Demographic and tumor characteristics were recorded. Handheld-RCM was performed and correlated with histology. Treatment, clearance, pathology, and follow-up were all recorded. RESULTS: Thirty-six EMPD lesions in 33 patients were included. Mean age was 71.7 years, and 23 were men. Mean number of surgical stages needed to clear margins was 1.9 (SD, 0.9; 1.0-3.0 stages), and mean margin needed to clear was 1.8 cm. Reflectance confocal microscopy correlated well with scouting punch biopsies (kappa, 0.93; p < .001). Disruption of the dermoepidermal junction was associated with invasive EMPD versus in situ (83.3% vs 25.9%) on histology (p = .01). LIMITATIONS: Relatively small sample size. CONCLUSION: Extramammary Paget disease is challenging, and lesion demarcation is of the utmost importance. Using a staged surgical excision approach, the mean margins needed were 1.8 cm, less than previously reported. Nonsurgical modalities, including radiation therapy, imiquimod, or photodynamic therapy can be considered if surgery is not pursued. Reflectance confocal microscopy is a valuable noninvasive imaging modality for the management of EMPD.

6.
J Am Acad Dermatol ; 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33497750

RESUMO

Cutaneous surgery has become critical to comprehensive dermatologic care, and dermatologists must therefore be equipped to manage the risks associated with surgical procedures. As complications may occur at any point along the continuum of care, assessing, managing and preventing risk from beginning to end becomes essential. This review focuses on preventing surgical complications pre- and post-operatively as well as during the surgical procedure.

9.
J Biophotonics ; : e202000207, 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33314673

RESUMO

We investigated the utility of the fluorescent dye Deep Red Anthraquinone 5 (DRAQ5) for digital staining of optically sectioned skin in comparison to acridine orange (AO). Eight fresh-frozen thawed Mohs discard tissue specimens were stained with AO and DRAQ5, and imaged using an ex vivo confocal microscope at three wavelengths (488 nm and 638 nm for fluorescence, 785 nm for reflectance). Images were overlaid (AO + Reflectance, DRAQ5 + Reflectance), digitally stained, and evaluated by three investigators for perceived image quality (PIQ) and histopathological feature identification. In addition to nuclear staining, AO seemed to stain dermal fibers in a subset of cases in digitally stained images, while DRAQ5 staining was more specific to nuclei. Blinded evaluation showed substantial agreement, favoring DRAQ5 for PIQ (82%, Cl 75%-90%, Gwet's AC 0.74) and for visualization of histopathological features in (81%, Cl 73%-89%, Gwet's AC 0.67), supporting its use in digital staining of multimodal confocal micrographs of skin.

11.
J Am Acad Dermatol ; 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33096134

RESUMO

BACKGROUND: There are no well-defined clinical factors to predict the risk of occult invasion in melanoma of the lentigo maligna type (LM) prior to complete histopathologic analysis. OBJECTIVE: To evaluate whether clinical size was a predictor of invasion in LM and subclinical extension. METHODS: Consecutive cases of LM were recorded in a prospectively maintained database from 2006 to 2019. Patient and tumor data were recorded during initial evaluation. 'LM clinical area' was calculated in square millimeters (length x width). All patients were treated with staged excision. RESULTS: We included 600 patients. Mean age was 65.9 years (SD 12.3; range 27 - 95 years); 62.8% (n=377) were males. The mean LM clinical area was 128.32 mm2 for in situ lesions vs 200.14 mm for invasive lesions (p=0.1). Based on quantile regression, the median margin required for complete removal increased with LM clinical area. LIMITATIONS: study performed in a tertiary cancer center with possible referral bias and more complex cases. CONCLUSIONS: LM can present with variable clinical size which may correlate with subclinical extension; however, the presence of invasion is not well estimated by LM clinical area.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33015527

