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PURPOSE: Late alopecia, defined as incomplete hair regrowth > 6 months following cytotoxic chemotherapy or > 6 months from initiation of endocrine therapy, negatively impacts quality of life and may affect dose intensity of adjuvant therapy. This study investigates the effect of oral minoxidil in women with chemotherapy and/or endocrine therapy-induced late alopecia. METHODS: The rate of clinical response was assessed by standardized photography and quantitated with trichoscopy. RESULTS: Two hundred and sixteen patients (mean age 57.8 ± 13.7) were included. The most common cancer diagnosis was breast, in 170 patients (79.1%). Alopecia developed after chemotherapy in 31 (14.4%) patients, endocrine monotherapy in 65 (30.1%) patients, and chemotherapy followed by endocrine therapy in 120 (55.6%) patients. In 119 patients, standardized photography assessments were used to determine clinical change in alopecia after a median of 105 (IQR = 70) days on oral minoxidil and revealed improvement in 88 (74%) patients. Forty-two patients received quantitative trichoscopic assessments at baseline and at follow-up after a median of 91 (IQR = 126) days on oral minoxidil. Patients had clinically and statistically significant increases in frontal hair shaft density (from 124.2 hairs/cm2 at initial to 153.2 hairs/cm2 at follow-up assessment, p = 0.008) and occipital shaft density (from 100.3 hairs/cm2 at initial to 123.5 hairs/cm2 at follow-up assessment. p = 0.004). No patients discontinued oral minoxidil due to adverse events. CONCLUSIONS: Overall, oral minoxidil was well tolerated by patients and may benefit both frontal and occipital late alopecia in cancer survivors treated with cytotoxic and/or endocrine therapy by increasing hair shaft and follicle density.
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The Reflectance Confocal Microscopy - Optical Coherence Tomography (RCM-OCT) device has shown utility in detecting and assessing depth of basal cell carcinoma (BCC) in vivo but is challenging for novices to interpret. Artificial intelligence (AI) applied to RCM-OCT could aid readers. We trained artificial intelligence (AI) models, using OCT rasters of biopsy-confirmed BCC, to detect and create 3D BCC rendering and automatically measure tumor depth. Trained AI models were applied to a separate test set containing rasters of BCC, benign lesions, and normal skin. Blinded reader analysis and tumor depth correlation with histopathology were conducted. BCC detection improved from viewing OCT rasters only (sensitivity 73.3%, specificity 45.5%) to viewing rasters with AI-generated BCC rendering (sensitivity 86.7%, specificity 48.5%). A Pearson Correlation r2 = 0.59 (p=0.02) was achieved for the tumor depth measurement between AI and histologic measured depths. Thus, addition of AI to the RCM-OCT device may expand its utility widely.
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BACKGROUND: Photodynamic therapy (PDT) with topical δ-Aminolevulinic acid (ALA) has efficacy in treating basal cell carcinoma (BCC) but is limited by incomplete penetration of ALA into the deeper dermis. This prospective open-label pilot trial investigated the safety and efficacy of photosensitizer jet injection for PDT (JI-PDT) for BCC treatment. It was performed with 15 patients (n = 15) with histologically confirmed, untreated, low-risk nodular BCCs at a single institution. METHODS: For the intervention, JI-PDT patients (n = 11) received two sessions of jet-injected ALA with PDT separated by four to 6 weeks. To further understand treatment technique, another group of patients (n = 4) received jet-injected ALA followed by tumor excision and fluorescence microscopy (JI-E). Treatment tolerability was assessed by local skin responses (LSR) score at five distinct time intervals. Fluorescence microscopy assessed protoporphyrin IX penetration depth and biodistribution within the tumor. At the primary endpoint, tumor clearance was evaluated via visual inspection, dermoscopy and reflectance confocal microscopy. Postinjection and postillumination pain levels, and patient satisfaction, were scored on a 0-10 scale. RESULTS: Fifteen participants with mean age of 58.3, who were 15/15 White, non-Hispanic enrolled. The median composite LSR score immediately after JI-PDT was 5 (interquartile range [IQR] = 3) which decreased to 0.5 (IQR = 1) at primary endpoint (p < 0.01). Immunofluorescence of excised BCC tumors with jet-injected ALA showed photosensitizer penetration into papillary and reticular dermis. Of the 13 JI-PDT tumors, 11 had tumor clearance confirmed, 1 recurred, and 1 was lost to follow-up. 1/11 patients experienced a serious adverse event of cellulitis. 70% of patients had local scarring at 3 months. Patients reported an average pain level of 5.6 (standard deviation [SD] = 2.3) during jet injection and 3.7 (SD = 1.8) during light illumination. CONCLUSIONS: Jet injection of ALA for PDT treatment of nodular low-risk BCC is tolerable and feasible and may represent a novel modality to improve PDT.
