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Some delay patterns are correlated to historical performance and can reflect the trend of delays in future flights. A typical example is the delay from an earlier inbound flight causing delayed departure of a connecting and downstream outbound flight. Specifically, if an arriving aircraft arrives late, the connecting airline may decide to wait for connecting passengers. Due to the consistent flow of passengers to various destinations during a travel season, similar delay patterns could occur in future days/weeks. Airlines may analyze such trends days or weeks before flights to anticipate future delays and redistribute resources with different priorities to serve those outbound flights that are likely to be affected by feeder delays. In this study, we use a hybrid recurrent neural network (RNN) model to estimate delays and project their impacts on downstream flights. The proposed model integrates a gated recurrent unit (GRU) model to capture the historical trend and a dense layer to capture the short-term dependency between arrival and departure delays, and, then, integrates information from both branches using a second GRU model. We trained and tuned the model with data from nine airports in North, Central, and South America. The proposed model outperformed alternate approaches with traditional structures in the testing phase. Most of the predicted delay of the proposed model were within the predefined 95% confidence interval. Finally, to provide operational benefits to airline managers, our analysis measured the future impact of a potentially delayed inbound feeder, (PDIF) in a case study, by means of identifying the outbound flights which might be affected based on their available connection times (ACTs). From an economic perspective, the proposed algorithm offers potential cost savings for airlines to prevent or minimize the impact of delays.

In this paper, we study the flow of signals through linear paths with the nonlinear condition that a node emits a signal when it receives external stimuli or when two incoming signals from other nodes arrive coincidentally with a combined amplitude above a fixed threshold. Sets of such nodes form a polychrony group and can sometimes lead to cascades. In the context of this work, cascades are polychrony groups in which the number of nodes activated as a consequence of other nodes is greater than the number of externally activated nodes. The difference between these two numbers is the so-called profit. Given the initial conditions, we predict the conditions for a vertex to activate at a prescribed time and provide an algorithm to efficiently reconstruct a cascade. We develop a dictionary between polychrony groups and graph theory. We call the graph corresponding to a cascade a chinampa. This link leads to a topological classification of chinampas. We enumerate the chinampas of profits zero and one and the description of a family of chinampas isomorphic to a family of partially ordered sets, which implies that the enumeration problem of this family is equivalent to computing the Stanley-order polynomials of those partially ordered sets.

Numerical modeling of physical phenomena frequently involves processes across a wide range of spatial and temporal scales. In the last two decades, the advancements in wavelet-based numerical methodologies to solve partial differential equations, combined with the unique properties of wavelet analysis to resolve localized structures of the solution on dynamically adaptive computational meshes, make it feasible to perform large-scale numerical simulations of a variety of physical systems on a dynamically adaptive computational mesh that changes both in space and time. Volumetric visualization of the solution is an essential part of scientific computing, yet the existing volumetric visualization techniques do not take full advantage of multi-resolution wavelet analysis and are not fully tailored for visualization of a compressed solution on the wavelet-based adaptive computational mesh. Our objective is to explore the alternatives for the visualization of time-dependent data on space-time varying adaptive mesh using volume rendering while capitalizing on the available sparse data representation. Two alternative formulations are explored. The first one is based on volumetric ray casting of multi-scale datasets in wavelet space. Rather than working with the wavelets at the finest possible resolution, a partial inverse wavelet transform is performed as a preprocessing step to obtain scaling functions on a uniform grid at a user-prescribed resolution. As a result, a solution in physical space is represented by a superposition of scaling functions on a coarse regular grid and wavelets on an adaptive mesh. An efficient and accurate ray casting algorithm is based just on these coarse scaling functions. Additional details are added during the ray tracing by taking an appropriate number of wavelets into account based on support overlap with the interpolation point, wavelet coefficient magnitude, and other characteristics, such as opacity accumulation (front to back ordering) and deviation from frontal viewing direction. The second approach is based on complementing of wavelet-based adaptive mesh to the traditional Adaptive Mesh Refinement (AMR) mesh. Both algorithms are illustrated and compared to the existing volume visualization software for Rayleigh-Benard thermal convection and electron density data sets in terms of rendering time and visual quality for different data compression of both wavelet-based and AMR adaptive meshes.

Intracellular Ca2+ dynamics in astrocytes can be triggered by neuronal activity and in turn regulate a variety of downstream processes that modulate neuronal function. In this fashion, astrocytic Ca2+ signaling is regarded as a processor of neural network activity by means of complex spatial and temporal Ca2+ dynamics. Accordingly, a key step is to understand how different patterns of neural activity translate into spatiotemporal dynamics of intracellular Ca2+ in astrocytes. Here, we introduce a minimal compartmental model for astrocytes that can qualitatively reproduce essential hierarchical features of spatiotemporal Ca2+ dynamics in astrocytes. We find that the rate of neuronal firing determines the rate of Ca2+ spikes in single individual processes as well as in the soma of the cell, while correlations of incoming neuronal activity are important in determining the rate of “global” Ca2+ spikes that can engulf soma and the majority of processes. Significantly, our model predicts that whether the endoplasmic reticulum is shared between soma and processes or not determines the relationship between the firing rate of somatic Ca2+ events and the rate of neural network activity. Together these results provide intuition about how neural activity in combination with inherent cellular properties shapes spatiotemporal astrocytic Ca2+ dynamics, and provide experimentally testable predictions.

Fungal infections have dramatically increased in the last decades in parallel with an increase of populations with impaired immunity, resulting from medical conditions such as cancer, transplantation or other chronic diseases. Such opportunistic infections result from a complex relationship between fungi and host, and can range from self-limiting to chronic or life-threatening infections. Modern medicine, characterized by a wide use of biomedical devices, offers new niches for fungi to colonize and form biofilm communities. The capability of fungi to form biofilms is well documented and associated with increased drug tolerance and resistance. In addition, biofilm formation facilitates persistence in the host promoting a persistent inflammatory condition. With a limited availability of antifungals within our arsenal, new therapeutic approaches able to address both host and pathogenic factors that promote fungal disease progression, i.e. chronic inflammation and biofilm-formation, could represent an advantage in the clinical setting. In this paper we discuss the antifungal properties of Myriocin, Fulvic Acid and Acetylcholine in light of their already known anti-inflammatory activity and as candidate dual action therapeutics to treat opportunistic fungal infections.

In this paper, we study the linear differential equation $$ frac{dx}{dt}=sum_{i=1}^n a_i(t) x b_i(t) + f(t) $$ in an associative but non-commutative algebra $mathcal{A}$, where the $b_i(t)$ form a set of commuting $mathcal{A}$-valued functions expressed in a time-independent spectral basis consisting of mutually annihilating idempotents and nilpotents. Explicit new closed solutions are derived, and examples are presented to illustrate the theory.

