CT-Guided Online Adaptive Hypofractionated Radiotherapy for Primary Bladder Cancer: A Report of Two Cases.

Trimodality treatment for bladder cancer, consisting of maximal transurethral resection of the tumor followed by concurrent chemoradiotherapy, is an attractive management option with curative and organ-sparing intent. However, such treatment can be associated with acute toxicities related to the large treatment margins required due to daily variation in bladder filling, with resultant bladder, bowel, and rectal toxicity. Adaptive radiation, which accounts for inter-fraction variations in bladder size, allows the confident delivery of radiation to bladder cancer with smaller margins, with the potential to reduce toxicities without the associated risk of compromising the target coverage. Herein, we present a case series of two patients with primary bladder cancer who were treated with computed tomography (CT)-based online adaptive hypofractionated radiotherapy using the Ethos system (Varian Medical Systems, Palo Alto, CA, USA). The first is an 83-year-old male with a remote history of prostate cancer treated with radiotherapy, who received adaptive radiotherapy as a means of decreasing the required margin size and optimizing planning based on adjacent bowel to reduce the risk of re-irradiation. The second patient is a 78-year-old male with node-positive bladder cancer, which necessitated whole pelvis radiotherapy, who underwent adaptive treatment (25 fractions) as a means of sparing cumulative dose to the bowel while ensuring suitable target coverage. In both cases, the clinical target volume consisted of the entire bladder (± nodes) with a planning target volume expansion of 7 mm. During treatment, daily cone-beam CT scans were acquired and used to generate adapted plans. These plans were compared to the original plans, with attention to target coverage and dose to organs at risk. For all 45 fractions, the adaptive plan was selected, primarily as a means of improving target coverage. This case series demonstrates that the adaptive Ethos system effectively delivers treatment for primary bladder cancer. Further data are needed for clinical toxicity outcomes and the efficacy of this approach.

IgG4 porta-hepatis pseudotumor mimicking a hilar cholangiocarcinoma.

A 60-year-old female with a BRCA2 mutation and a history of breast cancer presented with diffuse abdominal pain and elevated liver enzymes. Imaging revealed a porta-hepatis mass, prompting consideration of hilar cholangiocarcinoma or breast cancer metastasis. Further investigation including biopsy and 18F-fluorodeoxyglucose positron emission tomography/computed tomography findings were inconsistent with malignancy, leading to investigation of non-neoplastic causes. Elevated IgG4 levels suggested IgG4-related disease, a mass-forming fibroinflammatory condition. This case demonstrates IgG4-related disease exclusively impacting the portal vein and underscores the importance of considering IgG4-related disease in the differential diagnosis of hepatic masses.

Knowledge of HPV vaccination and associated HNC and treatment decision-making among minority populations.

OBJECTIVE: Understand vaccination knowledge and barriers to vaccination among minority adults. STUDY DESIGN: Cross-sectional survey. SETTING: Otolaryngology clinics at a safety net hospital and a tertiary academic center and a head and neck cancer screening event. METHODS: Survey was administered to consenting patients. Descriptive statistics and significance testing were used to characterize the data, with non-minority respondents as controls. Multivariate logistic regression was used to understand factors associated with vaccination. RESULTS: HPV vaccination among our 241 respondents (n = 41, 17.67 %) and their qualifying children (n = 52, 33.55 %) was low. Non-vaccinated minorities were significantly more likely to express interest in HPV vaccination (28.66 % vs 8.66 %, p = 0.016). Minority patients were significantly less knowledgeable about HPV causing cervical (88.64 % vs 72.45 %, p = 0.024) and head and neck (68.18 % vs 44.90 %, p = 0.005) cancer and were also less aware of HPV infection (95.45 % vs 81.12 %, p = 0.020) among non-women. Lack of knowledge about the HPV vaccine was the most cited reason why minority patients did not or were uninterested in vaccination for themselves or their children. In a multivariable logistic regression of factors associated with HPV vaccination, only increased age demonstrated a significant association with vaccination likelihood (OR = 0.91, 95 % CI = [0.88-0.95], p < 0.001). CONCLUSION: Reported HPV vaccination rates were low for both white and minority patients but did not significantly vary on univariate or multivariate analysis. However, minority respondents were significantly less knowledgeable about HPV and its manifestations; they most often cited inadequate knowledge as why did not receive or were uninterested in HPV vaccination. As such, HPV vaccination educational interventions may raise vaccination rates among minority populations.