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Ácido Aminolevulínico , Carcinoma Basocelular , Fotoquimioterapia , Fármacos Fotossensibilizantes , Neoplasias Cutâneas , Humanos , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/patologia , Projetos Piloto , Fotoquimioterapia/métodos , Feminino , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Masculino , Ácido Aminolevulínico/administração & dosagem , Ácido Aminolevulínico/uso terapêutico , Idoso , Pessoa de Meia-Idade , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/uso terapêutico , Estudos Prospectivos , Injeções a Jato , Resultado do Tratamento , Idoso de 80 Anos ou maisRESUMO
Doxorubicin is a commonly used anticancer agent that can cause debilitating and irreversible cardiac injury. The initiating mechanisms contributing to this side effect remain unknown, and current preventative strategies offer only modest protection. Using stem-cell-derived cardiomyocytes from patients receiving doxorubicin, we probed the transcriptomic landscape of solute carriers and identified organic cation transporter 3 (OCT3) (SLC22A3) as a critical transporter regulating the cardiac accumulation of doxorubicin. Functional validation studies in heterologous overexpression models confirmed that doxorubicin is transported into cardiomyocytes by OCT3 and that deficiency of OCT3 protected mice from acute and chronic doxorubicin-related changes in cardiovascular function and genetic pathways associated with cardiac damage. To provide proof-of-principle and demonstrate translational relevance of this transport mechanism, we identified several pharmacological inhibitors of OCT3, including nilotinib, and found that pharmacological targeting of OCT3 can also preserve cardiovascular function following treatment with doxorubicin without affecting its plasma levels or antitumor effects in multiple models of leukemia and breast cancer. Finally, we identified a previously unrecognized, OCT3-dependent pathway of doxorubicin-induced cardiotoxicity that results in a downstream signaling cascade involving the calcium-binding proteins S100A8 and S100A9. These collective findings not only shed light on the etiology of doxorubicin-induced cardiotoxicity, but also are of potential translational relevance and provide a rationale for the implementation of a targeted intervention strategy to prevent this debilitating side effect.
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Doxorrubicina/efeitos adversos , Traumatismos Cardíacos/induzido quimicamente , Traumatismos Cardíacos/tratamento farmacológico , Terapia de Alvo Molecular , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Animais , Criança , Regulação da Expressão Gênica , Traumatismos Cardíacos/fisiopatologia , Humanos , Camundongos , Miócitos Cardíacos/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/deficiência , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Análise de Sequência de RNARESUMO
PURPOSE: Patients with prostate cancer (PCa) treated with apalutamide frequently develop rash. We aim to characterize apalutamide-related dermatological adverse events (dAEs) and management. MATERIALS AND METHODS: We assessed 303 patients with PCa treated with apalutamide. DAE frequency and time to onset were calculated and clinicopathological features and management described. Associations between dAE occurrence and clinical trial participation, as well as abiraterone/prednisone exposure were detected using logistic regression models. RESULTS: Seventy-one (23.4%) patients had all-grade dAE occurring at a median of 77 (IQR: 30-135) days post-exposure. Twenty (6.6%) dAE-related therapy interruptions included: 8 (2.6%) with dose maintained on rechallenge, 7 (2.3%) with dose reduction and 5 (1.7%) with discontinuation. Common dAEs were maculopapular rashes (33.8%) and xerosis (32.4%). Seven (77.8%) of 9 histological analyses of skin biopsies supported a drug reaction. No significant differences in laboratory hematological, hepatic and renal function were detected between dAE and no dAE cohorts. Most treated grade 1/2 dAEs (29, 40.8%) required topical steroids (14, 19.7%); few required oral steroids (3, 4.2%) ± oral antihistamines. Most grade 3 dAEs (8, 11.3%) required oral/topical steroids (5, 7.0%); few required topical steroids (3, 4.2%) ± oral antihistamines. Clinical trial patients (180, 59.4%) were more likely to report dAEs than those in the off-trial setting (OR=5.1 [95% CI 2.55-10.12]; p <0.001). Of clinical trial patients, concomitant abiraterone/prednisone recipients (109 of 180, 60.6%) were more likely to report dAEs (OR=3.1 [95% CI 1.53-6.17]; p=0.002). CONCLUSIONS: Apalutamide-related dAEs are frequent and can be managed with topical ± oral steroids. With expanded approval of apalutamide, dAE identification and management are essential.