Candida albicans forms oral biofilms that cause disease and are difficult to treat with conventional antifungal agents. Tea tree oil (TTO) is a natural compound with reported antimicrobial and immunomodulatory activities. The aims of the study were to evaluate the antifungal efficacy of TTO and key derivatives against C. albicans biofilms, to assess the toxicological effects of TTO on a clinically relevant oral cell line, and to investigate its impact on inflammation. TTO and its derivatives were examined against 100 clinical strains of C. albicans. Planktonic minimum inhibitory concentrations (MICs) were determined using the CLSI M-27A broth microdilution method. Sessile MICs were determined using an XTT reduction assay. Inhibition, time-kill and mode of action studies were performed. OKF6-TERT2 epithelial cells were used for cytotoxicity and cytokine expression assays. Planktonic C. albicans isolates were susceptible to TTO, terpinen-4-ol (T-4-ol) and α-terpineol, with an MIC50 of 0.5, 0.25 and 0.25%, respectively. These three compounds also displayed potent activity against the 69 biofilm-forming strains, of which T-4-ol and α-terpineol displayed rapid kill kinetics. For all three compounds, 1 × MIC50 effectively inhibited biofilm growth when C. albicans were treated at 0, 1 and 2 h post adhesion. By SEM analysis and PI uptake, TTO and derivative components were cell membrane active. TTO and T-4-ol were cytotoxic at 1 × MIC50, whereas at 0.5 × MIC50 T-4-ol displayed no significant toxicity. Transcript and protein analysis showed a reduction of IL-8 when treated with TTO and T-4-ol. These data provide further in vitro evidence that TTO and its derivative components, specifically T-4-ol, exhibit strong antimicrobial properties against fungal biofilms. T-4-ol has safety advantages over the complete essential oil and may be suitable for prophylaxis and treatment of established oropharyngeal candidosis. A clinical trial of T-4-ol is worthy of consideration.

Carbohydrate derived fulvic acid (CHD-FA) is a heat stable low molecular weight, water soluble, cationic, colloidal material with proposed therapeutic properties. The aim of this study was to evaluate the antifungal activity of CHD-FA against Candida albicans, and to characterise its mode of action. A panel of C. albicans isolates (n=50) derived from a range of clinical specimens were grown planktonically and as biofilms, and the minimum inhibitory concentrations (MICs) determined. Scanning electron microscopy was performed to examine ultrastructural changes and different cell membrane assays were used to determine its mode of action. In addition, the role of C. albicans biofilm resistance mechanisms were investigated to determine their effects of CHD-FA activity. CHD-FA was active against planktonic and sessile C. albicans at concentrations 0.125% and 0.25% respectively, and was shown to be fungicidal, acting through disruption of the cell membrane activity. Resistance mechanisms, including matrix, efflux and stress, had a limited role upon CHD-FA activity. Overall, based on the promising in vitro spectrum of activity and minimal biofilm resistance of the natural and cheap antiseptic CHD-FA, further studies are required to determine its applicability for clinical use.

Abstract Racemic albuterol is an equimolar mixture of two isomers, (R) and (S). Whether (R) and (S) isomers and the combination of both exert different effects in immune activation is not well defined. We analyzed the effects of (R+S)-albuterol, (R)-albuterol and (S)-albuterol in a murine model of allergic pulmonary inflammation and in activated T cells. Mice (C57BL/6) sensitized and aerosol challenged with the allergen ovalbumin (OVA) or phosphate buffered saline (PBS) were treated with (R)-albuterol, (S)-albuterol or (R+S)-albuterol. Following administration of (R)-albuterol, allergen induced bronchoalveolar lavage eosinophils and IgE showed a decrease, albeit not significantly by ANOVA. As T cells are important in allergic inflammation, we asked whether (R+S), (R) or (S)-albuterol might differ in effects on T cells and on the activity of the inflammatory transcription factor NF-κB. In activated T cells, (R)-albuterol administration decreased levels of inflammatory cytokines and NF-κB activity. These studies suggest that (R)-albuterol decreases cytokine secretion and NF-κB activity in T cells.

The etiology of CTCL is a subject of extensive investigation. Researchers have explored links between CTCL and environmental chemical exposures, such as aromatic hydrocarbons (eg, pesticides and benzene), as well as infectious factors, including various viruses (eg, human T-lymphotropic virus [HTLV]-I and HTLV-II) and bacteria (eg, Staphylococcus aureus). There has been growing emphasis on the role of malignant inflammation in CTCL development. In this review, we synthesize studies of environmental and infectious exposures, along with research on the aryl hydrocarbon receptor and the involvement of pathogens in disease etiology, providing insight into the pathogenesis of CTCL., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Among liposarcomas, well-differentiated liposarcoma and dedifferentiated liposarcoma are the most common. The majority of these tumors are found in deep retroperitoneum or extremities. When found outside the retroperitoneum, these adipose-derived tumors are known as atypical lipomatous tumors (ALT). Superficial ALT are particularly rare; thus, little is known about their clinical presentation, genomic status, and management. Here, we present the case of a 54-year-old man with an intermittently bothersome, slowly growing mass on his left upper back for over 2 years, which was incidentally diagnosed as ALT. This patient's ALT, however, showed a profound degree of pleomorphism with MDM2 and control centromere 12 (CEP12) coamplification and negative CD34 and S100 and RB1 expression, unlike most other ALT described in the literature. This case report details the diagnostic workup and histopathological findings for adipose tumors and summarizes the different subtypes, including atypical spindle cell/pleomorphic lipomatous tumor, pleomorphic liposarcoma, and spindle cell/pleomorphic lipoma, with brief discussion on management., Competing Interests: L. J. Geskin has served as an investigator for and/or received research support from Helsinn Group, J&J, Mallinckrodt, Kyowa Kirin, Soligenix, Innate, Merck, BMS, and Stratpharma; on the speakers' bureau for Helsinn Group and J&J; and on the scientific advisory board for Helsinn Group, J&J, Mallinckrodt, Sanofi, Regeneron, and Kyowa Kirin. O. Adeuyan, E. R. Gordon, B. A. Lapolla, C. M. Schreidah, V. Jobanputra and A. A. Gru have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Conflicts of interest Dr LJG has served as an investigator for and/or received research support from Helsinn Group, J&J, Mallinckrodt, Kyowa Kirin, Soligenix, Innate, Incyte, Trillium, Merck, BMS, and Stratpharma; on the speakers’ bureau for Mallinckrodt and Recordati; and on the scientific advisory board for SciTech and Celsyntec. The other authors have no disclosures.