External Auditory Canal Exostosis and the California Surfer Population: A Cross-Sectional Study.

OBJECTIVES: California has the most surfers in the United States and a high prevalence of external auditory canal exostoses (EACEs) among them. We aimed to characterize their EACE knowledge, use of earplugs, and barriers toward earplug use. METHODS: A RedCap survey was distributed to online surfing forums and surfers at California beaches. Descriptive statistics and regression analyses were used to characterize responses. RESULTS: Our cohort included 334 primarily male (n = 269, 81.52%), college-educated (n = 237, 71.17%) surfers who were on average 30.79 years old (SD = 11.07). Two hundred and ninety-seven (90.00%) heard of EACE and 317 (96.06%) believed earplugs prevent EACE. However, 214 (64.85%) had never used earplugs. Multivariable logistic regression found increased age (OR = 1.04, 95% CI = [1.00-1.08], p = 0.03), higher EACE knowledge quiz scores (OR = 1.47, 95% CI = [1.19-1.80], p < 0.001), and primarily surfing in Southern California (OR = 2.19, 95% CI = [1.15-4.16], p = 0.02) increased the likelihood of earplug use. Common reasons against earplug use included reduced hearing, discomfort, and social hindrance. Two hundred and eighty-seven (86.45%) would wear earplugs following more EACE knowledge. They preferred learning from surf community members, doctors, and surf events. CONCLUSION: Low earplug use despite awareness of EACE preventability suggests a need for EACE education among California surfers and more accessible, user-friendly earplugs. Younger, less-skilled surfers who were more commonly unaware of EACE may represent a key intervention group. Education could be promoted through partnerships between health professionals and renowned surf organizations, as most participants indicated a willingness to use earplugs post-education. LEVEL OF EVIDENCE: N/A Laryngoscope, 2024.

TrachGPT: Appraisal of tracheostomy care recommendations from an artificial intelligent Chatbot.

Objective: Safe home tracheostomy care requires engagement and troubleshooting by patients, who may turn to online, AI-generated information sources. This study assessed the quality of ChatGPT responses to such queries. Methods: In this cross-sectional study, ChatGPT was prompted with 10 hypothetical tracheostomy care questions in three domains (complication management, self-care advice, and lifestyle adjustment). Responses were graded by four otolaryngologists for appropriateness, accuracy, and overall score. The readability of responses was evaluated using the Flesch Reading Ease (FRE) and Flesch-Kincaid Reading Grade Level (FKRGL). Descriptive statistics and ANOVA testing were performed with statistical significance set to p < .05. Results: On a scale of 1-5, with 5 representing the greatest appropriateness or overall score and a 4-point scale with 4 representing the highest accuracy, the responses exhibited moderately high appropriateness (mean = 4.10, SD = 0.90), high accuracy (mean = 3.55, SD = 0.50), and moderately high overall scores (mean = 4.02, SD = 0.86). Scoring between response categories (self-care recommendations, complication recommendations, lifestyle adjustments, and special device considerations) revealed no significant scoring differences. Suboptimal responses lacked nuance and contained incorrect information and recommendations. Readability indicated college and advanced levels for FRE (Mean = 39.5, SD = 7.17) and FKRGL (Mean = 13.1, SD = 1.47), higher than the sixth-grade level recommended for patient-targeted resources by the NIH. Conclusion: While ChatGPT-generated tracheostomy care responses may exhibit acceptable appropriateness, incomplete or misleading information may have dire clinical consequences. Further, inappropriately high reading levels may limit patient comprehension and accessibility. At this point in its technological infancy, AI-generated information should not be solely relied upon as a direct patient care resource.

Post-operative complications of cholecystectomy: what the radiologist needs to know.

Cholecystectomy is one of the most performed surgical procedures. The safety of this surgery notwithstanding, the sheer volume of operations results in a notable incidence of post-cholecystectomy complications. Early and accurate diagnosis of such complications is essential for timely and effective management. Imaging techniques are critical for this purpose, aiding in distinguishing between expected postsurgical changes and true complications. This review highlights current knowledge on the indications for cholecystectomy, pertinent surgical anatomy and surgical technique, and the recognition of anatomical variants that may complicate surgery. The article also outlines the roles of various imaging modalities in identifying complications, the spectrum of possible postsurgical anatomical changes, and the implications of such findings. Furthermore, we explore the array of complications that can arise post-cholecystectomy, such as biliary system injuries, gallstone-related issues, vascular complications, and the formation of postsurgical collections. Radiologists should be adept at identifying normal and abnormal postoperative findings to guide patient management effectively.