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Exantema , Neoplasias da Próstata , Antagonistas de Receptores de Andrógenos/efeitos adversos , Exantema/induzido quimicamente , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Tioidantoínas/efeitos adversosRESUMO
BACKGROUND: The prevalence of chronic liver disease (CLD) is rising, but it remains unclear if medical school curricula are emphasizing CLD to reflect its growing epidemiology. AIMS: To assess comfort levels and knowledge of CLD among recently graduated medical students METHODS: An anonymous survey was distributed to incoming categorical Internal Medicine (IM) interns at a single academic institution during a 2-year period. The survey consisted of 38 Likert-like questions evaluating comfort levels and self-assessed knowledge for several general medicine and liver diseases, as well as 12 multiple-choice questions to objectively test knowledge. Wilcoxon ranked sum and Fisher's exact test were then used. RESULTS: There was a 100% (n = 65) completion rate. Only 14 (22%) of those surveyed reported exposure to a hepatology rotation in medical school. Highest mean comfort levels (1 = not at all comfortable, 5 = very comfortable) were for managing congestive heart failure (3.59) and chronic obstructive pulmonary disease (3.77). Mean comfort levels for various liver diseases were significantly lower (2.22-3.03, all p < 0.01). Mean self-rated knowledge (1 = no knowledge, 5 = strong knowledge) was also low (2.14-3.13). Although 98% agreed that hepatology is critical to IM training, only 42% agreed that their hepatology education during medical school was adequate. CONCLUSIONS: Recently graduated medical students are less comfortable managing liver diseases compared to other general medical conditions. Only a minority report satisfaction with hepatology education during medical school. These findings suggest that medical curricula need to be modified to better emphasize CLD.
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Gastroenterologia , Hepatopatias , Estudantes de Medicina , Currículo , Gastroenterologia/educação , Humanos , Hepatopatias/epidemiologia , Inquéritos e QuestionáriosRESUMO
The NOD-, LRR-, and pyrin-domain-containing protein 3 (NLRP3) inflammasome is a node of intracellular stress pathways and a druggable target which integrates mitochondrial stress and inflammatory cascades. While a body of evidence suggests the involvement of the NLRP3 inflammasome in numerous diseases, a lack of reliable measurement techniques highlights the need for a robust assay using small quantities of biological samples. We present a literature overview on peripheral activation of the NLRP3 inflammasome in mood disorders, then outline a process to develop and validate a robust assay to measure baseline and activated intracellular levels of "apoptosis-associated speck-like protein containing a CARD" (ASC) as a key component of an inflammatory profile in peripheral blood mononuclear cells (PBMC). A consistent association between high NLRP3 mRNA levels and relevant cytokines was seen in the literature. Using our method to measure ASC, stimulation of PBMC with lipopolysaccharide and nigericin or adenosine triphosphate resulted in microscopic identification of intracellular ASC specks, as well as interleukin 1 (IL-1) beta and caspase-1 p10 in the periphery. This was abolished by dose-dependent pre-treatment with 100 nM MCC950. We also report the use of this technique in a small pilot sample from patients with bipolar disorder and depressive disorders. The results show that levels of intracellular ASC and IL-1 beta are sensitive to change upon activation and maintained over time, which may be used to improve the detection of NLRP3 activation and guide personalized therapeutic strategy in the treatment of patients.