There are no established maintenance protocols for cutaneous lymphomas. We aim to determine patient treatments and outcomes during the COVID-19 pandemic in order to uncover the most effective maintenance protocols for cutaneous lymphomas and impact of treatment interruption. Data was collected retrospectively from nine international institutions, including 149 patients. Younger patients had earlier stages of disease and were most frequently treated with skin-directed therapies including topical steroids, mechlorethamine gel, and phototherapy. Treatment interruption varied by treatment type and stage, with patients on topical therapies and earlier stages of disease being least likely to experience interruption. Treatment interruption was significantly associated with progression of disease and worse outcomes, with twice as many patients progressing who had interruption compared to those without interruption. This study may demonstrate the significance of continuous maintenance therapies, even in younger patients with early stages of disease.

Monoclonal Gammopathy of Undetermined Significance (MGUS) is a clonal plasma cell disorder that is considered preneoplastic, asymptomatic, and only requiring observation. However, MGUS may result in cutaneous complications, which are poorly understood, causing treatment delays and patient suffering. We present 30 patients with cutaneous findings associated with MGUS, characterizing clinical presentations, isoforms, treatments, and outcomes. These included: MGUS-associated 'rashes' (pruritic eczematous rashes), reactive and mucin-depositional conditions (pyoderma gangrenosum, scleromyxedema), M-protein-related deposition disorders (POEMS syndrome, Waldenstrom macroglobulinemia), and cutaneous lymphomas. Twelve of 30 (40%) patients received multiple myeloma drugs (MMDs). Eleven (92%) patients improved, and those not receiving MMDs rarely improved, suggesting that MMDs have efficacy for cutaneous manifestations of MGUS. Therefore, trialing MMDs may be warranted for patients with MGUS not responding to other therapies. Moreover, evaluation for monoclonal gammopathy in elderly patients with intractable pruritus or other chronic skin conditions that are non-responsive to skin-directed therapies should be considered.

Competing Interests: Conflicts of interest Dr Geskin has served as an investigator for and/or received research support from Helsinn Group, J&J, Mallinckrodt, Kyowa Kirin, Soligenix, Innate, Merck, BMS, and Stratpharma; on the speakers' bureau for Helsinn Group and J&J; and on the scientific advisory board for Helsinn Group, J&J, Mallinckrodt, Sanofi, Regeneron, and Kyowa Kirin. Authors Gordon, Chen, Adeuyan, and Lapolla; Dr Trager; Authors Fahmy and Schreidah; and Dr Wetter have no conflicts of interest to declare.

Nonmelanoma skin cancers (NMSCs) are among the top five most common cancers globally. NMSC is an area with great potential for novel application of diagnostic tools including artificial intelligence (AI). In this scoping review, we aimed to describe the applications of AI in the diagnosis and treatment of NMSC. Twenty-nine publications described AI applications to dermatopathology including lesion classification and margin assessment. Twenty-five publications discussed AI use in clinical image analysis, showing that algorithms are not superior to dermatologists and may rely on unbalanced, nonrepresentative, and nontransparent training data sets. Sixteen publications described the use of AI in cutaneous surgery for NMSC including use in margin assessment during excisions and Mohs surgery, as well as predicting procedural complexity. Eleven publications discussed spectroscopy, confocal microscopy, thermography, and the AI algorithms that analyze and interpret their data. Ten publications pertained to AI applications for the discovery and use of NMSC biomarkers. Eight publications discussed the use of smartphones and AI, specifically how they enable clinicians and patients to have increased access to instant dermatologic assessments but with varying accuracies. Five publications discussed large language models and NMSC, including how they may facilitate or hinder patient education and medical decision-making. Three publications pertaining to the skin of color and AI for NMSC discussed concerns regarding limited diverse data sets for the training of convolutional neural networks. AI demonstrates tremendous potential to improve diagnosis, patient and clinician education, and management of NMSC. Despite excitement regarding AI, data sets are often not transparently reported, may include low-quality images, and may not include diverse skin types, limiting generalizability. AI may serve as a tool to increase access to dermatology services for patients in rural areas and save health care dollars. These benefits can only be achieved, however, with consideration of potential ethical costs., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: None disclosed.

Objective: Automated identification of eligible patients is a bottleneck of clinical research. We propose Criteria2Query (C2Q) 3.0, a system that leverages GPT-4 for the semi-automatic transformation of clinical trial eligibility criteria text into executable clinical database queries., Materials and Methods: C2Q 3.0 integrated three GPT-4 prompts for concept extraction, SQL query generation, and reasoning. Each prompt was designed and evaluated separately. The concept extraction prompt was benchmarked against manual annotations from 20 clinical trials by two evaluators, who later also measured SQL generation accuracy and identified errors in GPT-generated SQL queries from 5 clinical trials. The reasoning prompt was assessed by three evaluators on four metrics: readability, correctness, coherence, and usefulness, using corrected SQL queries and an open-ended feedback questionnaire., Results: Out of 518 concepts from 20 clinical trials, GPT-4 achieved an F1-score of 0.891 in concept extraction. For SQL generation, 29 errors spanning seven categories were detected, with logic errors being the most common (n = 10; 34.48 %). Reasoning evaluations yielded a high coherence rating, with the mean score being 4.70 but relatively lower readability, with a mean of 3.95. Mean scores of correctness and usefulness were identified as 3.97 and 4.37, respectively., Conclusion: GPT-4 significantly improves the accuracy of extracting clinical trial eligibility criteria concepts in C2Q 3.0. Continued research is warranted to ensure the reliability of large language models., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cutaneous squamous cell carcinoma in-situ (SCCis) is an intraepithelial tumor with a good prognosis. Standard treatment includes both surgical and non-surgical interventions. We determined the clearance rate for SCCis and residual SCCis identified on frozen section during Mohs micrographic surgery (MMS) after treatment with topical fluorouracil 5% cream (5-FU). All MMS cases were initiated for biopsy-proven invasive squamous cell carcinoma (SCC). A retrospective chart review was conducted from January 2017-February 2024 at Columbia University Irving Medical Center (CUIMC) to identify patients with SCCis who were treated with topical 5-FU as primary therapy or adjuvant therapy (AT) for residual SCCis post-MMS for invasive SCC. 41 patients were included (80% males, 70.1 ± 11.8 years). The average follow-up time for the primary therapy group was 25.4 ± 12.8 months, and for the post-MMS AT group 22.5 ± 11.1 months. In the group treated with topical 5-FU as primary therapy (n = 28), 27 patients (96.43%, 95% confidence interval: 81.65-99.91%) achieved complete clearance. One patient had recurrence at 8 months post-treatment. Of the patients in the post-MMS adjuvant treatment group (n = 13), 12 (92.3% clearance, 95% confidence interval 63.97-99.81%) achieved complete clearance. One patient had recurrence at 8 months post-treatment. This study found that topical 5-FU cream is effective as both primary therapy for SCCis and as adjuvant therapy for residual SCCis following MMS of invasive SCC., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The field of dermatology is experiencing the rapid deployment of artificial intelligence (AI), from mobile applications (apps) for skin cancer detection to large language models like ChatGPT that can answer generalist or specialist questions about skin diagnoses. With these new applications, ethical concerns have emerged. In this scoping review, we aimed to identify the applications of AI to the field of dermatology and to understand their ethical implications. We used a multifaceted search approach, searching PubMed, MEDLINE, Cochrane Library and Google Scholar for primary literature, following the PRISMA Extension for Scoping Reviews guidance. Our advanced query included terms related to dermatology, AI and ethical considerations. Our search yielded 202 papers. After initial screening, 68 studies were included. Thirty-two were related to clinical image analysis and raised ethical concerns for misdiagnosis, data security, privacy violations and replacement of dermatologist jobs. Seventeen discussed limited skin of colour representation in datasets leading to potential misdiagnosis in the general population. Nine articles about teledermatology raised ethical concerns, including the exacerbation of health disparities, lack of standardized regulations, informed consent for AI use and privacy challenges. Seven addressed inaccuracies in the responses of large language models. Seven examined attitudes toward and trust in AI, with most patients requesting supplemental assessment by a physician to ensure reliability and accountability. Benefits of AI integration into clinical practice include increased patient access, improved clinical decision-making, efficiency and many others. However, safeguards must be put in place to ensure the ethical application of AI., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