Genetic and Epigenetic Characterization of Sarcoma Stem Cells Across Subtypes Identifies EZH2 as a Therapeutic Target.

High-grade complex karyotype soft tissue sarcomas (STS) are a heterogeneous and aggressive set of cancers that share a common treatment strategy. Disease progression and failure to respond to anthracycline based chemotherapy, standard first-line treatment, is associated with poor patient outcomes. To address this, we investigated the contribution of STS cancer stem cells (STS-CSCs) to doxorubicin resistance. We identified a positive correlation between CSC abundance and doxorubicin IC 50 in resistant cell lines. We investigated if a common genetic signature across STS-CSCs could be targeted. Utilizing patient derived samples from five sarcoma subtypes we identified Enhancer of Zeste homolog 2 (EZH2), a member of the polycomb repressive complex 2 (PRC2) responsible for H3K27 methylation as being enriched in the CSC population. EZH2 activity and a shared epigenetic profile was observed across subtypes. Targeting of EZH2 using Tazemetostat, an FDA approved inhibitor specifically ablated the STS-CSC population. Treatment of doxorubicin resistant cell lines with tazemetostat resulted in a decrease in the STS-CSC population. Further, co-treatment was not only synergistic in the parent cell lines, but restored chemosensitivity in doxorubicin resistant lines. These data confirm the presence of shared genetic programs across distinct subtypes of CSC-STS that can be therapeutically targeted.

Accuracy, readability, and understandability of large language models for prostate cancer information to the public.

BACKGROUND: Generative Pretrained Model (GPT) chatbots have gained popularity since the public release of ChatGPT. Studies have evaluated the ability of different GPT models to provide information about medical conditions. To date, no study has assessed the quality of ChatGPT outputs to prostate cancer related questions from both the physician and public perspective while optimizing outputs for patient consumption. METHODS: Nine prostate cancer-related questions, identified through Google Trends (Global), were categorized into diagnosis, treatment, and postoperative follow-up. These questions were processed using ChatGPT 3.5, and the responses were recorded. Subsequently, these responses were re-inputted into ChatGPT to create simplified summaries understandable at a sixth-grade level. Readability of both the original ChatGPT responses and the layperson summaries was evaluated using validated readability tools. A survey was conducted among urology providers (urologists and urologists in training) to rate the original ChatGPT responses for accuracy, completeness, and clarity using a 5-point Likert scale. Furthermore, two independent reviewers evaluated the layperson summaries on correctness trifecta: accuracy, completeness, and decision-making sufficiency. Public assessment of the simplified summaries' clarity and understandability was carried out through Amazon Mechanical Turk (MTurk). Participants rated the clarity and demonstrated their understanding through a multiple-choice question. RESULTS: GPT-generated output was deemed correct by 71.7% to 94.3% of raters (36 urologists, 17 urology residents) across 9 scenarios. GPT-generated simplified layperson summaries of this output was rated as accurate in 8 of 9 (88.9%) scenarios and sufficient for a patient to make a decision in 8 of 9 (88.9%) scenarios. Mean readability of layperson summaries was higher than original GPT outputs ([original ChatGPT v. simplified ChatGPT, mean (SD), p-value] Flesch Reading Ease: 36.5(9.1) v. 70.2(11.2), <0.0001; Gunning Fog: 15.8(1.7) v. 9.5(2.0), p < 0.0001; Flesch Grade Level: 12.8(1.2) v. 7.4(1.7), p < 0.0001; Coleman Liau: 13.7(2.1) v. 8.6(2.4), 0.0002; Smog index: 11.8(1.2) v. 6.7(1.8), <0.0001; Automated Readability Index: 13.1(1.4) v. 7.5(2.1), p < 0.0001). MTurk workers (n = 514) rated the layperson summaries as correct (89.5-95.7%) and correctly understood the content (63.0-87.4%). CONCLUSION: GPT shows promise for correct patient education for prostate cancer-related contents, but the technology is not designed for delivering patients information. Prompting the model to respond with accuracy, completeness, clarity and readability may enhance its utility when used for GPT-powered medical chatbots.