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Proteínas Adaptadoras de Sinalização CARD/sangue , Inflamação/sangue , Interleucina-1beta/sangue , Transtornos do Humor/sangue , Proteína 3 que Contém Domínio de Pirina da Família NLR/sangue , Adolescente , Animais , Apoptose/genética , Caspase 1/sangue , Feminino , Humanos , Inflamassomos/sangue , Inflamassomos/genética , Inflamação/genética , Inflamação/patologia , Leucócitos Mononucleares/metabolismo , Masculino , Mitocôndrias/genética , Transtornos do Humor/genética , Transtornos do Humor/patologiaRESUMO
Mitochondrial dysfunction is commonly observed in bipolar disorder (BD) and schizophrenia (SCZ) and may be a central feature of psychosis. These illnesses are complex and heterogeneous, which is reflected by the complexity of the processes regulating mitochondrial function. Mitochondria are typically associated with energy production; however, dysfunction of mitochondria affects not only energy production but also vital cellular processes, including the formation of reactive oxygen species, cell cycle and survival, intracellular Ca(2+) homeostasis, and neurotransmission. In this review, we characterize the upstream components controlling mitochondrial function, including 1) mutations in nuclear and mitochondrial DNA, 2) mitochondrial dynamics, and 3) intracellular Ca(2+) homeostasis. Characterizing and understanding the upstream factors that regulate mitochondrial function is essential to understand progression of these illnesses and develop biomarkers and therapeutics.
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Transtorno Bipolar/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Transtornos Psicóticos/metabolismo , HumanosRESUMO
Artificial intelligence (AI) chatbots are becoming a popular source of information but there are limited data on the quality of information on urological malignancies that they provide. Our objective was to characterize the quality of information and detect misinformation about prostate, bladder, kidney, and testicular cancers from four AI chatbots: ChatGPT, Perplexity, Chat Sonic, and Microsoft Bing AI. We used the top five search queries related to prostate, bladder, kidney, and testicular cancers according to Google Trends from January 2021 to January 2023 and input them into the AI chatbots. Responses were evaluated for quality, understandability, actionability, misinformation, and readability using published instruments. AI chatbot responses had moderate to high information quality (median DISCERN score 4 out of 5, range 2-5) and lacked misinformation. Understandability was moderate (median Patient Education Material Assessment Tool for Printable Materials [PEMAT-P] understandability 66.7%, range 44.4-90.9%) and actionability was moderate to poor (median PEMAT-P actionability 40%, range 0-40%The responses were written at a fairly difficult reading level. AI chatbots produce information that is generally accurate and of moderate to high quality in response to the top urological malignancy-related search queries, but the responses lack clear, actionable instructions and exceed the reading level recommended for consumer health information. PATIENT SUMMARY: Artificial intelligence chatbots produce information that is generally accurate and of moderately high quality in response to popular Google searches about urological cancers. However, their responses are fairly difficult to read, are moderately hard to understand, and lack clear instructions for users to act on.
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Neoplasias Testiculares , Neoplasias Urológicas , Masculino , Humanos , Inteligência Artificial , SoftwareRESUMO
Introduction: Kidney stones are common and morbid conditions in the general population with a rising incidence globally. Previous studies show substantial limitations of online sources of information regarding prevention and treatment. The objective of this study was to examine the quality of information on kidney stones from artificial intelligence (AI) chatbots. Methods: The most common online searches about kidney stones from Google Trends and headers from the National Institute of Diabetes and Digestive and Kidney Diseases website were used as inputs to four AI chatbots (ChatGPT version 3.5, Perplexity, Chat Sonic, and Bing AI). Validated instruments were used to assess the quality (DISCERN instrument from 1 low to 5 high), understandability, and actionability (PEMAT, from 0% to 100%) of the chatbot outputs. In addition, we examined the reading level of the information and whether there was misinformation compared with guidelines (5 point Likert scale). Results: AI chatbots generally provided high-quality consumer health information (median DISCERN 4 out of 5) and did not include misinformation (median 1 out of 5). The median understandability was moderate (median 69.6%), and actionability was moderate to poor (median 40%). Responses were presented at an advanced reading level (11th grade; median Flesch-Kincaid score 11.3). Conclusions: AI chatbots provide generally accurate information on kidney stones and lack misinformation; however, it is not easily actionable and is presented above the recommended reading level for consumer health information.