With an increase in number of patients on antithrombotic therapies, management of bleeding during dermatologic surgery is increasingly important. As described in Part 1, perioperative discontinuation of antithrombotic therapies may increase the risk of embolic events thus the risks and benefits must be weighed carefully when deciding whether to continue or suspend therapy. However, continuing oral anticoagulants may result in increased intraoperative and postoperative bleeding. Here we describe various methods to effectively achieve hemostasis which include: 1) mechanical methods to compress the vasculature 2) pharmacologic agents that induce vasoconstriction 3) physiologic agents that augment clot formation and 4) physical agents that promote platelet aggregation., (Copyright © 2024. Published by Elsevier Inc.)

Perioperative management of antithrombotic agents requires practical and medical considerations. Discontinuing antithrombotic therapies increases the risk of thrombotic adverse events including cerebrovascular accidents, myocardial infarction, pulmonary embolism, deep vein thrombosis, and retinal artery occlusion. Conversely, continuation of antithrombotic therapy during surgical procedures has associated bleeding risks. Currently, no guidelines exist regarding management of antithrombotic agents in the perioperative period for cutaneous surgeries and practice differs by surgeon. Here, we review the data on antithrombotic medications in patients undergoing cutaneous surgery including medication-specific surgical and postoperative bleeding risk if the medications are continued, and thromboembolic risk if the medications are interrupted. Specifically, we focus on vitamin K antagonist (VKA) (warfarin), direct-acting oral anticoagulants (DOAC) (rivaroxaban, apixaban, edoxaban, dabigatran), antiplatelet medications (aspirin, clopidogrel, prasugrel, ticagrelor, dipyridamole), unfractionated heparin, low molecular weight heparin (enoxaparin and dalteparin), fondaparinux, bruton tyrosine kinase inhibitors (BTKi) (ibrutinib, acalabrutinib), and dietary supplements (i.e., garlic, ginger, gingko)., (Copyright © 2024. Published by Elsevier Inc.)

Competing Interests: LJG has served as an investigator for and/or received research support from Helsinn Group, J&J, Mallinckrodt, Kyowa Kirin, Soligenix, Innate, Merck, BMS, and Stratpharma; on the speakers’ bureau for Helsinn Group and J&J; and on the scientific advisory board for Helsinn Group, J&J, Mallinckrodt, Sanofi, Regeneron, and Kyowa Kirin. OA, CMM, MHT, ERG, BAL, CMS and LMF have no conflicts of interest to declare.

Skin cancer mortality rates continue to rise, and survival analysis is increasingly needed to understand who is at risk and what interventions improve outcomes. However, current statistical methods are limited by inability to synthesize multiple data types, such as patient genetics, clinical history, demographics, and pathology and reveal significant multimodal relationships through predictive algorithms. Advances in computing power and data science enabled the rise of artificial intelligence (AI), which synthesizes vast amounts of data and applies algorithms that enable personalized diagnostic approaches. Here, we analyze AI methods used in skin cancer survival analysis, focusing on supervised learning, unsupervised learning, deep learning, and natural language processing. We illustrate strengths and weaknesses of these approaches with examples. Our PubMed search yielded 14 publications meeting inclusion criteria for this scoping review. Most publications focused on melanoma, particularly histopathologic interpretation with deep learning. Such concentration on a single type of skin cancer amid increasing focus on deep learning highlight growing areas for innovation; however, it also demonstrates opportunity for additional analysis that addresses other types of cutaneous malignancies and expands the scope of prognostication to combine both genetic, histopathologic, and clinical data. Moreover, researchers may leverage multiple AI methods for enhanced benefit in analyses. Expanding AI to this arena may enable improved survival analysis, targeted treatments, and outcomes., Competing Interests: LJG has served as an investigator for and/or received research support from Helsinn Group, J&J, Mallinckrodt, Kyowa Kirin, Soligenix, Innate, Incyte, Trillium, Merck, BMS, and Stratpharma; on the speakers’ bureau for Mallinckrodt and Recordati; and on the scientific advisory board for SciTech and Celsyntec. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Schreidah, Gordon, Adeuyan, Chen, Lapolla, Kent, Reynolds, Fahmy, Weng, Tatonetti, Chase, Pe’er and Geskin.)

Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory disorder, most often characterized by atrophic skin plaques located on female genitalia. Infrequently, LSA may present extragenitally; however, much is unknown about the temporal relationship between genital and extragenital LSA. Morphea, also known as localized scleroderma, is a rare inflammatory skin condition characterized by sclerotic plaques. Investigators debate whether LSA and morphea exist on the same spectrum of disease, with LSA representing a superficial variant of morphea involving genitalia, or if they are distinct but coincidental entities. Although researchers have described LSA and morphea occurring in different locations on the same patient, few reports describe LSA and morphea occurring in the same lesion and in the inguinal folds. Herein, we report a case of a 62-year-old woman with extragenital LSA-morphea overlap in the inguinal folds, who three months later developed genital LSA. Extragenital LSA-morphea in the same plaque, with no signs of genital lesions on initial exam, with later development of genital LSA, is especially uncommon. The temporal progression of extragenital LSA-morphea overlap to genital LSA over a three-month period is an important contribution to the literature, as the temporal relationship between extragenital and genital LSA is not previously discussed.