RESUMO

PURPOSE: To identify genomic alterations as potential therapeutic targets in extramammary Paget disease (EMPD) of the vulva. METHODS: We identified all patients with primary vulvar EMPD who were treated at our institution and underwent paired tumor-normal massively parallel sequencing of 410-468 cancer-related genes (MSK-IMPACT assay). EMPD of the vulva samples sequenced from 2014 to 2019 were reviewed and somatic mutations identified, with specific focus on mutations of potential therapeutic targets. Clinical data were abstracted from electronic medical records. Microsatellite instability (MSI) was assessed by MSIscore. RESULTS: Tumors of 26 patients with EMPD underwent genomic sequencing. At diagnosis, all patients had noninvasive or microinvasive (< 1 mm) disease; invasive disease eventually developed in 2 patients. Primary treatment was surgery for 19 patients (73%) and imiquimod topical therapy for 7 (27%). Seven patients had ≥ 2 surgeries as part of clinical course (1 patient had 5 vulvar resections). Samples had a median of 2 coding mutations in the genes analyzed (range, 0-29). The most common mutations were in PIK3CA (n = 9; 35%), ERBB2 (4 mutations and 3 copy number alterations; 27%), and TP53 (n = 7; 27%). MSIscore was available for 23 samples; all were microsatellite stable. After tumor genomic profiling, a patient who was initially treated with multiple resections and imiquimod was found to have a PIK3CA p.E542K mutation. She underwent PI3K-inhibitor treatment for 18 months before disease progression. CONCLUSION: EMPD of the vulva has a chronic and relapsing course, often requiring multiple surgical resections. Effective topical treatments are lacking. We identified targetable mutations (PIK3CA or ERBB2) in > 25% of a real-world clinical cohort. Additional prospective research implementing targetable therapies for EMPD treatment is warranted.

13.
J Cell Sci ; 133(18)2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32878942

RESUMO

Cellular polarization underlies many facets of cell behavior, including cell growth. The rod-shaped fission yeast Schizosaccharomyces pombe is a well-established, genetically tractable system for studying growth polarity regulation. S. pombe cells elongate at their two cell tips in a cell cycle-controlled manner, transitioning from monopolar to bipolar growth in interphase when new ends established by the most recent cell division begin to extend. We previously identified cytokinesis as a critical regulator of new end growth and demonstrated that Fic1, a cytokinetic factor, is required for normal polarized growth at new ends. Here, we report that Fic1 is phosphorylated on two C-terminal residues, which are each targeted by multiple protein kinases. Endogenously expressed Fic1 phosphomutants cannot support proper bipolar growth, and the resultant defects facilitate the switch into an invasive pseudohyphal state. Thus, phosphoregulation of Fic1 links the completion of cytokinesis to the re-establishment of polarized growth in the next cell cycle. These findings broaden the scope of signaling events that contribute to regulating S. pombe growth polarity, underscoring that cytokinetic factors constitute relevant targets of kinases affecting new end growth.This article has an associated First Person interview with Anthony M. Rossi, joint first author of the paper.

14.
J Cutan Pathol ; 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32989842

RESUMO

BACKGROUND: Accurate basal cell carcinoma (BCC) subtyping is requisite for appropriate management, but non-representative sampling occurs in 18% to 25% of biopsies. By enabling non-invasive diagnosis and more comprehensive sampling, integrated reflectance confocal microscopy-optical coherence tomography (RCM-OCT) may improve the accuracy of BCC subtyping and subsequent management. We evaluated RCM-OCT images and histopathology slides for the presence of two key features, angulation and small nests and cords, and calculated (a) sensitivity and specificity of these features, combined and individually, for identifying an infiltrative BCC subtype and (b) agreement across modalities. METHODS: Thirty-three RCM-OCT-imaged, histopathologically-proven BCCs (17 superficial and/or nodular; 16 containing an infiltrative component) were evaluated. RESULTS: The presence of angulation or small nests and cords was sufficient to identify infiltrative BCC on RCM-OCT with 100% sensitivity and 82% specificity, similar to histopathology (100% sensitivity, 88% specificity, kappa = 0.82). When both features were present, the sensitivity for identifying infiltrative BCC was 100% using either modality and specificity was 88% on RCM-OCT vs 94% on histopathology, indicating near-perfect agreement between non-invasive and invasive diagnostic modalities (kappa = 0.94). CONCLUSIONS: RCM-OCT can non-invasively identify key histopathologic features of infiltrative BCC offering a possible alternative to traditional invasive biopsy.

16.
Arch Dermatol Res ; 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32886149

RESUMO

Squamous cell carcinoma in situ (SCCIS) of the nail unit is a complex malignancy; with little understanding of rate of upstaging or occult invasion in these patients. We sought to evaluate the rate of upstaging in nail unit SCCIS after Mohs micrographic surgery (MMS). Retrospective review of 346 patients who referred for and underwent MMS for biopsy proven SCCIS on the hands and feet between January 1, 2000 and December 30, 2019. Only cases in the nail unit were included. Clinical, surgical details, histopathological features, HPV status, and rate of upstaging were recorded. Thirty-one cases met the inclusion criteria and were analyzed. Twenty-four patients were males (77.4%). The mean age was 55 years (SD 17.26, range 27-84). The mean clinical size was 9.9 mm; 19 cases tested for HPV, 15/19 were positive (78.9%), and 8/19 (42.1%) were associated with high-risk HPV. Three patients (9.7%) were upstaged to invasive on either MMS margins or tumor debulking. Limitations included a relatively small sample size and retrospective in nature. The rate of upstaging of SCCIS in the nail unit is not frequent, and when upstaging occurred it was focal, superficial, and with no PNI or bone invasion.