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Importance: The mainstream use of chatbots requires a thorough investigation of their readability and quality of information. Objective: To identify readability and quality differences in information between a free and paywalled chatbot cancer-related responses, and to explore if more precise prompting can mitigate any observed differences. Design, Setting, and Participants: This cross-sectional study compared readability and information quality of a chatbot's free vs paywalled responses with Google Trends' top 5 search queries associated with breast, lung, prostate, colorectal, and skin cancers from January 1, 2021, to January 1, 2023. Data were extracted from the search tracker, and responses were produced by free and paywalled ChatGPT. Data were analyzed from December 20, 2023, to January 15, 2024. Exposures: Free vs paywalled chatbot outputs with and without prompt: "Explain the following at a sixth grade reading level: [nonprompted input]." Main Outcomes and Measures: The primary outcome measured the readability of a chatbot's responses using Flesch Reading Ease scores (0 [graduate reading level] to 100 [easy fifth grade reading level]). Secondary outcomes included assessing consumer health information quality with the validated DISCERN instrument (overall score from 1 [low quality] to 5 [high quality]) for each response. Scores were compared between the 2 chatbot models with and without prompting. Results: This study evaluated 100 chatbot responses. Nonprompted free chatbot responses had lower readability (median [IQR] Flesh Reading ease scores, 52.60 [44.54-61.46]) than nonprompted paywalled chatbot responses (62.48 [54.83-68.40]) (P < .05). However, prompting the free chatbot to reword responses at a sixth grade reading level was associated with increased reading ease scores than the paywalled chatbot nonprompted responses (median [IQR], 71.55 [68.20-78.99]) (P < .001). Prompting was associated with increases in reading ease in both free (median [IQR], 71.55 [68.20-78.99]; P < .001)and paywalled versions (median [IQR], 75.64 [70.53-81.12]; P < .001). There was no significant difference in overall DISCERN scores between the chatbot models, with and without prompting. Conclusions and Relevance: In this cross-sectional study, paying for the chatbot was found to provide easier-to-read responses, but prompting the free version of the chatbot was associated with increased response readability without changing information quality. Educating the public on how to prompt chatbots may help promote equitable access to health information.
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Compreensão , Neoplasias , Humanos , Estudos Transversais , Letramento em Saúde , Informação de Saúde ao Consumidor/normas , InternetRESUMO
PURPOSE: Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, enabling early definitive treatment and potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of PNST in cancer predisposition syndrome NF1. EXPERIMENTAL DESIGN: cfDNA was isolated from plasma samples of a novel cohort of 101 NF1 patients and 21 healthy controls and underwent whole genome sequencing. We investigated diagnosis-specific signatures of copy number alterations (CNA) with in silico size selection as well as well as fragment profiles. Fragmentomics were analyzed using complementary feature types: bin-wise fragment size ratios, end-motifs, and fragment non-negative matrix factorization (NMF) signatures. RESULTS: The novel cohort of NF1 patients validated that our previous cfDNA CNA-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. CONCLUSIONS: Novel cfDNA fragmentomic signatures distinguish atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management. This study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 and provides a blueprint for de-centralizing non-invasive cancer surveillance in hereditary cancer syndromes.