Background: Individual reports have described lymphoproliferative disorders (LPDs) and cutaneous lymphomas emerging after administration of the COVID-19 vaccine; however, the relationship between reactions and vaccine types has not yet been examined., Objective: Determine if there are cases of cutaneous LPDs associated with certain COVID-19 vaccines and their outcomes., Methods: We analysed PubMed, the Vaccine Adverse Events Reporting System (VAERS), and our database for instances of biopsy-proven LPDs following COVID-19 vaccines., Results: Fifty cases of biopsy-proven LPDs arising after COVID-19 vaccination were found: 37 from medical literature, 11 from VAERS and two from our institution. Geographical distribution revealed the most cases in the United States, Italy, and Greece, with single cases in Spain, Colombia, Canada, Japan, and Romania. The average age of patients was 53; with a slight male predominance (male-to-female ratio of 1.5:1). The Pfizer-BioNTech vaccine was associated with LPDs in 36/50 (72%) cases, aligning with its 70% share of the global vaccine market. Histopathology revealed CD30+ in 80% of cases. The most prevalent form of LPD was lymphomatoid papulosis (LyP, 30%). All reported cases produced favourable outcomes (either complete or near-complete remission). Therapeutic approaches ranged from observation to treatment with steroids, methotrexate, or excision., Conclusion: LPDs after COVID-19 vaccination appear in the context of the same vaccines (proportionally to their global market shares), share clinical and pathological findings, and have indolent, self-limited character., Competing Interests: LJG has served as an investigator for and/or received research support from Helsinn Group, J&J, Mallinckrodt, Kyowa Kirin, Soligenix, Innate, Merck, BMS, and Stratpharma; on the speakers’ bureau for Helsinn Group and J&J; and on the scientific advisory board for Helsinn Group, J&J, Mallinckrodt, Sanofi, Regeneron, and Kyowa Kirin. ERG, BDK, CMS, LMF, OA, DQ, MHT, CMM have no conflicts of interest to declare., (© 2024 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Objectives:  Large language models (LLMs) like Generative pre-trained transformer (ChatGPT) are powerful algorithms that have been shown to produce human-like text from input data. Several potential clinical applications of this technology have been proposed and evaluated by biomedical informatics experts. However, few have surveyed health care providers for their opinions about whether the technology is fit for use., Methods:  We distributed a validated mixed-methods survey to gauge practicing clinicians' comfort with LLMs for a breadth of tasks in clinical practice, research, and education, which were selected from the literature., Results:  A total of 30 clinicians fully completed the survey. Of the 23 tasks, 16 were rated positively by more than 50% of the respondents. Based on our qualitative analysis, health care providers considered LLMs to have excellent synthesis skills and efficiency. However, our respondents had concerns that LLMs could generate false information and propagate training data bias.Our survey respondents were most comfortable with scenarios that allow LLMs to function in an assistive role, like a physician extender or trainee., Conclusion:  In a mixed-methods survey of clinicians about LLM use, health care providers were encouraging of having LLMs in health care for many tasks, and especially in assistive roles. There is a need for continued human-centered development of both LLMs and artificial intelligence in general., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Competing Interests: LJG has served as an investigator for and/or received research support from Helsinn Group, J&J, Mallinckrodt, Kyowa Kirin, Soligenix, Innate, Merck, BMS, and Stratpharma; on the speakers’ bureau for Helsinn Group and J&J; and on the scientific advisory board for Helsinn Group, J&J, Mallinckrodt, Sanofi, Regeneron, and Kyowa Kirin. OA, MHT, ERG, BAL, CMS, LMF, CC and CMM have no conflicts of interest to declare.

Individual reports described lymphoproliferative disorders (LPDs) after COVID-19 vaccination; however, the relationship between cases is unexamined. We aim to determine if there are cases of cutaneous LPDs associated with COVID-19 vaccination and their outcomes. We present a review of world literature, vaccine registries, and two unreported cases of LPDs after COVID-19 vaccination. Review of the medical literature, VAERS, and our two cases reveal predominance of Pfizer-BioNTech vaccine, younger patients, and males. All cases resulted in favorable outcomes. Approximately 84% of cases demonstrated CD30+ positivity in their skin biopsies, suggesting that an antigenic trigger may lead to a type IV adaptive immune response, with clonal expansion of CD30+ T-cells and subsequent oncogenic mutational hits eventuating in transient LPDs. LPDs after COVID-19 vaccination appear in the context of the same vaccines (proportionally to their global market shares), share clinical and pathological findings, and have indolent, self-limited character.

Sphingolipid metabolism is dysregulated in many cancers, allowing cells to evade apoptosis through increased sphingosine-1-phosphate (S1P) and decreased ceramides. Ceramidases hydrolyze ceramides to sphingosine, which is phosphorylated by sphingosine kinases to generate S1P. The S1P allows cells to evade apoptosis by shifting the equilibrium away from ceramides, which favor cell death. One tumor type that exhibits a shift in the sphingolipid balance towards S1P is glioblastoma (GBM), a highly aggressive brain tumor. GBMs almost always recur despite surgical resection, radiotherapy, and chemotherapy with temozolomide (TMZ). Understanding sphingolipid metabolism in GBM is still limited, and currently, there are no approved treatments to target dysregulation of sphingolipid metabolism in GBM. Carmofur, a derivative of 5-fluorouracil, inhibits acid ceramidase (ASAH1), a key enzyme in the production of S1P, and is in use outside the USA to treat colorectal cancer. We find that the mRNA for ASAH1, but not other ceramidases, is elevated in recurrent GBM. When TMZ-resistant GBM cells were treated with carmofur, decreased cell growth and increased apoptosis were observed along with cell cycle perturbations. RNA-sequencing identified decreases in cell cycle control pathways that were specific to TMZ-resistant cells. Furthermore, the transcription factor and G1 to S phase regulator, E2F8, was upregulated in TMZ-resistant versus parental GBM cells and inhibited by carmofur treatment in TMZ-resistant GBM cells, specifically. These data suggest a possible role for E2F8 as a mediator of carmofur effects in the context of TMZ resistance. These data suggest the potential utility of normalizing the sphingolipid balance in the context of recurrent GBM., (© 2023. The Author(s).)

Introduction: Cutaneous T-cell lymphoma (CTCL) is a heterogenous group of non-Hodgkin lymphomas. Similar presentation to benign conditions, significant genetic variation, and lack of definitive biomarkers contributes to diagnostic delay. The etiology of CTCL is unknown, and environmental exposures, such as geographic, occupational, chemicals, sunlight, and insects have been investigated., Evidence Acquisition: Review of the literature for CTCL and exposures was performed in PubMed and Google Scholar in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Extension for Scoping Reviews. This search yielded 193 total results, which were initially screened with defined inclusion and exclusion criteria. The 45 remaining articles were reviewed and classified by exposure type., Evidence Synthesis: The most frequently investigated CTCL exposure type was geographic (13/45 articles, 29%). Chemical exposures were commonly discussed (10/45 articles, 22%), along with occupational (10/45 articles, 22%). Insect exposures (6/45, 13%) and sun exposure (3/45, 7%) were also reviewed, along with articles describing multiple exposure types (3/45, 7%). Article types ranged from cases to systematic reviews and case-control studies. Evidence linking CTCL and these exposures was mixed. Limitations of this investigation include reliance on patient reporting and frequent speculation on disease association versus causality., Conclusions: This investigation synthesizes the current literature on exposures potentially implicated in the pathogenesis of CTCL, while offering guidance on patient history-taking to ensure potential exposures are captured. Awareness of these possible associations may improve understanding of disease pathogenesis and diagnosis. Moreover, these insights may help with public health decision-making and disease mitigation.