Associations Between Risk Perception and HPV Knowledge and Vaccine Uptake: Highlighting the LGBTQ+ Population.

INTRODUCTION: Gay and bisexual males and other LGBTQ+ communities are more frequently exposed to factors associated with an increased risk of human papillomavirus (HPV) acquisition. Vaccination is critical to protect against HPV+ head and neck cancer (HNC). We characterized the association of perceived level of risk of contraction with HPV knowledge, and vaccine decision-making. STUDY DESIGN: Cross-sectional cohort. SETTING: LGBTQ and general survey Reddit forums (control). METHODS: A survey was shared amongst the online forums. Descriptive statistics characterized the data. Multivariable logistic regression was used to understand factors associated with vaccination, self-perceived high risk, and knowledge of HPV + HNC. RESULTS: Of 718 respondents, most were female (41.09%), Caucasian (59.89%), college-educated (33.01%), and insured (77.15%) with a mean age of 30.75 years. Half were vaccinated (49.16%), with most unvaccinated endorsing interest (60.58%). Few dependents were vaccinated (25.91%), with interest in vaccination among parents of unvaccinated children (38.58%). Knowledge of HIV's association with HPV (62.95%), HPV causing HNC (55.57%), and the vaccine's efficacy against HNC (55.57%) was also moderate. Identifying female (P = .042), a self-perceived high-risk (P < .001), and having vaccinated children (P < .001) increased vaccination likelihood; transgender (P = .021), or lesbian or gay sexual identity (P < .001) decreased likelihood. Personal HNC diagnosis (P < .001), self-vaccination (P < .001), having vaccinated children (P < .001), having anal sex (P = .001) or no knowledge of past HPV status (P < .001) increased likelihood of high self-perceived risk. CONCLUSION: Efforts to improve public education regarding the association between HPV and HNC and vaccination efficacy are required to better inform vaccine decision-making among individuals at risk for HPV infection.

High-Specificity CRISPR-Mediated Genome Engineering in Anti-BCMA Allogeneic CAR T Cells Suppresses Allograft Rejection in Preclinical Models.

Allogeneic chimeric antigen receptor (CAR) T cell therapies hold the potential to overcome many of the challenges associated with patient-derived (autologous) CAR T cells. Key considerations in the development of allogeneic CAR T cell therapies include prevention of graft-vs-host disease (GvHD) and suppression of allograft rejection. Here, we describe preclinical data supporting the ongoing first-in-human clinical study, the CaMMouflage trial (NCT05722418), evaluating CB-011 in patients with relapsed/refractory multiple myeloma. CB-011 is a hypoimmunogenic, allogeneic anti-B-cell maturation antigen (BCMA) CAR T cell therapy candidate. CB-011 cells feature 4 genomic alterations and were engineered from healthy donor-derived T cells using a Cas12a CRISPR hybrid RNA-DNA (chRDNA) genome-editing technology platform. To address allograft rejection, CAR T cells were engineered to prevent endogenous HLA class I complex expression and overexpress a single-chain polyprotein complex composed of beta-2 microglobulin (B2M) tethered to HLA-E. In addition, T-cell receptor (TCR) expression was disrupted at the TCR alpha constant locus in combination with the site-specific insertion of a humanized BCMA-specific CAR. CB-011 cells exhibited robust plasmablast cytotoxicity in vitro in a mixed lymphocyte reaction in cell cocultures derived from patients with multiple myeloma. In addition, CB-011 cells demonstrated suppressed recognition by and cytotoxicity from HLA-mismatched T cells. CB-011 cells were protected from natural killer cell-mediated cytotoxicity in vitro and in vivo due to endogenous promoter-driven expression of B2M-HLA-E. Potent antitumor efficacy, when combined with an immune-cloaking armoring strategy to dampen allograft rejection, offers optimized therapeutic potential in multiple myeloma. See related Spotlight by Caimi and Melenhorst, p. 385.

Evaluation of Oropharyngeal Cancer Information from Revolutionary Artificial Intelligence Chatbot.