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Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of NF1 PNST. Using plasma samples from a novel cohort of 101 NF1 patients and 21 healthy controls, we validated that our previous cfDNA copy number alteration (CNA)-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. We therefore investigated the ability of fragment-based cfDNA features to differentiate NF1-associated tumors including binned genome-wide fragment length ratios, end motif analysis, and non-negative matrix factorization deconvolution of fragment lengths. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. Overall, this study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 patients using plasma cfDNA fragmentomics. In addition to screening applications, this novel approach distinguishes atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management.
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Isolated cecal necrosis (ICN) is a rare form of ischemic colitis that can mimic conditions such as appendicitis, malignancy, or diverticulitis. Most cases of ICN have been identified in patients with significant comorbidities that increase risk of vascular disease. We present a case of ICN mimicking a mass lesion in an elderly patient with few comorbid conditions. Although computed tomography was concerning for colonic mass, diagnostic colonoscopy revealed ischemic colon. The patient underwent right hemicolectomy, and pathology confirmed ICN. It is important to recognize conditions ICN can mimic, understand ICN can present without acute abdomen, and consider ICN in the differential diagnosis even in relatively healthy patients without a history of vascular disease.
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Importance: Consumers are increasingly using artificial intelligence (AI) chatbots as a source of information. However, the quality of the cancer information generated by these chatbots has not yet been evaluated using validated instruments. Objective: To characterize the quality of information and presence of misinformation about skin, lung, breast, colorectal, and prostate cancers generated by 4 AI chatbots. Design, Setting, and Participants: This cross-sectional study assessed AI chatbots' text responses to the 5 most commonly searched queries related to the 5 most common cancers using validated instruments. Search data were extracted from the publicly available Google Trends platform and identical prompts were used to generate responses from 4 AI chatbots: ChatGPT version 3.5 (OpenAI), Perplexity (Perplexity.AI), Chatsonic (Writesonic), and Bing AI (Microsoft). Exposures: Google Trends' top 5 search queries related to skin, lung, breast, colorectal, and prostate cancer from January 1, 2021, to January 1, 2023, were input into 4 AI chatbots. Main Outcomes and Measures: The primary outcomes were the quality of consumer health information based on the validated DISCERN instrument (scores from 1 [low] to 5 [high] for quality of information) and the understandability and actionability of this information based on the understandability and actionability domains of the Patient Education Materials Assessment Tool (PEMAT) (scores of 0%-100%, with higher scores indicating a higher level of understandability and actionability). Secondary outcomes included misinformation scored using a 5-item Likert scale (scores from 1 [no misinformation] to 5 [high misinformation]) and readability assessed using the Flesch-Kincaid Grade Level readability score. Results: The analysis included 100 responses from 4 chatbots about the 5 most common search queries for skin, lung, breast, colorectal, and prostate cancer. The quality of text responses generated by the 4 AI chatbots was good (median [range] DISCERN score, 5 [2-5]) and no misinformation was identified. Understandability was moderate (median [range] PEMAT Understandability score, 66.7% [33.3%-90.1%]), and actionability was poor (median [range] PEMAT Actionability score, 20.0% [0%-40.0%]). The responses were written at the college level based on the Flesch-Kincaid Grade Level score. Conclusions and Relevance: Findings of this cross-sectional study suggest that AI chatbots generally produce accurate information for the top cancer-related search queries, but the responses are not readily actionable and are written at a college reading level. These limitations suggest that AI chatbots should be used supplementarily and not as a primary source for medical information.