Novel strategies are needed to combat multidrug resistance in pancreatic ductal adenocarcinoma (PDAC). We applied genomic approaches to understand mechanisms of resistance in order to better inform treatment and precision medicine. Altered function of chromatin remodeling complexes contribute to chemoresistance. Our study generates and analyzes genomic and biochemical data from PDAC cells overexpressing HDAC1, a histone deacetylase involved in several chromatin remodeling complexes. We characterized the impact of overexpression on drug response, gene expression, HDAC1 binding, and chromatin structure using RNA-sequencing and ChIP-sequencing for HDAC1 and H3K27 acetylation. Integrative genomic analysis shows that HDAC1 overexpression promotes activation of key resistance pathways including epithelial to mesenchymal transition, cell cycle, and apoptosis through global chromatin remodeling. Target genes are similarly altered in patient tissues and show correlation with patient survival. We also demonstrate that direct targets of HDAC1 that also show altered chromatin are enriched near genes associated with altered GTPase activity. HDAC1 target genes identified using in vitro methods and observed in patient tissues were used to develop a clinically relevant nine-transcript signature associated with patient prognosis. Integration of multiple genomic and biochemical data types enables understanding of multidrug resistance and tumorigenesis in PDAC, a disease in desperate need of novel treatment strategies., (© 2023. The Author(s).)

The approval of immunotherapy for stage II-IV melanoma has underscored the need for improved immune-based predictive and prognostic biomarkers. For resectable stage II-III patients, adjuvant immunotherapy has proven clinical benefit, yet many patients experience significant adverse events and may not require therapy. In the metastatic setting, single agent immunotherapy cures many patients but, in some cases, more intensive combination therapies against specific molecular targets are required. Therefore, the establishment of additional biomarkers to determine a patient's disease outcome (i.e., prognostic) or response to treatment (i.e., predictive) is of utmost importance. Multiple methods ranging from gene expression profiling of bulk tissue, to spatial transcriptomics of single cells and artificial intelligence-based image analysis have been utilized to better characterize the immune microenvironment in melanoma to provide novel predictive and prognostic biomarkers. In this review, we will highlight the different techniques currently under investigation for the detection of prognostic and predictive immune biomarkers in melanoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Adeuyan, Gordon, Kenchappa, Bracero, Singh, Espinoza, Geskin and Saenger.)

Background: Patients facing a cutaneous lymphoma diagnosis frequently turn to the internet for information but finding patient-accessible education may be a challenge., Objective: To investigate accessibility and readability of patient-oriented online education on cutaneous lymphomas, including cutaneous T-cell and B-cell lymphoma subtypes., Methods: This study queried a search engine for 11 cutaneous lymphoma terms, resulting in 1083 webpages. Webpages were screened using defined inclusion/exclusion criteria; literature directed to physicians and scientists was excluded. Webpages were stratified by academic/nonacademic and dermatology/nondermatology hosts and assessed by order of appearance. Readability, including text complexity, was analyzed for grade level understanding using 5 established calculators. Overall readability was assessed by Flesch-Kincaid Reading Ease., Results: Academic webpages had earlier order of appearance. There was a dearth in dermatology-hosted webpages. Rarer cutaneous lymphomas yielded fewer patient-accessible results. Search term readability significantly exceeded the American Medical Association-recommended sixth grade level ( P  < .001∗), with higher grade levels for cutaneous T-cell lymphoma subtype webpages than cutaneous B-cell lymphoma subtypes., Limitations: Webpage quality, accuracy, and language were not assessed., Conclusion: Current online education for cutaneous lymphomas exceeds the American Medical Association's maximum readability recommendation. There is a need for more patient-accessible education amidst predominance of scientific literature, greater dermatology host websites, and enhanced readability of existing online education., Competing Interests: Dr Geskin has served as an investigator for and/or received research support from 10.13039/100008129Helsinn Group, J&J, Mallinckrodt, Kyowa Kirin, Soligenix, Innate, 10.13039/100004334Merck, BMS, and Stratpharma; on the speakers’ bureau for 10.13039/100008129Helsinn Group and J&J; and on the scientific advisory board for 10.13039/100008129Helsinn Group, J&J, Mallinckrodt, 10.13039/100004339Sanofi, 10.13039/100009857Regeneron, and Kyowa Kirin. Authors Schreidah, Fahmy, Lapolla, Gordon, and Dr Kwinta have no conflicts of interest to declare., (© 2023 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers based on five-year survival rates. Genes contributing to chemoresistance represent novel therapeutic targets that can improve treatment response. Increased expression of ANGPTL4 in tumors correlates with poor outcomes in pancreatic cancer., Methods: We used statistical analysis of publicly available gene expression data (TCGA-PAAD) to test whether expression of ANGPTL4 and its downstream targets, ITGB4 and APOL1, were correlated with patient survival. We measured the impact of ANGPTL4 overexpression in a common pancreatic cancer cell line, MIA PaCa-2 cells, using CRISPRa for overexpression and DsiRNA for knockdown. We characterized global gene expression changes associated with high levels of ANGPTL4 and response to gemcitabine treatment using RNA-sequencing. Gemcitabine dose response curves were calculated on modified cell lines by measuring cell viability with CellTiter-Glo (Promega). Impacts on cell migration were measured using a time course scratch assay., Results: We show that ANGPTL4 overexpression leads to in vitro resistance to gemcitabine and reduced survival times in patients. Overexpression of ANGPTL4 induces transcriptional signatures of tumor invasion and metastasis, proliferation and differentiation, and inhibition of apoptosis. Analyses revealed an overlapping signature of genes associated with both ANGPTL4 activation and gemcitabine response. Increased expression of the genes in this signature in patient PDAC tissues was significantly associated with shorter patient survival. We identified 42 genes that were both co-regulated with ANGPTL4 and were responsive to gemcitabine treatment. ITGB4 and APOL1 were among these genes. Knockdown of either of these genes in cell lines overexpressing ANGPTL4 reversed the observed gemcitabine resistance and inhibited cellular migration associated with epithelial to mesenchymal transition (EMT) and ANGPTL4 overexpression., Conclusions: These data suggest that ANGPTL4 promotes EMT and regulates the genes APOL1 and ITGB4. Importantly, we show that inhibition of both targets reverses chemoresistance and decreases migratory potential. Our findings have revealed a novel pathway regulating tumor response to treatment and suggest relevant therapeutic targets in pancreatic cancer., (© 2023. The Author(s).)