OBJECTIVE: With burgeoning popularity of artificial intelligence-based chatbots, oropharyngeal cancer patients now have access to a novel source of medical information. Because chatbot information is not reviewed by experts, we sought to evaluate an artificial intelligence-based chatbot's oropharyngeal cancer-related information for accuracy. METHODS: Fifteen oropharyngeal cancer-related questions were developed and input into ChatGPT version 3.5. Four physician-graders independently assessed accuracy, comprehensiveness, and similarity to a physician response using 5-point Likert scales. Responses graded lower than three were then critiqued by physician-graders. Critiques were analyzed using inductive thematic analysis. Readability of responses was assessed using Flesch Reading Ease (FRE) and Flesch-Kincaid Reading Grade Level (FKRGL) scales. RESULTS: Average accuracy, comprehensiveness, and similarity to a physician response scores were 3.88 (SD = 0.99), 3.80 (SD = 1.14), and 3.67 (SD = 1.08), respectively. Posttreatment-related questions were most accurate, comprehensive, and similar to a physician response, followed by treatment-related, then diagnosis-related questions. Posttreatment-related questions scored significantly higher than diagnosis-related questions in all three domains (p < 0.01). Two themes of the physician critiques were identified: suboptimal education value and potential to misinform patients. The mean FRE and FKRGL scores both indicated greater than an 11th grade readability level-higher than the 6th grade level recommended for patients. CONCLUSION: ChatGPT responses may not educate patients to an appropriate degree, could outright misinform them, and read at a more difficult grade level than is recommended for patient material. As oropharyngeal cancer patients represent a vulnerable population facing complex, life-altering diagnoses, and treatments, they should be cautious when consuming chatbot-generated medical information. LEVEL OF EVIDENCE: NA Laryngoscope, 134:2252-2257, 2024.

KSHV vIL-6 enhances inflammatory responses by epigenetic reprogramming.

Kaposi sarcoma-associated herpesvirus (KSHV) inflammatory cytokine syndrome (KICS) is a newly described chronic inflammatory disease condition caused by KSHV infection and is characterized by high KSHV viral load and sustained elevations of serum KSHV-encoded IL-6 (vIL-6) and human IL-6 (hIL-6). KICS has significant immortality and greater risks of other complications, including malignancies. Although prolonged inflammatory vIL-6 exposure by persistent KSHV infection is expected to have key roles in subsequent disease development, the biological effects of prolonged vIL-6 exposure remain elusive. Using thiol(SH)-linked alkylation for the metabolic (SLAM) sequencing and Cleavage Under Target & Release Using Nuclease analysis (CUT&RUN), we studied the effect of prolonged vIL-6 exposure in chromatin landscape and resulting cytokine production. The studies showed that prolonged vIL-6 exposure increased Bromodomain containing 4 (BRD4) and histone H3 lysine 27 acetylation co-occupancies on chromatin, and the recruitment sites were frequently co-localized with poised RNA polymerase II with associated enzymes. Increased BRD4 recruitment on promoters was associated with increased and prolonged NF-κB p65 binding after the lipopolysaccharide stimulation. The p65 binding resulted in quicker and sustained transcription bursts from the promoters; this mechanism increased total amounts of hIL-6 and IL-10 in tissue culture. Pretreatment with the BRD4 inhibitors, OTX015 and MZ1, eliminated the enhanced inflammatory cytokine production. These findings suggest that persistent vIL-6 exposure may establish a chromatin landscape favorable for the reactivation of inflammatory responses in monocytes. This epigenetic memory may explain the greater risk of chronic inflammatory disease development in KSHV-infected individuals.

Virally encoded interleukin-6 facilitates KSHV replication in monocytes and induction of dysfunctional macrophages.