17.
J Am Acad Dermatol ; 2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32827607

RESUMO

BACKGROUND: Radiation therapy (RT) is a treatment option for selected skin cancers. The histologic effects of RT on normal skin or skin cancers are not well-characterized. Dermoscopy, high frequency ultrasonography (HFUS), and reflectance confocal microscopy (RCM) are non-invasive imaging modalities that may help characterize RT response. OBJECTIVES: To describe changes in the tumor and surrounding skin of basal cell carcinoma (BCC) patients treated with RT. METHODS: The study was conducted between 2014-2018. Patients with biopsy-proven BCCs were treated with 42 Gy in 6 fractions using a commercially available brachytherapy device. Dermoscopy, HFUS, RCM were performed before treatment, 6 weeks, 3 months and 12 months after RT. RESULTS: 137 imaging assessments (RCM + dermoscopy + HFUS) were performed in 12 patients. Presence of BCC-specific features were present in 81.8%, 91% and 17% of patients imaged with dermoscopy, RCM and HFUS at baseline, prior to treatment. After treatment, resolution of these features was noted in 33.4%, 91.7%, and 100% of patients imaged with the respective modalities. No recurrences were seen after 31.7 months mean follow-up. LIMITATIONS: Small sample size and no histopathological correlation. CONCLUSION: Dermoscopy and HFUS were not as reliable as RCM at characterizing BCCs RT response.

18.
J Am Acad Dermatol ; 2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32781177

RESUMO

Long-term survival of cancer patients has risen dramatically during the last few decades. Despite this remarkable success, the same treatments that have enabled cure or remission often secondarily affect the skin, hair, and nails. Conditions including scarring, striae distensae, persistent alopecia, pigmentary changes, nail alterations, chronic radiation dermatitis, and radiation fibrosis have been associated with anxiety, depression, decreased quality of life, and impaired function. These dermatologic changes are cosmetically disfiguring, may limit activities, and are a visual reminder of past illness. Interventions towards improving these untoward sequelae and restoring the appearance and function of skin and appendages are critical for normalization and may contribute to improved quality of life in cancer survivors. Herein, we outline dermatologic sequelae of cancer therapies with a review of medical and procedural treatment strategies to restore dermatologic health in the survivorship population.

19.
Elife ; 92020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32628110

RESUMO

Temporal patterning of neural progenitors leads to the sequential production of diverse neurons. To understand how extrinsic cues influence intrinsic temporal programs, we studied Drosophila mushroom body progenitors (neuroblasts) that sequentially produce only three neuronal types: γ, then α'ß', followed by αß. Opposing gradients of two RNA-binding proteins Imp and Syp comprise the intrinsic temporal program. Extrinsic activin signaling regulates the production of α'ß' neurons but whether it affects the intrinsic temporal program was not known. We show that the activin ligand Myoglianin from glia regulates the temporal factor Imp in mushroom body neuroblasts. Neuroblasts missing the activin receptor Baboon have a delayed intrinsic program as Imp is higher than normal during the α'ß' temporal window, causing the loss of α'ß' neurons, a decrease in αß neurons, and a likely increase in γ neurons, without affecting the overall number of neurons produced. Our results illustrate that an extrinsic cue modifies an intrinsic temporal program to increase neuronal diversity.

20.
Dermatol Online J ; 26(3)2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32609441

RESUMO

The expanding role of social media in medical care has resulted in dermatology patients seeking support online regarding personal experience with diagnosis and treatment of skin cancer. Owing to increased privacy settings in closed Facebook groups, the current study analyzed themes of keratinocyte carcinoma patients' posts within a relatively private social media network. Although the majority of messages included sharing personal experience and provided psychosocial support (50%), there were a significant number of posts offering medical advice (35%), with the majority of such replies being unsupported by evidence-based medicine (87%). The level of medical misinformation and potential harm to patients seeking advice online is important for medical practitioners treating skin cancer and provides impetus for possible further research into online support and education groups that are moderated for misinformation.


Assuntos
Informação de Saúde ao Consumidor , Disseminação de Informação/métodos , Educação de Pacientes como Assunto/métodos , Grupos de Autoajuda , Neoplasias Cutâneas , Mídias Sociais , Comunicação , Medicina Baseada em Evidências , Humanos , Apoio Social
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