In the era of disability rights, medical schools retained the power to discriminate against applicants in wheelchairs. This article explores how medical schools set boundaries for admission into the profession, remained intransigent in their discrimination, and persuaded courts to side with them. Interviews with physicians in wheelchairs, legal documents, medical journal articles, and white papers demonstrate how medical schools established physical standards for entry into the profession specifically in response to applicants with disabilities. In the 1970s, medical schools created exclusionary physical requirements and persuaded the Supreme Court that these "technical standards" preserved patient safety. In the 1980s, schools asserted that students with disabilities would require expensive accommodations and lower educational standards. In the 1990s, medical schools strategically interpreted vague language in the Americans with Disabilities Act to justify continuing to exclude applicants with disabilities. This article complicates triumphalist histories of disability activism and reveals the continuation of exclusion in medical education, which had historically occurred based on race and gender. Interviews with successful applicants in wheelchairs provide powerful testimony against medical school policies and offer a clear path forward. Technical standards should change to value compassion and critical thinking over physical fitness. Physicians in wheelchairs perform most medical tasks and bring unique perspectives to a historically homogenous profession., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Glioblastoma (GBM) remains one of the most aggressive cancers, partially due to its ability to migrate into the surrounding brain. The sphingolipid balance, or the balance between ceramides and sphingosine-1-phosphate, contributes to the ability of GBM cells to migrate or invade. Of the ceramidases which hydrolyze ceramides, acid ceramidase (ASAH1) is highly expressed in GBM samples compared to non-tumor brain. ASAH1 expression also correlates with genes associated with migration and focal adhesion. To understand the role of ASAH1 in GBM migration, we utilized shRNA knockdown and observed decreased migration that did not depend upon changes in growth. Next, we inhibited ASAH1 using carmofur, a clinically utilized small molecule inhibitor. Inhibition of ASAH1 by carmofur blocks in vitro migration of U251 (GBM cell line) and GBM cells derived from patient-derived xenografts (PDXs). RNA-sequencing suggested roles for carmofur in MAPK and AKT signaling. We found that carmofur treatment decreases phosphorylation of AKT, but not of MAPK. The decrease in AKT phosphorylation was confirmed by shRNA knockdown of ASAH1. Our findings substantiate ASAH1 inhibition using carmofur as a potential clinically relevant treatment to advance GBM therapeutics, particularly due to its impact on migration.

Purpose: Our study used transcriptomic and metabolomic strategies to determine the molecular profiles of HGSOC patient samples derived from primary tumor and ascites cells. These data identified clinically relevant heterogeneity among and within patients and highlighted global and patient-specific cellular responses to neoadjuvant chemotherapy (NACT)., Experimental Design: Tissue from 61 treatment-naïve patients with HGSOC were collected. In addition, 11 benign, 32 ascites, and 18 post-NACT samples (matched to the individual patient's pre-NACT sample) were collected. RNA sequencing (RNA-seq) was performed on all samples collected. Two-dimensional spatial proteomic data was collected for two pairs of pre- and post-NACT. Untargeted metabolomics data using GCxGC-MS was generated for 30 treatment-naive tissues. Consensus clustering, analysis of differential expression, pathway enrichment, and survival analyses were performed., Results: Treatment-naïve HGSOC tissues had distinct transcriptomic and metabolomic profiles. The mesenchymal subtype harbored a metabolomic profile distinct from the other subtypes. Compared with primary tumor tissue, ascites showed significant changes in immune response and signaling pathways. NACT caused significant alterations in gene expression and WNT activity, and this corresponded to altered immune response. Overall, WNT signaling levels were inversely correlated with immune cell infiltration in HGSOC tissues and WNT signaling post-NACT was inversely correlated with progression-free survival., Conclusions: Our study concluded that HGSOC is a heterogenous disease at baseline and growing molecular differences can be observed between primary tumor and ascites cells or within tumors in response to treatment. Our data reveal potential exploratory biomarkers relevant for treatment selection and predicting patient outcomes that warrant further research., (©2022 American Association for Cancer Research.)

The multifaceted roles of metabolism in invasion have been investigated across many cancers. The brain tumor glioblastoma (GBM) is a highly invasive and metabolically plastic tumor with an inevitable recurrence. The neuronal glucose transporter 3 (GLUT3) was previously reported to correlate with poor glioma patient survival and be upregulated in GBM cells to promote therapeutic resistance and survival under restricted glucose conditions. It has been suggested that the increased glucose uptake mediated by GLUT3 elevation promotes survival of circulating tumor cells to facilitate metastasis. Here we suggest a more direct role for GLUT3 in promoting invasion that is not dependent upon changes in cell survival or metabolism. Analysis of glioma datasets demonstrated that GLUT3, but not GLUT1, expression was elevated in invasive disease. In human xenograft derived GBM cells, GLUT3, but not GLUT1, elevation significantly increased invasion in transwell assays, but not growth or migration. Further, there were no changes in glycolytic metabolism that correlated with invasive phenotypes. We identified the GLUT3 C-terminus as mediating invasion: substituting the C-terminus of GLUT1 for that of GLUT3 reduced invasion. RNA-seq analysis indicated changes in extracellular matrix organization in GLUT3 overexpressing cells, including upregulation of osteopontin. Together, our data suggest a role for GLUT3 in increasing tumor cell invasion that is not recapitulated by GLUT1, is separate from its role in metabolism and survival as a glucose transporter, and is likely broadly applicable since GLUT3 expression correlates with metastasis in many solid tumors.

Free L-tryptophan (L-Trp) stalls ribosomes engaged in the synthesis of TnaC, a leader peptide controlling the expression of the Escherichia coli tryptophanase operon. Despite extensive characterization, the molecular mechanism underlying the recognition and response to L-Trp by the TnaC-ribosome complex remains unknown. Here, we use a combined biochemical and structural approach to characterize a TnaC variant (R23F) with greatly enhanced sensitivity for L-Trp. We show that the TnaC-ribosome complex captures a single L-Trp molecule to undergo termination arrest and that nascent TnaC prevents the catalytic GGQ loop of release factor 2 from adopting an active conformation at the peptidyl transferase center. Importantly, the L-Trp binding site is not altered by the R23F mutation, suggesting that the relative rates of L-Trp binding and peptidyl-tRNA cleavage determine the tryptophan sensitivity of each variant. Thus, our study reveals a strategy whereby a nascent peptide assists the ribosome in detecting a small metabolite., (© 2021. The Author(s).)

The kidney proximal tubule is the primary site for solute reabsorption, secretion and where kidney diseases can originate, including drug-induced toxicity. Two-dimensional cell culture systems of the human proximal tubule cells (hPTCs) are often used to study these processes. However, these systems fail to model the interplay between filtrate flow, fluid shear stress (FSS), and functionality essential for understanding renal diseases and drug toxicity. The impact of FSS exposure on gene expression and effects of FSS at differing rates on gene expression in hPTCs has not been thoroughly investigated. Here, we performed RNA-sequencing of human RPTEC/TERT1 cells in a microfluidic chip-based 3D model to determine transcriptomic changes. We measured transcriptional changes following treatment of cells in this device at three different fluidic shear stress. We observed that FSS changes the expression of PTC-specific genes and impacted genes previously associated with renal diseases in genome-wide association studies (GWAS). At a physiological FSS level, we observed cell morphology, enhanced polarization, presence of cilia, and transport functions using albumin reabsorption via endocytosis and efflux transport. Here, we present a dynamic view of hPTCs response to FSS with increasing fluidic shear stress conditions and provide insight into hPTCs cellular function under biologically relevant conditions.

Background: Pancreatic ductal adenocarcinoma (PDAC) patients suffer poor outcomes, including a five-year survival of below 10%. Poor outcomes result in part from therapeutic resistance that limits the impact of cytotoxic first-line therapy. Novel therapeutic approaches are needed, but currently no targeted therapies exist to treat PDAC., Methods: To assess cellular resistance mechanisms common to four cytotoxic chemotherapies (gemcitabine, 5-fluorouracil, irinotecan, and oxaliplatin) used to treat PDAC patients, we performed four genome-wide CRISPR activation (CRISPR act ) and CRISPR knock-out (CRISPR ko ) screens in two common PDAC cell lines (Panc-1 and BxPC3). We used pathway analysis to identify gene sets enriched among our hits and conducted RNA-sequencing and chromatin immunoprecipitation-sequencing (ChIP-seq) to characterize top hits from our screen. We used scratch assays to assess changes in cellular migration with HDAC1 overexpression., Results: Our data revealed activation of ABCG2, a well-described efflux pump, as the most consistent mediator of resistance in each of our screens. CRISPR-mediated activation of genes involved in transcriptional co-repressor complexes also conferred resistance to multiple drugs. Expression of many of these genes, including HDAC1, is associated with reduced survival in PDAC patients. Up-regulation of HDAC1 in vitro increased promoter occupancy and expression of several genes involved in the epithelial-to-mesenchymal transition (EMT). These cells also displayed phenotypic changes in cellular migration consistent with activation of the EMT pathway. The expression changes resulting from HDAC1 activation were also observed with activation of several other co-repressor complex members. Finally, we developed a publicly available analysis tool, PancDS, which integrates gene expression profiles with our screen results to predict drug sensitivity in resected PDAC tumors and cell lines., Conclusion: Our results provide a comprehensive resource for identifying cellular mechanisms of drug resistance in PDAC, mechanistically implicate HDAC1, and co-repressor complex members broadly, in multi-drug resistance, and provide an analytical tool for predicting treatment response in PDAC tumors and cell lines.

Treatment for the lethal primary adult brain tumor glioblastoma (GBM) includes the chemotherapy temozolomide (TMZ), but TMZ resistance is common and correlates with promoter methylation of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT). To improve treatment of GBMs, including those resistant to TMZ, we explored the potential of targeting dopamine receptor signaling. We found that dopamine receptor 3 (DRD3) is expressed in GBM and is also a previously unexplored target for therapy. We identified novel antagonists of DRD3 that decreased the growth of GBM xenograft-derived neurosphere cultures with minimal toxicity against human astrocytes and/or induced pluripotent stem cell-derived neurons. Among a set of DRD3 antagonists, we identified two compounds, SRI-21979 and SRI-30052, that were brain penetrant and displayed a favorable therapeutic window analysis of The Cancer Genome Atlas data demonstrated that higher levels of DRD3 (but not DRD2 or DRD4) were associated with worse prognosis in primary, MGMT unmethylated tumors. These data suggested that DRD3 antagonists may remain efficacious in TMZ-resistant GBMs. Indeed, SRI-21979, but not haloperidol, significantly reduced the growth of TMZ-resistant GBM cells. Together our data suggest that DRD3 antagonist-based therapies may provide a novel therapeutic option for the treatment of GBM., Competing Interests: Dr. Ananthan and Southern Research generated the novel dopamine receptor antagonists and retain intellectual property rights for drug development. The authors declare no other potential conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials, but quantities of some compounds are limited although the structures are provided.

Bias toward legally protecting and prioritizing charismatic taxonomic groups, such as mammals and birds, and against others, such as insects and plants, is well documented. However, the relative costs of conserving various taxonomic groups and the potential of these costs to interact with existing biases have been much less explored. We analyzed conservation programs across more than 2,000 species in 3 countries to investigate the costs of conserving species within taxonomic groups and how these costs might affect conservation planning. For each data set, we tested for differences in mean annual cost among taxonomic groups. For the data set from the United States, recovery plans differed in duration, so we also tested for differences in total costs among taxonomic groups. Although the costs for individual species varied widely, there were strong international consistencies. For example, mammals cost 8-26 times more on average to conserve than plants and 13-19 times more to conserve than aquatic invertebrates. On average, bird species cost 5-30 times more to conserve than plants and 6-14 times more to conserve than aquatic invertebrates. These cost differences could exacerbate unequal resource allocation among taxonomic groups such that more charismatic groups both receive more attention and require more resources, leading to neglect of other taxonomic groups., (© 2019 Society for Conservation Biology.)

The tnaC regulatory gene from the tna operon of Escherichia coli controls the transcription of its own operon through an attenuation mechanism relying on the accumulation of arrested ribosomes during inhibition of its own translation termination. This free l-Trp-dependent mechanism of inhibition of translation termination remains unclear. Here, we analyzed the inhibitory effects of l-Trp on the function of two known E. coli translation termination factors, RF1 and RF2. Using a series of reporter genes, we found that the in vivo l-Trp sensitivity of tnaC gene expression is influenced by the identity of its stop codon, with the UGA stop codon producing higher expression efficiency of the tnaA-lacZ gene construct than the UAG stop codon. In vitro TnaC-peptidyl-tRNA accumulation and toe-printing assays confirmed that in the presence of l-Trp, the UGA stop codon generates higher accumulation of both TnaC-peptidyl-tRNA and arrested ribosomes than does the UAG stop codon. RF-mediated hydrolysis assays corroborated that l-Trp blocks RF2 function more than that of RF1. Mutational analyses disclosed that amino acids substitutions at the 246 and 256 residue positions surrounding the RF2-GGQ functional motif reduce l-Trp-dependent expression of the tnaC(UGA) tnaA-lacZ construct and the ability of l-Trp to inhibit RF2-mediated cleavage of the TnaC-peptidyl-tRNA. Altogether, our results indicate that l-Trp preferentially blocks RF2 activity during translation termination of the tnaC gene. This inhibition depends on the identities of amino acid residues surrounding the RF2-GGQ functional motif., (© 2019 Emmanuel et al.)