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus and the etiologic agent of Kaposi's sarcoma and hyperinflammatory lymphoproliferative disorders. Understanding the mechanism by which KSHV increases the infected cell population is crucial for curing KSHV-associated diseases. Using scRNA-seq, we demonstrate that KSHV preferentially infects CD14+ monocytes, sustains viral lytic replication through the viral interleukin-6 (vIL-6), which activates STAT1 and 3, and induces an inflammatory gene expression program. To study the role of vIL-6 in monocytes upon KSHV infection, we generated recombinant KSHV with premature stop codon (vIL-6(-)) and its revertant viruses (vIL-6(+)). Infection of the recombinant viruses shows that both vIL-6(+) and vIL-6(-) KSHV infection induced indistinguishable host anti-viral response with STAT1 and 3 activations in monocytes; however, vIL-6(+), but not vIL-6(-), KSHV infection promoted the proliferation and differentiation of KSHV-infected monocytes into macrophages. The macrophages derived from vIL-6(+) KSHV infection showed a distinct transcriptional profile of elevated IFN-pathway activation with immune suppression and were compromised in T-cell stimulation function compared to those from vIL-6(-) KSHV infection or uninfected control. Notably, a viral nuclear long noncoding RNA (PAN RNA), which is required for sustaining KSHV gene expression, was substantially reduced in infected primary monocytes upon vIL-6(-) KSHV infection. These results highlight the critical role of vIL-6 in sustaining KSHV transcription in primary monocytes. Our findings also imply a clever strategy in which KSHV utilizes vIL-6 to secure its viral pool by expanding infected monocytes via differentiating into longer-lived dysfunctional macrophages. This mechanism may facilitate KSHV to escape from host immune surveillance and to support a lifelong infection.

EUS-guided versus percutaneous liver biopsy: A prospective randomized clinical trial.

Background and Objectives: Prospective studies comparing EUS-guided liver biopsy (EUS-LB) to percutaneous LB (PC-LB) are scarce. We compared the efficacy and safety of EUS-LB with those of PC-LB in a prospective randomized clinical trial. Methods: Between 2020 and 2021, patients were enrolled and randomized (1:1 ratio). The primary outcome was defined as the proportion of patients with ≥11 complete portal tracts (CPTs). The sample size (n = 80) was calculated based on the assumption that 60% of those in the EUS-LB and 90% of those in the PC-LB group will have LB with ≥11 CPTs. The secondary outcomes included proportion of patients in whom a diagnosis was established, number of CPTs, pain severity (Numeric Rating Scale-Pain Intensity), duration of hospital stay, and adverse events. Results: Eighty patients were enrolled (median age, 53 years); 67.5% were female. Sixty percent of those in the EUS-LB and 75.0% of those in the PC-LB group met the primary outcome (P = 0.232). The median number of CPTs was higher in the PC-LB (17 vs 13; P = 0.031). The proportion of patients in whom a diagnosis was established was similar between the groups (92.5% [EUS-LB] vs 95.0% [PC-LB]; P = 1.0). Patients in the EUS-LB group had less pain severity (median Numeric Rating Scale-Pain Intensity, 2.0 vs 3.0; P = 0.003) and shorter hospital stay (2.0 vs 4.0 hours; P < 0.0001) compared with the PC-LB group. No patient experienced a serious adverse event. Conclusions: EUS-guided liver biopsy was safe, effective, better tolerated, and associated with a shorter hospital stay.

Evaluating the Effectiveness of Artificial Intelligence-powered Large Language Models Application in Disseminating Appropriate and Readable Health Information in Urology.

PURPOSE: The Internet is a ubiquitous source of medical information, and natural language processors are gaining popularity as alternatives to traditional search engines. However, suitability of their generated content for patients is not well understood. We aimed to evaluate the appropriateness and readability of natural language processor-generated responses to urology-related medical inquiries. MATERIALS AND METHODS: Eighteen patient questions were developed based on Google Trends and were used as inputs in ChatGPT. Three categories were assessed: oncologic, benign, and emergency. Questions in each category were either treatment or sign/symptom-related questions. Three native English-speaking Board-Certified urologists independently assessed appropriateness of ChatGPT outputs for patient counseling using accuracy, comprehensiveness, and clarity as proxies for appropriateness. Readability was assessed using the Flesch Reading Ease and Flesh-Kincaid Reading Grade Level formulas. Additional measures were created based on validated tools and assessed by 3 independent reviewers. RESULTS: Fourteen of 18 (77.8%) responses were deemed appropriate, with clarity having the most 4 and 5 scores (P = .01). There was no significant difference in appropriateness of the responses between treatments and symptoms or between different categories of conditions. The most common reason from urologists for low scores was responses lacking information-sometimes vital information. The mean (SD) Flesch Reading Ease score was 35.5 (SD=10.2) and the mean Flesh-Kincaid Reading Grade Level score was 13.5 (1.74). Additional quality assessment scores showed no significant differences between different categories of conditions. CONCLUSIONS: Despite impressive capabilities, natural language processors have limitations as sources of medical information. Refinement is crucial before adoption for this purpose.

Synthesis and Evaluation of a Monomethyl Auristatin E─Integrin αvß6 Binding Peptide-Drug Conjugate for Tumor Targeted Drug Delivery.

Many anticancer drugs exhibit high systemic off-target toxicities causing severe side effects. Peptide-drug conjugates (PDCs) that target tumor-specific receptors such as integrin αvß6 are emerging as powerful tools to overcome these challenges. The development of an integrin αvß6-selective PDC was achieved by combining the therapeutic efficacy of the cytotoxic drug monomethyl auristatin E with the selectivity of the αvß6-binding peptide (αvß6-BP) and with the ability of positron emission tomography (PET) imaging by copper-64. The [64Cu]PDC-1 was produced efficiently and in high purity. The PDC exhibited high human serum stability, integrin αvß6-selective internalization, cell binding, and cytotoxicity. Integrin αvß6-selective tumor accumulation of the [64Cu]PDC-1 was visualized with PET-imaging and corroborated by biodistribution, and [64Cu]PDC-1 showed promising in vivo pharmacokinetics. The [natCu]PDC-1 treatment resulted in prolonged survival of mice bearing αvß6 (+) tumors (median survival: 77 days, vs αvß6 (-) tumor group 49 days, and all other control groups 37 days).

KSHV vIL-6 Enhances Inflammatory Responses by Epigenetic Reprogramming.

Kaposi sarcoma-associated herpesvirus (KSHV) inflammatory cytokine syndrome (KICS) is a newly described chronic inflammatory disease condition caused by KSHV infection and is characterized by high KSHV viral load and sustained elevations of serum KSHV-encoded IL-6 (vIL-6) and human IL-6 (hIL-6). KICS has significant immortality and possesses greater risks of having other complications, which include malignancies. Although prolonged inflammatory vIL-6 exposure by persistent KSHV infection is expected to have key roles in subsequent disease development, the biological effects of prolonged vIL-6 exposure remain elusive. Using thiol-Linked Alkylation for the Metabolic Sequencing and Cleavage Under Target & Release Using Nuclease analysis, we studied the effect of prolonged vIL-6 exposure in chromatin landscape and resulting cytokine production. The studies showed that prolonged vIL-6 exposure increased Bromodomain containing 4 (BRD4) and histone H3 lysine 27 acetylation co-occupancies on chromatin, and the recruitment sites were frequently co-localized with poised RNAPII with associated enzymes. Increased BRD4 recruitment on promoters was associated with increased and prolonged NF-κB p65 binding after the lipopolysaccharide stimulation. The p65 binding resulted in quicker and sustained transcription bursts from the promoters; this mechanism increased total amounts of hIL-6 and IL-10 in tissue culture. Pretreatment with the BRD4 inhibitor, OTX015, eliminated the enhanced inflammatory cytokine production. These findings suggest that persistent vIL-6 exposure may establish a chromatin landscape favorable for the reactivation of inflammatory responses in monocytes. This epigenetic memory may explain the greater risk of chronic inflammatory disease development in KSHV-infected individuals.

Signalling by senescent melanocytes hyperactivates hair growth.

Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration1. Altering balanced niche signalling can lead to regenerative disorders. Melanocytic skin nevi in human often display excessive hair growth, suggesting hair stem cell hyperactivity. Here, using genetic mouse models of nevi2,3, we show that dermal clusters of senescent melanocytes drive epithelial hair stem cells to exit quiescence and change their transcriptome and composition, potently enhancing hair renewal. Nevus melanocytes activate a distinct secretome, enriched for signalling factors. Osteopontin, the leading nevus signalling factor, is both necessary and sufficient to induce hair growth. Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice, whereas germline and conditional deletions of either osteopontin or CD44, its cognate receptor on epithelial hair cells, rescue enhanced hair growth induced by dermal nevus melanocytes. Osteopontin is overexpressed in human hairy nevi, and it stimulates new growth of human hair follicles. Although broad accumulation of senescent cells, such as upon ageing or genotoxic stress, is detrimental for the regenerative capacity of tissue4, we show that signalling by senescent cell clusters can potently enhance the activity of adjacent intact stem cells and stimulate tissue renewal. This finding identifies senescent cells and their secretome as an attractive therapeutic target in regenerative disorders.