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Introduction: Transient ischaemic attack (TIA) is associated with increased risk of cognitive decline and dementia as early as one-year post-event. Regional brain atrophy measurements may predict future cognitive decline. Aims: 1) To determine whether Medial Temporal Atrophy (MTA) scores and interseptal distance (ISD) measurements are greater in patients with TIA compared to controls; and 2) To determine whether MTA and ISD predicts cognitive change one year after TIA. Methods: Baseline demographic, vascular risk factors, structural imaging and cognitive tests scores were compared between 103 Patients with TIA and 103 age-and-sex-matched controls from the Predementia Neuroimaging of Transient Ischaemic Attack (PREVENT) Study. MTA was assessed using the Schelten's Scale, and ISD was calculated as the distance between the septal nucleus of each hemisphere. Multiple linear regression models were used to evaluate how MTA and ISD related to cognitive change after adjusting for covariates. Results: Patients with TIA had larger ISD measurements (1.4 mm [SD=1.2] vs. 0.9 mm [SD=1.0]); p < 0.001) and higher right/left MTA scores (both p < 0.05) compared to controls. At baseline, controls performed significantly better on the RAVLT (total recall), BVMT (total and delayed recall) and the Trail Making Task (A and B) compared to patients with TIA. However, at one-year follow-up there was no evidence of decline in the patients with TIA compared with controls. Higher MTA and ISD scores were not associated with cognitive decline. Conclusions: Patients with TIA had higher MTA scores and ISD measurements than controls, but neither were predictors of cognitive decline at one year. Future studies with longer follow-up periods will be required to determine whether higher MTA scores and ISD predict risk of cognitive decline in patients with TIA.
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Chronic lymphocytic leukemia (CLL) is effectively treated with targeted therapies including Bruton tyrosine kinase inhibitors and BCL2 antagonists. When these become ineffective, treatment options are limited. Positive transcription elongation factor complex (P-TEFb), a heterodimeric protein complex composed of cyclin dependent kinase 9 (CDK9) and cyclin T1, functions to regulate short half-life transcripts by phosphorylation of RNA Polymerase II (POLII). These transcripts are frequently dysregulated in hematologic malignancies; however, therapies targeting inhibition of P-TEFb have not yet achieved approval for cancer treatment. VIP152 kinome profiling revealed CDK9 as the main enzyme inhibited at 100 nM, with over a 10-fold increase in potency compared with other inhibitors currently in development for this target. VIP152 induced cell death in CLL cell lines and primary patient samples. Transcriptome analysis revealed inhibition of RNA degradation through the AU-Rich Element (ARE) dysregulation. Mechanistically, VIP152 inhibits the assembly of P-TEFb onto the transcription machinery and disturbs binding partners. Finally, immune competent mice engrafted with CLL-like cells of Eµ-MTCP1 over-expressing mice and treated with VIP152 demonstrated reduced disease burden and improvement in overall survival compared to vehicle-treated mice. These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL.
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Leucemia Linfocítica Crônica de Células B , Fator B de Elongação Transcricional Positiva , Animais , Camundongos , Fator B de Elongação Transcricional Positiva/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Quinase 9 Dependente de Ciclina , Ciclina T/metabolismo , Fosforilação , Núcleo Celular/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
PURPOSE: Antibodies against insulin-like growth factor (IGF) type 1 receptor have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF type 1 receptor (IGF-1R) antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti-IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase inhibitor targeting YES, in patients with RMS (NCT03041701). PATIENTS AND METHODS: Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2). A 3+3 dose escalation design was used, and maximum tolerated dose (MTD) was determined on the basis of cycle 1 dose-limiting toxicities (DLT). RESULTS: Thirteen eligible patients, median age 18 years (range 8-29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneumonitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response for four cycles, and one had stable disease for six cycles. Genomic studies from cell-free DNA correlated with disease response. CONCLUSIONS: The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every 2 weeks was safe and tolerable. This combination had a disease control rate of 22% at 5 months.
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Rabdomiossarcoma , Quinases da Família src , Humanos , Animais , Camundongos , Criança , Adolescente , Adulto Jovem , Adulto , Dasatinibe/efeitos adversos , Fator de Crescimento Insulin-Like I , Receptor IGF Tipo 1 , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dose Máxima TolerávelRESUMO
Richter's Transformation (RT) is a poorly understood and fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. Protein arginine methyltransferase 5 (PRMT5) is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 develop a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice develop a highly aggressive disease with transformation that histologically resembles RT; where large-scale transcriptional profiling identifies oncogenic pathways mediating PRMT5-driven disease progression. Lastly, we report the development of a SAM-competitive PRMT5 inhibitor, PRT382, with exclusive selectivity and optimal in vitro and in vivo activity compared to available PRMT5 inhibitors. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases.